Structure activity relationships leading to the identification of the indirect activator of AMPK, R419.
Using an in-cell AMPK activation assay, we have developed structure-activity relationships around a hit pyridine dicarboxamide 5 that resulted in 40 (R419). A particular focus was to retain the on-target potency while also improving microsomal stability and reducing off-target activities, including hERG inhibition. We were able to show that removing a tertiary amino group from the piperazine unit of hit compound 5 improved microsomal stability while hERG inhibition was improved by modifying the substitution of the central core pyridine ring. The SAR resulted in 40, which continues to maintain on-target potency. Compound 40 was able to activate AMPK in vivo after oral administration and showed efficacy in animal models investigating activation of AMPK as a therapy for glucose control (both db/db and DIO mouse models).


Early myeloid cells expressing c-KIT isoforms differ in signal transduction, survival and chemotactic responses to Stem Cell Factor.
Isoforms of the receptor tyrosine kinase, c-KIT, differ in the presence or absence of a GNNK tetrapeptide in the extracellular juxtamembrane region. When expressed in murine NIH3T3 cells, these isoforms of c-KIT showed differential activation of signaling pathways and proliferation in response to Stem Cell Factor (SCF). However, c-KIT is not normally expressed by fibroblasts, but plays a key role in hematopoiesis. Because signaling pathways and cellular responses mediated by c-KIT differ in different cell types, we studied the effects of SCF stimulation on factor-dependent murine early myeloid cells expressing human GNNK+ or GNNK- c-KIT. As in fibroblasts, SCF activation of the GNNK- isoform resulted in stronger, more rapid receptor phosphorylation, and activation of Src kinases, while only a minor effect on the phosphatidylinositol 3-kinase pathway was observed. Similarly, more rapid Src kinase-dependent internalisation of the GNNK- isoform occurred in response to SCF. In contrast to fibroblasts, only minor differences in ERK activation were seen indicating that early hematopoietic cells, unlike fibroblasts, are not dependent on Src kinases for activation of this pathway in response to SCF. Enhanced SCF-dependent growth was observed in GNNK- c-KIT expressing cells due to lower cell attrition. The rate of cell division was similar. Importantly, cells expressing the GNNK- isoform showed a greater chemotactic response to SCF.


[Histogenesis of lung adenocarcinoma induced by oral adminstration of mycotoxins in mice].
To study the histogenesis and the putative mechanisms of adenocarcinoma induced by AFG1 and ST in NIH mice. Thirty-four cases of lung adenocarcinomas induced by AFG1 and ST in NIH mice were included in this study and 12 cases of normal lung tissues were used as control. The phenotype of the lung adenocarcinomas was determined by immunohistochemical expression of SP-C and CC-10 at protein level. The expression of P53, Ras P21 and PCNA was studied with immunohistochemical staining. The positive expression of SP-C was found in all the lung adenocarcinomas, while no expression of CC-10 could be seen. The labelling index of PCNA in the adenocarcinomas were significantly higher than that of control (P < 0.01). No positive expression of mutant P53 and Ras at protein level could be found. The lung adenocarcinomas induced by the two mycotoxins in NIH mice arise from alveolar type II cells and no expression of mutant P53 and Ras at protein level was found in the lung adenocarcinomas.


Reductive acetylation of tandemly repeated lipoyl domains in the pyruvate dehydrogenase multienzyme complex of Escherichia coli is random order.
In vitro deletion and site-directed mutagenesis of the aceF gene of Escherichia coli was used to generate dihydrolipoamide acetyltransferase (E2p) polypeptide chains containing various permutations and combinations of functional and non-functional lipoyl domains. A lipoyl domain was rendered non-functional by converting the lipoylatable lysine residue to glutamine. Two- and three-lipoyl domain E2p chains, with lipoyl-lysine (Lys244) substituted by glutamine in the innermost lipoyl domains (designated +/- and +/+/-, respectively), and similar chains with lipoyl-lysine (Lys143) substituted by glutamine in the outer lipoyl domains (designated -/+ and -/-/+), were constructed. In all instances, pyruvate dehydrogenase complexes were assembled in vivo around E2p cores composed of the modified peptide chains. All the complexes were essentially fully active in catalysis, although the complex containing the -/-/+ version of the E2p polypeptide chain showed a 50% reduction in specific catalytic activity. Similarly, active-site coupling in the complexes containing the +/-, +/+/- and -/+ constructions of the E2p chains was not significantly different from that achieved by the wild-type complex. However, active-site coupling in the complex containing the -/-/+ version of the E2p chain was slightly impaired, consistent with the reduced overall complex activity. These results indicate that during oxidative decarboxylation there is no mandatory order of reductive acetylation of repeated lipoyl domains within E2p polypeptide chains, and strongly suggest that the three tandemly repeated lipoyl domains in the wild-type E2p chain function independently in the pyruvate dehydrogenase complex.


Modulation of natural killer cell cytotoxicity and cytokine release by the drug glatiramer acetate.
Glatiramer acetate (GA or Copaxone) is a drug used to treat experimental autoimmune encephalomyelitis in mice and multiple sclerosis in human. Here, we describe a new mechanism of action for this drug. GA enhanced the cytolysis of human NK cells against autologous and allogeneic immature and mature monocyte-derived dendritic cells (DCs). This drug reduced the percentages of mature DCs expressing CD80, CD83, HLA-DR or HLA-I. In contrast, it did not modulate the percentages of NK cells expressing NKG2D, NKp30, or NKp44. Nonetheless, anti-NKp30 or anti-CD86 inhibited GA-enhanced human NK cell lysis of immature DCs. Hence, CD86, and NKp30 are important for NK cell lysis of immature DCs, whereas CD80, CD83, HLA-DR and HLA-I are important for the lysis of mature DCs when GA is used as a stimulus. Further, GA inhibited the release of IFN-gamma 24 h but increased the release of TNF-alpha 48 h after incubation with NK cells.


The management of confidentiality in general medical practice: a comparative study in the U.S.A. and The Netherlands.
This paper describes the results of two studies in New Jersey and the eastern part of the Netherlands into the management of confidentiality among physicians in general medical practice. The physicians were presented with vignettes about confidentiality and were asked what course of action they would pursue. The results suggest that the physicians in New Jersey are less willing to disclose information without the patient's consent to insurance physicians or occupational health physicians than their Dutch colleagues. However, in more conflicting situations the American physicians tend to favor more disclosure of information than their Dutch counterparts. Explanations of these differences include aspects of the legal system in New Jersey and the Netherlands.


Delinted cottonseed in diets for finishing sheep.
The use of agricultural by-products might provide an important alternative to improve animal agriculture and to reduce feeding costs. The effects of inclusion in the diet of four levels of delinted cottonseed (0, 80, 160, and 240 g/kg) on intake, digestibility, nitrogen balance, blood parameters, and the ingestive behaviour of confined sheep were studied. Twenty-four mixed-breed rams with an average body weight of 27.6 ± 2.9 kg were used in a completely randomised design with four treatments. The addition of delinted cottonseed (DCS) did not alter (P > 0.05) the intake of dry matter, crude protein, organic matter, neutral detergent fibre, or ether extract in the two forms calculated (g/day and % body weight). The use of different levels of DCS in sheep feed did not influence (P > 0.05) the voluntary water intake. The dietary DCS levels linearly affected (P < 0.05) the digestibility coefficients of the dry matter (DM), organic matter, neutral detergent fibre, ether extract, and non-fibrous carbohydrates. The DCS inclusion levels did not affect the nitrogen balance (P = 0.22), plasma concentrations of urea (P = 0.51), and glucose (P = 0.17).The feeding efficiency and rumination in g DM/h reduced linearly (P < 0.05) with the addition of DCS in the diet. Therefore, the addition of delinted cottonseed affects the intake, digestibility, and ingestive behaviour of confined sheep, and the addition of up to 80 g/kg delinted cottonseed in the diet of confined sheep is recommended.


Papanicolaou staining of exfoliated vaginal epithelial cells facilitates the prediction of ovulation in the giant panda.
The giant panda is seasonally monoestrus, experiencing a single estrous with spontaneous ovulation in the spring. Therefore, accurate monitoring of the estrous cycle to pinpoint the time of ovulation is critical for the success of timed mating or artificial insemination. Analysis of exfoliated vaginal epithelial cells is a simple technique that rapidly yields information about the estrous status of a panda. Vaginal swabs were obtained during five estrous cycles of two nulliparous females. Cells were stained with the trichrome Papanicolaou and classified as basophils, intermediates or superficials. The color of stained cells, basophilic, acidophilic or keratinized, was recorded as a characteristic independent of the three standard cell types. The day urinary conjugates of estrogen fell from peak levels was considered the day of ovulation. A chromic shift occurred 8-9 days before ovulation when the majority of exfoliated vaginal cells changed from basophilic (blue) to acidophilic (pink) without accompanying nuclear or cytoplasmic changes. A second chromic shift was consistently observed 2 days prior to ovulation when keratinized (orange) cells replaced acidophils as the majority of vaginal cells. Monochrome staining of vaginal cells is sufficient to quantify superficial cells, which is a useful adjunct to behavioral and endocrinological data in determining estrous in the giant panda. However, the timing and duration of superficial cell elevations are substantially different between and within individual females, which limits the accuracy of timing ovulation for artificial insemination. The predictive value of vaginal cytology was greatly enhanced with the trichrome stain and evaluation of cell color.


Transient fluctuations in cognitive functioning in schizophrenia based on single-case study methods.
The stability of cognitive performance in four schizophrenia patients was examined over a short time period. A cognitive battery highly sensitive to organismic state (the Repeatable Cognitive-Perceptual-Motor Battery, RCPM) was utilized. Single-case statistical methods tested for within-individual change across five assessments at two week intervals. All four subjects showed statistically significant post-baseline variation in a global measure of impairment (average impairment rating score) and in at least 50% of the individual tests having adequate test-retest reliability. Data are interpreted as providing suggestive evidence of transient fluctuations in performance within a stable window of impaired cognitive functioning. These fluctuations appear substantial enough to influence both research and clinical outcomes. The benefits of the single-case methodology employed are discussed. The data suggest that significant transient fluctuations in cognitive performance can be observed in schizophrenia in domains purported to represent vulnerability markers of the disorder. The importance of accounting for these transient fluctuations in the attempt to identify enduring, trait-like characteristics of cognitive functioning in schizophrenia is discussed.


