Korean red ginseng extract prevents bone loss in an oral model of glucocorticoid induced osteoporosis in mice.

The gut microbiota and barrier function play important roles in bone health. We previously demonstrated that chronic glucocorticoid (GC)-induced bone loss in mice is associated with significant shifts in gut microbiota composition and impaired gut barrier function. Korean Red Ginseng (KRG, Panax Ginseng Meyer, Araliaceae) extract has been shown to prevent glucocorticoid-induced osteoporosis (GIO) in a subcutaneous pellet model in mice, but its effect on gut microbiota and barrier function in this context is not known. The overall goal of this study was to test the effect of KRG extract in a clinically relevant, oral model of GIO and further investigate its role in modulating the gut-bone axis. Growing male mice (CD-1, 8 weeks) were treated with 75 µg/mL corticosterone (∼9 mg/kg/day) or 0.4% ethanol vehicle in the drinking water for 4 weeks. During this 4-week period, mice were treated daily with 500 mg/kg/day KRG extract dissolved in sterile water or an equal amount of sterile water via oral gastric gavage. After 4 weeks of treatment, we assessed bone volume, microbiota composition, gut barrier integrity, and immune cells in the bone marrow (BM) and mesenteric lymph nodes (MLNs). 4 weeks of oral GC treatment caused significant distal femur trabecular bone loss, and this was associated with changes in gut microbiota composition, impaired gut barrier function and altered immune cell composition. Importantly, KRG extract prevented distal femur trabecular bone loss and caused significant alterations in gut microbiota composition but had only modest effects on gut barrier function and immune cell populations. Taken together, these results demonstrate that KRG extract significantly modulates the gut microbiota-bone axis and prevents glucocorticoid-induced bone loss in mice.

A novel research competency framework for clinical research nurses and midwives.

BACKGROUND: Clinical research nurses and midwives (CRN/Ms) are highly specialised registered nurses. They combine their clinical nursing expertise with research knowledge and skills to aid in the delivery of rigorous, high-quality clinical research to improve health outcomes, the research participant's experience and treatment pathways ( Beer et al 2022 ). However, there is evidence that the transition into a CRN/M role is challenging for registered nurses. AIM: To discuss the development of a competency framework for CRN/Ms. DISCUSSION: The authors identified a gap in their organisation for standards that would support the development of CRN/Ms new to the role. The standards needed to be clear and accessible to use while encompassing the breadth of scope of CRN/Ms' practice. The authors used a systematic and inclusive process drawing on Benner's ( 1984 ) theory of competence development to develop a suitable framework. Stakeholders engaged in its development included research participants, inclusion agents and CRN/Ms. CONCLUSION: The project identified 15 elements that are core to the CRN/M role and the knowledge, skills and behaviours associated with it. IMPLICATIONS FOR PRACTICE: A large NHS trust has implemented the framework. It is also being shown to national and regional networks. Evaluation is under way.

Lactobacillus Reuteri 6475 Prevents Bone Loss in a Clinically Relevant Oral Model of Glucocorticoid-Induced Osteoporosis in Male CD-1 Mice.

Glucocorticoids (GCs) are commonly used anti-inflammatory medications with significant side effects, including glucocorticoid-induced osteoporosis (GIO). We have previously demonstrated that chronic subcutaneous GC treatment in mice leads to gut barrier dysfunction and trabecular bone loss. We further showed that treating with probiotics or barrier enhancers improves gut barrier function and prevents GIO. The overall goal of this study was to test if probiotics could prevent GC-induced gut barrier dysfunction and bone loss in a clinically relevant oral-GC model of GIO. Eight-week-old male CD-1 mice were treated with vehicle or corticosterone in the drinking water for 4 weeks and administered probiotics Lactobacillus reuteri ATCC 6475 (LR 6475) or VSL#3 thrice weekly via oral gavage. As expected, GC treatment led to significant gut barrier dysfunction (assessed by measuring serum endotoxin levels) and bone loss after 4 weeks. Serum endotoxin levels significantly and negatively correlated with bone volume. Importantly, LR 6475 treatment effectively prevented both GC-induced increase in serum endotoxin and trabecular bone loss. VSL#3 had intermediate results, not differing from either control or GC-treated animals. GC-induced reductions in femur length, cortical thickness, and cortical area were not affected by probiotic treatment. Taken together, these results are the first to demonstrate that LR 6475 effectively prevents the detrimental effects of GC treatment on gut barrier, which correlates with enhanced trabecular bone health in an oral mouse model of GIO. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Korean Red Ginseng extract treatment prevents post-antibiotic dysbiosis-induced bone loss in mice.

