A pilot randomized controlled trial of time-intensive Cognitive Behaviour Therapy for postpartum OCD:effects on maternal symptoms, mother-infant interactions and attachment

There is increasing recognition that perinatal anxiety disorders are both common and potentially serious for mother and child. Obsessive–compulsive disorder (OCD) can be triggered or exacerbated in the postpartum period, with mothers reporting significant effects on parenting tasks. However, there is little evidence concerning their effective treatment or the impact of successful treatment on parenting. A total of 34 mothers with OCD and a baby of 6 months old were randomized into either time-intensive cognitive–behaviour therapy (iCBT) or treatment as usual (TAU). iCBT took place after randomization at 6 months postpartum and was completed by 9 months. Maternal symptomatology, sensitivity in mother–infant interactions and parenting were assessed at baseline and reassessed at 12 months postpartum. At 12 months attachment was also assessed using Ainsworth's Strange Situation Procedure. A healthy control group of mothers and infants (n = 37) underwent the same assessments as a benchmark. iCBT was successful in ameliorating maternal symptoms of OCD (controlled effect size = 1.31–1.90). However, mother–infant interactions were unchanged by treatment and remained less sensitive in both OCD groups than a healthy control group. The distribution of attachment categories was similar across both clinical groups and healthy controls with approximately 72% classified as secure in each group. iCBT is an effective intervention for postpartum OCD. Sensitive parenting interactions are affected by the presence of postpartum OCD and this is not improved by successful treatment of OCD symptoms. However, the overall attachment bond appears to be unaffected. Longitudinal studies are needed to explore the impact of postpartum OCD as the child develops.<br/

Female Mucopolysaccharidosis IIIA Mice Exhibit Hyperactivity and a Reduced Sense of Danger in the Open Field Test

Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders

A pilot randomized controlled trial of time-intensive Cognitive Behaviour Therapy for postpartum OCD:effects on maternal symptoms, mother-infant interactions and attachment

BackgroundThere is increasing recognition that perinatal anxiety disorders are both common and potentially serious for mother and child. Obsessive–compulsive disorder (OCD) can be triggered or exacerbated in the postpartum period, with mothers reporting significant effects on parenting tasks. However, there is little evidence concerning their effective treatment or the impact of successful treatment on parenting.MethodA total of 34 mothers with OCD and a baby of 6 months old were randomized into either time-intensive cognitive–behaviour therapy (iCBT) or treatment as usual (TAU). iCBT took place after randomization at 6 months postpartum and was completed by 9 months. Maternal symptomatology, sensitivity in mother–infant interactions and parenting were assessed at baseline and reassessed at 12 months postpartum. At 12 months attachment was also assessed using Ainsworth's Strange Situation Procedure. A healthy control group of mothers and infants (n = 37) underwent the same assessments as a benchmark.ResultsiCBT was successful in ameliorating maternal symptoms of OCD (controlled effect size = 1.31–1.90). However, mother–infant interactions were unchanged by treatment and remained less sensitive in both OCD groups than a healthy control group. The distribution of attachment categories was similar across both clinical groups and healthy controls with approximately 72% classified as secure in each group.ConclusionsiCBT is an effective intervention for postpartum OCD. Sensitive parenting interactions are affected by the presence of postpartum OCD and this is not improved by successful treatment of OCD symptoms. However, the overall attachment bond appears to be unaffected. Longitudinal studies are needed to explore the impact of postpartum OCD as the child develops.</jats:sec

The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction:absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADME studies

The conceptual technology of small molecule glycomimetics, exemplified by compounds C1–4, has shown promising protective effects against lipid-induced endothelial dysfunction, restorative effects on diabetic endothelial colony forming cells, and preventative effects on downstream vascular calcification amongst other important in vitro and ex vivo studies. We report the optimised synthesis of an array of 17 small molecule glycomimetics, including the regio-, enantio- and diastereo-meric sulfated scaffolds of a hit structure along with novel desulfated examples. For the first time, the absolute stereochemical configurations of C1–4 have been clarified based on an identified and consistent anomaly with the Sharpless asymmetric dihydroxylation reaction. We have investigated the role and importance of sulfation pattern, location, regioisomers, and spatial orientation of distal sulfate groups on the modulation of endothelial dysfunction through their interaction with hepatocyte growth factor (HGF). In silico studies demonstrated the key interactions the persulfated glycomimetics make with HGF and revealed the importance of both sulfate density and positioning (both point chirality and vector) to biological activity. In vitro biological data of the most efficient binding motifs, along with desulfated comparators, support the modulatory effects of sulfated small molecule glycomimetics in the downstream signaling cascade of endothelial dysfunction. In vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) data demonstrate the glycomimetic approach to be a promising approach for hit-to-lead studies

The Interplay of SIRT1 and Wnt Signaling in Vascular Calcification

Vascular calcification is a major health risk and is highly correlated with atherosclerosis, diabetes, and chronic kidney disease. The development of vascular calcification is an active and complex process linked with a multitude of signaling pathways, which regulate promoters and inhibitors of osteogenesis, the balance of which become deregulated in disease conditions. SIRT1, a protein deacetylase, known to be protective in inhibiting oxidative stress and inflammation within the vessel wall, has been shown as a possible key player in modulating the cell-fate determining canonical Wnt signaling pathways. Suppression of SIRT1 has been reported in patients suffering with cardiovascular pathologies, suggesting that the sustained acetylation of osteogenic factors could contribute to their activation and in turn, lead to the progression of calcification. There is clear evidence of the synergy between β-Catenin and elevated Runx2, and with Wnt signaling being β-Catenin dependent, further understanding is needed as to how these molecular pathways converge and interact, in order to provide novel insight into the mechanism by which smooth muscle cells switch to an osteogenic differentiation programme. Therefore, this review will describe the current concepts of pathological soft tissue mineralization, with a focus on the contribution of SIRT1 as a regulator of Wnt signaling and its targets, discussing SIRT1 as a potential target for manipulation and therapy