Vladimir Voevodsky on mathematics and life.
This is a brief overview of Vladimir Voevodsky's (1966-2017) intellectual and professional biography, which is partly based on the author's personal memories. Voevodsky's biologically-motivated mathematical works are considered in the context of his research in the Algebraic Geometry and in the Univalent Foundations of mathematics. Some biographical details, which are important for understanding Voevodsky's achievements and his personality, are provided.


Decision fatigue in low-value prostate cancer screening.
Low-value prostate-specific antigen (PSA) testing is common yet contributes substantial waste and downstream patient harm. Decision fatigue may represent an actionable target to reduce low-value urologic care. The objective of this study was to determine whether low-value PSA testing patterns by outpatient clinicians are consistent with decision fatigue. Outpatient appointments for adult men without prostate cancer were identified at a large academic health system from 2011 through 2018. The authors assessed the association of appointment time with the likelihood of PSA testing, stratified by patient age and appropriateness of testing based on clinical guidelines. Appointments included those scheduled between 8:00 am and 4:59 pm, with noon omitted. Urologists were examined separately from other clinicians. In 1,581,826 outpatient appointments identified, the median patient age was 54 years (interquartile range, 37-66 years), 1,256,152 participants (79.4%) were White, and 133,693 (8.5%) had family history of prostate cancer. PSA testing would have been appropriate in 36.8% of appointments. Clinicians ordered testing in 3.6% of appropriate appointments and in 1.8% of low-value appointments. Appropriate testing was most likely at 8:00 am (reference group). PSA testing declined through 11:00 am (odds ratio [OR], 0.57; 95% CI, 0.50-0.64) and remained depressed through 4:00 pm (P < .001). Low-value testing was overall less likely (P < .001) and followed a similar trend, declining steadily from 8:00 am (OR, 0.48; 95% CI, 0.42-0.56) through 4:00 pm (P < .001; OR, 0.23; 95% CI, 0.18-0.30). Testing patterns in urologists were noticeably different. Among most clinicians, outpatient PSA testing behaviors appear to be consistent with decision fatigue. These findings establish decision fatigue as a promising, actionable target for reducing wasteful and low-value practices in routine urologic care. Decision fatigue causes poorer choices to be made with repetitive decision making. This study used medical records to investigate whether decision fatigue influenced clinicians' likelihood of ordering a low-value screening test (prostate-specific antigen [PSA]) for prostate cancer. In more than 1.5 million outpatient appointments by adult men without prostate cancer, the chances of both appropriate and low-value PSA testing declined as the clinic day progressed, with a larger decline for appropriate testing. Testing patterns in urologists were different from those reported by other clinicians. The authors conclude that outpatient PSA testing behaviors appear to be consistent with decision fatigue among most clinicians, and interventions may reduce wasteful testing and downstream patient harms.


Metabolic alterations mediated by STAT3 promotes drug persistence in CML.
Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.


Eflornithine. A new drug in the treatment of sleeping sickness.
Eflornithine (alpha-difluoromethylornithine; DFMO) is a recently developed drug against African trypanosomiasis (sleeping sickness). After a short description of trypanosomiasis and the current treatment, the mechanism of action of eflornithine is discussed, some clinical data is given and attention is paid to recently discovered analogues of eflornithine. Some examples of combination therapy with eflornithine and possible applications are mentioned.


Efficacy of cognitive therapy and behavior therapy for menopausal symptoms: a systematic review and meta-analysis.
T long-term effects of cognitive therapy and behavior therapy (CTBT) for menopausal symptoms are unknown, and whether the effects are different between natural menopause and treatment-induced menopause are currently unclear. Therefore, we sought to conduct an accurate estimate of the efficacy of CTBT for menopausal symptoms. We conducted searches of Cochrane Library, EMBASE, PsycINFO, PubMed, and Web of Science databases for studies from 1 January 1977 to 1 November 2021. Randomized controlled trials (RCTs) comparing intervention groups to control groups for menopausal symptoms were included. Hedge's g was used as the standardized between-group effect size with a random-effects model. We included 14 RCTs comprising 1618 patients with a mean sample size of 116. CTBT significantly outperformed control groups in terms of reducing hot flushes [g = 0.39, 95% confidence interval (CI) 0.23-0.55, I2 = 45], night sweats, depression (g = 0.50, 95% CI 0.34-0.66, I2 = 51), anxiety (g = 0.38, 95% CI 0.23-0.54, I2 = 49), fatigue, and quality of life. Egger's test indicated no publication bias. CTBT is an effective psychological treatment for menopausal symptoms, with predominantly small to moderate effects. The efficacy is sustained long-term, although it declines somewhat over time. The efficacy was stronger for natural menopause symptoms, such as vasomotor symptoms, than for treatment-induced menopause symptoms. These findings provide support for treatment guidelines recommending CTBT as a treatment option for menopausal symptoms.


Storage of proteins in the rough endoplasmic reticulum of human hepatocytes in a patient with normal blood proteins, on oral contraceptives.
Aspects of protein storage in the rough endoplasmic reticulum of hepatocytes, comparable with those reported in alpha1-antitrypsine (AAT) deficiency, have been observed in the course of jaundice in a woman presenting no evident abnormality in AAT or other blood proteins. In light microscopy, most hepatocytes contained characteristic globular inclusions but they were PAS negative and did not react with anti-AAT antibodies. This storage of protein ceased at the time the jaundice disappeared. Prolonged treatment with high doses of contraceptive steroids may have been involved in this peculiar reaction of the hepatocytes.


Dental anxiety, child-oral health related quality of life and self- esteem in children and adolescents: a systematic review and meta-analysis.
To identify the directions, strength and associations between dental anxiety, COHRQoL and self-esteem in children and adolescents. PRISMA guidelines were followed and the review registered (PROSPERO CRD42019140037). MEDLINE, Cochrane Library, Scopus, Science Direct, CINAHL, Joanna Briggs Institute (JBI), Grey Literature Report, and British Library EThOS using MeSH terms and keywords were searched. Three reviewers examined the abstracts of all articles, excluded duplicates and those not meeting inclusion criteria. All full-text papers were read by all reviewers. Meta-analysis association data including Pearson's or Spearman's correlation coefficient were extracted and effect sizes estimated. Twelve papers met the inclusion criteria, 7 assessed the relationship between child dental anxiety and COHRQoL; four between COHRQoL and self-esteem and one between child dental anxiety and self-esteem. Significant relationships were found between COHRQoL and the other child-related outcomes measures. An inverse relationship was shown for dental anxiety and COHRQoL. The meta-analysis found small associations between child dental anxiety and COHRQoL and moderate associations between COHRQoL and self-esteem. High heterogeneity between COHRQoL and self-esteem was noted. The association between child dental anxiety and self-esteem was limited. No source reported associations between all three variables. The studies were of varying quality and the degree of heterogeneity meant that only limited conclusions were possible. There is a need for high-quality evidence to underpin intervention designs to promote COHRQoL and self-esteem to reduce child dental anxiety.


Schisandrin C enhances cGAS-STING pathway activation and inhibits HBV replication.
Schisandra Chinensis (Turcz.) Baill. is a long-term used traditional Chinese medicine with the functions of tonifying the kidney and calming the heart, tonifying qi and engendering fluid. It can be used to treat insomnia and dreaminess, spermatorrhea, coughs, as well as liver and kidney deficiency of Yin or Yang Syndrome. Modern pharmacological studies have shown that Schisandra Chinensis regulates host immunity and exhibits anti-cancer, antiviral and liver-protecting effects. However, the specific mechanism by which Schisandra Chinensis modulates antiviral immunity is unknown. We sought to explore the therapeutic effect of the active components of Schisandra Chinensis on anti-viral immunity and further investigate the underlying mechanism. Immunoblotting, quantitative real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and immunoprecipitation were used to investigate the effect of schisandrin C (SC), one of the most abundant and biologically active components of Schisandra Chinensis, on the activation of cGAS-STING signaling pathway and the underlying mechanism. In addition, CMA-mediated STING activation and hydrodynamic injection-mediated HBV-replicating mouse model were used to investigate the effect of SC on the activation of STING signaling pathway and its antiviral effect in vivo. SC promoted cGAS-STING pathway activation, accompanied by increased production of interferon β (IFN β) and downstream gene expression. Moreover, SC also exerted anti-HBV effects, reducing HBeAg, HBcAg, HBsAg, and HBV DNA levels in hydrodynamic injection-mediated HBV-replicating mouse model and elevating the production of IFN β and expression of interferon-stimulated genes (IFIT1, ISG15, and CXCL10). Mechanistically, SC could facilitate the interaction between TANK-binding kinase 1 (TBK1) and STING, which is important for IRF3 phosphorylation and production of IFN β. Our study confirmed that SC enhances cGAS-STING pathway activation and inhibits HBV replication, as well as provides clues for chronic hepatitis B and other infectious diseases treated by SC.


Let's get specific: the relationship between specificity and affinity.
The factors that lead to high-affinity binding are a good fit between the surfaces of the two molecules in their ground state and charge complementarity. Exactly the same factors give high specificity for a target. We argue that selection for high-affinity binding automatically leads to highly specific binding. This principle can be used to simplify screening approaches aimed at generating useful drugs.


The correlations between steady-state concentration, duration of action and molecular weight of GLP-1RAs and their efficacy and gastrointestinal side effects in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.
To assess the influence of steady-state concentration, duration of action and molecular weight of glucagon-like peptide-1 receptor (GLP-1RA) on efficacy and gastrointestinal (GI) side effects in patients with type 2 diabetes mellitus (T2DM). PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to April 2022. Randomized controlled trials (RCTs) comparing GLP-1RA versus non-GLP-1RA agents in patients with T2DM were included. Sensitivity analyses on steady-state concentration, duration of action and molecular weight of GLP-1RA were conducted. 113 RCTs were included. Greater HbA1c reduction between GLP-1RA users versus non-GLP-1RA users was observed in the high-steady-state-concentration stratum and long-acting stratum compared with the low-steady-state-concentration stratum (Psubgroup difference = 0.0004) and short-acting stratum (Psubgroup difference<0.0001). The risk of GI adverse events in GLP-1RA users versus non-GLP-1RA users was decreased in the high-steady-state-concentration stratum, long-acting stratum and heavy-molecular-weight stratum compared with low-steady-state-concentration stratum (Psubgroup difference<0.0001), short-acting stratum (Psubgroup difference = 0.002) and light-molecular-weight stratum (Psubgroup difference = 0.0008). GLP-1RA with high steady-state concentration and long duration of action showed better hypoglycemic effect. GLP-1RA with high steady-state concentration, long duration of action and heavy molecular weight was associated with lower risk of GI adverse events.