Background: The intestinal microbiota is an important regulator of bone health. In previous studies we have shown that intestinal microbiota dysbiosis, induced by treatment with broad spectrum antibiotics (ABX) followed by natural repopulation, results in gut barrier dysfunction and bone loss. We have also shown that treatment with probiotics or a gut barrier enhancer can inhibit dysbiosis-induced bone loss. The overall goal of this project was to test the effect of Korean Red Ginseng (KRG) extract on bone and gut health using antibiotics (ABX) dysbiosis-induced bone loss model in mice. Methods: Adult male mice (Balb/C, 12-week old) were administered broad spectrum antibiotics (ampicillin and neomycin) for 2 weeks followed by 4 weeks of natural repopulation. During this 4-week period, mice were treated with vehicle (water) or KRG extract. Other controls included mice that did not receive either antibiotics or KRG extract and mice that received only KRG extract. At the end of the experiments, we assessed various parameters to assess bone, microbiota and in vivo intestinal permeability. Results: Consistent with our previous results, post-ABX- dysbiosis led to significant bone loss. Importantly, this was associated with a decrease in gut microbiota alpha diversity and an increase in intestinal permeability. All these effects including bone loss were prevented by KRG extract treatment. Furthermore, our studies identified multiple genera including Lactobacillus and rc4-4 as well as Alistipes finegoldii to be potentially linked to the effect of KRG extract on gut-bone axis. Conclusion: Together, our results demonstrate that KRG extract regulates the gut-bone axis and is effective at preventing dysbiosis-induced bone loss in mice.

Links between excessive daytime sleepiness and EEG power and activation in two subtypes of ADHD.

OBJECTIVES: This study aimed to replicate previously reported EEG characteristics between typically developing (TD) children and two subtypes of Attention Deficit Hyperactivity Disorder (ADHD) using a frontal, single-channel, dry-sensor portable EEG device, and explore whether differences are moderated by excessive daytime sleepiness (EDS). METHODS: Children with ADHD Inattentive (ADHD-I) and ADHD Combined presentation (ADHD-C) and typically-developing (TD) children (N = 34 in each group) had frontal EEG recorded during eyes-closed resting, eyes-open resting, and focus tasks. Participants also completed the Children's Self-Report Sleep Patterns - Sleepiness Scale as a measure of EDS. RESULTS: Consistent with previous literature, there were increases in frontal delta and theta power in the ADHD-C compared to ADHD-I and TD groups, in all conditions. Novel power and activation effects in ADHD subtypes, as well as significant group and EDS interactions for alpha and beta power were also found. CONCLUSIONS: These findings highlight the importance of considering ADHD subtypes and EDS when exploring EEG characteristics, and have important implications for the diagnosis and treatment of children with ADHD.

Use of Thyroid Hormones in Hypothyroid and Euthyroid Patients: A THESIS questionnaire survey of members of the Irish Endocrine Society.

