Phytochemical profiling of Symplocos tanakana Nakai and S. sawafutagi Nagam. leaf and identification of their antioxidant and anti-diabetic potential.
Symplocos sp. contains various phytochemicals and is used as a folk remedy for treatment of diseases such as enteritis, malaria, and leprosy. In this study, we discovered that 70% ethanol extracts of Symplocos sawafutagi Nagam. and S. tanakana Nakai leaves have antioxidant and anti-diabetic effects. The components in the extracts were profiled using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry; quercetin-3-O-(6''-O-galloyl)-β-d-galactopyranoside (6) and tellimagrandin II (7) were the main phenolic compounds. They acted as strong antioxidants with excellent radical scavenging activity and as inhibitors of non-enzymatic advanced glycation end-products (AGEs) formation. Mass fragmentation analysis demonstrated that compounds 6 and 7 could form mono- or di-methylglyoxal adducts via reaction with methylglyoxal, which is a reactive carbonyl intermediate and an important precursor of AGEs. In addition, compound 7 effectively inhibited the binding between AGE2 and receptor for AGEs as well as the activity of α-glucosidase. Enzyme kinetic study revealed that compound 7 acts as a competitive inhibitor of α-glucosidase, through interaction with the active site of the enzyme. Therefore, compounds 6 and 7, the major constituents of S. sawafutagi and S. tanakana leaves, are promising for developing drugs for preventing or treating diseases caused by aging and excessive sugar consumption.


Family-level factors of early childhood development: Evidence from rural China.
Family-level factors that characterize the home environment are critical inputs to early language and cognitive development, and potential mechanisms for improving developmental outcomes in vulnerable populations. Many studies conducted in high-income and Western settings highlight stimulating parenting, the home language environment, and parental self-efficacy as possible mechanisms of early development, though less is known about how these family-level factors impact child development in low- or middle-income settings. Even less is known about these family-level factors and early childhood development in rural China, where rates of cognitive and language delay in children aged 0-3 years are as high as 45% and 46%, respectively. Using data collected from 77 rural households with children aged 18-24 months in Southwestern China, this study examines the associations between stimulating parenting, the home language environment, and parental self-efficacy, and early cognitive and language development. The results indicate that stimulating parenting was significantly associated with cognitive, language, and overall development; the home language environment was only significantly associated with language development; and parental self-efficacy was not significantly associated with any developmental outcomes. The implications of such findings reveal mechanisms for supporting healthy child development in rural China.


A patient with a Mycobacterium avium complex infection complicated by systemic lupus erythematosus.
A 41-year-old woman was admitted to our hospital because of fever and polyarthralgia. A diagnosis of systemic lupus erythematosus (SLE) was made based on the findings of polyarthritis, leukocytopenia, lymphocytopenia, proteinuria, and positive reactions for antinuclear antibody (ANA) and anti-double strand (ds)DNA antibody. She had also been suffering from a pulmonary Mycobacterium avium complex (MAC) infection with such symptoms as cough and sputum for the past 3 years. Antimicrobial drugs for MAC infection were administered first, and later she was given cyclophosphamide pulse therapy, consisting of methylprednisolone (8 mg/day) and mizoribine (100 mg/day). Owing to these therapeutic regimens, SLE was successfully treated without an exacerbation of the MAC infection. The risk factors for MAC infection and SLE are also discussed.


Low grade central osteosarcoma--a diagnostic dilemma.
Low grade central osteosarcoma is a rare primary bone tumor. This fibro-osseous lesion shares some radiological and histopathological resemblance with fibrous dysplasia, which is a more common entity. Thus it may be mistaken as fibrous dysplasia and may receive inadequate treatment resulting in a more malignant recurrent bone tumor. We present a case of low grade central osteosarcoma of the right tibia, which was initially treated as fibrous dysplasia with curettage and bone grafting. Three years later the tumor recurred with greater soft tissue and bony involvement but without metastasis. The patient was treated with above knee amputation and has been asymptomatic for the last two years.


Manual and computerized measurement of coronal vertebral inclination on MRI images: a pilot study.
A pilot study that presents a systematic approach for evaluating the variability of manual and computerized measurements of coronal vertebral inclination (CVI) on images acquired by magnetic resonance imaging (MRI). Three observers identified the vertebral body corners of 28 vertebrae on two occasions on two-dimensional (2D) coronal MRI cross-sections, which served to evaluate CVI using six manual measurements (superior and inferior tangents, left and right tangents, mid-endplate and mid-wall lines). Computerized measurements were performed by evaluating CVI from the symmetry of vertebral anatomical structures of the same 28 vertebrae in 2D coronal MRI cross-sections and in three-dimensional (3D) MRI images. In terms of standard deviation (SD), the mid-endplate lines proved to be the manual measurements with the lowest intra- (1.0° SD) and interobserver (1.4° SD) variability. The computerized measurements in 3D yielded even lower intra- (0.8° SD) and interobserver (1.3° SD) variability. The strongest inter-method agreement (1.2° SD) was found among lines parallel to vertebral endplates (superior tangents, inferior tangents, mid-endplate lines). The computerized measurements in 3D were most in agreement with the mid-endplate lines (1.9° SD). The estimated intra- and interobserver variabilities of standard Cobb angle measurements were equal to 1.6° SD and 2.5° SD, respectively, for manual measurements, and to 1.1° SD and 1.8° SD, respectively, for computerized measurements. The mid-endplate lines proved to be the most reproducible and reliable manual CVI measurements. Computerized CVI measurements based on the evaluation of the symmetry of vertebral anatomical structures in 3D were more reproducible and reliable than manual measurements.


Benefits of applying molecular barcoding systems are not uniform across different genomic applications.
Despite the wide variety of Next Generation Sequencing (NGS)-based methods, it remains challenging to detect mutations present at very low frequencies. This problem is particularly relevant in oncology, where the limiting amount of input material, and its low quality, often limit the performance of the assays. Unique Molecular Identifiers (UMIs) are a molecular barcoding system often coupled with computational methods of noise suppression to improve the reliability of detection of rare variants. Although widely adopted, UMI inclusion imposes additional technical complexity and sequencing cost. Currently, there are no guidelines on UMI usage nor a comprehensive evaluation of their advantage across different applications. We used DNA sequencing data generated by molecular barcoding and hybridization-based enrichment, from various types and quantities of input material (fresh frozen, formaldehyde-treated and cell-free DNA), to evaluate the performance of variant calling in different clinically relevant contexts. Noise suppression achieved by read grouping based on fragment mapping positions ensures reliable variant calling for many experimental designs even without exogenous UMIs. Exogenous barcodes significantly improve performance only when mapping position collisions occur, which is common in cell-free DNA. We demonstrate that UMI usage is not universally beneficial across experimental designs and that it is worthwhile to critically consider the comparative advantage of UMI usage for a given NGS application prior to experimental design.


The impact of deficit reduction on the nursing labour market in Canada: unintended consequences of fiscal reform.
Beginning in 1992, governments throughout Canada began reducing expenditures in an effort to eliminate fiscal deficits and reduce their alarmingly high debt burden. As part of this deficit-fighting era, governments reduced hospital expenditure levels quite dramatically. Some of the current problems in the Canadian healthcare system - the recent unrest in the nursing labour market in particular - are often attributed to this hospital downsizing era. This article examines trends in the labour market for registered nurses in Canada during the hospital downsizing period. Of particular interest is the effect of hospital spending reforms on nurse employment levels in hospitals and on the age structure of the nursing workforce. After identifying the trends, the main factors driving the trends are discussed. Results indicate that a decrease in the demand for nursing labour resulted in large staff layoffs during the restructuring period, particularly among the youngest age groups. The evidence does not support the claim that deteriorating wages and working conditions in hospitals led nurses to quit their jobs during the hospital downsizing period.


Ultrasensitive Biosensor for the Detection of Vibrio cholerae DNA with Polystyrene-co-acrylic Acid Composite Nanospheres.
An ultrasensitive electrochemical biosensor for the determination of pathogenic Vibrio cholerae (V. cholerae) DNA was developed based on polystyrene-co-acrylic acid (PSA) latex nanospheres-gold nanoparticles composite (PSA-AuNPs) DNA carrier matrix. Differential pulse voltammetry (DPV) using an electroactive anthraquninone oligonucleotide label was used for measuring the biosensor response. Loading of gold nanoparticles (AuNPs) on the DNA-latex particle electrode has significantly amplified the faradaic current of DNA hybridisation. Together with the use of a reported probe, the biosensor has demonstrated high sensitivity. The DNA biosensor yielded a reproducible and wide linear response range to target DNA from 1.0 × 10-21 to 1.0 × 10-8 M (relative standard deviation, RSD = 4.5%, n = 5) with a limit of detection (LOD) of 1.0 × 10-21 M (R 2 = 0.99). The biosensor obtained satisfactory recovery values between 91 and 109% (n = 3) for the detection of V. cholerae DNA in spiked samples and could be reused for six consecutive DNA assays with a repeatability RSD value of 5% (n = 5). The electrochemical biosensor response was stable and maintainable at 95% of its original response up to 58 days of storage period.


An improved method of assessing esophageal emptying using the timed barium study following surgical myotomy for achalasia.
The timed barium study (TBS) is used to assess esophageal emptying in patients with achalasia. Improvement in emptying correlates with outcome after endoscopic therapy, but the results of the TBS have been variable after myotomy. Our aim was to evaluate a new method for assessing improvement in emptying after myotomy. A TBS was performed before and 3-6 months after myotomy in 30 patients. Emptying was assessed by measuring the percent difference in area of the barium column on films obtained 1 and 5 min after ingesting 150 ml of barium. Initial esophageal clearance was also assessed by comparing the area of the barium column on 1-min images obtained before and after therapy. Both measures were compared to clinical outcome. After myotomy, 21 patients (70%) had no symptoms, four (13%) had mild, and five (17%) had moderate/severe symptoms. Using the standard method, esophageal emptying before and after surgery were not significantly different (25% vs. 37%; p = 0.22) and did not correlate with clinical outcome. In contrast, initial esophageal clearance improved significantly (median 81%) and correlated with clinical outcome. Esophageal emptying measured by the standard method is not useful to assess outcome after myotomy. However, initial esophageal clearance correlates well with clinical outcome.