Endothelial Progenitor Cells: New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk

Over the past decade, we have witnessed an exponential growth of interest into the role of endothelial progenitor cells (EPCs) in cardiovascular disease. While the major thinking revolves around EPC angiogenic repair properties, we have used a hypothesis-driven approach to discover disease-related defects in their characteristics and based on these findings, have identified opportunities for functional enhancement, which offer an exciting avenue for translation into clinical intervention. In this review, we focus on two groups; circulating myeloid angiogenic cells (MACs) and late outgrowth endothelial colony forming cells (ECFCs), and will discuss the unique properties and defects of each population, as new insights have been gained into the potential function of each sub-type using current techniques and multiomic technology. We will discuss their role in inflammatory disorders and alterations in mitochondrial function. In addition, we share key insights into the glycocalyx, and propose this network of membrane-bound proteoglycans and glycoproteins, covering the endothelium warrants further investigation in order to clarify its significance in ECFC regulation of vascularization and angiogenesis and ultimately for potential translational therapeutic aspects

Loss of SIRT1 in diabetes accelerates DNA damage induced vascular calcification.

Aims: Vascular calcification is a recognised predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs). Methods and Results: Immunohistochemistry revealed decreased SIRT1 and increased DNA damage marker expression in diabetic calcified arteries compared to non-diabetic and non-calcified controls, strengthened by findings that vSMCs isolated from diabetic patients show elevated DNA damage and senescence, assessed by the Comet assay and telomere length. Hyperglycaemic conditions were used and induced DNA damage and enhanced senescence in vSMCs in vitro. Using H2O2 as a model of oxidative stress-induced DNA damage, pharmacological activation of SIRT1 reduced H2O2 DNA damage induced calcification, prevented not only DNA damage, as shown by reduced comet tail length, but also decreased yH2AX foci formation, and attenuated calcification. While ATM expression was reduced following DNA damage, in contrast, SIRT1 activation significantly increased ATM expression, phosphorylating both MRE11 and NBS1, thus allowing formation of the MRN complex and increasing activation of the DNA repair pathway. Conclusions: DNA damage induced calcification is accelerated within a diabetic environment and can be attenuated in vitro by SIRT1 activation. This occurs through enhancement of the MRN repair complex within vSMCs and has therapeutic potential within the diabetic patient. Translational perspective: Our study provides the first evidence that DNA damage is enhanced in the vasculature of the diabetic patient and that this process, in tandem with loss of SIRT1, exacerbates pathological smooth muscle cell calcification. We propose that current SIRT1 activators and their analogues may be useful as investigational tools, and further elucidation of downstream mechanisms of SIRT1 will aid the development of novel and more precise drug regimens

Novel Glycomimetics Protect Against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro by Attenuation of the RAGE/ERK/CREB Pathway

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against β-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI). We used an established osteogenic in vitro vascular smooth muscle cell (VSMC) model. Osteoprotegerin (OPG), sclerostin and glycation levels were all significantly increased in CLI serum compared to healthy controls, while the vascular calcification marker osteocalcin (OCN) was down-regulated in CLI patients vs. controls. Incubation with both CLI serum and g-LDL (10 µg/mL) significantly increased VSMC calcification vs. controls after 21 days, with CLI serum-induced calcification apparent after only 10 days. Glycomimetics (C2 and C3) significantly inhibited g-LDL and CLI serum-induced mineralisation, as shown by a reduction in alizarin red (AR) staining and alkaline phosphatase (ALP) activity. Furthermore, secretion of the osteogenic marker OCN was significantly reduced in VSMCs incubated with CLI serum in the presence of glycomimetics. Phosphorylation of cyclic AMP response element-binding protein (CREB) was significantly increased in g-LDL-treated cells vs. untreated controls, which was attenuated with glycomimetics. Blocking CREB activation with a pharmacological inhibitor 666-15 replicated the protective effects of glycomimetics, evidenced by elevated AR staining. In silico molecular docking simulations revealed the binding affinity of the glycomimetics C2 and C3 with the V domain of RAGE. In conclusion, these findings demonstrate that novel glycomimetics, C2 and C3 have potent anti-calcification properties in vitro, inhibiting both g-LDL and CLI serum-induced VSMC mineralisation via the inhibition of LDLR, RAGE, CREB and subsequent expression of the downstream osteogenic markers, ALP and OCN

Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression

ETS domain-containing protein-1 (ELK1) is a transcription factor important in regulating αvβ6 integrin expression. αvβ6 integrins activate the profibrotic cytokine Transforming Growth Factor β1 (TGFβ1) and are increased in the alveolar epithelium in idiopathic pulmonary fibrosis (IPF). IPF is a disease associated with aging and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where αvβ6 mediated TGFβ activation has been implicated. Here we identify that Elk1-knockout (Elk1−/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs of Elk1−/0 aged mice demonstrated increased collagen deposition, in particular collagen 3α1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression, Elk1−/0 animals developed hepatosteatosis and fibrosis. The loss of Elk1 also had differential effects on Itgb1, Itgb5 and Itgb6 expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1 in human disease we exposed human lung epithelial cells and murine lung slices to cigarette smoke extract, which lead to reduced ELK1 expression andmay explain the loss of ELK1 in human disease. These data support a fundamental role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke