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Grönros J, Wikström J, Brandt-Eliasson U, Forsberg GB, Behrendt M, Hansson GI, Gan LM. Effects of msuvastatin on cardiovascular morphology and function in an ApoE-knockout mouse model of athemsclerosis. Am JPhysiol Heart Circ Physiol 295: H2046-H2053, 2008. First published September 12,2008; doi:10.1152/ajpheart.00I33.2008.-This study investigated the effects of rosuvastatin on plaque progression and in vivo coronary artery function in apolipoprotein E-knockout (ApoE-KO) mice, using noninvasive high-resolution ultrasound techniques. Eightweek-old male ApoE-KO mice (n = 20) were fed a high-fat diet with or without rosuvastatin (10 μmol∙kg[sup-1∙ day[sup-1]) for 16 wk. When compared with control, rosuvastatin reduced total cholesterol levels (P < 0.05) and caused significant retardation of lesion progression in the brachiocephalic artery, as visualized in vivo using an ultrasound biomicroscope (P < 0.05). Histological analysis confirmed the reduction of brachiocephalic atherosclerosis and also revealed an increase in collagen content in the statin-treated group (P < 0.05). Coronary volumetric flow was measured by simultaneous recording of Doppler velocity signals and left coronary artery morphology before and during adenosine infusion. The hyperemic flow in response to adenosine was significantly greater in left coronary artery following 16 wk of rosuvastatin treatment (P < 0.001), whereas the baseline flow was similar in both groups. In conclusion, rosuvastatin reduced brachiocephalic artery atherosclerotic plaques in ApoE-KO mice. Coronary artery function assessed using recently developed in vivo ultrasoundbased protocols, also improved. [ABSTRACT FROM AUTHOR]

Objective: To explore and describe thoughts about and experiences of pregnancy, childbirth and reproductive healthcare in lesbian and bisexual women and transgender people (LBT) with an expressed fear of childbirth (FOC)., Design: Data were collected through semi-structured interviews with self-identified LBTs with an expressed FOC., Participants: 17 self-identified LBTs participated. 15 had an expressed FOC, and two were non-afraid partners., Findings: Participants' fears were similar to those previously described in research on FOC, e.g., fear of pain, injury, blood, death of the child or of the parent. However, minority stress, including fear and experiences of prejudicial treatment, in maternity care and at delivery wards add an additional layer to the fear of childbirth., Key Conclusions: LBTs with FOC are a particularly vulnerable group of patients, whose needs must be addressed in healthcare., Implication for Practice: The findings call attention to the need for LBT-competent treatment prior to, and throughout pregnancy and childbirth. In the most vulnerable patients, caregivers must work extensively to build trust, in order to explore and reduce FOC., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose of Review: To provide insight into the mechanisms underlying cerebral pathophysiology and to highlight possible methods for evaluation, screening, and surveillance of cerebral complications in preeclampsia., Recent Findings: The pathophysiology of eclampsia remains enigmatic. Animal studies show that the cerebral circulation in pregnancy and preeclampsia might be affected with increased permeability over the blood-brain barrier and altered cerebral blood flow due to impaired cerebral autoregulation. The increased blood pressure cannot be the only underlying cause of eclampsia and cerebral edema, since some cases of eclampsia arise without simultaneous hypertension. Findings from animal studies need to be confirmed in human tissues. Evaluation of brain alterations in preeclampsia and eclampsia is challenging and demands a multidisciplinary collaboration, since no single method can accurately and fully describe how preeclampsia affects the brain. Cerebral complications of preeclampsia are significant factors in maternal morbidity and mortality worldwide. No single method can accurately describe the full picture of how preeclampsia affects the brain vasculature and parenchyma. We recommend an international and multidisciplinary effort not only to overcome the issue of limited sample availability but also to optimize the quality of research.