Receptor-ligand binding: 'catch' bonds finally caught.
Leukocyte recruitment to sites of inflammation is initiated by the selectin family of adhesion receptors. Recent research reveals that P-selectin binding to its ligand exhibits 'catch' to 'slip' bond transition that may help explain the shear threshold phenomenon.


Factors contributing to the adverse drug reactions associated with the dipeptidyl peptidase-4 (DPP-4) inhibitors: A scoping review.
Adverse drug reactions are one of the contributors to increased hospital admission and length of hospital stay. Among the various antidiabetic agents prescribed, dipeptidyl peptidase-4 (DPP-4) inhibitors have gained wide recognition and shown more persistence than other novel hypoglycemic agents. We performed a scoping review to identify the risk factors contributing to the adverse drug reactions with DPP-4 inhibitors. We followed Preferred Reporting Items for Scoping Review (PRISMA-ScR) Guidelines for reporting the findings. Data sources such as PubMed/MEDLINE, Scopus, Embase, and Cochrane were assessed. We included studies that reported the risk factors contributing to the DPP-4 inhibitor-associated adverse drug reactions. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the methodological quality of the studies. Of the 6406 studies retrieved, 11 studies met our inclusion criteria. Of these 11 studies, seven were post-marketing surveillance studies, one nested case-control study, one comparator cohort study, one food and drug administration (FDA) adverse event reporting system (FAERS)-based observational study, and one questionnaire-based cross-sectional survey study. A total of eight factors were identified that contributed to the DPP-4 inhibitor-associated adverse drug reactions. The included studies suggested age >65 years, females, grade 4 and 5 renal impairment, concomitant drugs, disease and drug therapy duration, liver disease, non-smokers, and non-hypertension as risk factors. Further studies should be conducted to provide insight into these risk factors so that the appropriate use of DPP-4 inhibitors in the diabetic population can be encouraged to improve the health-related quality of life. CRD42022308764.


Role of institutional, cultural and economic factors in the effectiveness of lockdown measures.
This study considered the role of institutional, cultural and economic factors in the effectivemess of lockdown measures during the coronavirus pandemic. Earlier studies focusing on cross-sectional data found an association between low case numbers and a higher level of cultural tightness. Meanwhile, institutional strength and income levels revealed a puzzling negative relationship with the number of cases and deaths. Data available at the end of September 2021 were used to analyse the dynamic impact of these factors on the effectiveness of lockdowns. The cross-sectional dimension of country-level data was combined with the time-series dimension of pandemic-related measures, using econometric techniques dealing with panel data. Greater stringency of lockdown measures was associated with fewer cases. Institutional strength enhanced this negative relationship. Countries with well-defined and established laws performed better for a given set of lockdown measures compared with countries with weaker institutional structures. Cultural tightness reduced the effectiveness of lockdowns, in contrast to previous findings at cross-sectional level. Institutional strength plays a greater role than cultural and economic factors in enhancing the performance of lockdowns. These results underline the importance of strengthening institutions for pandemic control.


The influence of the adiponectin gene on adiponectin concentrations and parameters of metabolic syndrome in non-diabetic Korean women.
Concentrations of adiponectin, the protein product of the adipocyte C1q and collagen-domain-containing (ADIPOQ) gene are associated with type 2 diabetes and coronary artery disease. We investigate the association of single-nucleotide polymorphisms (SNPs) in the ADIPOQ gene with adiponectin concentrations, and to parameters of metabolic syndrome. 867 unrelated, non-diabetic Korean women, 20 to 69 y, were genotyped for 8 SNPs in the ADIPOQ gene (-11391G>A, -11377C>G, H241P, Y111H, G90S, R221S, 45T>G, 276G>T). Adiponectin, a homeostasis model assessment of insulin resistance (HOMA-IR), and metabolic parameters were measured. Carriers of genotype T/T at position 276 had significantly higher adiponectin concentrations than G/G carriers (P=0.005). Homozygous carriers of the TG haplotype (i.e., individuals who were T/T at 45 and G/G at 276) and heterozygous carriers of the TG haplotype (TG/X) had lower adiponectin concentrations than non-TG carriers (P<0.001). Significant associations between SNP at 276 and serum concentrations of triglyceride (P=0.013), insulin (P=0.013) and HOMA-IR (P=0.012) were found. The 45-276 haplotypes had associations identical to the 276G>T SNP. In subgroup analysis, subjects carrying the TG haplotype had significantly lower adiponectin concentrations than non-TG carriers in both normal weight (P<0.001) and overweight-obese (P=0.009) subgroups. The association of the TG haplotype with increasing insulin concentrations was significant among overweight-obese subjects (P=0.004), but was not significant among normal weight subjects. A similar association was found between the 45-276 haplotype and HOMA-IR. There is a strong association of the adiponectin SNP276 genotypes and the adiponectin 45-276 haplotypes with circulating adiponectin concentrations in non-diabetic Korean women. In addition, this haplotype is associated with increased insulin concentrations and insulin resistance index only in overweight-obese individuals.


Inhibition of Botrytis cinerea in tomatoes by allyl-isothiocyanate release from black mustard (Brassica nigra) seeds and detection by E-nose.
The aim of this work is to delayed the postharvest development of Botrytis cinerea in tomatoes by releasing allyl-isothiocyanate (AITC) from mustard seeds at room temperature, and to discriminate the aromatic profile by using an electronic device (E-nose). Olfactory sensory analysis showed that tomatoes inoculated in the presence of AITC did not develop the microorganisms until the eighth day of storage. The highest inhibitory concentration of AITC was found in Day 3 (175.18 ppb). However, tomatoes inoculated without the presence of AITC developed a moldy aroma on the third day of storage. The most prominent chemical groups were esters, ketones and alcohols. The compounds associated with a positive aroma were trimethyl orthoacetate, styrene, tridecan-7-amine and acetaldehyde, while compounds related to B. cinerea were hepten-2-one and butanoic acid. The E-nose was able to discriminate tomatoes based on their aromatic characteristics during the storage period. Moreover, it successfully quantified the mold defect aroma with the established Partial Least Squares (PLS) model.


Residency Training: Determinants of burnout of neurology trainees in Attica, Greece.
The purpose of our cross-sectional study was to estimate the rate of burnout and identify its determinants among neurology residents in Attica, Greece. In total, 131 placements for neurology training over 18 hospitals were available. All residents were approached and were asked to participate in the study by anonymously completing a questionnaire. Job demands and resources (JD-R) were examined via a 31-item questionnaire assessing 8 factors based on the JD-R model. Burnout was measured with the Maslach Burnout Inventory (MBI). The emotional exhaustion + 1 criterion was used to distinguish respondents with and without burnout. A total of 116 residents participated in the study (response rate 88.5%). In total, 18.1% of the participants were experiencing burnout. Multivariate analysis showed that each increased point in the total score of the factor regarding opportunities for professional development was associated with lowering the odds of burnout by 28.7%. Burnout among neurology residents is associated with decreased professional development. Educators and program directors need to identify those residents at high risk of burnout and design interventions to promote residents' resilience and mental health.


Effect of early unilateral visual deprivation on cholinergic muscarinic receptors and acetylcholinesterase in chick optic lobe.
Chicks of 1-8 days after hatching were submitted to unilateral visual deprivation and, in both optic lobes, muscarinic receptors, labeled with L-[3H]quinuclidinyl benzylate [( 3H]L-QNB) and acetylcholinesterase (AChE) were assayed. Between 1 and 6 days the number of [3H]L-QNB binding sites was lower in the contralateral optic lobe; the AChE underwent a drastic reduction (-42% at 2 days); later on the differences became not significant. The pre- and postsynaptic localization of the two cholinergic markers and the possible influence of light on axonal transport are discussed.


Carotid body tumor: atypical angiogram of a functional tumor.
Carotid body tumors (CBTs) are rare, usually benign, neoplasms of the extra-adrenal paraganglion system. They are almost always nonfunctional. The diagnosis is generally confirmed by an angiogram that shows a vascular tumor enlarging the space between the internal and external carotid arteries. A 55-year-old man with hypertension and episodes of flushing, palpitations, and dizziness was treated for a firm, nonmobile mass measuring 3 x 2 cm at the left carotid bifurcation. Plasma and urine catecholamines, and the vanilylmandelic acid/creatinine ratios were elevated. Carotid arteriograms showed a vascular mass displacing the vessels, but the space between the arteries was narrowed rather than enlarged, and an atherosclerotic plaque was present. At operation the CBT was removed by resection of the bifurcation and with a temporary shunt a saphenous vein graft was inserted between the common and internal carotid arteries. Pathologic examination revealed a typical paraganglionoma. Although most CBTs produce catecholamines, only 11 patients have been reported to have elevated plasma and urine levels, and most were symptomatic. Since these tumors slowly increase in size, early surgical removal is recommended, even in asymptomatic patients.


Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation.
Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient's own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.


Experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT1 receptor in the brainstem.
Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including the abnormal autonomic nervous system. We have demonstrated that the oxidative stress through AT(1) receptor in the brain activates sympathetic nervous system. The aim of the present study was to determine whether experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT(1) receptor in the cardiovascular center of the brainstem (rostral ventrolateral medulla; RVLM) or not. Experimental 'jet lag' was made to normotensive (Wister-Kyoto rat; WKY rat) and hypertensive rats (stroke-prone spontaneously hypertensive rats; SHRSP) by the exposure to a 12 hour phase advance for 5 days. In WKY, 'jet lag' increases blood pressure and the activity of sympathetic nervous system via oxidative stress through angiotensin II type 1 receptor in the RVLM for 2 days only, and the changes are improved at 3 day after the initiation of 'jet lag'. In SHRSP, 'jet lag' also increases blood pressure and the activity of sympathetic nervous system via oxidative stress through angiotensin II type 1 receptor in the RVLM, and the changes are greater compared to those in WKY, and are maintained for the period of 'jet lag'. These results suggest that experimental 'jet lag' causes sympathoexcitation via oxidative stress through AT(1) receptor in the brain, especially in hypertension.