BACKGROUND: Replacement of thyroid hormones (TH) with Levothyroxine (LT4) is the treatment of choice for hypothyroidism, however, there are aspects of treatment where uncertainties exist and practice varies. Factors influencing initiation and choice of TH replacement may impact patient satisfaction, safety, and health care costs. METHODS: The aim of the study was to examine the attitudes of Irish endocrinologists regarding the treatment of hypothyroid and euthyroid patients with TH. Members of the Irish Endocrine Society (IES) were invited to participate in an online survey. RESULTS: Forty-eight invitations were sent, and 39 (81.3%) participants responded. All respondents favoured LT4 tablet therapy for treatment of hypothyroidism, but 20.5% prescribed combination therapy (LT4 and liothyronine), and 13% regularly used desiccated thyroid extract. A significant proportion (51%) might prescribe TH in euthyroid patients; 41% for thyroid auto-antibody positive women seeking pregnancy, 18% for goitre and 5% for unexplained fatigue. Many (38%) consider combination therapy in patients with persistent symptoms. Respondents reported seeing LT4 treated patients with persistent symptomatology more frequently and perceive psychosocial factors and comorbidities to be the most common reasons for such symptoms. CONCLUSION: LT4 tablets are the treatment of choice for hypothyroidism in Ireland. Approximately a third of Irish endocrinologists either regularly use, or would consider, liothyronine for hypothyroid patients. A significant proportion would give TH to euthyroid individuals in specific circumstances. The prescription of TH amongst Irish endocrinologists was generally in keeping with recommended practice, and areas where practice deviated from guidance were typically where evidence was conflicting or insufficient.

Glucocorticoid-induced osteoporosis is prevented by dietary prune in female mice.

Glucocorticoid-induced osteoporosis (GIO) is a significant side effect of prolonged glucocorticoid (GC) treatment. Chronic GC treatment also leads to trabecular bone loss and gut microbiota dysbiosis in mice. The gut dysbiosis is mechanistically linked to GIO, which indicates that the microbiota can be targeted to prevent GIO. Prunes, a dried fruit and prebiotic, have emerged in the literature as an effective treatment for sex-steroid deficiency induced osteoporosis (primary osteoporosis). Prunes also significantly alter the composition of the gut microbiota in both rodent models and human studies. Therefore, we tested if dietary prune (DP) supplementation could prevent GC-induced bone loss and affect microbiota composition in an established model of GIO. Sixteen-week-old, skeletally mature, female C57BL/6J mice were treated with a subcutaneous 5 mg placebo or prednisolone pellet for 8 weeks and fed an AIN-93M control diet or a diet modified to include 5, 15, or 25% (w/w) dried California prune powder. As expected, GC treated mice developed significant trabecular bone loss in the distal femur. More importantly, as little as 5% DP supplementation effectively prevented trabecular bone loss. Further, dose dependent increases in trabecular bone volume fraction were observed in GC + 15% and GC + 25% DP mice. Amazingly, in the placebo (non-GC treated) groups, 25% DP supplementation caused a ∼3-fold increase in distal femur trabecular bone volume fraction; this sizable bone response has not been previously observed in healthy mice with gut targeted natural treatments. Along with the striking effect on bone health, GC treatment and 25% DP supplementation led to drastic shifts in gut microbiota composition and several specific changes are strongly associated with bone health. Taken together, these results are the first to demonstrate that DP supplementation effectively prevents the negative effects of prolonged GC therapy on trabecular bone health and strongly associates with shifts in the composition of the gut microbiota.

Exploring Resilience in UK-Based Domiciliary Care Workers before and during the COVID-19 Pandemic.

Domiciliary carers (DCs) provide an invaluable service that enables people living with dementia (PLWD) to remain living in their own homes for as long as possible. We know a lot about the negative impacts of providing domiciliary care and recent evidence suggests that this was exacerbated by the COVID-19 pandemic. However, we know much less about how these DCs manage the stressors associated with their roles. The current study adopts a resilience perspective to identify the resources that DCs caring for PLWD draw on to manage the stress associated with their roles before and during the COVID-19 pandemic. We conducted semi-structured interviews with 19 DCs from across the UK. Data were analysed using a directed qualitative content analysis. Themes included: healthy boundaries; motivation to care; psychological attributes; managing work; and support. The findings have implications for employers and may go some way towards improving DC working conditions, retaining staff, and attracting new DCs in the future.