Introduction: Our aim was to investigate the accuracy of postmortem fetal magnetic resonance imaging (MRI) compared with fetal autopsy in second trimester pregnancies terminated due to fetal anomalies. A secondary aim was to compare the MRI evaluations of two senior radiologists., Material and Methods: This was a prospective study including 34 fetuses from pregnancies terminated in the second trimester due to fetal anomalies. All women accepted a postmortem MRI and an autopsy of the fetus. Two senior radiologists performed independent evaluations of the MRI images. A senior pathologist performed the fetal autopsies. The degree of concordance between the MRI evaluations and the autopsy reports was estimated as well as the consensus between the radiologists., Results: Thirty-four fetuses were evaluated. Sixteen cases were associated with the central nervous system (CNS), five were musculoskeletal, one cardiovascular, one was associated with the urinary tract, and 11 cases had miscellaneous anomalies such as chromosomal aberrations, infections and syndromes. In the 16 cases related to the CNS, both radiologists reported all or some, including the most clinically significant anomalies in 15 (94%; CI 70%-100%) cases. In the 18 non-CNS cases, both radiologists reported all or some, including the most clinically significant anomalies in six (33%; CI 5%-85%) cases. In 21 cases (62%; CI 44%-78%), both radiologists held opinions that were consistent with the autopsy reports. The degree of agreement between the radiologists was high, with a Cohen's Kappa of 0.87., Conclusions: Postmortem fetal MRI can replace autopsy for second trimester fetuses with CNS anomalies. For non-CNS anomalies, the concordance is lower but postmortem MRI can still be of value when autopsy is not an option., (© 2019 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly, and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57, and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM&#95;173630.3:c.5648-5T>A in RTTN. The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP&#95;775901.3:p.Ala1883Glyfs*6)]. Brain MRI of one affected individual showed markedly reduced volume of cerebral lobes and enlarged sulci but without signs of neural migration defects. Our assessment of three adult cases with a biallelic RTTN variant shows that a predicted shortened Rotatin, lacking the C-terminal end, are associated with stationary clinical features into the seventh decade. Furthermore, our report adds brachydactyly to the phenotypic spectrum in this pleiotropic entity., (© 2019 Wiley Periodicals, Inc.)

Purpose of Review: To explore the relationship between early life trauma, hormonal sensitivity, and psychiatric disorders across female-reproductive life events, with a focus on the neurobiological mechanisms., Recent Findings: Childhood trauma significantly increases the risk of subsequent mood disorders during periods of intense hormonal fluctuation such as premenstrual, pregnancy, postpartum, and perimenopause. Neurobiological changes resulting from early trauma influence emotion regulation, which emerges as a key predisposing, exacerbating, and perpetuating factor to hormonal sensitivity and subsequent psychiatric symptoms. We identified altered stress response and allopregnanolone imbalance, bias in cognitive processing of emotions, neuroimage correlates and sleep disturbances as potential underlying neurobiological mechanisms. This review integrates cumulative findings supporting a theoretical framework linking early life trauma to hormonal sensitivity and mood disorders. We propose that some women might be more susceptible to such hormonal fluctuations because of emotion dysregulation following significant early life trauma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment., (© 2024. The Author(s).)

Capable of mediating efficient transfection and protein production without eliciting innate immune responses, chemically modified mRNA holds great potential to produce paracrine factors at a physiologically beneficial level, in a spatiotemporally controlled manner, and with low toxicity. Although highly promising in cardiovascular medicine and wound healing, effects of this emerging therapeutic on the microvasculature and its bioactivity in disease settings remain poorly understood. Here, we longitudinally and comprehensively characterize microvascular responses to AZD8601, a modified mRNA encoding vascular endothelial growth factor A (VEGF-A), in vivo. Using multi-parametric photoacoustic microscopy, we show that intradermal injection of AZD8601 formulated in a biocompatible vehicle results in pronounced, sustained and dose-dependent vasodilation, blood flow upregulation, and neovessel formation, in striking contrast to those induced by recombinant human VEGF-A protein, a non-translatable variant of AZD8601, and citrate/saline vehicle. Moreover, we evaluate the bioactivity of AZD8601 in a mouse model of diabetic wound healing in vivo. Using a boron nanoparticle-based tissue oxygen sensor, we show that sequential dosing of AZD8601 improves vascularization and tissue oxygenation of the wound bed, leading to accelerated re-epithelialization during the early phase of diabetic wound healing.