Salt and intramuscular fat modulate dynamic perception of flavour and texture in dry-cured hams.
The present study aimed to evaluate the influence of salt and intramuscular fat (IMF) content on the sensory characteristics of two different types of dry-cured hams (Iberian and Serrano) using the time-intensity (TI) method. All studied TI parameters of flavour attributes (overall flavour, saltiness, cured and rancid flavours) were significantly (p < 0.05) affected by variations in the salt and/or IMF content. However, regarding texture attributes only the maximum intensity (Imax) of hardness was significantly (p < 0.05) affected by the salt content of hams. Compared to Iberian dry-cured hams, the dynamic perception of the flavour and texture of Serrano dry-cured hams was less influenced by variations in salt and/or IMF content. The dynamic sensory techniques may be helpful to guarantee the quality of dry-cured products subjected to strategies of salt and fat reduction.


Clearance of exogenous parathyroid hormone-related protein in pregnant, non-pregnant and fetal sheep, goats and pigs.
In the sheep, goat and pig, radiolabelled parathyroid hormone related protein (PTHRP) and immunoreactive PTHRP(1-34) and (1-86) were rapidly cleared from the circulation. Metabolic clearance rates (MCR) were in the range of 1.25-7.5 ml/min per kg and were slightly slower than that of intact PTH in man (10 ml/min per kg); while the mean MCR of labelled PTHRP(1-86) in fetal sheep and goats was significantly faster than that in their respective mothers (14.4 vs 4.0 ml/min per kg respectively). This may reflect increased metabolism of PTHRP by fetal tissues, e.g. the placenta. Similar rates of clearance of radiolabelled PTHRP(1-141), (1-86) and (1-34) suggest that clearance involves the amino terminus of the molecule.


Balance of transforming growth factor-beta1 and platelet-derived growth factor-BB is associated with kidney allograft rejection.
About 50% of kidney-transplant patients undergo organ rejection within 10 years. Chronic allograft nephropathy (CAN) represents the dominant cause of kidney transplant failure and accounts for 50-80% of graft loss in long-term surviving patients. CAN pathogenesis is multifactorial and not-completely elucidated; several reports indicate TGF-beta1 and platelet-derived growth factor (PDGF)-BB expression in CAN suggesting a possible role of these factors in the allograft arteriosclerosis and graft failure. We investigated the plasma expression concentrations of human growth factors with enzyme-linked immunosorbent assays and appropriate statistical analysis. We present evidences showing statistically significant association of CAN with a specific balance between TGF Beat1 and PDGF-BB plasma concentrations, in 129 kidney-transplant patients and 15 healthy controls. Odds ratios were computed to correlate expression-levels with CAN occurrence. We believe these data may suggest a novel non-invasive method to identify early molecular markers of graft deterioration.


Development of HSP90 inhibitors-SN38 conjugates for cancer treatment.
Presently, chemotherapy remains to be one of the most important therapeutic approaches for malignant tumors. Ligands based drug conjugates are showing considerable promise as potential therapeutic agents delivery systems for cancer. Here, a series of HSP90 inhibitors-SN38 conjugates were developed through cleavable linkers for tumor-specific delivery of SN38 and reducing its side effects. In vitro assays showed that these conjugates exhibited acceptable stability in PBS and plasma, appreciable HSP90 binding affinity, and potent cytotoxic abilities. Cellular uptake behaviors also indicated that these conjugates could selectively target cancer cells in a time-dependent manner via HSP90. Among them, compound 10b with a glycine linkage exhibits appreciable in vitro and in vivo pharmacokinetic profiles, and excellent in vivo antitumor activity in Capan-1 xenograft models, demonstrating the selective targeting and accumulation of the active payload at tumor sites. Above all, these results suggest that compound 10b has the potential as a potent anticancer drug, meriting further evaluation in the future.


3D modelling, gene expression mapping and post-mapping image analysis in the developing human brain.
As human brain development proceeds, there are complex changes in size and shape, most notably in the developing forebrain. Molecular technologies enable us to characterise the gene expression patterns that underlie these changes. To interpret these patterns the location of expression must be identified and, often, gene expression patterns compared for several genes or across several developmental stages. To facilitate interpretation we have generated a set of three-dimensional models using a recently developed technique, optical projection tomography. The models act as a framework onto which gene expression patterns are mapped and anatomical domains identified using custom-designed software, MAPaint. Here, we demonstrate their use to compare forebrain development at two embryonic stages (Carnegie stages 18 and 21; 44 and 52 days post conception, respectively) and as a means of recording, storing and visualising gene expression data for three example genes EMX1, EMX2 and OTX2. Anatomical domains were also mapped to the models and the comparison of gene expression and anatomical data is demonstrated at Carnegie stage 21. The three-dimensional models and sophisticated software facilitate the analysis and visualisation of morphological changes and gene expression patterns during early brain development and can be applied to the development of other complex structures.


A Pre-Release Algorithm With a Confidence Map for Estimating the Attenuation Coefficient for Liver Fat Quantification.
To compare the estimates of attenuation coefficient (AC) for liver fat quantification between 2 Ultrasound systems and to evaluate the quality measure of a pre-released software. AC were obtained in 30 participants in this single-center IRB-approved, HIPAA compliant study. Images were obtained on the Philips Epiq Elite system using experimental software and the Canon Medical Systems Aplio i800 with released software. Five AC measurements were taken and the median and IQR/M were calculated. Region of interest placement was based on a confidence map. ROI was at the same depth and size for each system. The concordance was estimated using the Lin's concordance correlation coefficient (CCC), the r Pearson's correlation coefficient, the bias-correction factor (Cb), and the Bland-Altman method. The ACs varied from 0.45 to 1.0 dB/cm/MHz for the Philips system and 0.30 to 0.96 dB/cm/MHz for the Canon system. The CCC (95% CI) was 0.792 (0.666-0.918), Pearson's r was 0.839 with Cb of 0.944, and the mean difference was 0.03 (-0.101; 0.162) suggesting the 2 methods are considered to be in agreement. Based on a Philips confidence map to determine the best location for performing the measurements, a depth of 3.5 to 4.0 cm from the liver capsule was determined, which might be significantly different than that of the Canon system. Estimation of the AC of the 2 systems showed a high agreement, that is, a similar trend. Assessment of the placement of the measurement box based on the quality of the measurement might be different between the 2 systems.


Urinary interleukin-8 is a biomarker of stress in emergency physicians, especially with advancing age--the JOBSTRESS* randomized trial.
Emergency physicians are exposed to greater stress during a 24-hour shift (24 hS) than a 14-hour night shift (14 hS), with an impact lasting several days. Interleukin-8 (IL-8) is postulated to be a chronic stress biomarker. However, no studies have tracked IL-8 over several shifts or used it for monitoring short-term residual stress. The IL-8 response to the shifts may also increase with age. Conveniently, IL-8 can be measured non-intrusively from urine. We conducted a shifts-randomized trial comparing 17 emergency physicians' urinary IL-8 levels during a 24 hS, a 14 hS, and a control day (clerical work on return from leave). Mean levels of IL-8 were compared using a Wilcoxon matched-pairs test. Independent associations of key factors including shifts, stress, and age with IL-8 levels were further assessed in a multivariable generalized estimating equations model. Mean urinary IL-8 levels almost doubled during and after a 24 hS compared with a 14 hS or a control day. Furthermore, IL-8 levels failed to return to control values at the end of the third day after the shift despite a rest day following the 24 hS. In the multivariable model, engaging in a 24 hS, self-reported stress, and age were independently associated with higher IL-8 levels. A 24 hS significantly increased IL-8 levels by 1.9 ng (p = .007). Similarly, for every unit increase in self-reported stress, there was a 0.11 ng increase in IL-8 levels (p = .003); and for every one year advance in age of physicians, IL-8 levels also increased by 0.11 ng (p = .018). The 24 hS generated a prolonged response of the immune system. Urinary IL-8 was a strong biomarker of stress under intensive and prolonged demands, both acutely and over time. Because elevated IL-8 levels are associated with cardiovascular disease and negative psychological consequences, we suggest that emergency physicians limit their exposure to 24 hS, especially with advancing age.


Label-free and amplified aptasensor for thrombin detection based on background reduction and direct electron transfer of hemin.
In this work, we describe the development of a sensitive and label-free aptasensor for thrombin detection based on background noise reduction by exonuclease I (Exo I) and signal amplification by direct electron transfer (DET) of hemin. The thrombin binding aptamers (TBAs) are self-assembled on a sensing electrode. In the absence of the target thrombin, the TBAs are digested by Exo I, which avoids the association of hemin and significantly minimizes the background current noise. The presence of thrombin stabilizes the folded TBA G-quadruplex and prevents it from degrading by Exo I. The G-quadruplex bound hemin thus generates amplified signal output. In our sensing approach, the introduction of Exo I significantly enhances the signal to noise ratio of the sensor response and achieves sensitive detection of thrombin. Our new method is also coupled with good selectivity against other non-target proteins and thus holds great potential for the development of robust aptasensors for the detection of different types of targets.


Fasciola hepatica: development of monoclonal antibodies and their use to characterize a glycocalyx antigen in migrating flukes.
Using mice harbouring early Fasciola hepatica infections, six monoclonal antibodies were prepared against a tegumental antigen present in T1 granules and glycocalyx of flukes. Blocking tests indicated that all monoclonals bound the same T1 epitope (or epitopes in close proximity on the antigen molecule), but this was not the determinant recognized by sheep and cattle. Localization of antibody binding at light and electron microscope levels showed that T1-type antigen also occurred in metacercarial tegument and in glycocalyx of gut cells and excretory ducts in juvenile and adult flukes. This indicates that the natural host-antibody response to F. hepatica may be to one antigen early in the infection. Protein A-gold labelling of monoclonal treated fluke sections revealed that the epitope was probably a polypeptide, unmodified by glycosylation in Golgi bodies. When isolated by immunoadsorption and separated electrophoretically under reducing conditions T1-type antigen was found to consist of a polypeptide mol. wt. 50 000, possibly linked to smaller entities mol. wt. 25-40 000. Tissue-specific variations in the antigen molecule might be conferred by linkage of different polypeptides or carbohydrate side-chains to an antigenic core polypeptide. A component of T1-type antigen was found to have mol. wt. of 25 000, possibly resembling a polypeptide of mol. wt. 24 000 from Schistosoma mansoni tegument.


