Neurodevelopmental outcomes in individuals with fetal alcohol spectrum disorder (FASD) with and without exposure to neglect : clinical cohort data from a national FASD diagnostic clinic

Disentangling the relative developmental impact of prenatal alcohol exposure from postnatal neglect is clinically valuable for informing future service provision. In this study developmental outcomes across groups are compared in a ‘natural experiment’. Methods: Clinical data from 99 persons with fetal alcohol spectrum disorder (FASD) diagnoses were audited. Developmental outcomes (diagnosis of attention deficit hyperactivity disorder, ADHD; social and communication disorder, SCD; or autism spectrum disorder, ASD; Short Sensory Profile, SSP; Vineland II Adaptive Behaviour Scales) were compared across two exposure groups: prenatal alcohol only; and mixed prenatal alcohol and neglect. Results: ADHD (74%) and ASD/SCD (68%) were common, with no significant difference between groups (ADHD, P=0.924; ASD, P=0.742). Vineland age equivalence scores were lower than chronological age (11.1y—prenatal alcohol only—and 12.7y—neglect) across all domains, especially receptive language (3.7y for both groups). Age equivalence did not differ between groups, with the exception of domestic daily living (neglect: 7.7y vs prenatal alcohol only: 5.8y, P=0.027). A probable/definite difference on SSP was more common in the prenatal alcohol only (96% vs 67%, P=0.006). For the individual subscales of SSP, there were no significant differences by neglect category. Discussion: Postnatal neglect in this group did not make the developmental outcome any worse, suggesting that prenatal alcohol influences these outcomes independently. Professionals who support families looking after a child with both FASD and a history of neglect should be aware that the behavioural difficulties are likely to be related to prenatal alcohol exposure and not necessarily reflective of parenting quality

Experience of sexual self-esteem among men living with HIV

Much of the focus on sexual health for people living with HIV has been on promoting safe sex behaviours. However, also important for sexual health is a positive sexual self-esteem. This article reports on an interpretative phenomenological analysis of interviews with seven men about the impact that having HIV has had on their sense of sexual self. Five overarching themes were identified: the ‘destruction’ of a sexual self; feeling sexually hazardous; sexual inhibition; reclaiming a sexual self and finding a place through sero-sorting. With HIV now being a chronic illness, interventions are required to support people to lead sexually satisfying lives

Two-neutron knockout from neutron-deficient 34^{34}Ar, 30^{30}S, and 26^{26}Si

Two-neutron knockout reactions from nuclei in the proximity of the proton dripline have been studied using intermediate-energy beams of neutron-deficient $^{34}$Ar, $^{30}$S, and $^{26}$Si. The inclusive cross sections, and also the partial cross sections for the population of individual bound final states of the $^{32}$Ar, $^{28}$S and $^{24}$Si knockout residues, have been determined using the combination of particle and $\gamma$-ray spectroscopy. Similar to the two-proton knockout mechanism on the neutron-rich side of the nuclear chart, these two-neutron removal reactions from already neutron-deficient nuclei are also shown to be consistent with a direct reaction mechanism.Comment: Phys. Rev. C, rapid communication, in pres

Preconditioning of mesenchymal stromal cells with low-intensity ultrasound: influence on chondrogenesis and directed SOX9 signaling pathways