Comparative effects of human-equivalent low, moderate, and high dose oral prednisone intake on autoimmunity and glucocorticoid-related toxicity in a murine model of environmental-triggered lupus.

Autoimmune diseases can be triggered by environmental toxicants such as crystalline silica dust (cSiO2). Here, we characterized the dose-dependent immunomodulation and toxicity of the glucocorticoid (GC) prednisone in a preclinical model that emulates onset and progression of cSiO2-triggered lupus. Two cohorts of 6-wk-old female NZBWF1 mice were fed either control AIN-93G diet or one of three AIN-93G diets containing prednisone at 5, 15, or 50 mg/kg diet which span human equivalent oral doses (HED) currently considered to be low (PL; 5 mg/d HED), moderate (PM; 14 mg/d HED), or high (PH; 46 mg/d HED), respectively. At 8 wk of age, mice were intranasally instilled with either saline vehicle or 1 mg cSiO2 once weekly for 4 wk. The experimental plan was to 1) terminate one cohort of mice (n=8/group) 14 wk after the last cSiO2 instillation for pathology and autoimmunity assessment and 2) to maintain a second cohort (n=9/group) to monitor glomerulonephritis development and survival. Mean blood concentrations of prednisone's principal active metabolite, prednisolone, in mice fed PL, PM, and PH diets were 27, 105, 151 ng/ml, respectively, which are consistent with levels observed in human blood ≤ 12 h after single bolus treatments with equivalent prednisone doses. Results from the first cohort revealed that consumption of PM, but not PL diet, significantly reduced cSiO2-induced pulmonary ectopic lymphoid structure formation, nuclear-specific AAb production, inflammation/autoimmune gene expression in the lung and kidney, splenomegaly, and glomerulonephritis in the kidney. Relative to GC-associated toxicity, PM diet, but not PL diet, elicited muscle wasting, but these diets did not affect bone density or cause glucosuria. Importantly, neither PM nor PL diet improved latency of cSiO2-accelerated death. PH-fed mice in both cohorts displayed robust GC-associated toxicity including body weight loss, reduced muscle mass, and extensive glucosuria 7 wk after the final cSiO2 instillation requiring their early removal from the study. Taken together, our results demonstrate that while moderate doses of prednisone can reduce important pathological endpoints of cSiO2-induced autoimmunity in lupus-prone mice, such as upstream ectopic lymphoid structure formation, these ameliorative effects come with unwanted GC toxicity, and, crucially, none of these three doses extended survival time.

Baat Gene Knockout Alters Post-Natal Development, the Gut Microbiome, and Reveals Unusual Bile Acids in Mice.

Bile acids (BAs) are steroid detergents in bile that contribute to fat absorption, cell signaling, and microbiome interactions. The final step in their synthesis is amino acid conjugation with either glycine or taurine in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of Baat gene knockout. Baat-/- mice were underweight after weaning but quickly exhibited catch-up growth. At three weeks of age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, liver mass, glycogen staining in hepatocytes, and hepatic vitamin A stores, but these were less marked in adulthood. Additionally, KO mice had an altered microbiome in early life. Their BA pool was highly enriched in cholic acid but not completely devoid of conjugated BAs. KO animals had 27-fold lower taurine-conjugated BAs than wild type in their liver but similar concentrations of glycine-conjugated BAs and higher microbially conjugated BAs. Furthermore, the BA pool in Baat-/- was enriched in a variety of unusual BAs that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group mimicking taurine. Antibiotic treatment of KO mice indicated the microbiome was not the likely source of the unusual conjugations, instead, the unique BAs in KO animals were likely derived from the peroxisomal acyltransferases Acnat1 and Acnat2, which are duplications of Baat in the mouse genome that are inactivated in humans. This study demonstrates that BA conjugation is important for early life development of mice.

Longitudinal effects of growth restriction on the murine gut microbiome and metabolome.

Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (postweaning week 1) until PN80 (postweaning week 5) for gut microbiome and metabolome analyses. PUN mice exhibited the most alterations in gut microbiome and gut and liver metabolome compared with CON mice. These mice had altered fecal microbial ß-diversity (P = 0.001) and exhibited higher proportions of Bifidobacteriales [linear mixed model (LMM) P = 7.1 × 10-6), Clostridiales (P = 1.459 × 10-5), Erysipelotrichales (P = 0.0003), and lower Bacteroidales (P = 4.1 × 10-5)]. PUN liver and fecal metabolome had a reduced total bile acid pool (P < 0.01), as well as lower abundance of riboflavin (P = 0.003), amino acids [i.e., methionine (P = 0.0018), phenylalanine (P = 0.0015), and tyrosine (P = 0.0041)], and higher excreted total peptides (LMM P = 0.0064) compared with CON. Overall, protein restriction during lactation permanently alters the gut microbiome into adulthood. Although the liver bile acids, amino acids, and acyl-carnitines recovered, the fecal peptides and microbiome remained permanently altered into adulthood, indicating that inadequate protein intake in a specific time frame in early life can have an irreversible impact on the microbiome and fecal metabolome.NEW & NOTEWORTHY Undernutrition-induced early-life growth restriction not only leads to increased disease risk but also permanently alters the gut microbiome and gut-liver metabolome during specific windows of early-life development.

Maternal and fetal incidental findings on antenatal magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging (MRI) examinations are increasingly used in antenatal clinical practice. Incidental findings are a recognized association with imaging and although in some circumstances their identification can alter management, they are often associated with increased anxiety, for both patient and clinician, as well as increased health care costs. OBJECTIVE: This study aimed to evaluate the incidence of unexpected findings in both the mother and fetus during antenatal MRI examinations. MATERIALS AND METHODS: A retrospective study was undertaken over a five-year period at St.. Thomas' Hospital in London. Maternal incidental findings were recorded from all clinical reports of all fetal MRIs performed (for clinical reasons and in healthy volunteers) during this period. Fetal incidental findings were recorded only in cases where women with uncomplicated pregnancies were participating as healthy volunteers. RESULTS: A total of 2,569 MRIs were included; 17% of women had maternal incidental findings. Of these, 1,099 were women with uncomplicated pregnancies who undertook research MRIs as healthy volunteers; fetal incidental findings were identified in 12.3%. CONCLUSION: Incidental findings are a common occurrence in antenatal MRI. Consideration should be given to counseling women appropriately before imaging and ensuring that robust local protocols are in place for follow-up and further management of such cases.

Development of human white matter pathways in utero over the second and third trimester.

During the second and third trimesters of human gestation, rapid neurodevelopment is underpinned by fundamental processes including neuronal migration, cellular organization, cortical layering, and myelination. In this time, white matter growth and maturation lay the foundation for an efficient network of structural connections. Detailed knowledge about this developmental trajectory in the healthy human fetal brain is limited, in part, due to the inherent challenges of acquiring high-quality MRI data from this population. Here, we use state-of-the-art high-resolution multishell motion-corrected diffusion-weighted MRI (dMRI), collected as part of the developing Human Connectome Project (dHCP), to characterize the in utero maturation of white matter microstructure in 113 fetuses aged 22 to 37 wk gestation. We define five major white matter bundles and characterize their microstructural features using both traditional diffusion tensor and multishell multitissue models. We found unique maturational trends in thalamocortical fibers compared with association tracts and identified different maturational trends within specific sections of the corpus callosum. While linear maturational increases in fractional anisotropy were seen in the splenium of the corpus callosum, complex nonlinear trends were seen in the majority of other white matter tracts, with an initial decrease in fractional anisotropy in early gestation followed by a later increase. The latter is of particular interest as it differs markedly from the trends previously described in ex utero preterm infants, suggesting that this normative fetal data can provide significant insights into the abnormalities in connectivity which underlie the neurodevelopmental impairments associated with preterm birth.

The effect of maternal position on venous return for pregnant women during MRI.

Magnetic resonance imaging (MRI) in pregnancy is commonly undertaken in the left lateral tilt (LLT) position to prevent inferior vena cava (IVC) compression and supine hypotensive events, although this may be suboptimal for image quality. The supine position may also have an adverse effect on fetal well-being. The spinal venous plexus may provide an alternative pathway for venous return in the presence of IVC compression. This study assesses morphology and blood flow of the IVC and spinal venous plexus for pregnant women in LLT and supine positions to ascertain the effect of maternal position on venous return during MRI. Eighty-two pregnant women underwent phase contrast MRI (PC-MRI) of the IVC and spinal venous plexus in the supine position; 25 were also imaged in the LLT position. Differences in life monitoring, IVC, spinal venous plexus and total venous return between the two positions were assessed. A linear regression assessed the relationship between flow in the IVC and the spinal venous plexus in the supine position. Increasing gestational age and the right-sided position of the uterus on IVC and spinal venous plexus venous return were also evaluated. Hypotension symptoms were similar in supine (10%) and LLT (8%) positioning. Supine positioning decreased IVC height (p < 0.004) and flow (p = 0.045) but flow in the spinal venous plexus increased (p < 0.001) compared with the LLT position. Total venous return showed no difference (p = 0.989) between the two positions. Additional measurements of flow in the aorta also showed no significant difference between the two groups (p = 0.866). Reduced IVC flow in the supine position was associated with increasing gestational age (p = 0.004) and degree of right-sided uterine position (p = 0.004). Women in the left lateral decubitus position who then rotated supine had greater flow in the IVC (p = 0.008) and spinal venous plexus (p = 0.029) than those who started supine. For the majority of women, the spinal venous plexus acts as a complementary venous return system for pregnant women in the supine position, maintaining vascular homeostasis. Further study is needed to assess the effects on the health of the fetus.

Placental magnetic resonance imaging in chronic hypertension: A case-control study.

INTRODUCTION: We aimed to explore the use of magnetic resonance imaging (MRI) in vivo as a tool to elucidate the placental phenotype in women with chronic hypertension. METHODS: In case-control study, women with chronic hypertension and those with uncomplicated pregnancies were imaged using either a 3T Achieva or 1.5T Ingenia scanner. T2-weighted images, diffusion weighted and T1/T2* relaxometry data was acquired. Placental T2*, T1 and apparent diffusion coefficient (ADC) maps were calculated. RESULTS: 129 women (43 with chronic hypertension and 86 uncomplicated pregnancies) were imaged at a median of 27.7 weeks' gestation (interquartile range (IQR) 23.9-32.1) and 28.9 (IQR 26.1-32.9) respectively. Visual analysis of T2-weighted imaging demonstrated placentae to be either appropriate for gestation or to have advanced lobulation in women with chronic hypertension, resulting in a greater range of placental mean T2* values for a given gestation, compared to gestation-matched controls. Both skew and kurtosis (derived from histograms of T2* values across the whole placenta) increased with advancing gestational age at imaging in healthy pregnancies; women with chronic hypertension had values overlapping those in the control group range. Upon visual assessment, the mean ADC declined in the third trimester, with a corresponding decline in placental mean T2* values and showed an overlap of values between women with chronic hypertension and the control group. DISCUSSION: A combined placental MR examination including T2 weighted imaging, T2*, T1 mapping and diffusion imaging demonstrates varying placental phenotypes in a cohort of women with chronic hypertension, showing overlap with the control group.

EEG coherence during subjectively-rated psychological state variations.

BACKGROUND: Neurofeedback training aims to develop awareness and control of psychological states in order to self-regulate brain activity and while used widely therapeutically, important questions remain unanswered. Central to these aims is an assumed association between the live EEG-based feedback and the subjective experience of a psychological state. To date, there is little evidence to support this relationship. Previous studies examining the association between an EEG index and subjective experience have explored only the presence or absence of the state, or merely assumed state variations. The current study aims to examine this association by considering how different levels of a psychological state (i.e., attention) are reflected in EEG coherence. METHODS: Our approach aims to allow comparisons of EEG coherence between psychological states (attention vs. rest), and also within subjectively-rated levels of a psychological state (attention) through a purpose-designed questionnaire. Thirty healthy adult participants performed a resting eyes-open (REO) and attention modulation task, while 28 channels of EEG were recorded. Levels within the psychological state were subjectively-attested by participants on a trial-by-trial basis. RESULTS: The main analyses examined the effect of subjectively-rated attention levels (SRALs) on EEG coherence, with results suggesting that high and low SRALs may be represented by: 1) different levels of alpha and theta coherence at anterior and posterior electrodes of the frontal lobe bilaterally, and 2) different levels of alpha coherence between central and parietal lobes, also bilaterally. DISCUSSION: These findings provide partial, preliminary evidence for EEG correlates of SRALs. These findings may have implications for understanding underlying mechanisms of NFT, which is an underdeveloped area.

T2* Placental Magnetic Resonance Imaging in Preterm Preeclampsia: An Observational Cohort Study.

Placental dysfunction underlies the cause of pregnancies complicated by preeclampsia. The use of placental magnetic resonance imaging to provide an insight into the pathophysiology of preeclampsia and thus assess its potential use to inform prognosis and clinical management was explored. In this prospective observational cohort study, 14 women with preterm preeclampsia and 48 gestation-matched controls using 3-Tesla magnetic resonance imaging at median of 31.6 weeks (interquartile range [IQR], 28.6-34.6) and 32.2 weeks (IQR, 28.6-33.8), respectively, were imaged. The acquired data included T2-weighted images and T2* maps of the placenta, the latter an indicative measure of placental oxygenation. Placentae in women with preeclampsia demonstrated advanced lobulation, varied lobule sizes, high granularity, and substantial areas of low-signal intensity on T2-weighted imaging, with reduced entire placental mean T2* values for gestational age (2 sample t test, t=7.49) correlating with a reduction in maternal PlGF (placental growth factor) concentrations (Spearman rank correlation coefficient 0.76) and increased lacunarity values (t=3.26). Median mean T2* reduced from 67 ms (IQR, 54-73) at 26.0 to 29.8 weeks' gestation to 38 ms (IQR, 28-40) at 34.0 to 37.9 weeks' gestation in the control group. In women with preeclampsia, median T2* was 23 ms (IQR, 20-23) at 26.0 to 29.8 weeks' gestation and remained low (22 ms [IQR, 20-26] at 34.0-37.8 weeks' gestation). Histological features of maternal vascular malperfusion were only found in placentae from women with preeclampsia. Placental volume did not differ between the control group and women with preeclampsia. Placental magnetic resonance imaging allows both objective quantification of placental function in vivo and elucidation of the complex mechanisms underlying preeclampsia development.

Post-antibiotic gut dysbiosis-induced trabecular bone loss is dependent on lymphocytes.