Norepinephrine-mediated suppression of apomorphine-induced aggression and locomotor activity in the rat amygdala.
The effect of injections of norepinephrine (NE)-depleting toxin DSP-4 into the central amygdala (AMY) on apomorphine-induced fighting (AIF) was studied. In addition, the influence of such treatment on related parameters such as spontaneous activity, pain sensitivity and changes in locomotion after (+)3-PPP or apomorphine (1 mg/kg SC each) were verified. Finally, injections of NE or phenylephrine into the AMY five min before AIF were performed. DSP-4 induced marked (-71%) and selective fall in NE within the AMY accompanied by significant increase in aggressive response to 5 mg/kg of apomorphine. DSP-4-treated animals were less active in the open field and more sensitive to pain in a hot plate test. They were also more responsive to locomotor-augmenting action of apomorphine. Significant suppression of AIF was seen after injections of NE and phenylephrine into the AMY. The results suggest that NE input to the AMY plays an inhibitory role in dopamine-related locomotion and aggressivity. Moreover, amygdalar NE appears to be involved in general activity and pain perception modulation.


Lanthanide paramagnetic probes for NMR spectroscopic studies of fast molecular conformational dynamics and temperature control. Effective six-site proton exchange in 18-crown-6 by exchange spectroscopy.
(1)H and (13)C NMR measurements are reported for the CDCl(3) and CD(2)Cl(2) solutions of [La(18-crown-6)(NO(3))(3)] (I), [Pr(18-crown-6) (NO(3))(3)] (II), [Ce(18-crown-6)(NO(3))(3)] (III), and [Nd(18-crown-6)(NO(3))(3)] (IV) complexes. Temperature dependencies of the (1)H NMR spectra of paramagnetic II-IV have been analyzed using the dynamic NMR (DNMR) methods for six-site exchange. Two types of conformational dynamic processes were identified (the first one is conditioned by interconversion of complex enantiomeric forms and pseudorotation of a macrocycle molecule upon the C(2) symmetry axis; the second one is conditioned by macrocycle molecule inversion). Application of exchange spectroscopy (2D-EXSY) of DNMR for investigation of this dynamic system (II-IV) simplifies the assignment of the NMR signals and represents the first experimental study of multisite exchange. In the present work, the methodology of paramagnetic 4f (Ce, Pr, and Nd) probe applications for the study of free-energy, enthalpy, and entropy changes in chemical exchange processes, as well as the advantages of this method in a comparison with DNMR studies of diamagnetic substances, is discussed. In particular, as a result of paramagnetic chemical shifts in 4f complexes, the range of measurable rate constants expands considerably compared to the analogous range in diamagnetic compounds. Coordination compounds investigated in the paper represent new types of thermometric NMR sensors and lanthanide paramagnetic probes for in situ temperature control in solution.


Structural details on mdm2-p53 interaction.
Mdm2 is a cellular antagonist of p53 that keeps a balanced cellular level of p53. The two proteins are linked by a negative regulatory feedback loop and physically bind to each other via a putative helix formed by residues 18-26 of p53 transactivation domain (TAD) and its binding pocket located within the N-terminal 100-residue domain of mdm2 (Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., and Pavletich, N. P. (1996) Science 274, 948-953). In a previous report we demonstrated that p53 TAD in the mdm2-freee state is mostly unstructured but contains two nascent turns in addition to a "preformed" helix that is the same as the putative helix mediating p53-mdm2 binding. Here, using heteronuclear multidimensional NMR methods, we show that the two nascent turn motifs in p53 TAD, turn I (residues 40-45) and turn II (residues 49-54), are also capable of binding to mdm2. In particular, the turn II motif has a higher mdm2 binding affinity ( approximately 20 mum) than the turn I and targets the same site in mdm2 as the helix. Upon mdm2 binding this motif becomes a well defined full helix turn whose hydrophobic face formed by the side chains of Ile-50, Trp-53, and Phe-54 inserts deeply into the helix binding pocket. Our results suggest that p53-mdm2 binding is subtler than previously thought and involves global contacts such as multiple "non-contiguous" minimally structured motifs instead of being localized to one small helix mini-domain in p53 TAD.


The effects of phenformin and metformin on fat and carbohydrate metabolism.
In order to investigate the effects of two biguanide drugs, phenformin and metformin, on metabolic and hormonal changes with exercise, 6 healthy volunteers have been studied during and after 30 min of controlled moderate exercise on a bicycle ergometer on three occasions, two being for the drugs taken separately and the other without any drug, as a control study. Blood samples were taken for estimation of glucose, pyruvate, lactate, free fatty acids (FFA), glycerol, growth hormone (HGH) and insulin (IRI). Both drugs caused a greater rise in blood pyruvate and lactate concentrations during exercise compared with the changes in the control investigation. They also caused a delay in the disposal of pyruvate after exercise. In all investigations, the concentrations of FFA and glycerol rose to similar values at the end of exercise. In the control study, however, the pre-exercise value was achieved by the end of the investigation, whereas with the drugs the concentrations remained elevated. After exercise the rise of ketone-body concentrations was greater with the drugs. These observations indicate that the drugs interfere with aerobic utilization of metabolic fuels, reducing the utilization of pyruvate and glycerol and decreasing the rate of fat re-esterification: these metabolic effects are potentiated by exercise.


[The expression of ki-67, topoIIalpha in laryngeal squamous cell carcinoma].
To investigate the expression of ki-67 and topo II alpha in laryngeal squamous cell carcinoma, and the relationship between its intensity and the histological grade clinical stage and lymphoma metastasis. The levels of ki-67 and topo II alpha in larynx were measured by immunohistochemical method. The positive rate of ki-67 and topo II alpha in laryngeal squamous cell carcinoma were 43.86% and 45.74%, respectively, and that in the control group were 5.66% and 5.98%, respectively. And significant difference was found between the two groups (P < 0.01). The intensity of ki-67 and topo II alpha expression correlated with histological grade. topo II alpha/ki-67 has a relationship to lymphoma metastasis. The intensity of ki-67 and topo II alpha expression can evaluate the histological grade of carcinoma. topo II alpha/ki-67 is an indicator of prognosis of Laryngeal Squamous Cell carcinoma.


Complete response of early gastric cancer to uracil and tegafur.
A 74-year-old Japanese woman with early gastric cancer was successfully treated with uracil and tegafur (UFT). She was diagnosed by endoscopy (including endoscopic biopsy and endosonography) with an early gastric cancer, type IIa + IIc, on the greater curvature of the angulus. Surgical procedures or endoscopic therapy could not be performed because the patient had severe ischemic heart disease. Therefore, chemotherapy with UFT was administered at 300 mg/day for 15 months. Follow-up endoscopy, endosonography, and biopsy showed disappearance of the gastric cancer. To our knowledge, this is the first case report of the complete response of an early gastric cancer to UFT in the English-language literature.


Protein Z levels and central retinal vein or artery occlusion.
Central retinal vein occlusion (CRVO) and central retinal artery occlusion (CRAO) are common disorders associated with risk factors for atherosclerosis. Protein Z is a cofactor for the inactivation of activated factor X (Xa) by the protein Z dependent protease inhibitor. Protein Z deficiency was recently linked to increased risk of arterial thrombosis. We investigated whether CRVO and CRAO are associated with low protein Z levels. Patients with CRVO, CRAO or recurrent branch retinal vein occlusion were recruited to the study. Protein Z level, lupus anticoagulant (LAC), anticardiolipin antibodies (ACA) and activated protein C resistance (APCR) were determined in plasma from patients (n = 36) and healthy controls (n = 42). Thirty patients in the study group had traditional risk factors for retinal vessel occlusion and six patients had none. There was no significant difference in protein Z levels between the whole study group patients and controls (1995 +/- 810 vs. 2010 +/- 603 ng/mL, P = 0.922). However, patients with no risk factors for retinal vessel occlusion had significantly lower protein Z levels than controls (1379 +/- 682 vs. 2010 +/- 603 ng/mL, P = 0.022). Positive LAC was found in six patients and one control subject (P = 0.04). There were three patients and one control subject with abnormal APCR (P = 0.3) and none with positive ACA. Low protein Z level (lower than fifth percentile of control) was not associated with the presence of LAC or APCR. Low protein Z level may be another risk factor for retinal vessel occlusion in patients without traditional risk factors for these disorders.


Predictors of acute throat or esophageal patient reported pain during radiation therapy for head and neck cancer.
Acute pain during weekly radiotherapy (RT) to the head and neck is not well characterized. We studied dose-volume metrics and clinical variables that are plausibly associated with throat or esophageal pain as measured with a weekly questionnaire during RT. We prospectively collected weekly patient-reported outcomes from 122 head and neck cancer patients during RT. The pain score for each question consisted of a four-level scale: none (0), mild (1), moderate (2), and severe (3). Univariate and multivariate ordinal logistic regression analyses were performed to investigate associations between both esophageal and throat pain and clinical as well as dosimetric variables. In multivariate analysis, age was significantly associated with both types of pain, leading to odds ratio (OR) = 0.95 (p = 0.008) and OR = 0.95 (p = 0.007) for esophageal and throat pain, respectively. For throat pain, sex (OR = 4.12; p = 0.010), with females at higher risk, and fractional organ at risk (OAR) mean dose (OR = 3.30; p = 0.014) were significantly associated with throat pain. A fractional OAR mean dose of 1.1 Gy seems a reasonable cutoff for separating no or mild pain from moderate to severe esophageal and throat pain. Younger patients who received RT experienced more esophageal and throat pain. Females experienced more throat pain, but not esophageal pain.