Background: Continuous low-intensity ultrasound (cLIUS) facilitates the chondrogenic differentiation of human mesenchymal stromal cells (MSCs) in the absence of exogenously added transforming growth factor-beta (TGFβ) by upregulating the expression of transcription factor SOX9, a master regulator of chondrogenesis. The present study evaluated the molecular events associated with the signaling pathways impacting SOX9 gene and protein expression under cLIUS. Methods: Human bone marrow-derived MSCs were exposed to cLIUS stimulation at 14 kPa (5 MHz, 2.5 Vpp) for 5 min. The gene and protein expression of SOX9 was evaluated. The specificity of SOX9 upregulation under cLIUS was determined by treating the MSCs with small molecule inhibitors of select signaling molecules, followed by cLIUS treatment. Signaling events regulating SOX9 expression under cLIUS were analyzed by gene expression, immunofluorescence staining, and western blotting. Results: cLIUS upregulated the gene expression of SOX9 and enhanced the nuclear localization of SOX9 protein when compared to non-cLIUS-stimulated control. cLIUS was noted to enhance the phosphorylation of the signaling molecule ERK1/2. Inhibition of MEK/ERK1/2 by PD98059 resulted in the effective abrogation of cLIUS-induced SOX9 expression, indicating that cLIUS-induced SOX9 upregulation was dependent on the phosphorylation of ERK1/2. Inhibition of integrin and TRPV4, the upstream cell-surface effectors of ERK1/2, did not inhibit the phosphorylation of ERK1/2 and therefore did not abrogate cLIUS-induced SOX9 expression, thereby suggesting the involvement of other mechanoreceptors. Consequently, the effect of cLIUS on the actin cytoskeleton, a mechanosensitive receptor regulating SOX9, was evaluated. Diffused and disrupted actin fibers observed in MSCs under cLIUS closely resembled actin disruption by treatment with cytoskeletal drug Y27632, which is known to increase the gene expression of SOX9. The upregulation of SOX9 under cLIUS was, therefore, related to cLIUS-induced actin reorganization. SOX9 upregulation induced by actin reorganization was also found to be dependent on the phosphorylation of ERK1/2. Conclusions: Collectively, preconditioning of MSCs by cLIUS resulted in the nuclear localization of SOX9, phosphorylation of ERK1/2 and disruption of actin filaments, and the expression of SOX9 was dependent on the phosphorylation of ERK1/2 under cLIUS

High-levelexpression of functional recombinant human coagulation factor VII in insect cells

Abstract: Recombinant coagulation factor VII (FVII) is used as a potential therapeutic intervention in hemophilia patients who produce antibodies against the coagulation factors. Mammalian cell lines provide low levels of expression, however, the Spodoptera frugiperda Sf9 cell line and baculovirus expression system are powerful systems for high-level expression of recombinant proteins, but due to the lack of endogenous vitamin K-dependent carboxylase, expression of functional FVII using this system is impossible. In the present study, we report a simple but versatile method to overcome the defect for high-level expression of the functional recombinant coagulation FVII in Sf9 cells. This method involves simultaneous expression of both human γ-carboxylase (hGC) and human FVII genes in the host. It may be possible to express other vitamin K-dependent coagulation factors using this method in the future. Keywords: Baculovirus; γ-carboxylase; Coagulation FVII; Factor VII; Insect cel

Undergraduate medical textbooks do not provide adequate information on intravenous fluid therapy: a systematic survey and suggestions for improvement

<b>Background</b><p></p> Inappropriate prescribing of intravenous (IV) fluid, particularly 0.9% sodium chloride, causes post-operative complications. Fluid prescription is often left to junior medical staff and is frequently poorly managed. One reason for poor intravenous fluid prescribing practices could be inadequate coverage of this topic in the textbooks that are used.<p></p> <b>Methods</b><p></p> We formulated a comprehensive set of topics, related to important common clinical situations involving IV fluid therapy, (routine fluid replacement, fluid loss, fluids overload) to assess the adequacy of textbooks in common use. We assessed 29 medical textbooks widely available to students in the UK, scoring the presence of information provided by each book on each of the topics. The scores indicated how fully the topics were considered: not at all, partly, and adequately. No attempt was made to judge the quality of the information, because there is no consensus on these topics.<p></p> <b>Results</b><p></p> The maximum score that a book could achieve was 52. Three of the topics we chose were not considered by any of the books. Discounting these topics as “too esoteric”, the maximum possible score became 46. One textbook gained a score of 45, but the general score was poor (median 11, quartiles 4, 21). In particular, coverage of routine postoperative management was inadequate.<p></p> <b>Conclusions</b><p></p> Textbooks for undergraduates cover the topic of intravenous therapy badly, which may partly explain the poor knowledge and performance of junior doctors in this important field. Systematic revision of current textbooks might improve knowledge and practice by junior doctors. Careful definition of the remit and content of textbooks should be applied more widely to ensure quality and “fitness for purpose”, and avoid omission of vital knowledge

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis

Change from baseline in swollen (a) and tender (b) joint counts. *Error bars show upper SE for placebo and lower SE for namilumab. SE standard error, SJC swollen joint count, TJC tender joint count. (PDF 1292 kb