Binding of LcrV protein from Yersinia pestis to human T-cells induces apoptosis, which is completely blocked by specific antibodies.
The V antigen (LcrV) of the plague bacterium Yersinia pestis is a potent protective protein that is considered as a vaccine component for humans. LcrV mediates the delivery of Yop toxins into host cells and upregulates TLR2-dependent IL-10 production. Although LcrV can interact with the receptor-bound human interferon-γ (hIFN-γ), the significance of these interactions in plague pathogenesis is not known. In this study, we determined the parameters of specific interactions of LcrV and LcrV68-326 with primary human thymocytes and Jurkat T-leukemia cells in the presence of receptor-bound hIFN-γ. Although the C-terminal region of hIFN-γ contains a GRRA138-141 site needed for high-affinity binding of LcrV and LcrV68-326, in the hIFN-γ homodimer, these GRRA138-141 target sites becomes accessible for targeting by LcrV or LcrV68-326 only after immobilization of the hIFN-γ homodimer on the hIFN-γ receptors of thymocytes or Jurkat T-cells. The interaction of LcrV or LcrV68-326 with receptor-bound hIFN-γ on the thymocytes or Jurkat T-cells caused apoptosis of both cell types, which can be completely blocked by the addition of monoclonal antibodies specific to the LEEL32-35 and DEEI203-206 sites of LcrV. The ability of LcrV to utilize hIFN-γ is insidious and may account in part for the severe symptoms of plague in humans.


Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway.
We previously demonstrated that activation of sphingosine kinase 1 (SphK1)- sphingosine 1- phosphate (S1P) signaling pathway by high glucose (HG) plays a pivotal role in increasing the expression of fibronectin (FN), an important fibrotic component, by promoting the DNA-binding activity of transcription factor activator protein 1 (AP-1) in glomerular mesangial cells (GMCs) under diabetic conditions. As a multi-target anti-oxidative drug, polydatin (PD) has been shown to have renoprotective effects on experimental diabetes. However, whether PD could resist diabetic nephropathy (DN) by regulating SphK1-S1P signaling pathway needs further investigation. Here, we found that PD significantly reversed the upregulated FN and ICAM-1 expression in GMCs exposed to AGEs. Simultaneously, PD dose-dependently inhibited SphK1 levels at the protein expression and kinase activity and attenuated S1P production under AGEs treatment conditions. In addition, PD reduced SphK activity in GMCs transfected with wild-type SphK(WT) plasmid and significantly suppressed SphK1-mediated increase of FN and ICAM-1 levels under normal conditions. Furthermore, we found that the AGEs-induced upregulation of phosphorylation of c-Jun at Ser63 and Ser73 and c-Fos at Ser32, DNA-binding activity and transcriptional activity of AP-1 were blocked by PD. In comparison with db/db model group, PD treatment suppressed SphK1 levels (mRNA, protein expression, and activity) and S1P production, reversed the upregulation of FN, ICAM-1, c-Jun, and c-Fos in the kidney tissues of diabetic mice, and finally ameliorated renal injury in db/db mice. These findings suggested that the downregulation of SphK1-S1P signaling pathway is probably a novel mechanism by which PD suppressed AGEs-induced FN and ICAM-1 expression and improved renal dysfunction of diabetic models.


FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls.
Fibroblast growth factor (FGF)23 is a critical determinant of phosphate homeostasis. The role of FGF23, however, in regulating physiologic changes in serum phosphate and renal phosphate handling across childhood is not well described. In addition, animal models have suggested a role for FGF23 in regulating renal calcium excretion. To assess changes in FGF23 concentrations across childhood in relation to changes in mineral ions and hormones of mineral ion homeostasis. This was a cross-sectional study. The study was conducted at a Clinical Research Center at a tertiary care hospital. Ninety healthy girls ages 9 to 18 years were recruited from the surrounding community. The associations of intact and C-terminal FGF23 concentrations with measures of mineral ion homeostasis were determined by univariable and multivariable linear regression. Serum phosphate and renal phosphate excretion varied with age, as expected (R = -0.49, P < 0.001 and R = -0.48, P < 0.001, respectively). Neither intact nor C-terminal FGF23 varied with age, and FGF23 was not correlated with serum or urinary phosphate. Intact FGF23 was positively correlated with serum calcium (R = 0.39, P < 0.001) and negatively correlated with urinary calcium/creatinine ratio (R = -0.27, P = 0.011). The changes in serum and urinary phosphate handling across childhood do not appear to be determined by alterations in FGF23 concentrations. These data may point to a role for FGF23 in calcium regulation in human physiology.


Asphyxia induced by umbilical cord occlusion alters glutamatergic and GABAergic synaptic transmission in neurons of the superior colliculus in fetal rats.
Using optical recordings, we studied the effects of asphyxia on intracellular Cl(-) and Ca(2+) concentrations ([Cl(-)]i; [Ca(2+)]i) in the superior colliculus of fetal rats, which were connected via the umbilical cord to the dam. Acute asphyxia was induced by umbilical cord occlusion. The number of fetal superior colliculus neurons showing GABA-mediated increases in [Cl(-)]i (leading to hyperpolarization) following local synaptic electrical stimulation had decreased by 3 h post-asphyxiation, while the number showing GABA-mediated decreases in [Cl(-)]i (leading to depolarization) increased. [Ca(2+)]i rise, which occurred after acute asphyxiation, was antagonized by both non-NMDA and NMDA receptor antagonists. The increase in [Ca(2+)]i following focal superior colliculus stimulation was markedly attenuated at 3 h post-asphyxiation. These findings suggest that asphyxia induced by umbilical occlusion induces changes in glutamatergic and GABAergic synaptic transmission in the fetal brain.


When our thoughts are not our own: investigating agency misattributions using the mind-to-mind paradigm.
At the core of the sense of agency for self-produced action is the sense that I, and not some other agent, am producing and directing those actions. While there is an ever-expanding body of empirical research investigating the sense of agency for bodily action, there has, to date, been little empirical investigation of the sense of agency for thought. The present study uses the novel Mind-to-Mind paradigm, in which the agentive source of a target thought is ambiguous, to measure misattributions of agency. Seventy-two percent of participants made at least one misattribution of agency during a 5-min trial. Misattributions were significantly more frequent when the target thought was an arousing negative thought as compared to a neutral control. The findings establish a novel protocol for measuring the sense of agency for thought, and suggest that both contextual factors and emotional experience play a role in its generation.


Increasing prevalence of HIV and syphilis but decreasing rate of self-reported unprotected anal intercourse among men who had sex with men in Harbin, China: results of five consecutive surveys from 2006 to 2010.
To monitor the prevalence of HIV and syphilis as well as behaviours, a sentinel site for men who have sex with men was established in Harbin in 2002. With additional funding, the sentinel surveillance evolved into annual cross-sectional surveys since 2006. Behavioural and serological data collected in five consecutive cross-sectional surveys were analysed. SPSS 13.0 was applied to compare prevalence of HIV and syphilis as well as behavioural variables over time by demographic variables, bivariate and multivariate analysis. The prevalence of HIV and syphilis increased from 1.0% in 2006 to 7.5% in 2010 and from 9.2% in 2006 to 22.4% in 2009, respectively, whereas the rate of unprotected anal intercourse decreased from 61.3% in 2006 to 47.1% in 2010. Syphilis positivity and HIV infection are independently associated with each other across years. The rate of unprotected anal sex remains high although it has decreased over the years. Findings support an increasing prevalence of HIV and syphilis among men who have sex with men in Harbin. Targeted behavioural intervention and syphilis treatment are urgently needed to prevent the epidemic from growing.


Two- to three-year follow-up of patients with single-vessel coronary artery disease randomized to PTCA or medical therapy (results of a VA cooperative study). Veterans Affairs Cooperative Studies Program ACME Investigators. Angioplasty Compared to Medicine.
Despite increasing use of percutaneous transluminal coronary angioplasty (PTCA) to treat stenotic coronary artery disease, there are relatively few prospective studies evaluating its long-term effectiveness. We prospectively randomized 212 stable patients with provocable myocardial ischemia and single-vessel subocclusive coronary disease to receive primary therapy with either PTCA or medical therapy. This report presents the clinical follow-up of these patients at a mean, after randomization, of 2.4 years for interview and 3.0 years for exercise testing. Of the 212 patients originally randomized, 175 received an extended follow-up interview, and 132 underwent exercise testing; 62% of patients in the PTCA group were angina free compared with 47% of patients in the medical group (p <0.05). Furthermore, exercise duration as measured by treadmill testing was prolonged by 1.33 minutes over baseline in the PTCA group, whereas it decreased by 0.28 minutes in the medical group (p <0.04). Although the angina-free time on the treadmill was not different (p=0.50), fewer patients in the medical group developed angina on the treadmill at 3 years than those in the PTCA group (p=0.04). By 36 months, excluding the initial randomized PTCA, use of PTCA and use of coronary artery bypass surgery were not different in the 2 treatment groups. These data indicate that some of the early benefits derived from PTCA in patients with single-vessel coronary artery disease are sustained, making it an attractive therapeutic option for these patients.


Repeated in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure affects male gonads in offspring, leading to sex ratio changes in F2 progeny.
The effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the reproductive system of male rat offspring (F1) and the sex ratio of the subsequent generation (F2) were examined. Female Holtzman rats were gavaged with an initial loading dose of 400 ng/kg TCDD prior to mating, followed by weekly maintenance doses of 80 ng/kg during mating, pregnancy, and the lactation period. Maternal exposure to TCDD had no significant effects on fetus/pup (F1) mortality, litter size, or sex ratio on gestation day (GD) 20 or postnatal day (PND) 2. The TCDD concentration in maternal livers and adipose tissue on GD20 was 1.21 and 1.81 ng/kg, respectively, and decreased at weaning to 0.72 in the liver and 0.84 in the adipose tissue. In contrast, the TCDD concentration in pup livers was 1.32 ng/kg on PND2 and increased to 1.80 ng/kg at weaning. Ventral prostate weight of male offspring was significantly decreased by TCDD exposure on PND28 and 120 compared with that of controls. Weight of the testes, cauda epididymides, and seminal vesicle, and sperm number in the cauda epididymis were not changed by TCDD exposure at PND120. TCDD- or vehicle-exposed male offspring were mated with unexposed females. The sex ratio (percentage of male pups) of F2 offspring was significantly reduced in the TCDD-exposed group compared with controls. These results suggest that in utero and lactational TCDD exposures affect the development of male gonads in offspring (F1), leading to changes in the sex ratio of the subsequent generation (F2).