Aquaporins and Animal Gamete Cryopreservation: Advances and Future Challenges.
Cryopreservation is globally used as a method for long-term preservation, although freeze-thawing procedures may strongly impair the gamete function. The correct cryopreservation procedure is characterized by the balance between freezing rate and cryoprotective agents (CPAs), which minimizes cellular dehydration and intracellular ice formation. For this purpose, osmoregulation is a central process in cryopreservation. During cryopreservation, water and small solutes, including penetrating cryoprotective agents, cross the plasma membrane. Aquaporins (AQPs) constitute a family of channel proteins responsible for the transport of water, small solutes, and certain gases across biological membranes. Thirteen homologs of AQPs (AQP0-12) have been described. AQPs are widely distributed throughout the male and female reproductive systems, including the sperm and oocyte membrane. The composition of the male and female gamete membrane is of special interest for assisted reproductive techniques (ART), including cryopreservation. In this review, we detail the mechanisms involved in gamete cryopreservation, including the most used techniques and CPAs. In addition, the expression and function of AQPs in the male and female gametes are explored, highlighting the potential protective role of AQPs against damage induced during cryopreservation.


Age at onset predicts outcome in aquaporin-4-IgG positive neuromyelitis optica spectrum disorder from a United Kingdom population.
There are few studies exploring the prognostic factors in patients with aquaporin-4 (AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD). To assess the predictors of outcome in patients with AQP4-antibody positive NMOSD from a United Kingdom (UK) population. A retrospective study of 52 patients from 2 neuroscience centres in the UK Midlands. The most common initial presentations were acute myelitis and optic neuritis, with 22/52 cases (42.3%) each. Relapsing course was seen in 32 patients (61.5%) with mean annualised relapse rate of 0.43 (standard deviation 0.45) and a mean interval time to first relapse of 31 months (range 2-108). The median Expanded Disability Status Scale (EDSS) score at the last follow up was 4 (range 1-9). Age at onset was an independent predictor of disability in the whole cohort of patients with NMOSD. For every 10-year increase in age at disease onset, the risk of developing an EDSS score of ≥4 increased by 34%. Patients who presented initially with a longitudinally extensive transverse myelitis (LETM) showed a higher risk to develop disability, compared to other clinical presentations (median time of 4 years versus 13 years). Late onset (LO-NMOSD) patients were likely to reach an EDSS score of 4 more quickly, compared to early onset (EO-NMOSD) (median time of 7 years versus 13 years). Higher median EDSS score at last follow up was observed in LO-NMOSD compared to EO-NMOSD (6 versus 2). Increasing age at onset and LETM predict disability in AQP-4-IgG positive NMOSD patients.


Prolonged epididymal sperm storage, and the temporal dissociation of testicular and accessory gland activity in the common sheath-tail bat, Taphozous georgianus, of tropical Australia.
Peak spermatogenic activity of the common sheath-tail bat occurs in autumn, declines over winter and ceases in spring. Accessory glands enlarge in spring when mating occurs, but are regressed at other times of the year. Spermatozoa are stored in the cauda epididymidis throughout the year, and their numbers increase progressively from early summer to late autumn. Sperm storage permits asynchrony of male and female cycles and allows each to be optimally timed in relation to environmental conditions. The temporal separation of primary and secondary sexual functions in the male enables the insemination of females close to ovulation and is a consequence of the burden of sperm storage being placed upon the male.


Effects of chronic hypobaric hypoxia on contractile properties of rat sternohyoid and diaphragm muscles.
1. Chronic hypoxia occurs in a variety of circumstances, including respiratory disease and exposure to altitude, and is known to affect respiratory muscle structure. However, little is known about its effects on respiratory muscle contractile properties. 2. Rats were exposed to normoxia (n = 16) or hypobaric hypoxia (n = 16; barometric pressure 450 mmHg) for 6 weeks. Contractile properties were measured in isolated sternohyoid and diaphragm muscles in warmed, oxygenated Krebs' solution. Isometric twitch and tetanic tension, contraction time, half-relaxation time and tension-frequency relationship were determined using field stimulation with platinum electrodes. Fatigue was induced by stimulation at 40 Hz with 300 msec trains of 0.5 Hz for 5 min. 3. Chronic hypoxia had no effect on bodyweight, but did increase haematocrit. Chronic hypoxia increased specific force development in both muscles and increased sternohyoid fatigue. Chronic hypoxia had no effect on contractile kinetics in either muscle, but shifted the tension-frequency relationship to the left in the diaphragm. 4. Therefore, chronic hypoxia alters rat respiratory muscle force and fatigue, either due to the direct effects of hypoxia or to increased muscle activation.


Cytogenetic findings in 31 papillary thyroid carcinomas.
Chromosome studies performed on 31 papillary thyroid carcinomas (PTCs) revealed clonal numerical and structural abnormalities in 12 tumors. The numerical clonal aberrations found were trisomy 2, trisomy 7, and loss of the Y chromosome. A nonrandom telomeric association, tas(15;16)(p13;p13), was observed in one carcinoma. Structural alterations with a breakpoint at 10q11.2 were detected in two tumors. Other chromosomes involved in rearrangements were chromosomes 1, 2, 3, 5, 7, 9, 11, 12, and 14. The observation of clonal changes of chromosome 2 [i(2)(q10) and trisomy 2] in two tumors, which were both histologically classified as tall-cell PTC variants, suggests that gain of 2q may be important in the development of this morphological variant.


A near-infrared light-triggered nano-domino system for efficient biofilm eradication: Activation of dispersing and killing functions by generating nitric oxide and peroxynitrite via cascade reactions.
One of the serious threats to global public health is the bacterial biofilm, which results in numerous persistent and recurrent infections. Herein, we proposed a near-infrared (NIR) light-triggered "nano-domino" system with "dispersing and killing" functionality for biofilm eradication. The nanoplatform was fabricated by the self-assembly of chitosan conjugated with L-arginine (L-Arg, a natural nitric oxide (NO) donor) and indocyanine green (ICG, a phototherapy agent). Using an NIR irradiation "trigger", a series of reactive oxygen species (ROS) including singlet oxygen (1O2), hydrogen peroxide (H2O2), and superoxide anions (·O2-), as well as heat were generated from ICG aggregates. Subsequently, 1O2 and H2O2 catalyzed L-Arg to produce NO, which dispersed the biofilm and reacted with ·O2- to form peroxynitrite to kill bacteria with ROS collaboratively. Meanwhile, the generated heat increased the permeability of bacterial membranes, aggravating the damage to biofilm bacteria. The experiments on biofilm eradication demonstrated that this "nano-domino" system was capable to eradicate over 99.99% of biofilms formed by Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa under 5-min NIR irradiation. Notably, these integrated benefits allowed the system to promote the healing of MRSA biofilm-infected wounds in vivo with negligible toxicity. Overall, this reported NIR-triggered "nano-domino" system holds great promise for addressing the difficulties associated with bacterial biofilm eradication. STATEMENT OF SIGNIFICANCE: Novel agents for biofilm eradication are urgently needed due to the alarming rise in antimicrobial resistance to conventional antibiotics and the critical shortage of new drugs. In this study, we created a nano-domino system that uses near-infrared (NIR) light as a trigger to eradicate mature biofilms. In response to a short-term NIR irradiation, the proposed nanoplatform could generate nitric oxide and peroxynitrite to disperse the biofilm and kill the bacteria inside, respectively, leading to efficient eradication of Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa biofilms with minimal cytotoxicity. The findings, therefore, indicate that this nanoplatform with enhanced antibiofilm performance might provide a reliable and promising solution to biofilm-related problems.


Perspectives on quality control, risk management, and analytical quality management.
Quality control (QC) practices are changing in US laboratories as Centers for Medicare and Medicaid Services adopts individualized QC plans as a new option for compliance with the Clinical Laboratory Improvement Amendments regulations. The Joint Commission provides general guidance for applying risk management in health care organizations. The EP23A (Evaluation Protocol 23A) document from the Clinical and Laboratory Standards Institute provides specific guidance on the use of risk management for developing analytical QC plans. Medical laboratories should integrate risk management tools with existing quality management techniques and activities to provide an overall plan for analytical quality management.


DNA-responsive inflammasomes and their regulators in autoimmunity.
Upon sensing microbial and self-derived DNA, DNA sensors initiate innate immune responses. These sensors include the interferon (IFN)-inducible Toll-like receptor 9 (TLR9) and PYHIN proteins. Upon sensing DNA, cytosolic (murine Aim2 and human AIM2) and nuclear (IFI16) PYHIN proteins recruit an adaptor protein (ASC) and pro-caspase-1 to form an inflammasome, which activates caspase-1. The activated caspase-1 cleaves pro-IL-1β and pro-IL-18 to generate active forms. However, upon sensing cytosolic DNA, the IFI16 protein recruits STING to induce the expression of type I IFN. Recognition of self DNA by innate immune cells contributes to the production of increased levels of type I IFN. Given that the type I IFNs modulate the expression of inflammasome proteins and that the IFN-inducible proteins inhibit the activity of DNA-responsive inflammasomes, an improved understanding of the molecular mechanisms that regulate the activity of DNA-responsive inflammasomes is likely to identify new therapeutic targets to treat autoimmune diseases.


Higher BMI is associated with stronger effects of social cues on everyday snacking behaviour.
Discretionary food choices (snacks) contribute up to a third of the daily energy intake and potentially contribute to energy imbalance and weight gain. Individual snack intake behaviour is guided by internal and external cues, with social cues (seeing others eat, being alone) consistently showing large effects. A wide body of (mainly laboratory-based) research suggests marked differences in people's response to eating cues based on BMI. Here, we show that these BMI differences in cue responsiveness also pertain to everyday snacking behaviour. In two combined ecological momentary assessment studies, 122 participants with BMIs ranging from 18.34 to 45.71 kg/m2 logged their everyday snacking behaviour in real-time over two weeks along with the presence or absence of social cues. Random-effects modelling showed that people with higher BMI were more likely to consume high-energy snacks when alone, and were more likely to consume low-energy snacks in the presence of others eating. This suggests BMI differences in cue responsiveness that are in line with impression management theory and underlines the importance of social cues for snacking behaviour and provides avenues for both theory and intervention development.