Socioeconomic impacts of seafood sectors in the European Union through a multi-regional input output model.
Fisheries, aquaculture, and seafood transformation sectors are components of the Green Deal roadmap promoting the transformation of the European Union into a resource-efficient, climate-friendly, and competitive economy. Whilst several studies have shown these sectors' socioeconomic national contributions, the method developed in this article aimed at demonstrating their importance at the European level and at showing the interlinkages that exist between countries, at the sub sectorial level. This article presents the development of a seafood European multi-regional input-output model methodology and its potentialities. The seafood sectors were disaggregated for each country from national input-output tables through a double disaggregation algorithm thanks to proxy input-output tables and STECF data, which highlighted the purchase of intermediate products at the STECF subsector level. The resulting disaggregated economic data for the seafood sectors were then linked to the multiregional turnover, gross value added, and jobs multipliers inverted from the FIGARO multiregional input-output table to obtain the indirect and induced socioeconomic impacts of the seafood sectors at the European level. The results showed economic leakages illustrated by the gross value-added multiplier. While shellfish farming, passive gear fishing, and active gear fishing, were the sectors in which the generated economic wealth remained the most in the European Union territory, a third of generated economic wealth by saltwater finfish farming and seafood transformations was captured outside the EU borders. Moreover, although France, the UK, and Spain are the main turnover contributors across sectors (except for micro and small seafood transformation companies), the impacts generated by the seafood industries greatly benefit the German economy that capture more economic wealth than it contributes across all sectors. This method provides a baseline scenario for further studies on the evaluation of socio-economic benefits of changes in practices such as circular economy emphasizing the interdependencies of supply chains at the European level.


Does ovarian reserve affect outcomes in single ideal blastocyst transfers in women less than 40 years of age?
There is much debate whether diminished ovarian reserve is purely a quantitative issue, or if quality as determined by pregnancy potential of the ensuing oocytes is also affected. The purpose of this study was to determine whether diminished ovarian reserve, as established by one of three ways described below, affects pregnancy outcomes of women under 40 years old undergoing a single ideal blastocyst transfer. This was a retrospective cohort study, including 507 women undergoing an ideal quality single embryo transfer between August 2010 and March 2014. Logistic regression was used to control for age, duration of infertility, parity, body mass index, and smoking status. For analysis, women were stratified for: antral follicle counts (≤ 5 vs. > 5), basal serum FSH levels (< 13 vs. ≥ 13 IU/L), and quartile of total FSH dose required for stimulation. In stratifying women by antral follicle count (AFC) ≤ 5 vs. > 5, the pregnancy rate (40 vs. 53%, p = 0.04), clinical pregnancy rate (29 vs. 46%, p = 0.02), and live birth rate (13 vs. 43%, p = 0.001) were superior with AFC > 5. Using FSH levels (< 13 vs. ≥ 13 IU/L), the pregnancy rate (50 vs. 31%, p = 0.27), clinical pregnancy rate (40 vs. 13%, p = 0.45), and live birth rate (38 vs. 13%, p = 0.48) were similar. Examining quartiles of FSH stimulation, the pregnancy rates were similar (from lowest to highest: 45, 52, 54, 41%, p = 0.13); however, clinical pregnancy rate (36, 43, 47, 25%, p = 0.003) and live birth rate (32, 38, 44, 20%, p = 0.005) were superior in lower quartiles vs. the highest quartile. Ovarian reserve may affect embryo pregnancy potential and outcomes when measured by AFC and exogenous stimulation but not by basal FSH levels.


Fine-needle aspiration cytology of ductal adenoma: report of a case associated with a mucocele-like lesion.
Ductal adenoma (DA) is an uncommon breast lesion that can histologically and clinically mimic carcinoma. We performed a fine-needle aspiration (FNA) of a DA. Cytologically, the lesion had features overlapping with those of mucinous carcinoma (MC), mucocele-like lesion, lactating adenoma (LA), and in retrospect with intraductal papilloma (IP). The smears were highly cellular and contained numerous monolayered sheets of ductal cells with prominent punched-out, small vacuoles distending the cytoplasm. The nuclei were mostly round to oval and had bland chromatin. Occasionally cells with enlarged nuclei and conspicuous nucleoli were present. The background showed large mucin pools, scattered single cells with mild nuclear atypia, some with apocrine metaplasia, rare stripped nuclei, and a fibrovascular stromal component. Calcifications were also present. We compare our cytologic findings with those of the lesions considered in the differential diagnosis. Due to its rare incidence and unusual features. DA may represent a diagnostic pitfall on FNA. Increased awareness of its cytologic appearance may help prevent a misdiagnosis.


Tamoxifen affects the toxicokinetics of o,p'-DDT in male Nile Tilapia (Oreochromis niloticus).
The goal of the present study was to evaluate the role of Tamoxifen (TAM), in the distribution and/or elimination kinetics of o,p'-DDT, in male tilapias. A non-compartmental analysis was chosen to describe the time course of o,p'-DDT plasma concentrations. Mean plasma concentration of o,p'-DDT following IP administration indicates a very complex kinetic profile. Tamoxifen decreased the o,p'-DDT mean half-life (t½) from 20.38 to 16.11 days, the Mean Residence Time (MRT) from 28.7 to 23.23 days, and clearance (CL) from 0.0031 to 0.001 mL/min. The distribution pattern of o,p'-DDT in tissues and the clearance in plasma suggest that storage points mediated through the membrane-receptor lipophilicity can be involved.


Usability of a mobile application for health professionals in home care services: a user-centered approach.
The use of mobile devices by healthcare professionals has led to rapid growth in the development of mobile healthcare applications designed to improve healthcare services. This study was conducted to assess the acceptability and usability of a mobile application for health professionals in relation to their work in hospitalization at home. A mixed methods approach was used. Acceptance, included the satisfaction of the professionals, attitudes toward using the application, and intention or willingness to continue using the application. Usability tests were performed in laboratory analyzing five controlled clinical tasks, and the interaction of the participants with the mobile application was based on the six basic facial expressions published by the American Psychological Association. Perceived satisfaction was assessed using the computer system usability questionnaire. Thirty-two participants completed the task scenarios and questionnaire. More than 90 per cent of participants were able to complete the tasks with only some difficult with vital signs. Satisfaction had a score of 6.18/7 (SD: 0.76), and recommendation of the mobile application had a score of 6.21/7 (SD: 0.81). This study showed a significant usability and acceptability of this mobile application, in terms of effectiveness, efficiency, and satisfaction.


Sex therapy: considerations in the selection of patients.
Sex therapy has proven helpful for many patients with sexual dysfunctions. In judging the appropriateness of this new treatment procedure the clinician should determine the following: that a sexual dysfunction exists, that a stable couple relationship exists, that there are no major marital, psychiatric or physical problems that are etiologically important or that would interfere with treatment, and that both partners are willing to engage in a treatment program.


Effect of prior therapy on tumor mutational burden in NSCLC.
Higher tumor mutation burden (TMB) in advanced non-small cell lung cancer (NSCLC) is associated with superior outcomes with checkpoint inhibitor therapy. Tissue samples subject to TMB analysis may be acquired after DNA-damaging therapies such as chemotherapy or radiation. The impact of these therapies on TMB results is unclear. This retrospective analysis explored differences in TMB among treatment-naïve samples and treatment-experienced samples. NSCLC samples that underwent molecular profiling at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) and had available treatment and clinical history were identified. TMB was estimated by counting all coding variants (missense, nonsense, frameshift, in-frame InDels) identified by next-generation sequencing. Exceptions were synonymous mutations and any single nucleotide polymorphisms described as germline. History was reviewed under an IRB approved protocol to determine whether patients had received cytotoxic chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. TMB values were compared between cohorts using the Wilcoxon test. Smoking adjusted P values were calculated using the chi-squared test of deviance. TMB was calculated for 970 annotated tumor specimens. Of these, 155 patients received chemotherapy and/or radiation prior to tissue collection. The median TMB was 8 mut/Mb in both the treatment-naïve and treatment-experienced cohorts. After adjusting for smoking, there was no significant difference in TMB between these cohorts (P=0.22). When analyzed separately, neither prior chemotherapy nor prior radiation therapy influenced TMB. TMB was higher when the specimen source was collected from a metastatic site compared to the primary site. Prior exposure to chemotherapy or radiation therapy was not associated with a significant difference in TMB.


Will killing the last HIV1 particle cure AIDS patients? II: Second Part. Decrease of viral load and of T-suppressor cells, and increase of the cytotoxic cells, without effect on CD4, after the use of 10 virostatics applied in 3 or 4 drug combinations of different sequences. The time for CD4 immunotherapy?
We reported in the first part of this editorial and in an article AIDS therapy with five HIV1 virostatics applied in two then three, or initially three, or initially four agent combinations, given in 3 week sequences differing from each other due to drug rotation, the contrast between: a) the decrease of viral load, possible below the detectable level, b) the absence of effect on the helper CD4+, the CD8+ C57- cytotoxics and the CD8+ C57+ suppressor cells. We proposed a thesis according to which the HIV1-AIDS complex might have another pathogenic component other than HIV1, ie, a microchimerism graft-versus host reaction (GvH) or an autologous GvH-like reaction. Shifting from five to 10 virostatics owing to the availability of lamivudine or 3TC, stavudine or d4T and three HIV1 protease inhibitors, saquinavir, ritonavir and indinavir, applied according to the same modality, we have enhanced the reduction of viral load, and significantly decreased the CD8+ C57+ suppressor cell counts, and increased those of the CD8+ C57- cytotoxic cells. This result which indirectly shows the role of HIV1 in the increase of suppressor CD8+ cells, hence in the late loss of immune memory and of opportunistic infections, reinforces the thesis of a role, in AIDS pathogenesis, of a latent GvH reaction activated by HIV1 primo-infection, and its evolution from the hyperplastic phase to the hypoplastic one, which, inducing severe immune suppression, is responsible for HIV1 active infection relapse after the so-called latent phase. Hence the proposition we make, of an indication of CD4 modulation with non specific immunotherapy by bestatin, of which we showed the effect in another population of HIV1-AIDS complex patients. Its effect can be potentiated by tuftsin. When the suppressor cell number goes up over that of the cytotoxic one after the HIV1 active infection relapse, interferon gamma could be added, which, by amplifying the CD28 pathway on CD8+ cytotoxics, while suppressor cells lack CD28, which might reestablish a ratio of suppressor over cytotoxic cells nearer to normal. It remains that the role of the five secondarily included agents in the decrease of suppressor cells will only be attributed with certainty and entirely to their virostatic effect, if it is shown that none of them exerts a selective anti-suppressor cell action.