Optimization of γ-polyglutamic acid synthesis using response surface methodology of a newly isolated glutamate dependent Bacillus velezensis Z3.
A new glutamate-dependent γ-polyglutamic acid (γ-PGA) producer Z3 isolated from soil samples in Daxinganling forest region of China was identified, and its optimal medium components were investigated using response surface methodology. Strain Z3 was identified as Bacillus velezensis by physiology and biochemistry and 16S rDNA sequence analysis. This is the first report of glutamate-dependent B. velezensis with the ability to synthesize γ-PGA. Then, the optimum γ-PGA yield (5.58 g/L) was achieved with glutamate 86 g/L, glucose 36 g/L, yeast extract powder 5.5 g/L, and NaH2PO4 7.5 g/L. Furthermore, activities of enzymes participating in glutamate synthesis were assessed, and the results showed that lower ketoglutaric dehydrogenase activity (KGDH) and higher glutamate dehydrogenase activity (GDH) resulted in higher γ-PGA yield. Identification of glutamate-dependent γ-PGA producer named B. velezensis Z3 enriches microbiological resources with γ-PGA-producing capacity. B. velezensis optimization of nutrients and analysis of enzymes activities will not only help to increase γ-PGA productivity but also to understand the γ-PGA synthesis mechanism in B. velezensis Z3.


Activation of JNK pathway in persistent pain.
The c-Jun N-terminal kinase (JNK) is a stress-activated member of MAP kinase family. JNK activation has been strongly implicated in inflammatory responses, neurodegeneration, and apoptosis. Recent evidence shows that JNK pathway is also transiently activated in primary sensory neurons after tissue or nerve injury, which is required for the development of hyperalgesia and allodynia. In particular, JNK is persistently activated in astrocytes of the spinal cord after nerve injury, and this activation can maintain central sensitization and mechanical allodynia. In this mini-review, we will provide evidence for the involvement of JNK pathway in regulating persistent pain sensitization. We will also discuss possible upstream signaling mechanisms that cause JNK activation and downstream signaling mechanisms by which JNK modulates pain sensitivity. Thus, targeting JNK pathway might be a useful strategy to treat both neurodegeneration and chronic pain.


Distinct roles for metalloproteinases during traumatic brain injury.
Significant protease activations have been reported after traumatic brain injury (TBI). These proteases are responsible for cleavage of transmembrane proteins in neurons, glial, and endothelial cells and this results in the release of their extracellular domains (ectodomains). Two TBI models were employed here, representing both closed head injury (CHI) and open head injury (OHI). In situ zymography, immunohistochemistry, bright field and confocal microscopy, quantification of immunopositive cells and statistical analysis were applied. We found, using in situ zymography, that gelatinase activity of matrix metalloproteinases (MMP)-2 and MMP-9 was upregulated in cortex of both injury models. Using immunohistochemistry for several MPPs (Matrix metalloproteinases) and ADAMs (disintegrin and metalloproteinases), including MMP-2, -9, ADAM-10, -17, distinct patterns of induction were observed in the two TBI models. In closed head injury, an early increase in protein expression of MMP-2, -9 and ADAM-17 was found as early as 10 min post injury in cortex and peaked at 1 h for all 4 proteases examined. In contrast, after OHI the maximal expression was observed locally neighboring the impact site, at a later time-point, as long as 24 h after the injury for MMP-2 and MMP-9. Confocal microscopy revealed colocalization of the 4 proteases with the neuronal marker NeuN in CHI, but only MMP2 colocalized with NeuN in OHI. The findings may lead to a trauma-induced therapeutic strategy triggered soon after a primary insult to improve survival and to reduce brain damage following TBI.


Effect of obesity, lipids and adipokines on allergic rhinitis risk: a Mendelian randomization study.
Observational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. Summary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. After Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (OR = 0.870, 95% CI 0.765-0.990, p = 0.035; OR = 0.732, 95% CI 0.551-0.973, p = 0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. The study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. This was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.


Chondroid syringoma of the eyelid.
An 81-year-old man underwent excisional biopsy of a big cylindric painless mass of the right lower eyelid, which had been present for over 23 years. Histopathologic and immuno-histochemical examination showed a chondroid syringoma, an uncommon benign neoplasm of possible eccrine sweat gland origin, which occurs generally in the head and neck skin. In the eyelids, it has been previously described as a small nodule in the upper lid. Surgical excision of these tumours is recommendable because malignant transformation is possible, although rare.


SIgA in various pulmonary diseases.
Secretory immunoglobulin A (SIgA) is one of the most abundant immunoglobulin subtypes among mucosa, which plays an indispensable role in the first-line protection against invading pathogens and antigens. Therefore, the role of respiratory SIgA in respiratory mucosal immune diseases has attracted more and more attention. Although the role of SIgA in intestinal mucosal immunity has been widely studied, the cell types responsible for SIgA and the interactions between cells are still unclear. Here, we conducted a wide search of relevant studies and sorted out the relationship between SIgA and some pulmonary diseases (COPD, asthma, tuberculosis, idiopathic pulmonary fibrosis, COVID-19, lung cancer), which found SIgA is involved in the pathogenesis and progression of various lung diseases, intending to provide new ideas for the prevention, diagnosis, and treatment of related lung diseases.


Adams-based hierarchical features fusion network for image dehazing.
Recent developments in Convolutional Neural Networks (CNNs) have made them one of the most powerful image dehazing methods. In particular, the Residual Networks (ResNets), which can avoid the vanishing gradient problem effectively, are widely deployed. To understand the success of ResNets, recent mathematical analysis of ResNets reveals that a ResNet has a similar formulation as the Euler method in solving the Ordinary Differential Equations (ODE's). Hence, image dehazing which can be formulated as an optimal control problem in dynamical systems can be solved by a single-step optimal control method, such as the Euler method. This optimal control viewpoint provides a new perspective to address the problem of image restoration. Motivated by the advantages of multi-step optimal control solvers in ODE's, which include better stability and efficiency than single-step solvers, e.g. Euler, we propose the Adams-based Hierarchical Feature Fusion Network (AHFFN) for image dehazing with modules inspired by a multi-step optimal control method named the Adams-Bashforth method. Firstly, we extend a multi-step Adams-Bashforth method to the corresponding Adams block, which achieves a higher accuracy than that of single-step solvers because of its more effective use of intermediate results. Then, we stack multiple Adams blocks to mimic the discrete approximation process of an optimal control in a dynamical system. To improve the results, the hierarchical features from stacked Adams blocks are fully used by combining Hierarchical Feature Fusion (HFF) and Lightweight Spatial Attention (LSA) with Adams blocks to form a new Adams module. Finally, we not only use HFF and LSA to fuse features, but also highlight important spatial information in each Adams module for estimating the clear image. The experimental results using synthetic and real images demonstrate that the proposed AHFFN obtains better accuracy and visual results than that of state-of-the-art methods.


Pre-Treatment of Swine Oviductal Epithelial Cells with Progesterone Increases the Sperm Fertilizing Ability in an IVF Model.
Mammalian spermatozoa are infertile immediately after ejaculation and need to undergo a functional modification, called capacitation, in order to acquire their fertilizing ability. Since oviductal epithelial cells (SOECs) and progesterone (P4) are two major modulators of capacitation, here we investigated their impact on sperm functionality by using an IVF swine model. To that, we treated SOECs with P4 at 10, 100, and 1000 ng/mL before the coincubation with spermatozoa, thus finding that P4 at 100 ng/mL does not interfere with the cytoskeleton dynamics nor the cells' doubling time, but it promotes the sperm capacitation by increasing the number of spermatozoa per polyspermic oocyte (p < 0.05). Moreover, we found that SOECs pre-treatment with P4 100 ng/mL is able to promote an increase in the sperm fertilizing ability, without needing the hormone addition at the time of fertilization. Our results are probably due to the downregulation in the expression of OVGP1, SPP1 and DMBT1 genes, confirming an increase in the dynamism of our system compared to the classic IVF protocols. The results obtained are intended to contribute to the development of more physiological and efficient IVF systems.


Neuroanatomic characterization of schizoaffective disorder using MRI: a pilot study.
For over 50 years, there has been uncertainty in the conceptual understanding and neuropathogenesis of the diagnosis of schizoaffective disorder (SCA). In order to better characterize SCA, we performed a quantitative assessment of MRI neuroanatomical structures in patients with SCA (n = 12), compared to patients with bipolar disorder (BPD) (n = 12) and healthy volunteers (HV) (n = 12). Patients diagnosed with SCA exhibited regional abnormalities on the striatum that resemble those seen in BPD. This study suggests that SCA has some neuroanatomical characteristics similar to BPD.


OSTA program: A French follow up intervention program for suicide prevention.
Attempted suicide is a strong risk factor for subsequent suicidal behavior. In recent years, a particular interest has been given to follow-up interventions as a potential effective strategy in preventing recurrent suicidal behavior. We developed a follow-up intervention program called OSTA (organization of a suitable monitoring for suicide attempters) aimed at addressing this issue and tested its effectiveness in a 1-year randomized controlled trial. Individuals who attempted suicide and were admitted to the emergency department (ED) of Bicêtre Hospital (n=320) were randomly allocated to receive either the OSTA program or a control treatment. On an intention to treat basis, the proportion of patients who reattempted suicide did not differ significantly between the interventional group (IG) 14.5% (22/152) and the control group (CG) 14% (21/150). There were also no significant differences, between the two arms, in the number of suicide attempts. Although no significant difference has been found between the OSTA program and the control treatment concerning the rate of suicide reattempts, we believe that further studies should be conducted to test the effectiveness of more standardized follow-up studies in suicide prevention.


MYC in DLBCL: partners matter.
In this issue of Blood, Copie-Bergman et al demonstrate that MYC rearrangements (MYC-Rs) with IG genes, but not with other partner genes, have a negative prognostic impact in patients with diffuse large B-cell lymphomas (DLBCLs) treated with immunochemotherapy.


A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors.
Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5' end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analog inhibitors can be bonded to nsp9 and fit into a previously unknown "Nuc-pocket" in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an "induce-and-lock" mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs but also provide a strategy to design antiviral drugs.