Fast-growing squamous cell lung cancer.
We here report a case of squamous cell carcinoma of the lung, with an unusually fast tumor growth rate, so fast that its early detection was impossible even with two sequential chest roentgenograms taken only 36 days apart. Literature related to the concept of cell growth kinetics was reviewed, and the tumor volume doubling time that characterizes any measurable tumor was calculated for our case accordingly, based on the single lesion found on the plain chest film, with the best possible estimation of its volume. We concluded that, to the best of our knowledge, a squamous cell carcinoma of the lung that grew so fast (with a tumor doubling time less than 7.5 days) has not yet been reported to date; neither has a bronchogenic carcinoma of any cell type been reported with such a presentation. Given that a patient aged 81 belonged to a group usually with slower growth in tumor cell kinetics, the behavior of his tumor was indeed uncommon.


Can machine learning 'transform' peptides/peptidomimetics into small molecules? A case study with ghrelin receptor ligands.
There has been considerable interest in transforming peptides into small molecules as peptide-based molecules often present poorer bioavailability and lower metabolic stability. Our studies looked into building machine learning (ML) models to investigate if ML is able to identify the 'bioactive' features of peptides and use the features to accurately discriminate between binding and non-binding small molecules. The ghrelin receptor (GR), a receptor that is implicated in various diseases, was used as an example to demonstrate whether ML models derived from a peptide library can be used to predict small molecule binders. ML models based on three different algorithms, namely random forest, support vector machine, and extreme gradient boosting, were built based on a carefully curated dataset of peptide/peptidomimetic and small molecule GR ligands. The results indicated that ML models trained with a dataset exclusively composed of peptides/peptidomimetics provide limited predictive power for small molecules, but that ML models trained with a diverse dataset composed of an array of both peptides/peptidomimetics and small molecules displayed exceptional results in terms of accuracy and false rates. The diversified models can accurately differentiate the binding small molecules from non-binding small molecules using an external validation set with new small molecules that we synthesized previously. Structural features that are the most critical contributors to binding activity were extracted and are remarkably consistent with the crystallography and mutagenesis studies.


Influence of age and gender in the sensory nerve fibers excitability.
To assess the influence of age and gender on sensory nerve axonal excitability parameters. Thirty-three healthy subjects (21 women) were included, with a mean age of 34.6 (range 21-76). Median sensory nerve excitability measurements (index finger) were performed using the TRONDNF nerve excitability protocol of the QTRAC program. Peak sensory nerve action potential (SNAP) amplitude was significantly higher among women (27.1 vs. 9.2 μV; p = .022), and strength-duration time constant (SDTC) was significantly higher in men (0.7 vs. 0.5; p = .011), not dependent on age. Greater age was negatively correlated with resting I/V slope, not dependent on gender (r = -0.4; p = .024). No other changes in excitability properties with increasing age were found. Physiological features like as age and gender do not have a relevant impact on sensory nerve excitability measurements, which can have implications regarding pharmacological treatments.


Fabrication of cell culture-derived influenza vaccine dissolvable microstructures and evaluation of immunogenicity in guinea pigs.
Microstructure patches provide an opportunity for simple, effective, and safe vaccine administration, while achieving the desired immune response. We have evaluated the MicroCor transdermal system for cell culture-derived trivalent influenza vaccine administration. Influenza monovalent purified bulk vaccines (monobulks) (H1N1, H3N2, B) were concentrated by tangential flow filtration, lyophilized, and formulated with biocompatible excipients to form the microstructure array dissolvable tips. Standard single radial immunodiffusion (SRID) determined that the influenza antigens retained potency through the formulation and microstructure array fabrication processes. Array stability was evaluated for storage in both refrigerated and room temperature conditions. Microstructure mechanical strength was confirmed by application to excised pig skin, resulting in successful skin penetration and tip dissolution within 5 min of microstructure insertion. Guinea pigs immunized with influenza vaccine-loaded microstructures had hemagglutinin inhibition (HI) and IgG titers comparable to those obtained by intramuscular injection. After two immunizations, serum HI titers for all immunized groups were greater than 40 (>4-fold higher than the untreated group). These data demonstrate the feasibility for the development of skin delivery technologies that are compatible with cell culture-derived influenza vaccines.


Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1.
The novel hydroxylamine derivative, bimoclomol, has been shown previously to act as a co-inducer of several heat shock proteins (Hsp-s), enhancing the amount of these proteins produced following a heat shock compared to heat shock alone. Here we show that the co-inducing effect of bimoclomol on Hsp expression is mediated via the prolonged activation of the heat shock transcription factor (HSF-1). Bimoclomol effects are abolished in cells from mice lacking HSF-1. Moreover, bimoclomol binds to HSF-1 and induces a prolonged binding of HSF-1 to the respective DNA elements. Since HSF-1 does not bind to DNA in the absence of stress, the bimoclomol-induced extension of HSF-1/DNA interaction may contribute to the chaperone co-induction of bimoclomol observed previously. These findings indicate that bimoclomol may be of value in targeting HSF-1 so as to induce up-regulation of protective Hsp-s in a non-stressful manner and for therapeutic benefit.


Improving the design of phase II trials of cytostatic anticancer agents.
This paper examines the design of phase II trials in oncology and recommends departing from the traditional uncontrolled trial design. Entrance into phase II clinical evaluation represents a key milestone in the development of any new cancer therapy. As novel molecular-targeted therapies are introduced, whose primary action is to slow the growth of tumors, it will be important to ensure that the clinical trial design will effectively capture any clinical benefit of these agents. The objective of a phase II trial should, in addition to identifying active therapies, be extended to identifying those that are likely to be successful in pivotal trials. It is therefore necessary to quantify the likelihood of either incorrectly halting the development of an active agent or continuing development of an ineffective agent. We believe only randomized studies with comparative intent and including a concurrent active control, can reliably assess these risks corresponding to significance and power. Given that the objective of phase II studies is to identify promising treatments, it is important not be constrained by conventional levels of significance. This paper will review the various approaches to phase II trial design in oncology and provide a framework for fully powered randomized trials of a moderate size. For example, a randomized trial of just 100 patients could lead to the termination of development of 90% of inactive agents whereas at least 80% of agents with a meaningful and realistic increase in progression-free survival would be identified for confirmatory study. We believe randomized studies with progression-free survival endpoints are the most powerful and economical method of determining the clinical activity of new cytostatic agents.


Adherence to the dietary approaches to stop hypertension-style diet is inversely associated with chronic kidney disease: a systematic review and meta-analysis of prospective cohort studies.
No conclusive information is available about the association between the Dietary Approaches to Stop Hypertension (DASH)-style diet and chronic kidney disease (CKD). Hence, we aimed to summarize the findings of prospective cohort studies on the relationship between adherence to the DASH-style diet and risk of CKD. A systematic search was done using relevant keywords in the online databases for relevant publications up through July 2018. In total, we included 6 studies in the current systematic review and meta-analysis, with a total sample size of 568 156 individuals and 9249 cases of CKD. Combining 6 effect sizes from 6 studies revealed a significant inverse association between adherence to the DASH diet and risk of CKD (Combined effect size: 0.72, 95% CI: 0.61-0.85, P < .001). In addition, adherence to a DASH-style diet was inversely associated with a risk of rapid decline in estimated glomerular filtration rate (eGFR) (Combined effect size: 0.74, 95% CI: 0.54-0.99, P = .04) and microalbuminuria (Combined effect size: 0.61, 95% CI: 0.43-0.88, P = .009), but not with low eGFR. Adherence to the DASH-style diet, as a healthy dietary pattern, might be beneficial for the prevention of CKD.


The non-enzymic glycosylation of bovine lens proteins by glucosamine and its inhibition by aspirin, ibuprofen and glutathione.
Cataract is a long-term complication of diabetes mellitus. Diabetics have increased glucosamine levels and it is possible that the non-enzymic glycosylation of the lens structural proteins by glucosamine induces conformational changes in the lens that contribute to cataract formation. Aspirin and aspirin-like analgesics may protect against glycosylation. In this paper the binding of glucosamine to bovine lens proteins and the effects of aspirin, paracetamol and ibuprofen on this reaction were investigated. Significant binding of glucosamine to the lens proteins was found. Gel-chromatography indicated that beta H-crystallin was most reactive to the amino-sugar. Of the analgesics studied, aspirin was the most effective inhibitor of glycosylation, followed by the other anti-inflammatory drug, ibuprofen. Preincubation of the lens homogenate with aspirin was no more effective at decreasing binding of glucosamine than was simultaneous incubation with aspirin. Glutathione significantly inhibited glucosamine binding. Glucosamine is active in non-enzymic glycosylation but the reaction can be inhibited by agents thought to protect against cataract.


The assignment of PRKCI to bovine chromosome 1q34-->q36 by FISH suggests a new assignment to human chromosome 3.
Two bovine BAC clones were identified by PCR as containing the bovine gene PRKCI. Both clones were assigned by FISH to bands q34-->q36 on BTA1. The sequence information derived from genomic DNA and from both clones was identical and showed a high degree of homology to human PRKCI (HSAXq21.3, 95.5% homology), and mouse Prkcl (MMU3, 13.8 cM, 87.6% homology) and rat Prkcl (88.8% homology). This assignment could suggest a disruption of the synteny conservation of mammalian X-linked genes, but most likely suggests a misassignment of this gene to the human X.