Sexual behaviour and sexual and reproductive health education: a cross-sectional study in Romania.
Up-to-date, genuine sexual and reproductive health (SRH) education programmes have been possible in Romania only since communism collapsed in 1990. Since 2006, Romania has had no national strategy in this field. Under current global circumstances (high labour mobility, internationally mixed marriages), issues previously considered solely national have become worldwide concerns. In 2011-2012, 1215 respondents homogeneously distributed on background, gender, educational level and age group (18-74) were sampled. This article uses a 96-item questionnaire about family and SRH, presenting results on nine items: first intercourse (FI), virginity, knowing first sexual partner, safe sex, number of sexual partners and sexual education. The data were analysed using Pearson chi-square tests and latent class analysis. Some participants (7.2%) engaged in FI at age 15 or earlier. The average age at FI was lower for men (18.08), for individuals with a lower education level (18.07) and for those in rural areas (18.27), compared with that for women, those with more education and those in urban areas, respectively. The average age at FI was over 2.5 years lower for people aged 18-24 (16.99) than for those aged 60-74 (p < 0.001). More than 60% were not married or partnered with their FI partner, and 17.8% engaged in FI less than a month after meeting their partner. Less than one-fourth practiced safe sex at FI, with higher proportions for the urban sample, those with an average level of education and those aged 18-35 (p < 0.001). Higher average numbers of sexual partners were found among men (6.56, compared with 2.37 among women), in urban areas (5.07, compared with 3.75 in rural areas) and among those with higher levels of education (p < 0.005). On average, subjects first received information on SRH at 15.39 years of age, with only 10% listing the school, doctors or medics as a source. Unsafe sex, early initiation of sexual activity and poor SRH education from schools, experts and parents require a multidisciplinary approach within prevention programmes, especially among the populations at risk: rural residents, those with low levels of education and youth.


Odontogenic responses of human dental pulp cells to collagen/nanobioactive glass nanocomposites.
Collagen-based nanocomposite incorporating nanobioactive glass (Col/nBG) was developed as a scaffolding matrix for dentin-pulp regeneration. The effects of the novel matrix on the proliferation of human dental pulp cells (hDPCs) and their differentiation into odontoblastic lineage were investigated. Nanocomposite scaffold was prepared by incorporating nBG within the Col solution and then reconstituting them into a membrane form. Cell growth by MTS assay, adhesion by scanning electron microscopy (SEM), and odontoblastic differentiation by alkaline phosphatase (ALP) activity, mineralization, and the mRNA expression of differentiation-related genes of DPCs on each scaffold were evaluated. The introduction of nBG significantly improved the bone mineral-like apatite formation in the simulated body fluid, suggesting excellent acellular bone-bioactivity. The hDPCs cultured on the Col/nBG nanocomposite have shown active growth behavior during culture for 14 days. The mRNA levels of major organic extracellular matrix of dentin, collagen type I and III were highly expressed in the Col/nBG matrix. Moreover, the alkaline phosphatase (ALP) activity and the mineralized nodule formation were increased in the Col/nBG nanocomposite compared to those in Col. Odontoblatic differentiation genes, including dentin sialophosphoprotein, dentin matrix protein I, ALP, osteopontin and osteocalcin were significantly stimulated in the Col containing nBG. Moreover, the key adhesion receptor integrin components α2 and β1, specifically binding to collagen molecule sequence, were upregulated in Col/nBG compared to Col, suggesting that odontogenic stimulation was closely related to the integrin-mediated process. In our study, the nanocomposite Col/nBG matrix induced the growth and odontogenic differentiation more effectively than Col alone, providing a promising scaffold condition for regeneration of dentin-pulp complex tissue.


An alginate-based macroporous hydrogel matrix to trap cancer cells.
To overcome the radioresistance of glioblastoma (GBM) cells infiltrated in the brain, we propose to attract these cancer cells into a trap to which a lethal radiation dose can be delivered safely. Herein, we have prepared and characterized a sodium alginate-based macroporous hydrogel as a potential cancer cell trap. Microcomputed X-ray tomography shows that the hydrogel matrices comprise interconnected pores with an average diameter of 300 μm. The F98 GBM cells migrated in the pores and mainly accumulated in the center of the matrix. Depending on the number of cancer cells added, the grafting of RGD cell-adhesion peptides to the alginate resulted in a 4 to 10 times increase in the number of F98 cells (which overexpress the associated αvβ3 and αvβ5 binding integrins) retained in the matrix. Finally, a radiation dose of 25 Gy eliminated all F98 cells trapped in the matrix, without significantly altering the matrix mechanical properties.


"Binaural rivalry": dichotic listening as a tool for the investigation of the neural correlate of consciousness.
Since about two decades neuroscientists have systematically faced the problem of consciousness: the aim is to discover the neural activity specifically related to conscious perceptions, i.e. the biological properties of what philosophers call qualia. In this view, a neural correlate of consciousness (NCC) is a precise pattern of brain activity that specifically accompanies a particular conscious experience. Almost all studies aimed at investigating the NCC have been carried out in the visual system. One of the most promising paradigms is based on sensory stimuli which elicit bistable percepts, as they allow to decouple subjective perception from the characteristics of the physical stimulation. Such kind of perception can be produced in the visual modality by using particular images (e.g. Rubin's vase/face figure) or by presenting two dissimilar stimuli separately to the two eyes (binocular rivalry). The stimuli compete for perceptual dominance and each image is visible in turn for a few seconds, while the other is suppressed. The use of this methodology has led to important findings concerning visual consciousness, which are briefly discussed. For the investigation of auditory consciousness, a similar stimulation paradigm can be achieved by using dichotic listening, consisting in two different stimuli presented each to one ear, which compete for perception (binaural rivalry). The principal aim of the present mini-review is to discuss the few contributes facing the issue of auditory consciousness and to advance the use of dichotic listening and binaural rivalry as valid tools for its investigation.


Beneficial effect of trimetazidine on folic acid-induced acute kidney injury in mice: Role of HIF-1α/HO-1.
Acute kidney injury (AKI) is a complex syndrome associated with a decrease in renal function and a significant impact on patient outcomes. Injection of folic acid (FA) in mice is used for studying the pathogenesis of AKI. This study investigated the impact of trimetazidine (a metabolic modulator-antianginal drug; TMZ), against FA-induced AKI. AKI was induced by FA (250 mg/kg, ip) in mice. Two doses of TMZ were administered orally for 10 days. Administration of TMZ at a high dose (20 mg/kg) exhibited significant decreases in the renal somatic index (RSI), serum levels of lactate dehydrogenase (LDH), creatinine (Cr), blood urea nitrogen (1), and proteins level in urine. Moreover, TMZ significantly increased creatinine clearance (CCr), serum albumin, urine creatinine, and urine urea levels. This improvement in markers of kidney damage was associated with marked renal antioxidant effects (↓NO and ↓lipid peroxidation, normalized reduced glutathione (GSH) level and superoxide dismutase (SOD) activity, and increased HIF-1α/HO-1 level). Furthermore, TMZ significantly decreased FA-induced expression of MPO and inflammatory cytokine IL-18, TNF-α, and NF-κB p65 subunit. Renal apoptosis, along with apoptotic markers, were enhanced by FA injection and suppressed by TMZ administration (↓Caspase-3, ↓Bax, and ↑Bcl2 expression). Finally, TMZ amended FA-induced histopathological changes in kidneys. By mitigating functional alteration, oxidative stress, and preventing the development of inflammatory and apoptosis signals, TMZ provides dose-dependent defense against FA-induced AKI mainly via stimulation of hypoxia-inducible factor-1 alpha (HIF-1α)/heme oxygenase-1 (HO-1) pathway.


Near-field observation of carrier diffusion in GaAs quantum structures under high magnetic fields.
Photoluminescence from a two-dimensional electron-gas system in GaAs single hetero-structures was investigated using a scanning near-field optical microscope (SNOM) operated at cryogenic temperatures under high magnetic fields. The local intensity of the luminescence increased 600-fold that at 0 T as the magnetic field was increased up to 6 T. The enhancement depended on the spatial resolution of the SNOM. These characteristics are explained by the suppression of the diffusion of photocarriers caused by the Lorentz force in magnetic fields.


Epileptic discharges induced by pentylenetetrazol: ultrastructural alterations in identified neurons and glial cells (Helix pomatia).
The effects of sustained epileptic activity induced by pentylenetetrazol on morphology of buccal ganglia of Helix pomatia were investigated. Neuronal somata and processes as well as glial cells were evaluated after 5 hours of epileptic activity and after 5 hours under control conditions. After epileptic activity neurons showed signs of degeneration consisting of condensation of nuclear chromatin, decreased activity of Golgi apparatus, increased numbers of lamellar bodies and multivesicular bodies, clusters of vesicles and vacuoles, loss of microtubuli, and scattered lamellar bodies. Neuronal somata and large neuronal processes appeared less affected than the smaller processes. Glial cells showed signs of phagocytotic activity as increased cell size, numerous degenerating neuronal processes within the cytoplasm as well as lysosome like bodies and vacuoles. The changes developing along with epileptic activity were interpreted to indicate degeneration and subsequent phagocytotic activity of neuronal processes in synaptic regions of the ganglia. Thus, evidence is presented for synaptically induced degenerative processes in an intact nervous tissue that is not affected by seizure-induced alterations of respiration or systemic circulation.