Gonadal regulation of corticotropin-releasing factor immunoreactivity in hypothalamus.
The effect of gonadectomy and subsequent gonadal steroid administration on hypothalamic corticotropin-releasing factor immunoreactivity (CRF-ir) in male and female rats was determined using a radioimmunoassay specific for rat CRF. When compared to appropriate controls, gonadectomy resulted in significantly decreased CRF-ir in both males and females (p less than 0.025). Short-term replacement with testosterone or estradiol did not significantly alter hypothalamic CRF-ir. Acute IC administration of gonadotropin-releasing hormone to male rats significantly decreased CRF-ir in the median eminence 15 minutes later. Chronic administration of estradiol for 3 weeks significantly reduced CRF-ir in ovariectomized rats (p less than 0.005). This decrease was shown not to correlate to the marked increase in anterior pituitary weight (r2 = 0.063, not significant). Chronic administration of estradiol to hypophysectomized female rats significantly decreased hypothalamic CRF-ir (p less than 0.01), an effect localized to the median eminence (p less than 0.005). These data imply that the gonadectomy-induced reduction in hypothalamic CRF-ir was not directly mediated by the loss of gonadal steroids. Chronic estradiol treatment decreased hypothalamic CRF-ir, by a non-pituitary mechanism. These data show significant effects of the gonadal axis in the regulation of CRF in the hypothalamus in both sexes.


A monoclonal anti-idiotope antibody reacting with a determinant of the cross-reactive idiotype on anti-p-azobenzenearsonate antibodies of A/J mice.
A hybrid cell line, 14A1, was produced that secretes antibodies reacting with a monoclonal A/J anti-p-azobenzenearsonate (ABA) antibody, 7.1.3, previously shown to have all of the determinants of the cross-reactive idiotype (CRI) defined by rabbit anti-idiotype sera. 14A1 were detected using a sensitive assay that is specific for antibodies against idiotypic, but not allotypic nor isotypic, determinants. This was confirmed by demonstrating that 14A1 antibodies bind 7.1.3 but not other A/J monoclonal antibodies of the same class or CRI- monoclonal anti-ABA antibodies. The idiotypic determinant recognized by 14A1 is located at or near the hapten-binding site of 7.1.3, as ABA-conjugated tyrosine is capable of blocking this interaction. RAbbit anti-CRI antibodies are prevented from binding to 7.1.3 by the addition of 14A1, demonstrating the spatial proximity of the 14A1 idiotope with determinant(s) of the CRI. All A/J anti-ABA antibodies that have the 14A1 idiotope are also CRI+, while anti-ABA antibodies from other strains of mice to not express this idiotope. Furthermore, antibodies from A/J mice immunologically suppressed for the CRI also fail to interact with 14A1 antibodies. These results have implications both for the nature of the CRI and for the regulation of the immune response by anti-idiotype antibodies.


Restricted utilization of VH and DH genes in leukemic rabbit B cells.
Polyclonal B cell leukemias have been generated in 17- to 20-day old Emu-myc transgenic rabbits. To analyze the repertoire of VH genes utilized in early B cells, eight VDJ genes were cloned from these leukemic cells. The nucleotide sequences of these genes indicated that seven of the eight VDJ genes encoded prototype VHa1, VHa2 or VHa3 allotypes. The two VDJ genes encoding VHa1 molecules had VH segments with identical nucleotide sequences; similarly, the VH segments of the four VDJ genes encoding VHa2 molecules were identical, with the exception of a single base pair. These data suggest that a limited repertoire of VH genes were utilized in the generation of these VDJ genes. The DH segments of these genes were limited to two DH families, D1 and D2, indicating that a restricted repertoire of DH genes also had been utilized. Since these leukemic cells probably developed early in ontogeny, we suggest that this restricted utilization of VH and DH genes is representative of B cells from developmentally immature rabbits.


The epidemiology of major depressive disorder and subthreshold depression in Izmir, Turkey: Prevalence, socioeconomic differences, impairment and help-seeking.
Subclinical and clinical depression is common, widely distributed in the general population, and usually associated with role impairment and help-seeking. Reliable information at the population level is needed to estimate the disease burden of depression and associated care needs in Turkey. The cross-sectional study aimed to assess the prevalence of subthreshold (SubD) and clinical major depressive disorder (MDD) in Izmir, Turkey. In the 5242 eligible households, a total of 4011 individuals were successfully interviewed, yielding a response rate of 76.5%. Prevalence estimates of MDD and SubD depression were formed by using the responses to the questions of the CIDI section E. Short Form 36 (SF-36) to assess health status and functional impairments in eight scaled scores during the last four weeks. All respondents were questioned about receiving 12-month treatment for any psychological complaints, the route of help-seeking, as well as prescribed medicines and any hospitalization. The one year prevalence estimate for CIDI/DSM IV MDD was 8.2% (95% CI, 7.4-9.1). Less educated, low income, uninsured, low SES, unemployed/disabled and housewives, slum area residents had higher one year MDD prevalence. Determined prevalence of help seeking from mental health services of SubD and MDD cases were 23.6%, 30.6% respectively. Only 24.8% of clinically depressive patients received minimally adequate treatment. Cross sectional design. Higher MDD prevalence correlates with younger ages, female gender, unemployment, less education, lower monthly income, lower SES and uninsurance. Help seeking from mental health services were low. There are treatment gap and impairment in depressive group.


Accuracy of administrative claims prescription fill data to estimate glucocorticoid use and dose in patients with rheumatoid arthritis.
To assess accuracy of administrative claims prescription fill-based estimates of glucocorticoid use and dose, and approximate bias from glucocorticoid exposure misclassification. We identified adults with rheumatoid arthritis with linked Medicare and CorEvitas registry data. An algorithm identifying glucocorticoid use and average dose over 90 days from Medicare prescription fills was compared to physician-reported measures from a CorEvitas visit during the same period, using weighted kappa to compare doses (none, ≤5 mg, 5-10 mg, >10 mg/day). A deterministic sensitivity analysis examined the effect of exposure misclassification on estimated glucocorticoid-associated infection risk from a prior study. We identified 621 observations among 494 patients. Prescription fills identified glucocorticoid use in 41.9% of observations versus 31.1% identified by CorEvitas physician-report. For glucocorticoid use (yes/no), prescription fills had sensitivity 88.1% (95% CI 82.7-92.3), specificity 79.0% (74.8-82.7), PPV 65.4% (59.3-71.2), NPV 93.6% (90.6-95.9), and 81.8% agreement with CorEvitas, with kappa 0.61 (moderate to substantial agreement). There was 89.5% agreement between prescription fills and physician-reported doses, with weighted kappa 0.56 (moderate agreement). Applying these results to a prior Medicare study evaluating glucocorticoid-associated infection risk [risk ratio 1.44 (95% CI 1.41-1.48)] led to an externally adjusted risk ratio of 1.74 when accounting for exposure misclassification, representing -17% bias in infection risk estimate. This study supports the use of claims data to estimate glucocorticoid use and dose, but investigators should account for exposure misclassification, which may lead to underestimates of glucocorticoid risks. Our results could be applied to adjust risk estimates in other studies that use prescription fills to estimate glucocorticoid use.


Clinicopathological features to distinguish malignant solitary fibrous tumors of the prostate from prostatic stromal tumors.
Mesenchymal tumors of the prostate are rare but encompass a wide differential diagnosis. In our study, we aimed to investigate the clinicopathological features that can be used to differentiate malignant solitary fibrous tumors (mSFTs) occurring in the prostate from prostatic stromal tumors. A total of 15 patients with mesenchymal tumors of the prostate were identified in Nanjing Drum Tower Hospital from 2009 to 2019, including 3 mSFTs, 9 stromal tumors of uncertain malignant potential (STUMPs), and 3 prostatic stromal sarcomas (PSSs). Immunohistochemical stains for signal transducer and activator of transcription 6 (STAT6), aldehyde dehydrogenase 1 (ALDH1), CD34, desmin, smooth muscle actin (SMA), progesterone receptor (PR), CD117, and cytokeratin (CK) were performed on representative sections from each tumor, and the clinical features, histology, and immunophenotype of these three groups were analyzed. There was no significant difference in mean patient age of patients diagnosed with mSFTs, STUMPs, and PSSs. mSFTs and PSSs showed significantly increased tumor size (p < 0.05), Ki-67 proliferation index (p < 0.0001), and mitotic activity (p < 0.05) when compared with STUMPs. mSFTs showed significantly higher expression of STAT6 compared with both PSSs and STUMPs (p < 0.0001, p < 0.0001). PR showed significantly more expression in STUMPs than in mSFTs or PSSs (p < 0.0001, p < 0.0001). Desmin and SMA showed significantly more expression in STUMPs than in mSFTs (p < 0.05). ALDH1, CD117, CK, and CD34 showed no significant difference in staining between mSFTs, STUMPs, and PSSs. Therefore, a limited panel of STAT6, PR, and Ki-67 may be useful in distinguishing between mSFTs, STUMPs, and PSSs.


Carbetocin in comparison with oxytocin in several dosing regimens for the prevention of uterine atony after elective caesarean section in the Netherlands.
The aim of the study was to compare the prophylactic effects of carbetocin with those of oxytocin for the prevention of uterine atony in patients undergoing elective caesarean section (CS) in the Netherlands. The primary endpoint was the need for additional uterotonic medication. Each of the five participating Dutch hospitals treated 50-100 term patients with 100 μg of intravenous carbetocin on prescription. Each centre retrieved charts of 250 patients treated with oxytocin according to the hospital's policy for the prevention of uterine atony (oxytocin bolus 5 IU, bolus 10 IU or bolus 5 IU followed by 10 IU in 2 h). In the carbetocin group 462 subjects were included and in the oxytocin group 1,122. The proportion of subjects needing additional uterotonic treatment was 3.1 % (95 % CI 1.7-5.1 %) after carbetocin and 7.2 % (5.8-8.9 %) after oxytocin; relative risk 0.41 (0.19-0.85); p = 0.0110. Carbetocin was most effective compared with the oxytocin 5 IU bolus subgroup with less need for additional uterotonic medication (3.1 vs. 9.3 %, p = 0.0067) and blood transfusions (2.2 vs. 3.6 %, p = 0.0357). Compared with oxytocin, prophylaxis of uterine atony with carbetocin after an elective CS diminished the need for additional uterotonics by more than 50 %.


