Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity

Aims/hypothesis

Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity.

Methods

Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined.

Results

Maternal insulin increased from a fasting level of 67?±?25 pmol/l (mean ± SD) to 918?±?492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4?±?0.3 to 7.4?±?1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297?±?99 to 235?±?84 ms (p?=?0.01) and then remained stable until 120 min (235?±?84 vs 251?±?91 ms, p?=?0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r?=?0.68, p?=?0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283?±?79 ms) than those of insulin-sensitive mothers (178?±?46 ms, p?=?0.03).

Conclusions/interpretation

Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.     

Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity

Ocular dominance (OD) plasticity in mouse primary visual cortex (V1) declines during postnatal development and is absent beyond postnatal day 110 if mice are raised in standard cages (SCs). An enriched environment (EE) promotes OD plasticity in adult rats. Here, we explored cellular mechanisms of EE in mouse V1 and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Using in vivo optical imaging, we observed that monocular deprivation in adult EE mice (i) caused a very strong OD plasticity previously only observed in 4-wk-old animals, (ii) restored already lost OD plasticity in adult SC-raised mice, and (iii) preserved OD plasticity after a stroke in the primary somatosensory cortex. Using patch-clamp electrophysiology in vitro, we also show that (iv) local inhibition was significantly reduced in V1 slices of adult EE mice and (v) the GABA/AMPA ratio was like that in 4-wk-old SC-raised animals. These observations were corroborated by in vivo analyses showing that diazepam treatment significantly reduced the OD shift of EE mice after monocular deprivation. Taken together, EE extended the sensitive phase for OD plasticity into late adulthood, rejuvenated V1 after 4 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. The EE effect was mediated most likely by preserving low juvenile levels of inhibition into adulthood, which potentially promoted adaptive changes in cortical circuits.Ocular dominance (OD) plasticity induced by monocular deprivation (MD) is one of the best studied models of experience-dependent plasticity in the mammalian cortex (1, 2). OD plasticity in primary visual cortex (V1) of C57BL/6J mice is maximal at 4 wk of age, declines after 2–3 mo, and is absent beyond postnatal day 110 (PD110) if animals are raised in standard cages (SCs) (3–6). In 4-wk-old mice, 4 d of MD are sufficient to induce an OD shift to the open eye; therefore, neurons in the binocular V1, which are usually dominated by the contralateral eye in rodents (3, 7), become activated more equally by both eyes (5, 8). This juvenile OD shift is predominantly mediated by a decrease in the visual cortical responses to the deprived eye (1, 9–11), whereas significant OD shifts in older animals up to PD110 need 7 d of MD and are mediated primarily by increased open-eye responses in V1. Raising animals in an enriched environment (EE) gives them the opportunity of enhanced physical, social, and cognitive stimulation and influences brain physiology and behavior in many ways (12, 13). It has been shown previously that EE enhances visual system development in rats (14) and mice (15–17), increases levels of the brain-derived neurotrophic factor and serotonin (18), reduces both extracellular GABA levels (18, 19) and the density of ECM perineuronal nets (PNNs) (19), and promotes OD plasticity in adult and aging rats (18–21). Here, we explored cellular mechanisms of EE in V1 of mice and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Furthermore, we studied whether EE would prolong the sensitive phase for OD plasticity into adulthood and also restore this form of plasticity in mice that were raised in SC until PD110 (i.e., in animals that were already beyond their sensitive phase for OD plasticity). Despite pharmacological detection of in vivo GABA levels, suggesting that EE reduces intracortical inhibition, direct electrophysiological evidence is still missing. We therefore recorded GABA, AMPA, and NMDA currents in slices from EE- and SC-raised mice and also tested the efficacy of diazepam injections to abolish OD plasticity of EE mice in vivo. Finally, we studied whether raising mice in EE would protect them from lesion-induced impairments of OD plasticity. Our results show that raising mice in EE preserved OD plasticity into late adulthood rejuvenated the brain after 3 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. Our electrophysiological measurements and diazepam treatment indicate that the plasticity-promoting effect of EE was primarily mediated by reduced intracortical inhibition compared with SC-raised mice. These results suggest EE as a preventive intervention to enhance and preserve plasticity in adulthood and after a cortical lesion.     

Incidence of microcracks after preparation of straight and curved root canals with three different NiTi instrumentation techniques assessed by micro‐CT

This study evaluated the effect of three different NiTi instrumentation techniques on the incidence of microcracks after the preparation of straight and curved root canals using micro‐CT. Roots from mandibular premolars and maxillary molars (n = 66) with the same mean canal curvatures were assigned to three groups of straight and three groups of curved roots (n = 11). After preoperative micro‐CT scans, root canals were prepared with Reciproc, OneShape and ProTaper Next to size 25. Specimens were scanned again, and pre‐ and post‐operative cross‐sectional images (n = 75 263) were screened to identify the presence of dentinal microcracks. Overall, microcracks were detected in 2.97% (n = 2236) of the cross‐sectional images. No new dentinal microcracks were observed after root canal instrumentation of straight and curved canals with the tested NiTi systems. Instrumentation with Reciproc, OneShape and ProTaper Next did not induce the formation of dentinal microcracks irrespective of canal curvature.     

Comparison of clonidine and midazolam as anxiolytic premedication before wisdom tooth surgery: a randomized, double-blind, crossover pilot study

Purpose

Anxiolytic and possible side effects of clonidine 150?μg compared to midazolam 7.5?mg for premedication in surgical wisdom tooth extraction were evaluated.

Methods

In a prospective, randomized, double-blind crossover trial, ten patients undergoing bilateral wisdom tooth surgery received clonidine or midazolam orally 1?h before the treatment. Patients receiving midazolam for the first surgery received clonidine at the second surgery and vice versa. The anxiolytic efficacy was evaluated with a visual analogue scale (VAS) upon admission and 30, 50 and 60?min after administration of the medication. Patient satisfaction was recorded on a VAS after surgery and 7?days postoperatively.

Results

As soon as 30?min after administration of midazolam (p?<?0.03) and clonidine (p?<?0.02), an anxiolytic effect was recorded. Both medications did not differ in patient satisfaction.

Conclusion

Oral administration of clonidine 150?μg and midazolam 7.5?mg were rated as medications with equal anxiolytic effects before wisdom tooth surgery under local anesthesia.     

Modulation of cardiac contractility by serine/threonine protein phosphatase type 5

Background

Protein phosphatase 5 (PP5) a serine/threonine phosphatase is ubiquitously expressed in mammalian tissues including the heart, but its physiological role in the heart is still unknown. Therefore, we used a transgenic mouse model to get a first insight into the cardiac role of PP5.

Methods and results

We generated transgenic mice with cardiac myocyte specific overexpression of PP5. Successful overexpression of PP5 was demonstrated by Western blotting, immunohistochemistry and enhanced arachidonic acid-stimulated protein phosphatase activity in transgenic hearts. Cardiac function was examined on the level of isolated cardiac myocytes, isolated organs and in intact animals. Whereas Ca²⁺ transients and cell shortening remained unchanged, L-type Ca²⁺ currents were decreased in isolated cardiac myocytes from transgenic mice. Ventricular contractility was reduced in isolated perfused hearts under basal conditions and after β-adrenergic stimulation. In intact animals, echocardiography revealed increased left ventricular diameters and decreased contractility and invasively measured hemodynamic performance by left ventricular catheterization demonstrated a reduced response to β-adrenergic stimulation in transgenic mice compared to wild type.

Conclusions

Overexpression of PP5 affected contractility and β-adrenergic signaling in the hearts of transgenic mice. Taken together, these findings are indicative of a regulatory role of PP5 in cardiac function.     

Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance

Background

The levels and clinical relevance of Th17 cells and other interleukin-17-producing cells have not been analyzed in chronic lymphocytic leukemia. The objective of this study was to quantify blood and tissue levels of Th17 and other interleukin-17-producing cells in patients with this disease and correlate blood levels with clinical outcome.

Design and Methods

Intracellular interleukin-17A was assessed in blood and splenic mononuclear cells from patients with chronic lymphocytic leukemia and healthy subjects using flow cytometry. Interleukin-17A-producing cells were analyzed in formalin-fixed, paraffin-embedded spleen and lymph node sections using immunohistochemistry and immunofluorescence.

Results

The absolute numbers of Th17 cells in peripheral blood mononuclear cells and the percentages of Th17 cells in spleen cell suspensions were higher in patients with chronic lymphocytic leukemia than in healthy subjects; in six out of eight paired chronic lymphocytic leukemia blood and spleen sample comparisons, Th17 cells were enriched in spleen suspensions. Circulating Th17 levels correlated with better prognostic markers and longer overall survival of the patients. Two “non-Th17” interleukin-17-expressing cells were identified in chronic lymphocytic leukemia spleens: proliferating cells of the granulocytic lineage and mature mast cells. Granulocytes and mast cells in normal spleens did not express interleukin-17. Conversely, both chronic lymphocytic leukemia and healthy lymph nodes contained similar numbers of interleukin-17+ mast cells as well as Th17 cells.

Conclusions

Th17 cells are elevated in chronic lymphocytic leukemia patients with better prognostic markers and correlate with longer survival. Furthermore, non-Th17 interleukin-17A-expressing cells exist in chronic lymphocytic leukemia spleens as maturing granulocytes and mature mast cells, suggesting that the microenvironmental milieu in leukemic spleens promotes the recruitment and/or expansion of Th17 and other IL-17-expressing cells. The pathophysiology of Th17 and non-Th17-interleukin-producing cells in chronic lymphocytic leukemia and their distributions and roles in this disease merit further study.     

Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala

Major depression has been repeatedly associated with amygdala hyper‐responsiveness to negative (but not positive) facial expressions at early, automatic stages of emotion processing using subliminally presented stimuli. However, it is not clear whether this “limbic bias” is a correlate of depression or represents a vulnerability marker preceding the onset of the disease. Because childhood maltreatment is a potent risk factor for the development of major depression in later life, we explored whether childhood maltreatment is associated with amygdalar emotion processing bias in maltreated but healthy subjects. Amygdala responsiveness to subliminally presented sad and happy faces was measured by means of fMRI at 3 T in N = 150 healthy subjects carefully screened for psychiatric disorders. Childhood maltreatment was assessed by the 25‐item childhood trauma questionnaire (CTQ). A strong association of CTQ‐scores with amygdala responsiveness to sad, but not happy facial expressions emerged. This result was further qualified by an interaction of emotional valence and CTQ‐scores and was not confounded by trait anxiety, current depression level, age, gender, intelligence, education level, and more recent stressful life‐events. Childhood maltreatment is apparently associated with detectable changes in amygdala function during early stages of emotion processing which resemble findings described in major depression. Limbic hyper‐responsiveness to negative facial cues could be a consequence of the experience of maltreatment during childhood increasing the risk of depression in later life. Limitation: the present association of limbic bias and maltreatment was demonstrated in the absence of psychopathological abnormalities, thereby limiting strong conclusions. Hum Brain Mapp 34:2899–2909, 2013. © 2012 Wiley Periodicals, Inc.     

Haunting self-images? The role of negative self-images in adolescent social anxiety disorder

Background and objectivesNegative distorted self-images (NSI) allegedly maintain social anxiety in adults suffering from social anxiety disorder (SAD). These NSI are activated in feared social situations and are often linked to past socially traumatic events. However, because empirical evidence on the presence and characteristics of such NSI in adolescents suffering from SAD is limited, the aim of the present study is to examine the nature of NSI in adolescent SAD patients.MethodsUsing a semi-structured interview, 31 adolescents with a primary diagnosis of SAD and 31 healthy adolescents (HA) who were matched for age and gender, completed a questionnaire set assessing the characteristics of NSI, social anxiety and depression.ResultsRelative to the HA-group, those suffering from SAD reported experiencing NSI significantly more frequently, more vividly, and with greater distress. No significant differences between the groups emerged regarding a link between the NSI and an autobiographical event. However, NSI were reported as more often having an observer-perspective in the SAD as compared to the HA-group. Hierarchical regression analysis revealed that certain characteristics of the NSI predict social anxiety beyond the influence of depression in adolescents with SAD.DiscussionNSI seem to be an important feature of adolescent SAD and phenomenological comparable to NSI in adults suffering from SAD.ConclusionsSpecific interventions aiming to correct NSI, which have proven to be highly effective in adults, should be developmentally-adapted and evaluated in future studies.     

Too tight to give birth? Assessment of pelvic floor muscle function in 277 nulliparous pregnant women

Introduction and hypothesis

Theoretically, tight or strong pelvic floor muscles may impair the progress of labor and lead to instrumental deliveries. We aimed to investigate whether vaginal resting pressure, pelvic floor muscle strength, or endurance at midpregnancy affect delivery outcome.

Methods

This was a prospective cohort study of women giving birth at a university hospital. Vaginal resting pressure, pelvic floor muscle strength, and endurance in 300 nulliparous pregnant women were assessed at mean gestational week 20.8 (±1.4) using a high precision pressure transducer connected to a vaginal balloon. Delivery outcome measures [acute cesarean section, prolonged second stage of labor (> 2 h), instrumental vaginal delivery (vacuum and forceps), episiotomy, and third- and fourth-degree perineal tear) were retrieved from the hospital’s electronic birth records.

Results

Twenty-three women were lost to follow-up, mostly because they gave birth at another hospital. Women with prolonged second stage had significantly higher resting pressure than women with second stage less than 2 h; the mean difference was 4.4 cmH₂O [95 % confidence interval (CI) 1.2–7.6], p?<?0.01, adjusted odds ratio 1.049 (95 % CI 1.011–1.089, p?=?0.012). Vaginal resting pressure did not affect other delivery outcomes. Pelvic floor muscle strength and endurance similarly were not associated with any delivery outcomes.

Conclusions

While midpregnancy vaginal resting pressure is associated with prolonged second stage of labor, neither vaginal resting pressure nor pelvic floor muscle strength or endurance are associated with operative delivery or perineal tears. Strong pelvic floor muscles are not disadvantageous for vaginal delivery.