[Tissue engineering of vascularized myocardial prosthetic tissue. Biological and solid matrices].
Tissue engineering of bioartificial myocardial tissue will become an increasingly important therapeutic approach in the near future but supply of oxygen and nutrients as well as evacuation of metabolic products represent a critical obstacle in tissues with a thickness of 100 µm and above. Viability of seeded cells in the myocardial patch is positively correlated with its function and thus early sufficient vascularization is mandatory. The choice of substrate, structure of matrices, specific cellular seeding and addition of growth factors contribute to this necessary vascularization process.This review article gives an overview of the current state of research on recent myocardial tissue engineering utilizing natural and solid substrates (urinary bladder, gall bladder, small intestine, stomach, peritoneum, omentum, uterus, skeletal muscle, diaphragm and cardiac muscle) with a special focus on the results of vascularization of bioartificial tissue for each approach.


Non-Invasive Monitoring of Increased Fibrotic Tissue and Hyaluronan Deposition in the Tumor Microenvironment in the Advanced Stages of Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinomas are characterized by a complex and robust tumor microenvironment (TME) consisting of fibrotic tissue, excessive levels of hyaluronan (HA), and immune cells. We utilized quantitative multi-parametric magnetic resonance imaging (mp-MRI) methods at 14 Tesla in a genetically engineered KPC (KrasLSL-G12D/+, Trp53LSL-R172H/+, Cre) mouse model to assess the complex TME in advanced stages of tumor development. The whole tumor, excluding cystic areas, was selected as the region of interest for data analysis and subsequent statistical analysis. Pearson correlation was used for statistical inference. There was a significant correlation between tumor volume and T2 (r = -0.66), magnetization transfer ratio (MTR) (r = 0.60), apparent diffusion coefficient (ADC) (r = 0.48), and Glycosaminoglycan-chemical exchange saturation transfer (GagCEST) (r = 0.51). A subset of mice was randomly selected for histological analysis. There were positive correlations between tumor volume and fibrosis (0.92), and HA (r = 0.76); GagCEST and HA (r = 0.81); and MTR and CD31 (r = 0.48). We found a negative correlation between ADC low-b (perfusion) and Ki67 (r = -0.82). Strong correlations between mp-MRI and histology results suggest that mp-MRI can be used as a non-invasive tool to monitor the tumor microenvironment.


The electrical activity of canine cardiac Purkinje fibers in sodium-free, calcium-rich solutions.
Propagated action potentials can be obtained in canine cardiac Purkinje fibers exposed to Na-free solutions containing no inorganic cation other than Ca and K. Essentially similar action potentials are obtained if Na is replaced by tetraethylammonium (TEA), tetramethylammonium (TMA), or choline. In a solution containing 128 mM TEA and 16.2 mM Ca the characteristics of these electrical responses were: maximum diastolic potential, -59 +/- 3.3 mV; overshoot, 20 +/- 6.8 mV; maximum upstroke velocity, 3.7 +/- 2.3 V/s; conduction velocity, 0.1 m/s; and action potential duration, 360 +/- 45 ms. The magnitude of the overshoot varied with log Ca(o) with a slope of about 30 mV/10-fold concentration change. The upstroke velocity was an approximately linear function of Ca(o). The active response was greatly diminished or abolished by Mn and D-600 but was unaffected by tetrodotoxin. These Ca-dependent responses appeared in a region of transmembrane potential (about -50 mV) at which the rapid Na-dependent upstroke is abolished even when Na is present.


Symptom patterns in childhood arterial ischemic stroke: Analysis of a population-based study in Germany.
Die zeitliche Verzögerung zwischen Symptombeginn und Diagnose ist eine Herausforderung in der Behandlung von Kindern mit arteriell ischämischem Schlaganfall. Frühere Studien zur klinischen Präsentation beschäftigten sich v. a. mit kumulativen Symptomen. Ziel dieser Studie ist es, mögliche Symptommuster aufzuzeigen. In einer aktiven Beobachtungsstudie zwischen 01/2015 und 12/2016 (ESPED-Studie) wurden Kinder mit Erstdiagnose eines arteriell ischämischen Schlaganfalls eingeschlossen. Isoliert auftretende Erstsymptome wurden verschiedenen Symptomkombinationen gegenübergestellt. Zudem wurde untersucht, inwieweit ein als "akut" oder "progredient" klassifiziertes Auftreten der Symptome Rückschlüsse auf die zugrundeliegende Ätiologie erlaubt. Es wurden 99 Kinder in die Studie eingeschlossen. Unabhängig vom Alter traten überwiegend fokale Symptome auf (86%). Krampfanfälle als Initialsymptom wurden insbesondere bei Säuglingen beschrieben (67%), wohin-gegen diffuse, unspezifische Symptome vor allem bei Vorschulkindern (38%) und älteren Kindern (59%) auftraten. Isoliert traten fokale Symptome bei 37 Kindern auf, 48 Kinder zeigten zusätzlich unspezifische Symptome, darunter auch 9 Kinder mit Krampfanfällen. Isolierte unspezifische Symptome zeigten sich lediglich bei 7 Kindern, 2 Kinder wurden nur mit Krampfanfällen symptomatisch. Die Akuität des Symptombeginns wurde bei 53/78 als "akut" und bei "25/78 Fällen als "progredient" klassifiziert, lieferte jedoch keinen Hinweis auf die zugrundeliegende Ätiologie. Jedes neue fokal neurologische Defizit sollte unabhängig vom Auftreten (isoliert oder kombiniert, akut oder progredient) an einen kindlichen Schlaganfall denken lassen. Time delay between onset of clinical symptoms and diagnosis is a challenge in childhood arterial ischemic stroke. Most previous studies reported cumulative symptoms. We attempted to identify typical symptom patterns and assessed their emergence in childhood stroke. Prospective active surveillance in ESPED, a hospital based Pediatric Surveillance Unit for rare diseases in Germany, between January 2015 and December 2016. Case definition: first diagnosis of a radiologically confirmed arterial ischemic stroke. Symptom patterns were identified as occurring in isolation or in combination. We distinguished acute vs. progressive onset. We ascertained risk factors to identify the possible etiology. 99 children with childhood arterial ischemic stroke were reported. Focal symptoms were the predominant presenting feature (86%), independent of age. Seizures were more often seen in infants < 1 year (67%), whereas diffuse symptoms were more present in pre-school children (38%) and older children (59%). 37 children had focal features alone and 48 additional non-specific features, including 9 with seizures. Isolated non-specific features accounted for 7 cases, and 2 children had (focal) seizures as the only symptom. In 77% of all cases at least one risk factor was identified. The emergence of symptoms was acute in 53/78 cases and progressive in 25/78 cases. The pattern of emergence was unrelated to the underlying etiology. Any new focal neurological deficit in isolation, or associated with seizures or further non-specific symptoms should alert to childhood stroke.


Necrotizing enterocolitis in multiple-birth infants.
Over a 5-year period, 20 infants of multiple-gestation births (16 twin, 2 triplet) developed necrotizing enterocolitis (NEC) (15 infants) or suspected NEC (5 infants). During the same period, 532 infants of multiple gestations were admitted to our neonatal intensive care unit, yielding a NEC incidence in this population of 3.8%. In two twin sets, both infants developed NEC or suspected NEC, and in three sets only the affected twin was transferred to our nursery. Five infants required surgical intervention (25%) and three infants died (overall mortality, 15%). Fifteen siblings who did not develop NEC served as a control group. Analysis showed that the 1-minute Apgar score was the most significant factor in predicting NEC (P less than .028) and need for surgical intervention (P less than .020). In this series, 82% of the infants with 1-minute Apgar less than 6 developed NEC, whereas 31% with 1-minute Apgar greater than 6 developed NEC.


New aspects of exanthematous diseases of childhood.
The childhood exanthems include a spectrum of common and uncommon disorders caused by a variety of pathogens. In this article, timely issues relating to immunization for measles and varicella are discussed. Recently reported exanthematous illnesses, including papular-purpuric gloves and socks syndrome, unilateral laterothoracic exanthem, and eruptive pseudo-angiomatosis, are described. The current research and debate about bacterial toxins as the cause of Kawasaki syndrome are presented.


[Protective effect of ganfukang capsule on hepatocytes in rats with experimental hepatic fibrosis].
To observe the protective effect of ganfukang capsule on hepatocytes of rats with experimental hepatic fibrosis rat. SD rat model of liver fibrosis was induced by CCl4. The effect of ganfukang capsule on liver function, histological change and ultrastructural were examined. Liver function, histological change and ultrastructural were significantly improved. The degree of steatosis was significantly decreased. Ganfukang capsule might protect hepatocytes, mitochondria from the injury induced by CCl4 and improve liver function.


Cytosine deaminase as a negative selective marker for Arabidopsis.
Cytosine deaminase (CD), produced by prokaryotes but not by higher eukaryotes including plants, deaminates cytosine to uracil. The enzyme likewise converts 5-fluorocytosine (5FC), which by itself is not toxic, to 5-fluorouracil (5FU), which is toxic. The Escherichia coli codA-coding sequence encoding CD, together with appropriate regulatory elements, was introduced into Arabidopsis. Neither untransformed controls, nor transgenic plants expressing no CD mRNA, were sensitive to 5FC. Conversely, for most transgenic plants expressing CD mRNA, in the presence of 5FC calli and seedlings failed to proliferate, and seeds failed to germinate. A few transgenic plants with many codA copies expressed less CD mRNA and remained insensitive to 5FC, which likely reflected epigenetic repeat-induced gene silencing. Thus 5FC, presumably through conversion by the enzyme to 5FU, can be used to select against plants that express CD.