Recent studies in mouse models have shown that gut microbiota significantly influences bone health. We demonstrated that 2-week oral treatment with broad spectrum antibiotics followed by 4 weeks of recovery of the gut microbiota results in dysbiosis (microbiota imbalance)-induced bone loss in mice. Because gut microbiota is critical for the development of the immune system and since both microbiota and the immune system can regulate bone health, in this study, we tested the role of the immune system in mediating post-antibiotic dysbiosis-induced bone loss. For this, we treated wild-type (WT) and lymphocyte deficient Rag2 knockout (KO) mice with ampicillin/neomycin cocktail in water for 2 weeks followed by 4 weeks of water without antibiotics. This led to a significant bone loss (31% decrease from control) in WT mice. Interestingly, no bone loss was observed in the KO mice suggesting that lymphocytes are required for dysbiosis-induced bone loss. Bray-Curtis diversity metrics showed similar microbiota changes in both the WT and KO post-antibiotic treated groups. However, several operational taxonomic units (OTUs) classified as Lactobacillales were significantly higher in the repopulated KO when compared to the WT mice, suggesting that these bacteria might play a protective role in preventing bone loss in the KO mice after antibiotic treatment. The effect of dysbiosis on bone was therefore examined in the WT mice in the presence or absence of oral Lactobacillus reuteri treatment for 4 weeks (post-ABX treatment). As hypothesized, mice treated with L. reuteri did not display bone loss, suggesting a bone protective role for this group of bacteria. Taken together, our studies elucidate an important role for lymphocytes in regulating post-antibiotic dysbiosis-induced bone loss.

Loss of interleukin-10 exacerbates early Type-1 diabetes-induced bone loss.

Type-1 diabetes (T1D) increases systemic inflammation, bone loss, and risk for bone fractures. Levels of the anti-inflammatory cytokine interleukin-10 (IL-10) are decreased in T1D, however their role in T1D-induced osteoporosis is unknown. To address this, diabetes was induced in male IL-10 knockout (KO) and wild-type (WT) mice. Analyses of femur and vertebral trabecular bone volume fraction identified bone loss in T1D-WT mice at 4 and 12 weeks, which in T1D-IL-10-KO mice was further reduced at 4 weeks but not 12 weeks. IL-10 deficiency also increased the negative effects of T1D on cortical bone. Osteoblast marker osterix was decreased, while osteoclast markers were unchanged, suggesting that IL-10 promotes anabolic processes. MC3T3-E1 osteoblasts cultured under high glucose conditions displayed a decrease in osterix which was prevented by addition of IL-10. Taken together, our results suggest that IL-10 is important for promoting osteoblast maturation and reducing bone loss during early stages of T1D.

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis.

Glucocorticoids (GCs) are potent immune-modulating drugs with significant side effects, including glucocorticoid-induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined. To test this, male C57/Bl6J mice were treated for 8 weeks with GC (prednisolone, GC-Tx) in the presence or absence of broad-spectrum antibiotic treatment (ABX) to deplete the microbiota. Long-term ABX prevented GC-Tx-induced trabecular bone loss, showing the requirement of gut microbiota for GIO. Treatment of GC-Tx mice with a probiotic (Lactobacillus reuteri [LR]) prevented trabecular bone loss. Microbiota analyses indicated that GC-Tx changed the abundance of Verrucomicobiales and Bacteriodales phyla and random forest analyses indicated significant differences in abundance of Porphyromonadaceae and Clostridiales operational taxonomic units (OTUs) between groups. Furthermore, transplantation of GC-Tx mouse fecal material into recipient naïve, untreated WT mice caused bone loss, supporting a functional role for microbiota in GIO. We also report that GC caused intestinal barrier breaks, as evidenced by increased serum endotoxin level (2.4-fold), that were prevented by LR and ABX treatments. Enhancement of barrier function with a mucus supplement prevented both GC-Tx-induced barrier leakage and trabecular GIO. In bone, treatment with ABX, LR or a mucus supplement reduced GC-Tx-induced osteoblast and osteocyte apoptosis. GC-Tx suppression of Wnt10b in bone was restored by the LR and high-molecular-weight polymer (MDY) treatments as well as microbiota depletion. Finally, we identified that bone-specific Wnt10b overexpression prevented GIO. Taken together, our data highlight the previously unappreciated involvement of the gut microbiota and intestinal barrier function in trabecular GIO pathogenesis (including Wnt10b suppression and osteoblast and osteocyte apoptosis) and identify the gut as a novel therapeutic target for preventing GIO. © 2019 American Society for Bone and Mineral Research.