Correction to: Prenatal attachment: Using measurement invariance to test the validity of comparisons across eight culturally diverse countries

Archives of Women's Mental Health - A Correction to this paper has been published: https://doi.org/10.1007/s00737-021-01122-7     

Dysregulated TGF‐β signaling alters bone microstructure in a mouse model of Loeys‐Dietz syndrome

Loeys‐Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor‐β (TGF‐β) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF‐β type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein‐labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three‐point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF‐β1–induced Smad2 and Erk1/2 phosphorylation and upregulated TGF‐β1 ligand mRNA expression, compatible with G357W as a loss‐of‐function mutation in the TGF‐β type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross‐activation of TGF‐β–related receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF‐β receptor signaling in bone. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1447–1454, 2015.     

Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: a double blind, placebo controlled pilot study

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) experience excess morbidity and mortality due to coronary artery disease (CAD) that cannot be fully explained by the classical CAD risk factors. Among emerging CAD risk factors, oxidative stress is currently being emphasized. We evaluated the effects of longterm antioxidant vitamins on markers of oxidative stress and antioxidant defense and endothelial function in 39 patients with SLE. METHODS: Patients were randomized to receive either placebo or vitamins (500 mg vitamin C and 800 IU vitamin E daily) for 12 weeks. Markers of oxidative stress included malondialdehyde (MDA) and allantoin. Antioxidants measured included erythrocyte superoxide dismutase and glutathione peroxidase, plasma total antioxidant power (as FRAP value), and ascorbic acid and vitamin E concentrations. Endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery and plasma concentration of von Willebrand factor (vWF) and plasminogen activator inhibitor type 1 (PAI-1). Primary outcome of the study included the change in lipid peroxidation as revealed by MDA levels. Secondary outcomes included changes in allantoin and antioxidant levels and change in endothelial function. RESULTS: After treatment, plasma ascorbic acid and alpha-tocopherol concentrations were significantly (p < 0.05) increased only in the vitamin-treated group, associated with a significant decrease (p < 0.05) in plasma MDA. Other oxidative stress markers and antioxidant levels remained unchanged in both groups. FMD and vWF and PAI-1 levels remained unchanged in both groups. CONCLUSION: Combined administration of vitamins C and E was associated with decreased lipid peroxidation, but did not affect endothelial function in patients with SLE after 3 months of therapy.     

Pregnant Women Living with HIV (WLH) Supported at Clinics by Peer WLH: A Cluster Randomized Controlled Trial

Throughout Africa, Peer Mentors who are women living with HIV (WLH) are supporting pregnant WLH at antenatal and primary healthcare clinics (McColl in BMJ 344:e1590, 2012). We evaluate a program using this intervention strategy at 1.5 months post-birth. In a cluster randomized controlled trial in KwaZulu-Natal, South Africa, eight clinics were randomized for their WLH to receive either: standard care (SC), based on national guidelines to prevent mother-to-child transmission (4 clinics; n = 656 WLH); or an enhanced intervention (EI; 4 clinics; n = 544 WLH). The EI consisted of four antenatal and four postnatal small group sessions led by Peer Mentors, in addition to SC. WLH were recruited during pregnancy and 70 % were reassessed at 1.5 months post-birth. EI’s effect was ascertained on 16 measures of maternal and infant well-being using random effects regressions to control for clinic clustering. A binomial test for correlated outcomes evaluated EI’s overall effectiveness. Among EI WLH reassessed, 87 % attended at least one intervention session (mean 4.1, SD 2.0). Significant overall benefits were found in EI compared to SC using the binomial test. However, it is important to note that EI WLH were significantly less likely to adhere to ARV during pregnancy compared to SC. Secondarily, compared to SC, EI WLH were more likely to ask partners to test for HIV, better protected their infants from HIV transmission, and were less likely to have depressed mood and stunted infants. Adherence to clinic intervention groups was low, yet, there were benefits for maternal and infant health at 1.5 months post-birth.     

Evaluating the Connect with Pharmacy web-based intervention to reduce hospital readmission for older people

International Journal of Clinical Pharmacy - Background The patient transition from a hospital to a&nbsp;post-discharge healthcare setting has potential to disrupt continuity of medication...     

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.Estimates suggest that 1–2% of the population of the United States and United Kingdom take prescribed glucocorticoids (GCs) for the treatment of a broad spectrum of inflammatory and autoimmune diseases (1, 2). Despite the efficacy of GCs, 70% of patients experience an adverse systemic side-effect profile. The resultant Cushingoid features include central obesity, proximal myoatrophy, hypertension, skin thinning, osteoporosis, hepatic steatosis, insulin resistance, and type 2 diabetes (3, 4). Collectively, this contributes to increased risk of cardiovascular morbidity and mortality (5, 6). These features are replicated in patients with much rarer endogenous GC excess (Cushing syndrome), as first described by Harvey Cushing in 1932 (7). Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited.GC availability and action depend not only upon circulating levels but also on tissue-specific intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). Key metabolic tissues including liver, adipose tissue, and skeletal muscle express 11β-HSD type 1 (11β-HSD1), which coverts inactive cortisone to active cortisol [11-dehydrocorticosterone (11DHC) and corticosterone (CORT) in rodents, respectively] (8). In the setting of GC excess, the relative contribution to the metabolic effects induced by GCs of simple delivery of active GCs (cortisol or CORT) to a target tissue, compared with the regeneration of active GCs by 11β-HSD1 within the tissue, has not been determined.Type 2 11β-HSD (11β-HSD2) is predominately expressed in the kidney, colon, and salivary gland and catalyzes the inactivation of cortisol to cortisone (CORT to 11DHC in rodents). This not only protects the mineralocorticoid receptor from occupancy by cortisol but also crucially provides substrate for 11β-HSD1 in peripheral tissues.Transgenic animal models have highlighted the critical role of 11β-HSD1 in the regulation of metabolic phenotype in individual tissues. Mice overexpressing 11β-HSD1, specifically in adipose tissue, develop visceral obesity, insulin resistance, dyslipidemia, and hypertension (9, 10). Similarly, liver-specific 11β-HSD1 overexpression results in insulin resistance and hypertension, but not obesity (11). Importantly, circulating CORT levels were not elevated in either model, suggesting increased intracellular GC availability underpins the observed phenotypes. Indeed, this was confirmed in the adipose-specific 11β-HSD1–overexpressing mice, where twofold higher intraadipose CORT levels were recorded in comparison with WT controls (9). Ultimately, this has led to the development of selective 11β-HSD1 inhibitors as a potential treatment for patients with diabetes, obesity, and hypertension (12, 13).Although it is clear that 11β-HSD1 has a critical role to play in governing GC availability, its potential dynamic role in the setting of GC excess has not been fully explored (14–16). We have previously reported a patient with Cushing disease who was protected from the classic Cushing phenotype, owing to a functional defect in 11β-HSD1 activity, as evidenced by serum and urinary biomarkers (17). Based on this observation, we have hypothesized that tissue intrinsic 11β-HSD1 activity is the major determinant of the manifestations of GC excess and that 11β-HSD1 deletion will ameliorate the associated metabolic abnormalities. To determine the relative tissue-specific contribution to this effect, we have generated tissue-specific 11β-HSD1 deletions in liver and adipose tissue.