Sequential endoscopy and biopsy of intact rat stomach. A new simple technique.
This paper describes the technique of sequential endoscopy and biopsy of the intact rat stomach. It is recommended that this procedure be performed on fasted animals with access to water only, when a mortality of only 4% can be achieved.


The influence of walking performed immediately before meals with moderate fat content on postprandial lipemia.
Postprandial lipemia is an independent risk factor for coronary heart disease. Single bouts of moderate exercise may lower this risk, but the minimum duration of moderate intensity exercise that still lowers postprandial lipemia is not known. We, therefore, performed a dose-response study with a normal, daily life setting, to identify the minimum duration of moderate intensity walking that lowers postprandial lipemia in sedentary, healthy young men. Sixteen men performed three activity trials (30, 60, or 90 min of treadmill walking at 50% of their individual VO2max) and a control trial with no physical activity in a repeated measures crossover design. The subjects walked immediately before ingestion of the first of two mixed meals, which were served 3 h apart. The meals had a moderate fat content (0.5 g per kg body mass and 33% of total energy per meal) and a macronutrient composition corresponding to current recommendations. Each meal provided one third of the subject's estimated daily energy requirement. Venous blood samples were taken in the fasted state, and then hourly for 6 h after the first meal to assess the postprandial phase. Postprandial lipemia (the incremental area under the curve (dAUC) of triacylglycerol) was compared with a mixed model analysis and Tukey's adjustment. Postprandial lipemia (dAUC of triacylglycerol) was, compared to the control trial, +2% (P = 1.00), -14% (P = 0.24), and -15% (P = 0.23) in the 30, 60, and 90 min walking trials, respectively. Moderate intensity walking of 60 and 90 min duration slightly, but insignificantly, reduced postprandial lipemia after two mixed meals with moderate fat content in sedentary, healthy young men, compared to inactivity. Therefore, it should be reconsidered if the acute exercise-induced reduction in postprandial lipemia usually observed in studies using high fat meals is of importance in a real, daily life setting.


Timing of Presentation and Outcomes of Women with Stage IV Pregnancy-Associated Breast Cancer (PABC).
Pregnancy-associated breast cancer (PABC) and concurrent, or early development of, stage IV disease is uncommon. Given this rarity, and complexities surrounding pregnancy, data are limited regarding PABC treatment and outcomes. We evaluated oncologic, obstetric, and fetal outcomes of women with stage IV PABC in relation to presentation timing and treatment. Our retrospective review of an institutional database identified women with stage IV PABC from 1998 to 2018. PABC was defined as diagnosis during pregnancy or ≤ 1 year postpartum. Clinicopathologic, treatment, and outcome variables were compared between women diagnosed during pregnancy versus postpartum. We identified 77 women (median age 35 years; interquartile range [IQR] 32-37 years): 51 (66%) in the postpartum group and 26 (34%) in the pregnant group, including 9 with therapeutic or spontaneous abortion. Among 17 women who continued pregnancy, no obstetric or fetal complications were noted. Clinicopathologic and treatment variables did not differ between groups. Of 43 women dead from disease, 15 had triple negative (TN) tumors. Median overall survival (OS) of TN tumors was 14 months (range 5-39 months); OS was associated with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) positive tumors (p < 0.01). At 31 months (range 0-137 months) median follow-up, the 5-year OS was 34% (95% confidence interval 21-46%), and did not differ among pregnant and postpartum groups (p = 0.2). Women with stage IV TN PABC had high mortality rates despite multimodality therapy. Timing of presentation did not affect management decisions or OS, even for women who completed pregnancy. Further research to understand PABC biology, focusing on TN tumors, is warranted.


Current concepts in the radiographic evaluation of the rotator cuff.
This review discusses the disease of the rotator cuff and evaluates our current tools for imaging it. The rotator cuff consists of the cojoined tendons of the short rotator muscles of the shoulder. Derangements of the cuff, which can result from degeneration, trauma, or overuse, are frequent causes of shoulder pain. Until the present decade, imaging of the cuff depended on injection of contrast into either the underlying joint (arthrogram) or overlying bursa (bursogram). Computed tomography (CT) has added additional dimensions to arthrography but has not played a major role in the diagnosis of cuff pathology. Ultrasonography (US) has been shown to be of diagnostic value in imaging cuff tears and has shown promise in defining pathology in the intact cuff. Magnetic resonance imaging (MRI) has the potential for imaging the cuff; its roles here are not yet defined.


Oestrogens in milk.
The steroid oestrogens oestradiol-17 beta, oestrone and oestradiol-17 alpha have all been adequately identified in various body fluids and tissues of cattle. There is also good evidence for the presence of oestrone sulphate. Oestriol (or similar triols) may also be present. The oestrogens found in the systemic plasma of cattle are present in milk in similar concentrations; whether their passage into milk involves metabolism by the mammary gland is uncertain. Oestrone sulphate, at least at relatively high levels of secretion, is believed to be found only in pregnant cattle and measurement of its concentration in milk is in use as a practical test for pregnancy. A close correlation has been found between the concentrations of oestradiol-17 beta in systemic plasma and milk of non-pregnant cows and levels of this oestrogen in milk may, together with those of progesterone, now be used in studies of post-partum ovarian function.


[Further studies of continuous human and animal cell lines for the manufacture of viral vaccines and diagnostic kits].
Long-term experiments have provided conditions for the optimal conditions for reproduction of vaccine strains of poliomyelitis, measles, tick-borne and Japan encephalitis on the continuous cell lines. This makes it possible to solve one of the most urgent problems of modern biotechnology, namely to refuse to use primary cell cultures in vaccinology and to apply a more accessible, safe, and reference biological substrate that are stable cell lines.


Medical students' personal experiences, religion, and spirituality explain their (dis)comfort with a patient's religious needs.
Physicians often avoid discussing patients' religious and spiritual concerns, even though most patients (i.e., 50-94%) want integrated care. To address this gap, medical students interviewed a Standardized Patient (SP) who was upset because the daughter did not confront her fiancée about converting to Orthodox Judaism. Students reflected on how their own religion and spirituality affected engaging with their patient. With a 97% response rate, 231 first-year medical students responded to open-ended questions about their patient encounter. For this quantitative content analysis, we used inductive reasoning, identifying three themes: (1) impact of students' own religion on their comfort, (2) change in comfort, and (3) their learning. We used deductive reasoning to compare qualitative results from half of the students who began the curriculum with a questionnaire about their own spirituality with the other students completing afterwards. Most students said being religious positively influenced their comfort, whether they were also Orthodox Jewish or from a different religion. Among uncomfortable students (6.5%), some attributed this to not being religious. Some students (4.8%) grew more comfortable discussing the religious issue, and 18.2% became uncomfortable due to lacking knowledge of Orthodox Judaism and the awkwardness of the topic. Students who had completed the questionnaire beforehand gave more comments about connecting with their patients than students who completed the questionnaire afterwards (X2=11.047, p<.001). Students' own religion influenced their comfort with discussing religious concerns, with some feeling more connected and others becoming uncomfortable. This finding helps inform medical educators about teaching mind-body-spirit care.Résumé.


An overview of environmental and toxicological aspects of aromatic hydrocarbons. II. Toluene.
The salient aspects of the exposure to toluene were reviewed via an initial examination of the production, use, occurrence and disposition of toluene, as well as populations at potential risk. Special note should be taken as to the increasing use of toluene as a "safe" replacement for benzene in solvent applications and its increasing use in many consumer products. There is a broad potential for exposure by industrial workers and the general public (via vehicle exhausts and consumer products). The effects on humans and animals as well as the genetic effects of toluene were also reviewed following an initial consideration for its absorption and elimination. The narcotic and neurotoxic properties of toluene represent the main recognized health hazards to humans.


Selective inhibition of noradrenaline and serotonin uptake by C 49802-B-Ba and CGP 6085 A.
The effects of two new compounds, 1-(1-methylamino-2-hydroxy-3-propyl)-dibenzo[b,e]bicyclo[2,2,2]octadiene-HCl (C 49802-B-Ba) and 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A), on noradrenaline (NA) and serotonin (5-HT) uptake were investigated in different test systems, CGP 6085 A is a very potent and selective inhibitor of 5-HT uptake in rat brain (ED50 1-4 mg/kg p.o., depending on test system). Doses up to 1000 mg/kg p.o. did not inhibit NA uptake. C 49802-B-Ba is a potent and selective inhibitor of NA uptake in rat brain (ED50 5-10 mg/kg p.o. depending on test system) and heart (ED50 1.5 mg/kg p.o.). At 300 mg/kg p.o., this compound caused no inhibition of 5-HT uptake.


Interventional radiology in pregnancy complications: indications, technique, and methods for minimizing radiation exposure.
Complications of pregnancy, whether they occur during gestation or postpartum, often pose complex challenges because they affect two patients (mother and fetus or infant) and because both short- and long-term outcomes must be considered in management decision making. Interventional radiologists play a critical role in treating complications such as ectopic implantation, postpartum hemorrhage, symptomatic ovarian cyst, post-cesarean section fluid collection, obstructive uropathy, and vesicouterine fistula. Interventional radiology offers therapeutic options that obviate surgery, thereby minimizing morbidity and mortality and maximizing the potential for fertility preservation. Such options include chemical injection of an ectopic gestational sac, uterine artery embolization, aspiration and drainage, percutaneous nephrostomy, and suprapubic cystostomy catheter placement. All these procedures are performed with the use of radiologic imaging for guidance. The levels of radiation to which the mother and fetus may be exposed during such procedures are of concern because of potential negative effects on long-term health. However, various methods can be used to lower maternal and fetal radiation dose levels to the minimum needed to accomplish the clinical objective.


VIM- and IMP-type metallo-beta-lactamase-producing Pseudomonas spp. and Acinetobacter spp. in Korean hospitals.
We determined the occurrence of acquired metallo-b-lactamase (MBL)-producing bacteria in Korean hospitals. Among the isolates nonsusceptible to imipenem that were collected from 28 hospitals from 2000 to 2001, 44 (11.4%) of 387 Pseudomonas spp. and 38 (14.2%) of 267 Acinetobacter spp. produced MBL and had alleles of blaVIM-2 or blaIMP-1. MBL-producing isolates were detected in 60.7% of the hospitals.


Sinonasal Secretory Carcinoma of Salivary Gland with High Grade Transformation: A Case Report of this Under-Recognized Diagnostic Entity with Prognostic and Therapeutic Implications.
Secretory carcinoma (SC) is a recently described salivary gland carcinoma with characteristic ETV6-NTRK3 fusion. In this case report, we described a SC of the maxillary sinus that underwent high grade transformation in a 61-year-old patient. The diagnosis was confirmed by the presence of ETV6 translocation. Within the sinonasal tract, SC is an important differential diagnosis especially of sinonasal adenocarcinoma, non-intestinal type (non-ITAC), as these two entities bears histologic and immunophenotypic similarity. Distinction between these two tumors can be challenging based on the morphology alone and may require additional immunohistochemical and molecular studies. It is important to recognize that SC can occur in the sinonasal tract as correctly diagnosing SC may be prognostic relevant and may provide new targeted therapeutic avenues for these patients.


Newborn screening for biliary atresia in the United States.
Despite advances in our understanding of the pathogenesis of biliary atresia (BA), BA remains the most common cause of end-stage liver disease in children and the leading indication for pediatric liver transplantation. Age at time of Kasai portoenterostomy (KPE), performed to provide bile drainage, strongly correlates with transplant-free survival, mostly due to progression of intrahepatic fibrosis to cirrhosis. Unfortunately, challenges remain in recognizing that a jaundiced infant may have BA. To better diagnose infants with BA at an earlier age, population-based screening programs in countries such as Taiwan, Japan, and China have utilized stool color cards. Early results have been promising demonstrating earlier diagnosis, earlier KPE, and, hence, improved outcomes. Cost-effectiveness studies focused on stool color card screening in North America where the incidence of BA is much lower also project improved transplant-free survival rate with a savings in terms of healthcare expenditure. There is also evidence that postnatal serum bilirubin levels may also be effective as a screening tool given that all infants with BA exhibit hyperbilirubinemia at birth. The American Academy of Pediatrics (AAP) recently advocated studying the implementation of newborn screening for BA in the United States. Further efforts and analyses within the United States are ongoing, but current evidence is supportive of screening for BA even in low incidence countries.


A Joint Model Approach for Longitudinal Data with no Time-Zero and Time-To-Event with Competing Risks.
The joint modeling of longitudinal and time-to-event data is an active area in biostatistics research. The focus of this article is on developing a modeling framework for these joint models when the longitudinal and time-to-event data do not have a meaningful time-zero. The motivating example is the study of a longitudinal assessment of station during child labor and it's relationship to time-to-delivery. A good predictor of delivery type and timing would help obstetricians better manage the end of pregnancy and better facilitate delivery. One measure of labor progression is station, a measure of the position of the fetus' head in relation to the pelvis of the pregnant women, may be a good marker for delivery time and type. However, women enter the hospital, where their station is closely monitored, at arbitrary points in their labor process, resulting in no clear time zero. In addition, since delivery may be of various types, the competing risks due to type need to be accounted for. We develop a joint model of longitudinal and time-to-event data for this situation. The model is formulated through shared random effects between the survival and longitudinal processes, and parameter estimation is conducted through a Bayesian approach. The model is illustrated with longitudinal data on station where the relationship between station and event-time is studied and the model is used to assess the ability of longitudinal measures of station to predict the type and timing of pregnancy. We illustrate the methodology with longitudinal data taken during labor.


The Prevalence of Uterine Fibroids in African American Women with Hemoglobin SS Sickle Cell Disease as Determined by Pelvic Magnetic Resonance Imaging.
This study explores the relationship between the development of uterine fibroids and hemoglobin SS sickle cell disease (SCD) by examining the prevalence of uterine fibroids as detected by pelvic magnetic resonance imaging (MRI) in African American (AA) women with and without SCD. A single-center, retrospective review was performed of all adult AA women at a large, academic medical center who received pelvic MRI from January 1, 2007 to December 31, 2018. Propensity score matching conditional on age and ZIP code evaluated the differences in fibroid prevalence between the two groups. Subanalyses by age in 10-year intervals were also performed. Twenty-one (23.9%) of 88 patients with SCD had fibroids on pelvic MRI versus 1493 (52.1%) of 2868 patients without SCD (p value <0.001). After propensity score matching, 21 (24.7%) of 85 patients with SCD compared to 52 (61.2%) of 85 patients without SCD had fibroids (p value <0.001). Subanalyses in 10-year age intervals showed significance for patients between 30 and 39 years old in which 4 (13.8%) of 29 SCD patients versus 374 (65.3%) of 573 no SCD patients had fibroids (p value <0.001), and for patients between 40 and 49 years old in which 9 (42.9%) of 21 SCD patients versus 667 (73.8%) of 904 no SCD patients had fibroids (p value = 0.002). These findings indicate an overall significantly lower prevalence of uterine fibroids in AA women with SCD, suggesting that SCD may be protective against the development of uterine fibroids in these patients.


Screening and identification of Lassa virus endonuclease-targeting inhibitors from a fragment-based drug discovery library.
Lassa virus (LASV) belongs to the Old World genus Mammarenavirus, family Arenaviridae, and order Bunyavirales. Arenavirus contains a segmented negative-sense RNA genome, which is in line with the bunyavirus and orthomyxoviruses. The segmented negative-sense RNA viruses utilize a cap-snatching strategy to provide primers cleavaged from the host capped mRNA for viral mRNA transcription. As a similar strategy and the conformational conservation shared with these viruses, the endonuclease (EN) would serve as an attractive target for developing broad-spectrum inhibitors. Using the LASV minigenome (MG) system, we screened a fragment-based drug discovery library and found that two hits, F1204 and F1781, inhibited LASV MG activity. Both hits also inhibited the prototype arenavirus Lymphocytic choriomeningitis virus (LCMV) MG activity. Furthermore, both hits effectively inhibited authentic LCMV and severe fever with thrombocytopenia syndrome virus (SFTSV) infections. Similarly, both hits could inhibit the activity of LASV, LCMV, and SFTSV EN. The combination of either compound with an arenavirus entry inhibitor had significant synergistic antiviral effects. Moreover, both hits were found to be capable of binding to LASV EN with a binding affinity at the micromolar level. These findings provide a basis for developing the hits as potential candidates for the treatment of segmented negative-sense RNA virus infections.


On Holobionts, Holospecies, and Holoniches: the Role of Microbial Symbioses in Ecology and Evolution.
My goal in writing this is to increase awareness of the roles played by microbial symbionts in eukaryote ecology and evolution. Most eukaryotes host one or more species of symbiotic microorganisms, including prokaryotes and fungi. Many of these have profound impacts on the biology of their hosts. For example, microbial symbionts may expand the niches of their hosts, cause rapid adaptation of the host to the environment and re-adaptation to novel conditions via symbiont swapping, facilitate speciation, and fundamentally alter our concept of the species. In some cases, microbial symbionts and multicellular eukaryote hosts have a mutual dependency, which has obvious conservation implications. Hopefully, this contribution will stimulate a reevaluation of important ecological and evolutionary concepts including niche, adaptation, the species, speciation, and conservation of multicellular eukaryotes.


Predicting Health Care Utilization After Behavioral Health Referral Using Natural Language Processing and Machine Learning.
Mental health problems are an independent predictor of increased healthcare utilization. We created random forest classifiers for predicting two outcomes following a patient's first behavioral health encounter: decreased utilization by any amount (AUROC 0.74) and ultra-high absolute utilization (AUROC 0.88). These models may be used for clinical decision support by referring providers, to automatically detect patients who may benefit from referral, for cost management, or for risk/protection factor analysis.


Regulation of estrogen receptor protein and messenger ribonucleic acid by estradiol and progesterone in rat uterus.
The objective of this study was to examine the mechanisms of estrogen receptor (ER) processing and replenishment in the uterus of ovariectomized rats after estradiol and progesterone treatment. Uterine ER binding activity, ER protein and ER mRNA were measured by receptor binding exchange assay, Western blot and slot blot, respectively. The regulation of ER levels in rat uterus by estradiol and progesterone was very dramatic. Changes in ER protein were faithfully reflected by changes in binding activity. Estradiol caused receptor "processing" within 4 h of administration followed by recovery or "replenishment" of ER levels to the initial level by 20 h. The term "processing" has previously been used to describe the loss of ER binding activity in the early phase of estradiol-action, but it was never clear whether the ligand binding site was inactivated by processing or if the receptor molecule actually disappeared. This study shows that receptor "processing" constitutes disappearance of receptor protein and the later "replenishment" phase represents new ER protein rather than recycling of "processed" receptor. Progesterone-action, on the other hand, influenced only the "replenishment" phase by blocking recovery of ER protein. ER mRNA was suppressed by estradiol at 8 h, after the receptor was "processed" and "replenishment" already initiated. Progesterone, on the other hand, did not alter the steady state level of the message. Other mechanisms, such as regulation of translation rate of existing mRNA and changes in the rate of degradation of ER proteins are more likely involved in acute regulation of ER by these ovarian steroid hormones.


Direct observation of solid-phase adsorbate concentration profile in powdered activated carbon particle to elucidate mechanism of high adsorption capacity on super-powdered activated carbon.
Decreasing the particle size of powdered activated carbon (PAC) by pulverization increases its adsorption capacities for natural organic matter (NOM) and polystyrene sulfonate (PSS, which is used as a model adsorbate). A shell adsorption mechanism in which NOM and PSS molecules do not completely penetrate the adsorbent particle and instead preferentially adsorb near the outer surface of the particle has been proposed as an explanation for this adsorption capacity increase. In this report, we present direct evidence to support the shell adsorption mechanism. PAC particles containing adsorbed PSS were sectioned with a focused ion beam, and the solid-phase PSS concentration profiles of the particle cross-sections were directly observed by means of field emission-scanning electron microscopy/energy-dispersive X-ray spectrometry (FE-SEM/EDXS). X-ray emission from sulfur, an index of PSS concentration, was higher in the shell region than in the inner region of the particles. The X-ray emission profile observed by EDXS did not agree completely with the solid-phase PSS concentration profile predicted by shell adsorption model analysis of the PSS isotherm data, but the observed and predicted profiles were not inconsistent when the analytical errors were considered. These EDXS results provide the first direct evidence that PSS is adsorbed mainly in the vicinity of the external surface of the PAC particles, and thus the results support the proposition that the increase in NOM and PSS adsorption capacity with decreasing particle size is due to the increase in external surface area on which the molecules can be adsorbed.