Permeability of uncharged organic molecules in reverse osmosis desalination membranes.
Reverse osmosis (RO) membranes are primarily designed for removal of salts i.e. for desalination of brackish and seawater, but they have also found applications in removal of organic molecules. While it is clear that steric exclusion is the dominant removal mechanism, the fundamental explanation for how and why the separation occurs remains elusive. Until recently there was no strong microscopic evidences elucidating the structure of the active polyamide layers of RO membranes, and thus they have been conceived as "black boxes"; or as an array of straight capillaries with a distribution of radii; or as polymers with a small amount of polymer free domains. The knowledge of diffusion and sorption coefficients is a prerequisite for understanding the intrinsic permeability of any organic solute in any polymer. At the same time, it is technically challenging to accurately measure these two fundamental parameters in very thin (20-300 nm) water-swollen active layers. In this work we have measured partition and diffusion coefficients and RO permeabilities of ten organic solutes in water-swollen active layers of two types of RO membranes, low (SWC4+) and high flux (XLE). We deduced from our results and recent microscopic studies that the solute flux of organic molecules in polyamide layer of RO membranes occurs in two domains, dense polymer (the key barrier layer) and the water filled domains.


Validating intrinsic capacity to measure healthy aging in an upper middle-income country: Findings from the ELSI-Brazil.
While efforts have been made to validate intrinsic capacity (IC) as a multidimensional indicator of healthy aging in high-income countries, we still need evidence from lower-income countries. We examined associations of IC with wide ranges of activities of daily living in a nationally representative sample of Brazilians aged≥50 years. This cross-sectional analysis included 7175 participants from the Brazilian Longitudinal Study of Aging. IC domains (cognitive, psychological, sensory, locomotor, and vitality) were determined using self-reported and physical performance measures. IC was operationalized through factorial analysis. We investigated associations of IC and its domains with functional ability in basic, instrumental, and advanced activities of daily living (ADL, IADL, and AADL) using logistic regressions adjusted for sociodemographic, clinical, and modifiable risk factors. The IC bi-factorial model revealed satisfactory goodness-of-fit. Preserved ability in ADL and IADL, respectively, ranged from 69% and 29% to 89% and 74% across IC quartiles. In adjusted analyses, every standard deviation increment in IC composite score was associated with almost twice the odds of preserved ADL (OR=1·72; 95%CI=1·54-1·93), preserved IADL (OR=1·95; 95%CI=1·77-2·16), and high performance in AADL (OR=1·79; 95%CI=1·59-2·00). Similar results were reported using the IC domains as predictors. Although age, race/ethnicity, and education did not modify associations of IC with functional ability, we found sex differences with stronger relationships of IC with preserved ADL or IADL in females. Our results support IC validity and reliability to measure healthy aging in diverse socioeconomic and cultural settings. Incorporating IC in routine practices can promote holistic and person-centered care approaches in aging societies. The Brazilian Ministry of Health and Ministry of Science, Technology, Innovation, and Communication.


Clock genes are expressed in cementum and regulate the proliferation and mineralization of cementoblasts.
Circadian clock genes are present in the ameloblasts, odontoblasts, and dental pulp cells. The cementum plays a vital role in connecting the roots of teeth to the alveolar bone by anchoring the periodontal ligament. The present study aimed at confirming the existence of clock genes and describing the potential regulatory effects of REV-ERBα in the cementum. The tooth-periodontal ligament-alveolar bone complexes of 6-week-old mice were analyzed using immunohistochemistry. OCCM-30 cells, an immortalized cementoblast cell line, were synchronized with dexamethasone. We used RT-PCR to detect the expression of clock genes in the absence or presence of SR8278, an effective antagonist of REV-ERBα. We performed a cell counting kit-8 (CCK-8) assay to determine the effect of SR8278 on cell proliferation. RT-PCR and Western blot were used to measure the expression of mineralization-related markers in mineralization-induced OCCM-30 cells, with or without SR8278 treatment. Finally, we used Alizarin red staining, and ALP staining and activity to further verify the effect of SR8278 on mineralization of OCCM-30 cells on macro-level. In our study, clock protein expression was confirmed in the murine cementum. Clock genes were shown to oscillate continuously in OCCM-30 cells. SR8278-induced inactivation of REV-ERBα inhibited the proliferation but promoted the mineralization of OCCM-30 cells. The present study confirmed the presence of clock genes in the cementum, where they potentially participate in cell proliferation and mineralization. Our findings may inspire new research directions for periodontal regeneration via clock gene manipulation.


Characterisation of a potyvirus and a potexvirus from Chinese scallion.
Molecular analyses of viruses infecting Chinese scallion (Allium chinense G. Don) showed that the plants did not contain any of the poty-, carla- or allexiviruses that are common in garlic plants in China. The complete sequences of a potyvirus and a potexvirus were determined and these were shown to represent different viruses from any in the databases. They could be transmitted mechanically to scallion but not to other Allium species (including garlic) or to Narcissus. The potyvirus, tentatively named Scallion mosaic virus, has a distant relationship (c. 62% nucleotide identity over the entire genome) to Turnip mosaic virus and Japanese yam mosaic virus, with which it grouped in phylogenetic analyses. Its genome is 9324 nts long, encoding a 341.3 kDa polyprotein of 3001 amino acids. The potexvirus, tentatively named Scallion virus X, has a genome 6987 nts long and its organisation was similar to that of the other potexviruses but with only 46.3-63.2% nucleotides identical to them. It is most closely related to Narcissus mosaic virus but phylogenetic analyses indicate that it should be considered a distinct species. Neither of the viruses have been detected in garlic, although the two host plants are closely related.


Evaluation of xanthotoxol for central nervous system activity.
Xanthotoxol (XT), 8-hydroxypsoralen, exhibited dose-graded sedative activity in dogs, cats, rats, mice and hamsters. At doses of 5-20 mg/kg intraperitoneally (i.p.) in cats and 3-100 mg/kg orally (p.o.) in dogs, XT blocked predatory mouse/rat killing behavior. In mice, XT (10-300 mg/kg i.p.) exhibited a dose-dependent reduction in locomotor activity but was less potent in this regard than reference diazepam (10-100 mg/kg i.p.). XT in mice (0.1-10.0 mg/kg i.p.) and in hamsters (0.1-10.0 mg/kg p.o.) antagonized amphetamine-induced hypermobility but was less potent than diazepam. XT elevated the electrical threshold in foot-shock-induced fighting behavior in rats. XT (0.1-30.0 mg/kg p.o.) potentiated pentobarbital-induced narcosis in hamsters at otherwise subeffective doses of pentobarbital. Conditioned avoidance responses in rats were not significantly altered with 1-3 mg/kg i.p. and 30-100 mg/kg p.o. doses of XT but 300 mg/kg p.o. blocked both conditioned and unconditioned response. Doses of 100-1000 mg/kg i.p. of XT in mice were used to study 48-h acute toxicity of XT and its LD50 was estimated to be 468 mg/kg. Doses of 10, 40 and 80 mg/kg p.o. were used to study the chronic toxicity of XT in rats for 6 months and no side effects or abnormalities in reproductive activity or endocrine integrity were noted. The F1 generation of rats from 6-month XT-treated parents were free of teratogenic effects.


Low-cost, safe, and effective smoke evacuation device for surgical procedures in the COVID-19 age.
Smoke is generated by energy-based surgical instruments. The airborne by-products may have potential health implications. We developed a simple way to use de conventional surgical evacuator coupled with de electrosurgical pen attached to a 14G bladder catheter for open surgery. It was used in ten prospective patients with breast cancer. We notice a high reduction in surgical smoke during all breast surgery. A questionnaire was used for all participants of the surgery to answer the impression that they had about the device. The subjective impression was that the surgical smoke in contact whit the surgical team was reduced by more than 95%. Surgical smoke is the gaseous by-product produced by heat-generating devices in various surgical procedures. Surgical smoke may contain chemicals particles, bacteria, and viruses that are harmful and increase the risk of infection for surgeons and all the team in the operation room due to long term exposure of smoke mainly in coronavirus disease 2019 age. The adapted device described is a very simple and cheaper way to use smoke evacuators attached with the monopolar electrosurgical pen to reduce smoke exposure to the surgical team worldwide.


Changes in quantitative SPECT thallium-201 results associated with the use of energy-weighted acquisition.
The effect of utilizing energy-weighted acquisition on quantitative analysis of SPECT thallium-201 images was evaluated by simultaneously acquiring energy-weighted and windowed projection images in ten patients. The paired image sets were processed identically and evaluated by probability analysis of defect magnitude as indicated by a commercially available software analysis package. It was predicted that defect magnitude would increase as a result of improved image contrast. This was confirmed experimentally. One should be cautious in relying on strict quantitative criteria in cardiac studies with thallium-201, especially when major changes in the imaging system or technique are introduced.


Selective metabolic stimulation of the subfornical organ and pituitary neural lobe by peripheral angiotensin II.
The subfornical organ is a major receptor area for one of the principal stimuli of thirst, the octapeptide, angiotensin II. In conscious water-sated rats, we examined the effects of intravenous infusion of angiotensin II on the rate of glucose utilization in the subfornical organ and in structures anatomically and functionally connected with it. Angiotensin II produced pressor and drinking responses and increased glucose utilization selectively in the subfornical organ and pituitary neural lobe and in no other brain structure. Treatment with the angiotensin II antagonist, sar1-leu8-angiotensin II, before intravenous administration of angiotensin II prevented metabolic stimulation of the subfornical organ and neural lobe. Captopril, an inhibitor of angiotensin-converting enzyme, was administered to homozygous Brattleboro rats, which normally have elevated rates of glucose utilization in the subfornical organ. Captopril reduced subfornical organ glucose metabolism to a level similar to that found in control animals. These results demonstrate that peripheral angiotensin II stimulates glucose metabolism in the subfornical organ under conditions in which it provokes drinking and pressor responses. The findings suggest that circulating angiotensin II is responsible for the high rate of glucose utilization observed in the subfornical organ of Brattleboro rats homozygous for diabetes insipidus.


Childhood trauma mediates repetitive transcranial magnetic stimulation efficacy in major depressive disorder.
Childhood trauma is one of the most prominent risk factors in developing major depressive disorder (MDD) and may lead to unfavorable outcomes of pharmacotherapy and psychotherapy in MDD. While how it modulates the treatment outcome of the repetitive transcranial magnetic stimulation (rTMS) and how sex difference may play a role in mediating this relationship remain unknown. To evaluate this question, 51 (37 women) MDD patients were treated with 10 Hz rTMS to the left dorsolateral prefrontal cortex (lDLPFC). The experience of childhood trauma was quantified by the Childhood Traumatic Questionnaire (CTQ). The depressive severity was assessed by Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI) as the primary and secondary assessments. Beck Hopelessness Scale (BHS) and Hamilton Anxiety Scale (HAMA) were also assessed for further confirmation. Thirty-six (70.6%) participants showed a response including 17 (33.3%) achieving remission to the rTMS treatment. The alleviation of depressive symptoms was negatively correlated with the CTQ scores, specifically in women but not men, in subjective BDI and BHS, but not objective HAMD or HAMA. We demonstrate that childhood trauma negatively affects the subjective perception of rTMS-lDLPFC treatment outcomes in female MDD patients. This highlights the importance of measuring childhood trauma-related symptoms in routine clinical rTMS treatment, as they may impact perceived efficacy.


Combination chemotherapy of advanced lung cancer: a randomized trial.
A controlled clinical trial comparing two-drug and three-drug combination chemotherapy was performed in 206 patients with advanced bronchogenic carcinoma, comprised of 26.2% with epidermoid carcinoma, 30.1% with small cell anaplastic carcinoma, 27.2% with adenocarcinoma, and 15.6% with large cell carcinoma. Each drug combination consisted of agents with different modes of action and included a cell-cycle-stage nonsensitive and a cell-cycle-state-sensitive agent. The overall response rate was highest for small cell carcinoma (48.2%) and adenocarcinoma (23.6%); it was less than 10% in epidermoid and large cell carcinoma. Similarly, the overall median survival was twice as long for the first two cell types (7 months) as compared with that recorded for the other two cell types (3 1/2 months). The combination of 1 (2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cyclophosphamide, and methotrexate was shown to be statistically superior to cyclophosphamide and methotrexate with regard to objective respones rate, duration of response, and median survival for adenocarcinoma. Responders lived significantly longer than nonresponders (254 versus 90 days for small cell anaplastic carcinoma patients and 244 versus 184 days for adenocarcinoma patients). No difference in survival or objective response rate was observed between the different treatments for the other two cell types of lung cancer.


[Cervical epidural anesthesia for upper extremity surgery using three different formulations of local anesthetics].
To evaluate the efficiency and safety of the cervical epidural blockade (CEB) in upper extremity surgery, using lidocaine 2%, bupivacaine 5% and a mixture of both local analgesics. Eighty five patients were submitted to upper limb surgery under CEB. They were assigned into one of three groups: group I received 100 mg of 2% lidocaine; group II received 30 mg of 0.5% bupivacaine, and group III received a mixture of 60 mg of 2% lidocaine and 15 mg of 0.5% bupivacaine. We evaluated their effects on vital signs, blockade quality, adverse effects, and patient comfort. Anesthesiologist and surgeon evaluated the technique as "good" in 80% of the patients. Significant differences were found for motor blockade. Group II developed complete motor block (100%). Observed adverse effects were vomiting in groups II and III and dural puncture was present in 6.7% of the cases in group II. This study confirms the safety of cervical epidural anesthesia for upper limb surgery using three different formulations of local anesthetics.


The quality of online information regarding non-surgical aesthetic procedures.
The rapid growth of non-surgical aesthetics has led to a scarcity of regulation that raises concerns for serious consequences to public health. Services are advertised primarily through websites which are not necessarily centrally monitored or maintained to a set gold standard. We quantitatively assess the quality of online information regarding non-surgical procedures in order to promote patient safety and informed decision making. Google and Bing, search engines that represent 95.27of global searches, were queried with the expanded search terms "facial filler" and "Botox". The top 100 results were sampled and two validated tools were used to assess the quality of healthcare information retrieved; the DISCERN instrument and the JAMA benchmark criteria. Once duplicates were removed, a total of 77 unique websites were retrieved by the search. The majority of websites were published by private marketing firms. The median score for website quality across all included websites was 'fair' (42) when assessed according to the DISCERN instrument, and 'poor' (1) when assessed against the JAMA criteria. Private websites had the lowest quality of information online and institutional websites had the highest. Non-surgical aesthetics are becoming increasingly popular with patients and clinicians due to their convenience, scope of treatment, and novel and strategic marketing. Online information available to patients, however, is often of poor quality, dominated by private clinics and commercial entities, and thus presents a significant risk of misinforming patients desiring to undertake these procedures. Significant reform and regulation of information is required in order to make this industry safer for patients.


Associations between initial serum pH value and outcomes of pediatric out-of-hospital cardiac arrest.
Pediatric out-of-hospital cardiac arrest (OHCA) is one of the most critical conditions seen in the emergency department (ED). Although initial serum pH value is reported to be associated with outcome in adult OHCA patients, the association is unclear in pediatric OHCA patients. Thus, we aimed to identify the association between initial pH value and outcome among pediatric OHCA patients. This study was a retrospective analysis of a multicenter prospective cohort registry (Japanese Association for Acute Medicine out-of-hospital cardiac arrest registry) from 87 hospitals in Japan. We included pediatric OHCA patients younger than 16 years of age who were registered in this registry between June 2014 and December 2017. Of the 34,754 patients in the database, 458 patients were ultimately included in the analysis. We equally divided the patients into four groups, based on their initial pH value, and conducted a multivariate logistic regression analysis to calculate the adjusted odds ratios of the initial pH value on hospital arrival with their 95% confidence intervals for the primary outcome. The median (interquartile range) age was 1 (0-6) year, and 77.9% (357/458) of the first monitored rhythm was asystole. The primary outcome was 1-month survival. The overall 1-month survival was 13.3% (61/458), and a 1-month favorable neurologic outcome was seen in 5.2% (24/458) of cases. The adjusted odds ratios and 95% confidence intervals for the pH 6.81-6.64, pH 6.63-6.47, pH <6.47, and pH unknown groups compared with the pH ≥6.82 group for 1-month survival were 0.39 (0.16-0.97), 0.13 (0.04-0.44), 0.03 (0.00-0.24), and 0.07 (0.02-0.21), respectively. This study demonstrated the association between the initial pH value on hospital arrival and 1-month survival among pediatric OHCA patients.


Co-utilizing milk vetch, rice straw, and lime reduces the Cd accumulation of rice grain in two paddy soils in south China.
The danger posed by cadmium (Cd) pollution to rice production is continuously increasing. Co-utilizing milk vetch (Astragalus sinicus L.) and rice straw is a good practice for rice yield and soil fertility in south China. However, its effects on Cd availability in soil-rice systems remain unclear. A micro-plot trial of two typical paddy soils (alluvial sandy soil and reddish clayey soil) in south China was conducted to investigate the effects of milk vetch, rice straw, lime, and their combined application on Cd availability and the related mechanisms. Soil chemical properties, CaCl2-extractable Cd (CaCl2-Cd), total content of Cd (Total-Cd), Cd fractionation (BCR sequential-extraction method), and Cd accumulation in rice were measured. Results showed that the co-utilization of milk vetch, rice straw, and lime (GRFL) decreased the Cd content in rice grain by 91.43% and 15.63% in early rice of two soils, respectively. Cd was not detected in late rice grains. CaCl2-Cd decreased by 0.025 mg kg-1 in late rice of alluvial sandy soil, 0.057 and 0.044 mg kg-1 decreased in early and late rice of reddish clayey soil, and Total-Cd decreased by 19.4% and 9.1% for early rice of two soils, respectively. Co-utilizing milk vetch, rice straw, and lime changed the distribution of different chemical forms of Cd, decreased the content of bioavailable Cd in soil by reducing the Aci-Cd and RedCd, and benefited the formation of more stable residual fraction (ResCd). Redundancy analysis showed that the improvement in soil pH, dissolved organic matter (DOM), and other soil properties was the main cause of the transformation of Cd form. Among the soil properties, pH and DOM had the greatest impacts on Cd availability. In conclusion, co-utilizing milk vetch and rice straw can alleviate the danger of soil Cd in rice production, and this effect could be strengthened by applying lime.


A Meta-Analysis of Rhesus Macaques (Macaca mulatta), Cynomolgus Macaques (Macaca fascicularis), African green monkeys (Chlorocebus aethiops), and Ferrets (Mustela putorius furo) as Large Animal Models for COVID-19.
Animal models are at the forefront of biomedical research for studies of viral transmission, vaccines, and pathogenesis, yet the need for an ideal large animal model for COVID-19 remains. We used a meta-analysis to evaluate published data relevant to this need. Our literature survey contained 22 studies with data relevant to the incidence of common COVID-19 symptoms in rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), African green monkeys (Chlorocebus aethiops), and ferrets (Mustela putorius furo). Rhesus macaques had leukocytosis on Day 1 after inoculation and pneumonia on Days 7 and 14 after inoculation, in frequencies that were similar enough to humans to reject the null hypothesis of a Fisher exact test. However, the differences in overall presentation of disease were too different from that of humans to successfully identify any of these 4 species as an ideal large animal of COVID-19. The greatest limitation to the current study is a lack of standardization in experimentation and reporting. To expand our understanding of the pathology of COVID-19 and evalu- ate vaccine immunogenicity, we must extend the unprecedented collaboration that has arisen in the study of COVID-19 to include standardization of animal-based research in an effort to find the optimal animal model.


Proteomic and molecular evidences of Il1rl2, Ric8a, Krt18 and Hsp90b1 modulation during experimental hepatic fibrosis and pomegranate supplementation.
The inspection of variations in the proteomic aspects conspire the biomarker discovery in diagnostics of peculiar diseases. Recent developments in high-throughput proteomic techniques have provided leverage in the discovery of biomarkers during the etiology of various diseases. We identified potential biomarkers by utilizing proteomics, bioinformatics and gene expression studies. Meticulous assessment of collagen and hydroxyproline levels along with the glycogen and protein carbonyl levels exhibited deterioration in the N' - Nitrosodiethylamine (NDEA) administered rat livers and subsequent salubrious effect of pomegranate juice. The immunohistochemical inspection of iNOS and nitrite estimation indicated the peccant fibrotic alterations. 2D proteome profiling and MALDI-TOF MS/MS furthered the significant biomarkers to be analyzed for the gene ontology by PANTHER, cluster analysis by DAVID and network simulation by STRING 10.0. Several genes found relevant after MALDI analysis were evaluated by real-time PCR (RTPCR). Our data revealed CYP2b15, HSP70, TRFE, HPT, Il1rl2, Ric8a, Krt18, Hsp90b1 and iNOS as novel biomarkers for the mechanism of pomegranate against liver fibrosis. It can be inferred that NDEA-induced liver fibrosis actuates various biological pathways by the identified biomarkers and pomegranate juice modifies them.