Simple and rapid simultaneous profiling of minor components of honey by size exclusion chromatography (SEC) coupled to ultraviolet diode array detection (UV-DAD), combined with chemometric methods.
This paper discusses the importance of profiling UV-responsive components, properly integrated with chemometric techniques, in detecting indicative parameters for quality control of honey. The minor components in honeys of different botanical and geographical origins were investigated by size SEC-UV-DAD. We diluted honey with mobile phase before injection into the chromatographic apparatus and a single chromatographic run gave a fast profile of high- (proteins and enzymes), intermediate- (e.g. terpenoid glycosides in lime tree honey) and low-molecular-weight components (secondary metabolites, e.g. kynurenic acid in chestnut honey). The analysis of a total number of 32 honey samples from different regions (Italy, Western Balkan countries, Brazil, Cameroon, Kenya) and of different botanical origins (herbal flower and arboreal flower nectars/honeydews) showed peculiar and characteristic distribution of these markers, which were basically related to their floral origin. Chemometric examination carried out using principal component analysis (PCA) and hierarchical cluster analysis (HCA) of the chromatograms (RT vs. absorption) detected four main clusters in which the groups of (i) chestnut honeys, (ii) honeys from rain forests and (iii) counterfeit/adulterated honeys were clearly separated from the main group of flower nectar honeys. The method is fast, requiring minimal sample handling, and the chromatographic data can be analyzed by multivariate statistical techniques to obtain descriptive information about the honey's quality and composition.


Slaving and release in co-infection control.
Animal and human infection with multiple parasite species is the norm rather than the exception, and empirical studies and animal models have provided evidence for a diverse range of interactions among parasites. We demonstrate how an optimal control strategy should be tailored to the pathogen community and tempered by species-level knowledge of drug sensitivity with use of a simple epidemiological model of gastro-intestinal nematodes. We construct a fully mechanistic model of macroparasite co-infection and use it to explore a range of control scenarios involving chemotherapy as well as improvements to sanitation. Scenarios are presented whereby control not only releases a more resistant parasite from antagonistic interactions, but risks increasing co-infection rates, exacerbating the burden of disease. In contrast, synergisms between species result in their becoming epidemiologically slaved within hosts, presenting a novel opportunity for controlling drug resistant parasites by targeting co-circulating species. Understanding the effects on control of multi-parasite species interactions, and vice versa, is of increasing urgency in the advent of integrated mass intervention programmes.


TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel.
Hematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium-based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel-associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease-free survival in CRC patients. Gain- and loss-of-function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial-mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte-conditional Tcaf2-knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro-metastatic effects of TPCs from the perspective of cold-sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM.


Diabetes and driving safety.
Diabetes is one of the most common chronic disease in the world. The complications of diabetes both during the disease progression and treatment may cause problem escpecially in traffic. A training on driving safety should be given to diabet patients after diagnosis. Necessary training and legal arrangements should be made in order to increase the awareness in both driving schools and care centers of diabetic patients.


Insulin resistance, serum adiponectin, and proinflammatory markers in young subjects with the metabolic syndrome.
Insulin resistance is the underlying metabolic abnormality in the metabolic syndrome. The low-grade chronic inflammation may be associated with metabolic risk factors and atherogenesis. The aim of our study was to establish the link between the metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP) criteria, and insulin sensitivity, serum adiponectin, and parameters of chronic inflammation in young subjects. The group of 223 subjects (mean age, 25.86 +/- 5.49 years; body mass index, 28.04 +/- 6.91 kg/m2) was studied. Oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and estimation of serum adiponectin and proinflammatory factors were performed. The NCEP-defined metabolic syndrome was present in 49 subjects (21.97%). The higher the number of NCEP criteria fulfilled was, the bigger were the decrease in insulin sensitivity (P < .0001) and adiponectin (P < .0001) and the increase in fasting and postload insulin (both Ps < .0001), C-reactive protein (P < .0001), interleukin 18 (P < .0001), interleukin 6 (P < .0001), and soluble tumor necrosis factor-alpha receptors sTNFR1 (P < .0001) and sTNFR2 (P < .0001) observed. Multiple regression analysis revealed that adiponectin and inflammatory factors predicted NCEP score independent of insulin sensitivity (all adjusted beta values between .16 and .32, all Ps < .01). Young subjects with metabolic syndrome demonstrate an increased inflammatory response and lower adiponectin concentration.


The dissipation of ethofenprox in cabbage and soil under open conditions.
The dissipation of ethofenprox in cabbage and soil under open conditions was investigated at two primary cabbage-growing regions, Beijing and Kunming in China. Samples were extracted with acetonitrile and determined by ultra-performance liquid chromatography with a single quadrupole detector. Dissipation of ethofenprox from cabbage and soil can be best explained by a first-order decay process. The half-lives of ethofenprox were 1.9 and 2.3 days in cabbage and 20.0 and 13.0 days in soil at Beijing and Kunming, respectively. The concentration of ethofenprox residue was reduced by 90% taking 7 and 60 days in cabbage and soil. Dissipation rates in cabbage and soil at two geographically separated experimental fields differed, suggesting that this was affected by complicated factors, such as local climate and soil characteristics. These data could provide guidance for the proper and safe use of this pesticide on cabbage in China.


A novel application of radiomimetic compounds as antibiotic drugs.
This study aims to examine the potential of radiomimetic compounds as antimicrobial therapeutics, as the recent advances in radiomimetic targeting as well as rapid increase of multidrug resistant bacteria make these compounds attractive for future development. Representative radiomimetics from each of the three major categories was examined; C-1027 and neocarzinostatin from the protein-chromophore enediyne family; Calicheamicin from the non-protein chromophore enediyne family and Bleomycin and Tallysomycin S10b from the glycopeptide family. The activity of these compounds was examined against 12 distinct bacteria species. Inhibition was determined using disc diffusion assays and a subsequent examination of minimum inhibitory concentration of a representative organism. The onset of action of the compounds was also determined by incubating the organisms with drug in liquid media, before plating, and then determining if growth occurred. We found that the radiomimetic glycopeptides were more active against Gram-negative species, while the enediynes were more effective against Gram-positive species. The radiomimetics also maintained their rapid onset of action, working as quickly as 5 min. Radiomimetic compounds have activity against a wide variety of microorganisms and would support the development of radiomimetic-antibody conjugates as potential antibiotics as an option against severe bacterial infections.


Accuracy in Rietveld quantitative phase analysis: a comparative study of strictly monochromatic Mo and Cu radiations.
This study reports 78 Rietveld quantitative phase analyses using Cu Kα1, Mo Kα1 and synchrotron radiations. Synchrotron powder diffraction has been used to validate the most challenging analyses. From the results for three series with increasing contents of an analyte (an inorganic crystalline phase, an organic crystalline phase and a glass), it is inferred that Rietveld analyses from high-energy Mo Kα1 radiation have slightly better accuracies than those obtained from Cu Kα1 radiation. This behaviour has been established from the results of the calibration graphics obtained through the spiking method and also from Kullback-Leibler distance statistic studies. This outcome is explained, in spite of the lower diffraction power for Mo radiation when compared to Cu radiation, as arising because of the larger volume tested with Mo and also because higher energy allows one to record patterns with fewer systematic errors. The limit of detection (LoD) and limit of quantification (LoQ) have also been established for the studied series. For similar recording times, the LoDs in Cu patterns, ∼0.2 wt%, are slightly lower than those derived from Mo patterns, ∼0.3 wt%. The LoQ for a well crystallized inorganic phase using laboratory powder diffraction was established to be close to 0.10 wt% in stable fits with good precision. However, the accuracy of these analyses was poor with relative errors near to 100%. Only contents higher than 1.0 wt% yielded analyses with relative errors lower than 20%.


Occurrence and characterization of Acanthamoeba similar to genotypes T4, T5, and T2/T6 isolated from environmental sources in Brasília, Federal District, Brazil.
Species of Acanthamoeba can cause keratitis and brain infections. The characterization of environmental isolates is necessary to analyze the risk of human infection. We aimed at identifying and genotyping Acanthamoeba isolates from soil, swimming pools, and water features in Brasília, Federal District, Brazil, as well as determining their physiological characteristics and pathogenic potential. Among the 18 isolates studied, eight were similar to genotype T5, five to T4, and one to T2/T6, classified by the sequence analysis of 18S rDNA. Genotypes of four isolates were not determined. Ten isolates (55%) grew at 37 °C and seven (39%) grew in media with 1.5M mannitol, which are the physiological parameters associated with pathogenic Acanthamoeba; also, four isolates from swimming pools presented high pathogenic potential. Our results indicate a widespread distribution of potentially pathogenic Acanthamoeba T4, T5, and T2/T6 in different environmental sources in Brasília, revealing the potential risk of human infection and the need of preventive measures.


Uterine artery Doppler velocimetry and maternal weight gain by the mid-second trimester for prediction of fetal growth restriction.
To investigate whether assessment of maternal weight gain up to mid-second trimester improves the predictive value of uterine artery Doppler velocimetry (UAD) for the prediction of fetal growth restriction (FGR). Department of Obstetrics and Gynecology, Yonsei University College of Medicine. Prospective Doppler measurements coupled to retrospective chart review. A total of 10,970 women delivering at the institution. Maternal weight gain up to mid-second trimester and Doppler ultrasonography on bilateral uterine arteries between 20 and 24 weeks' gestation. Low weight gain was defined as <0.2 kg/week and FGR as birthweight of <10th percentile. ith that combined with the measurement of maternal weight gain for the prediction of the FGR. The odd ratios for FGR were 2.56 (95% CI 1.59-4.12) in the group with normal UAD and abnormal weight gain (normal-abnormal group), 1.91 (95% CI 0.98-3.7) in the abnormal-normal group and 40.3 (95% CI 16.9-96.4) in the abnormal-abnormal group. UAD independent of weight gain had a sensitivity of 31.5%, a specificity of 88%, a positive predictive value (PPV) of 24.5% and a negative predictive value (NPV) of 91.2%. When mid-trimester maternal weight gain was accounted for, the sensitivity of UAD was 64.9%, specificity 64.1%, PPV 73.3% and NPV 93.6%. The diagnostic performance of UAD for FGR improved significantly when the degree of maternal weight gain until the mid-second trimester was taken into account. Closer antenatal surveillance might be required in women with abnormal uterine Doppler velocimetry if their mid-second trimester weight gain is poor.


High Nrf2 expression in alveolar type I pneumocytes is associated with low recurrences in primary spontaneous pneumothorax.
Recurrent primary spontaneous pneumothorax (PSP) is a troublesome problem and a major concern for the patients. This study examined whether nuclear factor erythroid 2-related factor 2 (Nrf2) expression in alveolar type I pneumocytes was associated with the clinical manifestations of PSP patients including disease recurrence. Eighty-eight PSP patients who were managed with needlescopic video-assisted thoracoscopic surgery (NVATS) were included in this study. Immunohistochemistry (IHC) was assessed to determine Nrf2 expression in resected lung tissues and the results were correlated with clinicopathological characteristics by the chi-square or the Fisher's exact test. The prognostic value of Nrf2 for overall recurrence was evaluated by univariate and multivariable Cox regression model. The expression of Nrf2 was observed in type I pneumocytes of lung tissues from PSP patients by IHC. We found that low Nrf2 expression in PSP patients, especially in young (age ≤ 20, p = 0.033) and body mass index (BMI) ≥18 kg/m2 (p = 0.019) groups, was significantly correlated with PSP recurrence. In the univariate and multivariate analyses, high Nrf2 expression was a significant protective factor for overall recurrence in PSP patients (univariate: p = 0.026; multivariate: p = 0.004). The expression level of Nrf2 in alveolar type I pneumocytes was a potential factor involved in PSP recurrence. Our findings suggest that elevated Nrf2 expression in PSP patients may be a promising way for reducing PSP recurrence.


Viewing time as a measure of bisexual sexual interest.
Studies of bisexual sexual interest have focused mostly on measures of genital arousal in bisexual men and have generally failed to find evidence of a bisexual pattern of genital arousal. Bisexual women have rarely been studied and other measures of sexual interest have not been used to study bisexual interest in either sex. In this study, we examined a non-genital measure of sexual interest, viewing time, among 16 bisexual men, 19 bisexual women, 15 heterosexual men, 15 heterosexual women, 15 homosexual men, and 10 homosexual women. Sexual orientation was determined from a self-report questionnaire. Stimuli were pictures of males and females of all five Tanner stages of sexual development. Participants were asked to rate the sexual appeal of the individuals depicted in the pictures, while the time taken to provide a response was covertly measured. Using a signed index that compared viewing times to pictures of sexually mature males and females, bisexual men and bisexual women did not look longer at pictures of one gender, whereas the other four groups had longer viewing times for pictures of one gender. Using an absolute index, the three groups of women showed a similar (and low) degree of gender preference. All groups showed longer viewing times for sexually mature individuals than for sexually immature individuals, suggesting that the viewing time responses of bisexual men and women were not produced by a general tendency to look indiscriminately at all pictures. There were small to moderate correlations between viewing times and rated sexual appeal in all groups. Results suggest that viewing time can be used to detect a bisexual pattern of sexual interest in bisexual men and bisexual women.


Assessment of lithogenic risk in children based on a morning spot urine sample.
The Bonn Risk Index has been used to evaluate the risk of urinary calcium oxalate stone formation. According to the original method, risk should be determined based on 24-hour urine collection. We studied whether the Bonn Risk Index could be measured in spot urine samples and which part of the day is most suitable for this purpose. We collected total and fractionated 24-hour urine (in a 6-hour nocturnal portion and 9 consecutive 2-hour diurnal samples) in 42 children and adolescents with calcium oxalate urolithiasis and 46 controls. Bonn Risk Index values determined from each of the urine fractions were compared to those obtained from related 24-hour urine collections. Both groups exhibited similar circadian patterns of Bonn Risk Index values. Median Bonn Risk Index for the nighttime portion of urine in the stone group was 1.4 times higher than that obtained from the total 24-hour urine. The morning hours between 08:00 and 10:00 showed the peak lithogenic risk, and this fraction had the highest sensitivity and selectivity regarding discrimination between stone formers and healthy subjects. The afternoon hours demonstrated lower and less fluctuating crystallization risk. Despite diurnal fluctuations in Bonn Risk Index, there was still a well-defined cutoff between the groups. Bonn Risk Index determined from urine samples collected between 08:00 and 10:00 appears optimal in separating stone formers from healthy subjects, and appears as useful as the value determined from 24-hour urine collection. Investigation of this diurnal sample simplifies diagnosis in pediatric stone disease without loss of clinical information.


A Base Editing Platform Shows Function of Cancer-Associated Variants.
A resource was developed to introduce and interrogate cancer-associated single-nucleotide variants.


Setting organ allocation priorities: should we care what the public cares about?
To investigate the nature of public preferences in the allocation of donor liver grafts for transplantation. A qualitative study based upon the transcripts of four focus groups. Derby, Derbyshire, UK. Twenty-two members of the public in the Derby locality, recruited to one of four focus groups through local community groups. The views of focus group members as to the importance (or otherwise) of several potential discriminating factors which could be used in the prioritization of patients on the waiting list for liver transplantation were ascertained. The factors included were expected posttransplantation prognosis, the age of the patient, whether the patient was personally responsible for their illness, the time spent on the waiting list, re-transplantation or primary transplant and the social background of the patient. Group members explored the criteria from a number of perspectives, and made some unexpected linkages between the criteria and wider moral principles. They did not come to firm conclusions about the relative desirability of the criteria, but their approach was notably flexible and thoughtful, with the exception of a few instances where they appeared to resort to arguments based on what is 'obvious' and 'natural'. The results of these discussions suggest that members of the public would be able and willing to respond positively to a more open and consultative system of donor liver prioritization than exists presently within the UK.


Twenty-first century oocyte cryopreservation-in vitro maturation of immature oocytes from ovarian tissue cryopreservation in cancer patients: A systematic review.
Our review aimed to consolidate the latest update on the application of in vitro maturation among immature oocyte harvest in combination with ovarian tissue cryopreservation known as ovarian tissue oocyte-in vitro maturation. A thorough search for relevant studies was conducted via PubMed, Google Scholar, EMBASE, and clinical.gov databases up to December 2020. The primary outcome was the oocyte maturation rate, which measured the number of immature oocytes (geminal vesicle stage) that progressed to mature oocytes (meiosis II stage) following in vitro maturation. The secondary outcomes were the fertilization rate following intracytoplasmic sperm injection/in vitro fertilization of these oocytes for the embryo cryopreservation cohort. Our review included pre-pubertal girls and women with cancer who underwent ovarian tissue oocyte-in vitro maturation as fertility preservation. The primary search identified 207 studies. Twelve manuscripts were selected for inclusion in our review following duplication assessment, title and abstract screening, and full-text evaluation tailored to our inclusion criteria. All the population belonged to a cancer group and underwent concurrent ovarian tissue oocyte-in vitro maturation. A total of 5724 immature oocytes were obtained following ovarian tissue cryopreservation. Approximately 33.84% of the immature oocytes successfully matured via in vitro maturation, which were cryopreserved as oocytes or fertilized as embryos and subsequently stored for future use. Our review proposed the potential application of ovarian tissue oocyte-in vitro maturation in increasing the number of mature oocytes. The acceptable improvement in oocyte maturation rate following in vitro maturation indicates that improving oocyte outcomes is an excellent cost-effective strategy for fertility preservation among women with cancer.


Tumor cells derived-exosomes as angiogenenic agents: possible therapeutic implications.
Angiogenesis is a multistep process and various molecules are involved in regulating it. Extracellular vesicles are cell-derived particles, secreted from several types of cells and are known to mediate cell-to-cell communication. These vesicles contain different bio-molecules including nucleic acids, proteins, and lipids, which are transported between cells and regulate physiological and pathological conditions in the recipient cell. Exosomes, 30-150 nm extracellular vesicles, and their key roles in tumorigenesis via promoting angiogenesis are of great recent interest. In solid tumors, the suitable blood supply is the hallmark of their progression, growth, and metastasis, so it can be supported by angiogenesis. Tumor cells abundantly release exosomes containing different kinds of biomolecules such as angiogenic molecules that contribute to inducing angiogenesis. These exosomes can be trafficked between tumor cells or between tumor cells and endothelial cells. The protein and nucleic acid cargo of tumor derived-exosomes can deliver to endothelial cells mostly by endocytosis, and then induce angiogenesis. Tumor derived-exosomes can be used as biomarker for cancer diagnosis. Targeting exosome-induced angiogenesis may serve as a promising tool for cancer therapy. Taken together, tumor derived-exosomes are the major contributors in tumor angiogenesis and a supposed target for antiangiogenic therapies. However, further scrutiny is essential to investigate the function of exosomes in tumor angiogenesis and clinical relevance of targeting exosomes for suppressing angiogenesis.


An efficient approach to study the toxicological effects of complex mixtures.
In vitro studies in the field of inhalation toxicology suffer a number of problems due to the difficulties in exposing cells of the respiratory tract directly to inhalable substances in a way that is comparable to the in vivo situation. The most promising approach is based on a biphasic cell culture technique, where cells are grown on microporous membranes at an air-liquid interface. In this way, the cells can be nutrified from the basal side of the membrane whereas the apical part with the cultivated cells is in direct contact with the test atmosphere, meaning gaseous and/or particulate compounds. This type of exposure requires (1) a special exposure device and conditions, (2) a close contact between the cultivated cells and the inhalable substances without the interference of medium as well as (3) precise control of the pollutant levels. Exposure of cells under these conditions results in dose-dependent reactions with regard to cyto- and genotoxicity or cell activation associated, for example, with the release of bioactive mediators. Such an experimental approach is not only suitable for cultivated cells, but it can also be used in a modified Ames assay for the detection of mutagenicity by exposing bacteria to gaseous compounds or complex mixtures. This is not only true under laboratory conditions but can also be achieved under real indoor situations.


Cognitive neuroscience: searching for the bottleneck in the brain.
People simply cannot do two things at once, as shown by research on the so-called psychological refractory period. A new neuroimaging study has now localized the response-selection bottleneck underlying the psychological refractory period to a frontoparietal network.