Incontinence and loneliness among Chinese older adults with multimorbidity in primary care: A cross-sectional study.
To evaluate the associations between incontinence and loneliness among the Chinese elderly with multimorbidity in primary care, with the specific aim to look into the relationship of incontinence with social and emotional subdomains of loneliness. This cross-sectional study included older patients with multimorbidity in public primary care clinics in Hong Kong. Loneliness was assessed by the De Jong Gierveld Loneliness Scale (DJGLS). Tobit models were used to evaluate the association between incontinence and loneliness before and after adjustment for socio-demographics, lifestyle behaviors, physical and psychological conditions, social support and living status. A total of 741 patients were included. Before adjustment, incontinence was associated with higher levels of emotional loneliness (coefficient = 0.74, 95% CI = 0.43-1.06, p < .001) and higher levels of overall loneliness (coefficient = 0.81, 95% CI = 0.34-1.27, p = .001), but not social loneliness (coefficient = 0.34, 95% CI = -0.41 - 1.09, p = .38). After adjustment, incontinence was still significantly associated with higher levels of emotional loneliness (coefficient = 0.35, 95% CI = 0.07-0.64, p = .01). Incontinence is independently associated with emotional loneliness. Healthcare professionals should pay special attention to emotional loneliness among older patients with incontinence. Further studies are needed to look into the potential mechanisms and interventions.


Comparative in vivo biodistribution of cells labelled with [89Zr]Zr-(oxinate)4 or [89Zr]Zr-DFO-NCS using PET.
In vivo monitoring of cell biodistribution using positron emission tomography (PET) provides a quantitative non-invasive method to further optimize cell therapies and related new developments in the field. Our group has earlier optimized and evaluated the in vitro properties of two radiotracers,[89Zr]Zr-(oxinate)4 and [89Zr]Zr-DFO-NCS, for the radiolabelling of different cell types. Here, we performed a microPET study to assess the in vivo biodistribution of cells in rats using these two radiotracers. Human decidual stromal cells (hDSC) and rat macrophages (rMac) were radiolabelled with [89Zr]Zr-(oxinate)4 or [89Zr]Zr-DFO-NCS. Rats were intravenously injected with radiolabelled cells, and the in vivo biodistribution was monitored with microPET/CT imaging for up to day 7. Organ uptake was evaluated and presented as a percentage of injected activity per gram tissue (%IA/g) and total absorbed organ doses (mSv/MBq). The biodistribution in vivo showed an immediate uptake in the lungs. Thereafter, [89Zr]Zr-(oxinate)4 labelled cells migrated to the liver, while the signal from [89Zr]Zr-DFO-NCS labelled cells lingered in the lungs. The differences in the in vivo behaviour for the same cell type appeared related to the radiotracer labelling. After 24 h, [89Zr]Zr-(oxinate)4 labelled cells had over 70% higher liver uptake for both hDSC and rMac compared to [89Zr]Zr-DFO-NCS labelled cells, whereas [89Zr]Zr-DFO-NCS labelled cells showed over 60% higher uptake in the lungs compared to [89Zr]Zr-(oxinate)4 labelled cells. This difference in both lung and liver uptake continued until day 7. Dosimetry calculations showed a higher effective dose (mSv/MBq) for [89Zr]Zr-DFO-NCS compared to [89Zr]Zr-(oxinate)4, for both cell types. Although the bone uptake was higher for [89Zr]Zr-(oxinate)4 labelled cells, the prolonged uptake in the lungs contributed to a significant crossfire to bone marrow resulting in a higher bone dose. The [89Zr]Zr-DFO-NCS labelled cells suggest a prolonged accumulation in the lungs, while [89Zr]Zr-(oxinate)4 suggests quicker clearance of the lungs followed by accumulation in the liver. Accumulation of radiolabelled cells in the liver corresponds to other cell-tracking methods. Further studies are required to determine the actual location of the [89Zr]Zr-DFO-NCS labelled cell.


Renography with a semiautomated algorithm for diuretic decision 7 min postradiopharmaceutical administration: a feasibility study.
The F+10 method for diuretic renography (diuretics given 10 min after the radiopharmaceutical) could be a time-conserving method. This method involves a 30-min dynamic acquisition where diuretics are administered only when necessary by the Nuclear Medicine technologist performing the examination. The purpose of this study was to assess the method's performance and to discover the optimal threshold of residual activity for a diuretic administration 7 min into the F+10 renography by reprocessing raw data from prior performed examinations with 20-min acquisitions without diuretics. Retrospectively, raw data from 320 original examinations of adult patients performed from 2013 to 2015 were reprocessed into 7-min series and categorized as requiring diuretic or not. The diuretic decisions made by an expert panel were used as a reference. A receiver-operating characteristic curve was drawn to assess the optimal cutoff value for the residual renal activity. Sensitivity, specificity, positive and negative predictive values, as well as the Youden J index were calculated. The experts classified 50% (160 examinations) as in need of diuretics. The receiver-operating characteristic curve demonstrated the theoretical optimal cutoff value at 7 min to be 94% of maximum activity (sensitivity 0.93, specificity 0.81, Youden J index 0.73). A clinically acceptable threshold is suggested to be 85% (sensitivity 0.99, specificity 0.59, Youden J index 0.58). Tc-mercaptoacetyltriglycine renography with the F+10 method and the threshold 85% for diuretic decision 7 min into the renography is a feasible and acceptable method in clinical practice.


Knockdown of glucose-regulated protein 78 decreases the invasion, metalloproteinase expression and ECM degradation in hepatocellular carcinoma cells.
We have reported previously that overexpression of glucose-regulated protein 78 (GRP78) promotes the invasion of hepatocellular carcinoma. However, whether GRP78 knockdown affects the extracellular matrix degradation has not been elucidated. Here we are going to determine whether GRP78 knockdown affect the ECM degradation and the role of MMP-2 and MMP-9 in these process in hepatocellular carcinoma cells. Human hepatocellular carcinoma cell line SMMC7721 and HepG2 were cultured in DMEM supplemented with 10% FBS, RT-PCR and western blot were used to detect the endogenous expression of GRP78, MMP-2, MMP-9 and TIMP-2 in SMMC7721 and HepG2. GRP78 shRNAs were transfected using lipofection2000. Transwell assay and wound healing assay were used to analyze the invasion of each transfectant. Gelatin zymography and FITC-gelatin degradation assay were employed to investigate the capabilities of ECM degradation of each transfectant. MTT assay was used to determine the proliferation status. Western blot was employed to detect the expression of matrix metalloproteinase 2(MMP-2), MMP-9, MMP-14, and tissue inhibitor of metalloproteinases 2(TIMP-2), focal adhesion kinase (FAK), ERK1/2, JNK and Src. According to the expression levels of GRP78, MMP-2, MMP-9, MMP-14 and TIMP-1 in hepatocellular carcinoma cell lines SMMC7721 and hepG2, we used SMMC7721 as the in vitro invasion model for further functional analysis. Using this model, we found that GRP78 knockdown decreased the invasion of tumor cells, and this inhibitory effect was independent of cell proliferation. In hepatocellular carcinoma cells, Grp78 knockdown inhibited ECM degradation and the decreased activity and expression of MMP-2, but not MMP-9 contributed largely to this impact. Further analysis revealed that the decreased activity and expression of MMP-2 is mediated by JNK. Knockdown of GRP78 decreases ECM degradation, and downregulates the expression and activity of MMP-2 and TIMP-2. These results further demonstrate that GRP78 is a potential target for inhibiting the invasion of hepatocellular carcinoma cells.


The effect of CenteringPregnancy group prenatal care on preterm birth in a low-income population.
The purpose of this study was to evaluate the impact of group prenatal care on rates of preterm birth. We conducted a retrospective cohort study of 316 women in group prenatal care that was compared with 3767 women in traditional prenatal care. Women self-selected participation in group care. Risk factors for preterm birth were similar for group prenatal care vs traditional prenatal care: smoking (16.9% vs 20%; P = .17), sexually transmitted diseases (15.8% vs 13.7%; P = .29), and previous preterm birth (3.2% vs 5.4%; P = .08). Preterm delivery (<37 weeks' gestation) was lower in group care than traditional care (7.9% vs 12.7%; P = .01), as was delivery at <32 weeks' gestation (1.3% vs 3.1%; P = .03). Adjusted odds ratio for preterm birth for participants in group care was 0.53 (95% confidence interval, 0.34-0.81). The racial disparity in preterm birth for black women, relative to white and Hispanic women, was diminished for the women in group care. Among low-risk women, participation in group care improves the rate of preterm birth compared with traditional care, especially among black women. Randomized studies are needed to eliminate selection bias.


Jan Evangelista Purkyně/Purkinje (1787-1869) and the establishment of cellular physiology--Wrocław/Breslau as a central European cradle for a new science.
Being a professor of physiology in Wrocław/Breslau till the half of nineteenth century, Jan Evangelista Purkyně/Purkinje made, along with his students, many crucial discoveries combining original experimental approaches with new advanced microscopy and histology techniques. Here, he established first Institute of Physiology worldwide and created a framework for the new science of cellular physiology. With his work, he not only substantially contributed to the establishment of cellular and protoplasmic concepts in biology but represented a rare type of Central European scholar by bridging communities separated by ethnicity and language.


Anti-proliferative and cytotoxic effect of cannabidiol on human cancer cell lines in presence of serum.
Cannabinoids are able to reduce tumor growth in xenograft models, but their therapeutic potential as anti-cancer drugs in humans is unclear yet. In vitro studies of the effect of cannabinoids on cancer cells are often carried out in absence of serum or in low serum concentration (i.e. 0.5% serum), conditions that limit cellular growth and therefore can increase the response of cells to additional challenges such as the presence of cannabinoids. However, the tumor microenvironment can be teaming with growth factors. In this study we assessed the viability and proliferation of cancer cells treated with cannabidiol in presence of a serum concentration that commonly sustains cell growth (10% serum). The results show that cannabidiol exerts a markedly different effect on the viability of the human HT-29 cancer cell line when cultured in presence of 0.5% serum in comparison to 10% serum, displaying a cytotoxic effect only in the former situation. In presence of 10% serum, no inhibitory effect of cannabidiol on DNA replication of HT-29 cells was detected, and a weak inhibition was observed for other cancer cell lines. These results indicate that the effect of cannabidiol is cell context-dependent being modulated by the presence of growth factors.


Assignment of Ptprn2, the gene encoding receptor-type protein tyrosine phosphatase IA-2beta, a major autoantigen in insulin-dependent diabetes mellitus, to mouse chromosome region 12F.
The receptor-type protein tyrosine phosphatase IA-2beta gene (mouse gene symbol Ptprn2) encodes a major autoantigen in insulin-dependent diabetes mellitus. We physically mapped Ptprn2 by fluorescence in situ hybridization to band F of mouse chromosome 12, a region that lacks diabetes susceptibility loci. The mapping confirms the proposed synteny of mouse 12F with band q36 of human chromosome 7.


Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth.
All-trans retinoic acid (ATRA) treatment causes CAOV3 ovarian carcinoma cells to growth arrest in the G0/G1 phase and to elevate the level of Rb2/p130 protein. PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130, thereby increasing the half-life of Rb2/p130 in the cell. In order to further characterize the interaction between Rb2/p130 and PP2A upon ATRA treatment, we examined the posttranslational modification of PP2A. ATRA treatment leads to hypophosphorylation of PP2A catalytic subunit (PP2Ac) that correlates with increased PP2A activity. In addition, the N-terminus of PP2Ac binds directly to NLS sequences located in the C-terminus of Rb2/p130. Furthermore, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the wt C-terminus grew more aggressively and were less sensitive to ATRA treatment when compared to parental CAOV3 cells. In contrast, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the C-terminus in which the NLS sites were mutated and which could not interact with PP2A, were as sensitive to ATRA treatment as parental CAOV3 cells. These studies suggest that ATRA treatment suppresses the growth of CAOV3 cells via a novel posttranscriptional mechanism involving PP2A.


T cell receptor (TCR) signal strength controls arthritis severity in proteoglycan-specific TCR transgenic mice.
T cell receptor transgenic (TCR-Tg) mice specific for the arthritogenic 5/4E8 epitope in the G1 domain of cartilage proteoglycan were generated and back-crossed into arthritis-prone BALB/c background. Although more than 90% of CD4(+) T cells of all TCR-Tg lines were 5/4E8-specific, one (TCR-TgA) was highly sensitive to G1-induced or spontaneous arthritis, while another (TCR-TgB) was less susceptible. Here we studied whether fine differences in TCR signalling controlled the onset and severity of arthritis. Mice from the two TCR-Tg lines were immunized side by side with purified recombinant human G1 (rhG1) domain for G1 domain of cartilage proteoglycan (PG)-induced arthritis (GIA). TCR-TgA mice developed severe and early-onset arthritis, whereas TCR-TgB mice developed weaker arthritis with delayed onset, although TCR-TgB CD4(+) T cells expressed approximately twice more TCR-Vβ4 chain protein. The more severe arthritis in TCR-TgA mice was associated with higher amounts of anti-G1 domain-specific antibodies, larger numbers of B cells and activated T helper cells. Importantly, TCR-TgB CD4(+) T cells were more sensitive to in vitro activation-induced apoptosis, correlating with their higher TCR and CD3 expression and with the increased TCR signal strength. These findings indicate that TCR signal strength determines the clinical outcome of arthritis induction: 'optimal' TCR signal strength leads to strong T cell activation and severe arthritis in TCR-TgA mice, whereas 'supra-optimal' TCR signal leads to enhanced elimination of self-reactive T cells, resulting in attenuated disease.


[Comparison of manual versus mechanical cervical anastomosis in a prospective series of patients with esophagectomy due to cancer].
The scarce existing literature suggests having a lower rate of anastomotic leakage and less late stricture formation after stapled esophagogastric anastomosis compared to the manual anastomosis technique. The aim of the present study is to compare the surgical outcomes of termino-lateral manual cervical anastomosis versus mechanical anastomosis by later lateral stapling, after transhiatal esophagectomy for cancer. A retrospective review of patients undergoing transhiatal esophagectomy with manual or mechanical anastomosis for neoplasia was performed at three institutions in Medellin, between 2011 and 2018. Endpoints included leak rate, morbidity, mortality, hospital stay, and endoscopically identified anastomotic strictures requiring dilatation. 68 patients (40 men, 59%) were evaluated, 37 with manual anastomosisand 31 with mechanical anastomosis with similar demographic characteristics. Anastomotic leaks occurred in 13 patients (19.1%), with no difference found between manual and mechanical anastomosis (18.9 vs. 19.3%; p=0.93). Overall morbidity (61%), in-hospital mortality (3%) and length of hospital stay (median 12 days) were not affected by anastomotic technique. Follow-up endoscopic evaluation was available in all patients and anastomotic stricture associated or not with leak was detected in 18 patients (22%), in cases of stricture without leak is more frequent with manual than mechanical anastomosis technique (21.6 vs 6.4%; p=0.07) with longer duration of surgical procedure in case of manual anastomosis (p=0.05). Our non-randomized study suggests that the manual anastomosis technique results in a shorter surgical time and a lower stricture rate than mechanical anastomosis in cervical esophagogastric reconstruction after transhiatal esophagectomy, with a similar rateof leakage, hospital stay and morbidity and mortality.


Serotonin reciprocally regulates melanocortin neurons to modulate food intake.
The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.


Formalin treatment of refractory hemorrhagic cystitis.
Severe hemorrhagic cystitis can be a devastating complication of chemotherapy. Intravesical formalin may obviate the need for radical surgery in the face of failure of other conservative measures. Open instillation is favored in order to reduce the risk of complications.


Triglyceride-Glucose Index Is a Useful Marker for Predicting Future Cardiovascular Disease and Mortality in Young Korean Adults: A Nationwide Population-Based Cohort Study.
The triglyceride-glucose (TyG) index, the product of fasting triglycerides and glucose, is a useful and cost-effective marker of insulin resistance (IR). Furthermore, the TyG index is a known IR screening tool in healthy young adults but not in those with atherosclerotic cardiovascular disease (CVD). Thus, this study aimed to evaluate the TyG index as a predictor of CVD in healthy young adults. This study enrolled 6,675,424 adults aged 20-39 years without CVD from the National Health Information Database. We categorized them by TyG index quartile from 2009-2017. The study outcomes were stroke, myocardial infarction (MI), and mortality. All outcomes were analyzed by Cox proportional hazards regression analysis while controlling for baseline covariates. During a mean 7.4 years of follow-up, 8,506 cases of stroke, 12,312 cases of MI, and 22,667 deaths were recorded. Multivariable-adjusted hazard ratios (HRs) for participants in the highest TyG index quartile demonstrated that they were at higher risk for stroke (HR, 1.253; 95% confidence interval [CI], 1.167-1.346), MI (HR, 1.258; 95% CI, 1.187-1.334), and mortality (HR, 1.151; 95% CI, 1.104-1.200) than those in the lowest TyG index quartile independent of age, sex, smoking, alcohol consumption, physical activity, income, body mass index, blood pressure, and total cholesterol. The HRs for outcomes in the highest quartiles were higher when the TyG index was applied than when triglyceride or fasting glucose alone was applied. TyG index, a simple measure reflecting IR, can predict CVD and mortality in young and healthy populations.


Posterior capsule reopacification after neodymium:YAG laser capsulotomy.
We report a case of complete posterior capsule reopacification after successful neodymium:YAG (Nd:YAG) capsulotomy in an adult. Review of the records of all patients who had an Nd:YAG capsulotomy at our hospital revealed an incidence of reopacification of 0.7%. All affected patients were younger than 50 years at the time of cataract surgery.


Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits.
Although several protein-protein interactions have been reported between transient receptor potential (TRP) channels, they are all known to occur exclusively between members of the same group. The only intergroup interaction described so far is that of TRPP2 and TRPC1; however, the significance of this interaction is unknown. Here, we show that TRPP2 and TRPC1 assemble to form a channel with a unique constellation of new and TRPP2/TRPC1-specific properties. TRPP2/TRPC1 is activated in response to G-protein-coupled receptor activation and shows a pattern of single-channel conductance, amiloride sensitivity and ion permeability distinct from that of TRPP2 or TRPC1 alone. Native TRPP2/TRPC1 activity is shown in kidney cells by complementary gain-of-function and loss-of-function experiments, and its existence under physiological conditions is supported by colocalization at the primary cilium and by co-immunoprecipitation from kidney membranes. Identification of the heteromultimeric TRPP2/TRPC1 channel has implications in mechanosensation and cilium-based Ca(2+) signalling.


Association of selenium and cadmium with heart failure and mortality based on the National Health and Nutrition Examination Survey.
The association of selenium and cadmium with heart failure and mortality has not been thoroughly explored. We analysed data from the National Health and Nutrition Examination Survey (NHANES) database over 12 years (1999-2000, 2003-2004 and 2011-2018), which includes blood selenium and cadmium. Multivariable logistic regression and Cox proportional hazards regression were used. In total, 15,689 participants were enrolled. The multivariate analysis showed that low blood selenium (odds ratio [OR] = 0.952, p < 0.001) and high blood cadmium (OR = 1.345, p < 0.001) were independent risk factors of heart failure. During 96802 person-year follow-up, 1697 deaths occurred. The multivariable adjusted hazard ratio (HR) for all-cause mortality was 0.82 (95% confidence interval [CI] = 0.71-0.95) for middle selenium levels and 0.76 (95% CI = 0.65-0.88) for high selenium levels compared to low selenium levels. Taking the low cadmium levels as reference, the multivariable adjusted HR for all-cause mortality among high cadmium levels was 1.68 (95% CI = 1.44-1.96). Furthermore, the association between selenium, cadmium and cardiovascular mortality was similar to that of all-cause mortality. A subgroup analysis of the study population showed that in individuals with heart failure, although selenium levels were not associated with risk of all-cause mortality, high selenium levels were associated with a lower risk of cardiovascular mortality (HR = 0.33, p = 0.0032). Low blood selenium and high blood cadmium were independent risk factors of heart failure. Blood selenium was inversely associated with all-cause mortality and cardiovascular mortality, whereas blood cadmium was positively associated with them. Furthermore, blood selenium was associated with a lower risk of cardiovascular mortality in individuals with heart failure.