Background: There are different opinions of the clinical value of MRS of the brain. In selected materials MRS has demonstrated good results for characterisation of both neoplastic and non-neoplastic lesions. The aim of this study was to evaluate the supplemental value of MR spectroscopy (MRS) in a clinical setting., Material and Methods: MRI and MRS were re-evaluated in 208 cases with a clinically indicated MRS (cases with uncertain or insufficient information on MRI) and a confirmed diagnosis. Both single voxel spectroscopy (SVS) and chemical shift imaging (CSI) were performed in 105 cases, only SVS or CSI in 54 and 49 cases, respectively. Diagnoses were grouped into categories: non-neoplastic disease, low-grade tumour, and high-grade tumour. The clinical value of MRS was considered very beneficial if it provided the correct category or location when MRI did not, beneficial if it ruled out suspected diseases or was more specific than MRI, inconsequential if it provided the same level of information, or misleading if it provided less or incorrect information., Results: There were 70 non-neoplastic lesions, 43 low-grade tumours, and 95 high-grade tumours. For MRI, the category was correct in 130 cases (62%), indeterminate in 39 cases (19%), and incorrect in 39 cases (19%). Supplemented with MRS, 134 cases (64%) were correct, 23 cases (11%) indeterminate, and 51 (25%) incorrect. Additional information from MRS was beneficial or very beneficial in 31 cases (15%) and misleading in 36 cases (17%)., Conclusion: In most cases MRS did not add to the diagnostic value of MRI. In selected cases, MRS may be a valuable supplement to MRI., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Cerebral complications are the main reasons for morbidity and mortality in preeclampsia and eclampsia. As yet, we do not know whether the pathophysiology entails hypo- or hyperperfusion of the brain, or how and when edema emerges, due to the difficulty of examining the cerebral circulation., Material and Methods: We have used a non-invasive diffusion weighted-magnetic resonance imaging technique, intravoxel incoherent motion, to study cerebral perfusion on the capillary level and cerebral edema in women with preeclampsia (n = 30), normal pregnancy (n = 32), and non-pregnant women (n = 16). Estimates of cerebral blood volume, blood flow, and edema were measured in 5 different regions. These points were chosen to represent blood supply areas of both the carotid and vertebrobasilar arteries, and to include both white and gray matter., Results: Except for the caudate nucleus, we did not detect any differences in cerebral perfusion measures on a group level. In the caudate nucleus, we found lower cerebral blood volume and lower blood flow in preeclampsia than in either normal pregnancy (P = .01 and P = .03, respectively) or non-pregnant women (both P = .02). No differences in edema were detected between study groups., Conclusion: The cerebral perfusion measures were comparable between the study groups, except for a portion of the basal ganglia where hypoperfusion was detected in preeclampsia but not in normal pregnancy or non-pregnant women., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in patients with DAI., Methods: Fifty-two patients with severe TBI (median age 24 years, range 9-61 years), who had undergone ICP monitoring and had DAI on MRI, as determined using T2*-weighted gradient echo, susceptibility-weighted imaging, and diffusion-weighted imaging (DWI) sequences, were enrolled. The proportion of good monitoring time (GMT) with ICP > 20 mm Hg during the first 120 hours postinjury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression., Results: All patients had episodes of ICP > 20 mm Hg. The mean proportion of GMT with ICP > 20 mm Hg was 5%, and 27% of the patients (14/52) spent more than 5% of GMT with ICP > 20 mm Hg. The Glasgow Coma Scale motor score at admission (p = 0.04) and lesions on DWI sequences in the substantia nigra and mesencephalic tegmentum (SN-T, p = 0.001) were associated with the proportion of GMT with ICP > 20 mm Hg. In multivariable linear regression, lesions on DWI sequences in SN-T (8% of GMT with ICP > 20 mm Hg, 95% CI 3%-13%, p = 0.004) and young age (-0.2% of GMT with ICP > 20 mm Hg, 95% CI -0.07% to -0.3%, p = 0.002) were associated with increased ICP., Conclusions: Increased ICP occurs in approximately one-third of patients with severe TBI who have DAI. Age and lesions on DWI sequences in the central mesencephalon (i.e., SN-T) are associated with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in patients with DAI.

Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that overexpress Oxtr specifically in the heart., Methods and Results: Cardiac-specific overexpression of Oxtr was obtained by having the α-major histocompatibility complex promoter drive the mouse Oxtr gene (α-Mhc-Oxtr). Left ventricular (LV) function and remodeling were assessed by magnetic resonance imaging and echocardiography. In α-Mhc-Oxtr TG mice, LV ejection fraction was severely compromised at 14 weeks of age compared with wild-type (WT) littermates (25 ± 6% vs 63 ± 3%; P < .001). LV end-diastolic volume was larger in the TG mice (103 ± 6 µL vs 67 ± 5 µL; P < .001). α-Mhc-Oxtr TG animals displayed cardiac fibrosis, atrial thrombus, and increased expression of pro-fibrogenic genes. Mortality of α-Mhc-Oxtr TG animals was 45% compared with 0% (P < .0001) of WT littermates by 20 weeks of age. Most cardiomyocytes of α-Mhc-Oxtr TG animals but not WT littermates (68.0 ± 12.1% vs 5.6 ± 2.4%; P = .008) were positive in staining for nuclear factor of activated T cells (NFAT). To study if thrombin inhibitor prevents thrombus formation, a cohort of 7-week-old α-Mhc-Oxtr TG mice were treated for 12 weeks with AZD0837, a potent thrombin inhibitor. Treatment with AZD0837 reduced thrombus formation (P < .05) and tended to attenuate fibrosis and increase survival., Conclusions: Cardiac-specific overexpression of Oxtr had negative consequences on LV function and survival in mice. The present findings necessitate further studies to investigate potential adverse effects of chronic Oxt administration. We provide a possible mechanism of Oxtr overexpression leading to heart failure by nuclear factor of activated T cell signaling. The recapitulation of human heart failure and the beneficial effects of the antithrombin inhibitor render the α-Mhc-Oxtr TG mice a promising tool in drug discovery for heart failure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A lead generation campaign identified indole-based sPLA 2 -X inhibitors with a promising selectivity profile against other sPLA 2 isoforms. Further optimization of sPLA 2 selectivity and metabolic stability resulted in the design of (-)- 17 , a novel, potent, and selective sPLA 2 -X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)- 17 was tested in an ApoE -/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA 2 -X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)- 17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis., Competing Interests: The authors declare no competing financial interest.

Background: Cerebral complications contribute substantially to mortality in preeclampsia. Pregnancy calls for extensive maternal adaptations, some associated with increased propensity for seizures, but the pathophysiology behind the eclamptic seizures is not fully understood. Plasma osmolality and sodium levels are lowered in pregnancy. This could result in extrusion of cerebral organic osmolytes, including the excitatory neurotransmitter glutamate, but this remains to be determined. The hypothesis of this study was that cerebral levels of organic osmolytes are decreased during pregnancy, and that this decrease is even more pronounced in women with preeclampsia., Methods: We used proton magnetic resonance spectroscopy to compare levels of cerebral organic osmolytes, in women with preeclampsia (n = 30), normal pregnancy (n = 32), and nonpregnant controls (n = 16). Cerebral levels of organic osmolytes were further correlated to plasma osmolality and plasma levels of glutamate and sodium., Results: Compared to nonpregnant women, women with normal pregnancy and preeclampsia had lower levels of the cerebral osmolytes, myo-inositol, choline and creatine (P = 0.001 or less), and all these metabolites correlated with each other (P < 0.05). Women with normal pregnancies and preeclampsia had similar levels of osmolytes, except for glutamate, which was significantly lower in preeclampsia. Cerebral and plasma glutamate levels were negatively correlated with each other (P < 0.008), and myo-inositol, choline and creatine levels were all positively correlated with both plasma osmolality and sodium levels (P < 0.05)., Conclusions: Our results indicate that pregnancy is associated with extrusion of cerebral organic osmolytes. This includes the excitatory neurotransmitter glutamate, which may be involved in the pathophysiology of seizures in preeclampsia.

In reanimation surgery, effortless smile can be achieved by a nonfacial donor nerve. The underlying mechanisms for this smile development, and which is the best nonfacial neurotizer, need further clarification. The aim of the present study was therefore to further explore the natural coactivation between facial mimic muscles and muscles innervated by the most common donor nerves used in smile reanimation. The study was conducted in 10 healthy adults. Correlation between voluntary facial muscle movements and simultaneous electromyographic activity in muscles innervated by the masseter, hypoglossal, and spinal accessory nerves was assessed. The association between voluntary movements in the latter muscles and simultaneous electromyographic activity in facial muscles was also studied. Smile coactivated the masseter and tongue muscles equally. During the seven mimic movements, the masseter muscle had fewer electromyographically measured coactivations compared with the tongue (two of seven versus five of seven). The trapezius muscle demonstrated no coactivation during mimic movements. Movements of the masseter, tongue, and trapezius muscles induced electromyographically recorded coactivation in the facial muscles. Bite resulted in the strongest coactivation of the zygomaticus major muscle. The authors demonstrated coactivation between voluntary smile and the masseter and tongue muscles. During voluntary bite, strong coactivation of the zygomaticus major muscle was noted. The narrower coactivation pattern in the masseter muscle may be advantageous for central relearning and the development of a spontaneous smile. The strong coactivation between the masseter muscle and the zygomaticus major indicates that the masseter nerve may be preferred in smile reanimation.

The mechanisms linking ovarian hormones to negative affect are poorly characterized, but important clues may come from the examination of the brain's intrinsic organization. Here, we studied the effects of both the menstrual cycle and oral contraceptives (OCs) on amygdala and salience network resting-state functional connectivity using a double-blind, randomized, and placebo-controlled design. Hormone levels, depressive symptoms, and resting-state functional connectivity were measured in 35 healthy women (24.9±4.2 years) who had previously experienced OC-related negative affect. All participants were examined in the follicular phase of a baseline cycle and in the third week of the subsequent cycle during treatment with either a combined OC (30 μg ethinyl estradiol/0.15 mg levonorgestrel) or placebo. The latter time point targeted the midluteal phase in placebo users and steady-state ethinyl estradiol and levonorgestrel concentrations in OC users. Amygdala and salience network connectivity generally increased with both higher endogenous and synthetic hormone levels, although amygdala-parietal cortical connectivity decreased in OC users. When in the luteal phase, the naturally cycling placebo users demonstrated higher connectivity in both networks compared with the women receiving OCs. Our results support a causal link between the exogenous administration of synthetic hormones and amygdala and salience network connectivity. Furthermore, they suggest a similar, potentially stronger, association between the natural hormonal variations across the menstrual cycle and intrinsic network connectivity.

Istockphoto.com REFERENCES 1 Wester K, Stridbeck U, Syse A, Wikström J. Re-evaluation of medical findings in alleged shaken baby syndrome and abusive head trauma in Norwegian courts fails to support abuse diagnoses. Wester et al examined 17 criminal abusive head trauma cases tried by the Norwegian courts by scrutinising the medical documents.1 After they re-evaluated the medical findings, the authors disagreed with the original conclusions of the court-appointed experts in 16 of the 17 cases. 3 Wester K, Wikström J. Corrigendum to the paper 'Re-evaluation of medical findings in alleged shaken baby syndrome and abusive head trauma in Norwegian courts fails to support abuse diagnoses'. [Extracted from the article]