The effects of age and shiftwork on perceived sleep problems: results from the VISAT-combined longitudinal and cross-sectional study.
With the workforces in industrialized countries getting older, this study sought to determine how shiftworking affects sleep in later life. Longitudinal data were collected from a large sample in 1996, 2001, and 2006 from employees who were 32, 42, 52, and 62 years old in 1996. The effects of shift work were most apparent in the early and middle years of working life. Former shiftworkers reported more sleep problems than both current shiftworkers and those who had never worked shifts. Giving up shift work off-set the age-related accumulation of sleep problems, with the net result that former shiftworkers showed little or no change in sleep problems over the three measurement occasions. The effects of shift work on sleep may persist for a long time after giving up shift work but they are not permanent.


Neurosporaside, a tetraglycosylated sphingolipid from Neurospora crassa.
The new tetraglycosylceramide neurosporaside (1a) has been isolated from the fungus Neurospora crassa. Neurosporaside is a tetraglycosylated glycosphingolipid characterized by a sugar chain unprecedented among natural glycoconjugates. The structure of neurosporaside was elucidated by extensive spectroscopic analysis and microscale degradation analysis, which allowed full structure elucidation using less than 1 mg of compound.


Mineral-rich Jeju lava sea water suppresses lipid accumulation in 3T3-L1 adipocytes and ameliorates high-fat diet-induced obesity in C57BL/6 J mice.
This research aimed to evaluate the potential inhibitory effect of mineral-rich Jeju lava sea water (JLSW) on lipid accumulation. This study optimized the calcium (Ca): magnesium (Mg) ratio (5:1, 2.5:1, 1:1) of JLSW and evaluated the effect on lipid accumulation in 3T3-L1 cells using Oil Red O staining. JLSW with a high Ca:Mg ratio (5:1) suppressed lipid accumulation in 3T3-L1 adipocytes. Based on these in-vitro results, the effects of JLSW on lipid accumulation were investigated in C57BL/6 J mice fed high-fat diets for 14 weeks. Epididymal adipose tissue weight was significantly decreased in mice that received JLSW with a hardness of 800 or 100 mg/L compared to HFD. Adipocyte size was significantly reduced in mice treated with JLSW with a hardness of 20 mg/L in comparison with HFD. Thus, long-term intake of JLSW may be expected to have anti-obesity effects due to the reduction of lipid accumulation.


Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.
Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants. To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing. This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form. Number of pathogenic or likely pathogenic (P/LP) variants identified. This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen. Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.


High-sensitivity qualitative and quantitative analysis of human, bovine and goat milk glycosphingolipids using HILIC-MS/MS with internal standards.
Glycosphingolipids (GSLs) in human milk regulate the immune system, support intestinal maturation, and prevent gut pathogens. The structural complexity and low abundance of GSLs limits their systematic analysis. Here, we coupled the use of monosialoganglioside 1-2-amino-N-(2-aminoethyl) benzamide (GM1-AEAB) derivatives as internal standards with HILIC-MS/MS to qualitatively and quantitatively compare GSLs in human, bovine, and goat milk. One neutral glycosphingolipid (GB) and 33 gangliosides were found in human milk, of which 22 were newly detected and three were fucosylated. Five GB and 26 gangliosides were identified in bovine milk, of which 21 were newly discovered. Four GB and 33 gangliosides were detected in goat milk, 23 of them newly reported. GM1 was the main GSL in human milk; whereas disialoganglioside 3 (GD3) and monosialogangloside 3 (GM3) were dominant in bovine and goat milk, respectively; N-acetylneuraminic acid (Neu5Ac) was detected in >88 % of GSLs in bovine and goat milk. N-hydroxyacetylneuraminic acid (Neu5Gc)-modified GSLs were 3.5 times more abundant in goat than in bovine milk; whereas GSLs modified with both Neu5Ac and Neu5Gc were 3 times more abundant in bovine than in goat milk. Given the health benefits of different GSLs, these results will facilitate the development of custom-designed human milk-based infant formula.


Flow cytometric analysis of mouse sperm using monoclonal anti-sperm antibody OBF13.
The variable reactivity of OBF13 monoclonal antibody to mouse sperm was studied using a fluorescein activated cell sorter. Sperm from cauda epididymis were incubated with ionophore A23187, subjected to indirect immunostaining and analyzed by a cell sorter. Three peaks showing different fluorescence intensities were observed. These peaks contained (i) not stained (N), (ii) acrosomal cap or anterior region stained (A) and (iii) head stained (H) sperm, respectively. H type sperm showed more intense integral fluorescence than A type sperm. It was also noted that the H type were observed when cauda epididymal sperm were incubated with A23187, but not among non-incubated, or A23187 treated caput epididymal sperm. When sperm were pre-categorized as "dead" or "alive" by propidium iodide staining, no A type were observed in the "live" population. These results suggest that the sperm exhibiting the OBF13 antigen in the acrosome region lost their viability before they accomplished a "true" acrosome reaction.


Cost-benefit analysis of screening colonoscopy in 40- to 50-year-old first-degree relatives of patients with colorectal cancer.
As shown previously, 40- to 50-year-old first-degree relatives of patients with colorectal cancer (CRC) have significantly more colorectal adenomas than controls of the same age. Screening colonoscopy of these persons at risk between 40 and 50 years might be cost beneficial. We prepared a detailed cost-benefit analysis of screening colonoscopy and possible repeat endoscopies according to current expenditures for endoscopic procedures in Germany. Since screening colonoscopy is generally offered and reimbursed from 55 years on in Germany, we analysed the period between 45 and 55 years, taking an annual interest rate of 5% into account. Costs were analysed based on the results of a former study [11] depending on various participation rates in a general screening programme. Based on the available 1994 figure of about 20,000 euros for diagnosis and treatment of one cancer case, screening colonoscopy is cost beneficial when participation is high. Under a more realistic assumption of currently about 40,000 euros per cancer case, screening colonoscopy is cost beneficial in any case. Our data support that systematic screening colonoscopy in first-degree relatives of patients with CRC by the age of 45 years most likely demonstrates an economic benefit.


Translational regulation during oogenesis and early development: the cap-poly(A) tail relationship.
Metazoans rely on the regulated translation of select maternal mRNAs to control oocyte maturation and the initial stages of embryogenesis. These transcripts usually remain silent until their translation is temporally and spatially required during early development. Different translational regulatory mechanisms, varying from cytoplasmic polyadenylation to localization of maternal mRNAs, have evolved to assure coordinated initiation of development. A common feature of these mechanisms is that they share a few key trans-acting factors. Increasing evidence suggest that ubiquitous conserved mRNA-binding factors, including the eukaryotic translation initiation factor 4E (eIF4E) and the cytoplasmic polyadenylation element binding protein (CPEB), interact with cell-specific molecules to accomplish the correct level of translational activity necessary for normal development. Here we review how capping and polyadenylation of mRNAs modulate interaction with multiple regulatory factors, thus controlling translation during oogenesis and early development.


Effectiveness of a novel real-time dosimeter in interventional radiology: a comparison of new and old radiation sensors.
Radiation dose management is important in interventional radiology (IR) procedures, such as percutaneous coronary intervention, to prevent radiation-induced injuries. Therefore, radiation dose should be monitored in real time during IR. This study evaluated the fundamental characteristics of a novel real-time skin dosimeter (RTSD) developed at our institution. In addition, we compared the performance of our new and old radiation sensors and that of a skin dose monitor (SDM), with ion chamber reference values. We evaluated the fundamental characteristics (e.g., energy dependence, dose dependence, and angular dependence) of the RTSD developed by us in the diagnostic X-ray energy range. The performance of our RTSD was similar to that of the SDM. In particular, the new radiation sensor of our RTSD demonstrated better dose rate dependence compared to the old sensor. In addition, the new sensor had the advantage of being small in size and thus minimally affecting the X-ray images compared to the old sensor. Therefore, the developed skin dosimeter and radiation sensor may be useful in real-time measurement of patients' exposure to and multi-channel monitoring of radiation in IR procedures. The new dosimeter system can be recommended for visualization and management of the radiation dose to which the patients' skin is exposed.


Clinical risk prediction models and informative cluster size: Assessing the performance of a suicide risk prediction algorithm.
Clinical visit data are clustered within people, which complicates prediction modeling. Cluster size is often informative because people receiving more care are less healthy and at higher risk of poor outcomes. We used data from seven health systems on 1,518,968 outpatient mental health visits from January 1, 2012 to June 30, 2015 to predict suicide attempt within 90 days. We evaluated true performance of prediction models using a prospective validation set of 4,286,495 visits from October 1, 2015 to September 30, 2017. We examined dividing clustered data on the person or visit level for model training and cross-validation and considered a within cluster resampling approach for model estimation. We evaluated optimism by comparing estimated performance from a left-out testing dataset to performance in the prospective dataset. We used two prediction methods, logistic regression with least absolute shrinkage and selection operator (LASSO) and random forest. The random forest model using a visit-level split for model training and testing was optimistic; it overestimated discrimination (area under the curve, AUC = 0.95 in testing versus 0.84 in prospective validation) and classification accuracy (sensitivity = 0.48 in testing versus 0.19 in prospective validation, 95th percentile cut-off). Logistic regression and random forest models using a person-level split performed well, accurately estimating prospective discrimination and classification: estimated AUCs ranged from 0.85 to 0.87 in testing versus 0.85 in prospective validation, and sensitivity ranged from 0.15 to 0.20 in testing versus 0.17 to 0.19 in prospective validation. Within cluster resampling did not improve performance. We recommend dividing clustered data on the person level, rather than visit level, to ensure strong performance in prospective use and accurate estimation of future performance at the time of model development.