Molecular epidemiology of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae in Seville.
Due to the emergence of drug-resistant pneumococcal isolates, new fluoroquinolones have been recommended for the treatment of pneumococcal infections. The purpose of this study was to establish surveillance, and to conduct molecular characterization, of fluoroquinolone-resistant Streptococcus pneumoniae in Seville. Norfloxacin-resistant S. pneumoniae isolates were characterized by quinolone resistance-determining region (QRDR) substitutions, reserpine-sensitive efflux, serotype and by pulsed-field gel electrophoresis (PFGE) patterns. Fourteen isolates (5.1%) showed an MIC>16 μg/ml to norfloxacin. Eight of 10 adult isolates were susceptible to levofloxacin. The 4 infant isolates with norfloxacin MIC>16 μg/ml were susceptible to levofloxacin. Seven of these 12 low-level-resistant isolates had mutations in ParC, while mutations both in ParC and GyrA genes were only detected in one of the two high-level-resistant isolates. All the isolates without QRDR substitutions that remained norfloxacin-resistant were positive for reserpine-inhibited efflux. The serotyping and PFGE revealed significant heterogeneity. We obtained 9 different profiles, 3 of which had two isolates each. Two of the isolates with the same pulsotype were from the same patient. The first isolate showed a mutation in the QRDR of ParC, and the second one had an additional GyrA mutation. In our study a levofloxacin resistance rate of 0.7% was found among invasive isolates. Although resistance level is low, surveillance is necessary, especially to prevent cases of in vivo resistance development as reported.


Presence of histone mRNA sequences in high molecular weight RNA of HeLa cells.
Pulse-labeled HeLa cell RNA centrifuged under denaturing conditions was hybridized with DNA of recombinant phages containing sea urchin histone genes. This cross-hybridization showed the presence of histone mRNA sequences in high molecular weight RNA molecules. Treatment of the cells with actinomycin to stop RNA synthesis resulted in the rapid decay of this high molecular weight RNA followed by an increase of 9S histone mRNA in the cytoplasm. The results are consistent with the presence in HeLa cells of a high molecular weight precursor to histone messengers.


"I don't know" My Cancer Risk: Implications for Health Behavior Engagement.
Many people report uncertainty about their cancer risk. We examined whether such uncertainty was related to cancer prevention and detection behaviors. National Health Interview Survey data from 2005 to 2010 were analyzed. Participants reported their perceived risk for colorectal and breast cancers. Responses were coded as "valid" (i.e., less/as/more likely than average) or "don't know." In bivariate analyses for both cancer sites and survey years, "don't know" responders (DKR) engaged in less physical activity than "valid" responders (p < 0.05). DKR had lower mammography adherence than "valid" responders in 2005 and lower colorectal screening adherence in 2010 (p < 0.05). DKR had marginally lower colorectal screening adherence and fruit/vegetable consumption in 2005 (p < 0.06). Multivariable models indicated that the DKR-behavior relationship could be largely accounted for by education. Interventions that help people understand their cancer risk may provide particular benefit to people with low education and might consequently reduce health disparities.


Caregivers' and Physicians' Perspectives on Alpha-Mannosidosis: A Report from Italy.
Alpha-mannosidosis is a rare lysosomal storage disorder that generally presents in early childhood. It is a progressive, highly heterogeneous disease that is difficult to recognize, and a diagnosis is usually reached after referrals to multiple specialists. It is important to understand the challenges faced by patients and their caregiver up to and after a diagnosis of alpha-mannosidosis. In this report, we describe the process of alpha-mannosidosis diagnosis and treatment from the caregivers' and physicians' perspectives. For the caregivers' perspective, the mothers of two patients with alpha-mannosidosis ('Adele' aged 35 years and 'Amedeo' aged 40 years) were interviewed in their homes in Italy, and anonymized transcripts were used to describe their experiences. Adele lived in a large city with access to hospitals and specialized centers and was diagnosed with alpha-mannosidosis before 3 years of age. Amedeo was from a small village and was diagnosed when he was 10-11 years old. In both cases, their mothers sought help from pediatricians and other specialists for recurrent infections and delayed speech and motor development in the first years of their lives, but diagnosis was delayed. Although the diagnostic pathway was concerning and frustrating for her mother, Adele was able to live at home and receive multidisciplinary care and psychosocial support locally, but the transition from pediatric to adult services was difficult. She is currently waiting for access to enzyme replacement therapy. Amedeo had to travel widely and frequently to receive a diagnosis and access supportive treatment. The cumulative morbidity resulting from the delays and poor access to care necessitated long-term residential care. From the physicians' perspective, greater awareness of alpha-mannosidosis is required among healthcare professionals and more support is needed for patients and caregivers, particularly those living in rural areas or small centers.


The response of nematodes in vivo and in vitro to some anthelmintics.
Dietary feeding of drugs for 5 days to mice infected with Nematospiroides dubius and Hymenolepis nana detected all modern anthelmintics examined except stilbazium. A simple test using eggs of Nematodirus spathiger and adult Nippostrongylus brasillensis to detect anthelmintics in vitro is reported.


A developmental study on the neural circuitry mediating response flexibility in bipolar disorder.
Cross-sectional neuroimaging studies are an important first step in examining developmental differences in brain function between adults and youth with bipolar disorder (BD). Impaired response flexibility may contribute to reduced ability to modify goal-directed behavior in BD appropriately. We compared neural circuitry mediating this process in child (CBD) vs. adult BD (ABD) and age-matched healthy subjects. fMRI data from 15 CBD, 23 ABD, 20 healthy children, and 27 healthy adults were acquired during a response flexibility paradigm, a task where subjects inhibit a prepotent response and execute an alternative response. When successfully executing an alternate response, CBD showed frontal, parietal, and temporal hyperactivation relative to healthy children and ABD, while ABD hypoactivated these regions relative to healthy adults. Previous studies of response flexibility in healthy volunteers revealed frontal, temporal, and parietal cortex hyperactivation in children and hypoactivation in adults. Relative to age-matched healthy subjects, we found hyperactivation in these regions in CBD and hypoactivation in ABD. This suggests that our findings in patients may represent the extreme extension of the age-related response flexibility activation differences found in healthy subjects. Future studies should use longitudinal fMRI to examine the developmental trajectory of the neural circuitry mediating response flexibility in BD.


The patient centered medical home as curricular model: perceived impact of the "education-centered medical home".
The patient-centered medical home (PCMH) model aims to provide patient-centered care, lower costs, and improve health outcomes. Medical students have not been meaningfully integrated in this model. To test the feasibility of a longitudinal clerkship based on PCMH principles and anchored by PCMH educational objectives. Two community-based family medicine clinics, one academic internal medicine clinic, and one pediatric clinic affiliated with an urban medical school. 56 medical student volunteers. We embedded student teams in existing faculty practices and recruited a high-risk patient panel for each team. Clinical education occurred through a traditional clinic preceptor model and was augmented by 3rd and 4th year students directly observing 1st and 2nd year students. Didactic content included monthly Grand Rounds conferences. Students attended 699 clinics, recruited 273 continuity patients, and participated in 9 Grand Rounds conferences. Student confidence with PCMH principles increased and attitudes regarding continuity were highly positive. "Continuity," "early clinical exposure," and "peer teaching" were the most powerful themes expressed by students. Faculty response to the pilot was highly positive. An Education-Centered Medical Home (ECMH) is feasible and is highly rated by students and faculty. Expansion of this model is underway.


Storage stability of ketones on carbon adsorbents.
Activated coconut carbon constitutes the more widely used sorbent for preconcentration of volatile organic compounds in sampling workplace air. Water vapour is always present in the air and its adsorption on the activated carbon surface is a serious drawback, mainly when sampling polar organic compounds, such as ketones. In this case, the recovery of the compounds diminishes; moreover, ketones can be decomposed during storage. Synthetic carbons contain less inorganic impurities and have a lower capacity for water adsorption than coconut charcoal. The aim of this work was to evaluate the storage stability of various ketones (acetone, 2-butanone, 4-methyl-2-pentanone and cyclohexanone) on different activated carbons and to study the effect of adsorbed water vapour under different storage conditions. The effect of storage temperature on extraction efficiencies was significant for each ketone in all the studied sorbents. Recovery was higher when samples were stored at 4 degrees C. The results obtained for storage stability of the studied ketones showed that the performance of synthetic carbons was better than for the coconut charcoals. The water adsorption and the ash content of the carbons can be a measure of the reactive sites that may chemisorb ketones or catalize their decomposition. Anasorb 747 showed good ketone stability at least for 7 days, except for cyclohexanone. After 30-days storage, the stability of the studied ketones was excellent on Carboxen 564. This sorbent had a nearly negligible ash content and the adsorbed water was much lower than for the other sorbents tested.


Ratio of von Willebrand factor antigen to ADAMTS13 activity is a useful biomarker for acute-on-chronic liver failure development and prognosis in patients with liver cirrhosis.
Acute-on-chronic liver failure (ACLF) is associated with a high risk of short-term mortality after progression to multiple organ failure. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). An imbalance between ADAMTS13 enzyme and VWF substrate is associated with liver cirrhosis progression that induces ACLF. This study examined the relationship between ADAMTS13 and VWF and ACLF development to determine whether ADAMTS13 and VWF are useful predictive biomarkers for ACLF development and prognosis of patients with liver cirrhosis. The study enrolled 67 patients with Child-Pugh class A and B liver cirrhosis. ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. The ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) was used to divide patients into two groups according to the classification and regression tree based on Gray model survival analysis. Compared with patients with Child-Pugh class A liver cirrhosis, class B patients had a higher VWF:Ag/ADAMTS13:AC and a higher risk of ACLF development. Cumulative incidence of ACLF was significantly higher in patients with high (>7.9) versus low (≤7.9) VWF:Ag/ADAMTS13:AC (hazard ratio [HR], 6.50; 95% CI, 2.31-18.29; p < 0.001). Cumulative survival was significantly lower in cirrhotic patients with high versus low VWF:Ag/ADAMTS13:AC (HR 5.11; 95% CI, 1.85-14.14; p = 0.002). For patients with liver cirrhosis, VWF:Ag/ADAMTS13:AC is associated with functional liver reserve and predicts the development of ACLF and the prognosis.