Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

Acute and Chronic Altitude-Induced Cognitive Dysfunction in Children and Adolescents.

OBJECTIVE To assess whether exposure to high altitude induces cognitive dysfunction in young healthy European children and adolescents during acute, short-term exposure to an altitude of 3450 m and in an age-matched European population permanently living at this altitude. STUDY DESIGN We tested executive function (inhibition, shifting, and working memory), memory (verbal, short-term visuospatial, and verbal episodic memory), and speed processing ability in: (1) 48 healthy nonacclimatized European children and adolescents, 24 hours after arrival at high altitude and 3 months after return to low altitude; (2) 21 matched European subjects permanently living at high altitude; and (3) a matched control group tested twice at low altitude. RESULTS Short-term hypoxia significantly impaired all but 2 (visuospatial memory and processing speed) of the neuropsychological abilities that were tested. These impairments were even more severe in the children permanently living at high altitude. Three months after return to low altitude, the neuropsychological performances significantly improved and were comparable with those observed in the control group tested only at low altitude. CONCLUSIONS Acute short-term exposure to an altitude at which major tourist destinations are located induces marked executive and memory deficits in healthy children. These deficits are equally marked or more severe in children permanently living at high altitude and are expected to impair their learning abilities.

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

Usability and Acceptability of ASSESS MS: Assessment of Motor Dysfunction in Multiple Sclerosis Using Depth-Sensing Computer Vision

Background: Sensor-based recordings of human movements are becoming increasingly important for the assessment of motor symptoms in neurological disorders beyond rehabilitative purposes. ASSESS MS is a movement recording and analysis system being developed to automate the classification of motor dysfunction in patients with multiple sclerosis (MS) using depth-sensing computer vision. It aims to provide a more consistent and finer-grained measurement of motor dysfunction than currently possible. Objective: To test the usability and acceptability of ASSESS MS with health professionals and patients with MS. Methods: A prospective, mixed-methods study was carried out at 3 centers. After a 1-hour training session, a convenience sample of 12 health professionals (6 neurologists and 6 nurses) used ASSESS MS to capture recordings of standardized movements performed by 51 volunteer patients. Metrics for effectiveness, efficiency, and acceptability were defined and used to analyze data captured by ASSESS MS, video recordings of each examination, feedback questionnaires, and follow-up interviews. Results: All health professionals were able to complete recordings using ASSESS MS, achieving high levels of standardization on 3 of 4 metrics (movement performance, lateral positioning, and clear camera view but not distance positioning). Results were unaffected by patients’ level of physical or cognitive disability. ASSESS MS was perceived as easy to use by both patients and health professionals with high scores on the Likert-scale questions and positive interview commentary. ASSESS MS was highly acceptable to patients on all dimensions considered, including attitudes to future use, interaction (with health professionals), and overall perceptions of ASSESS MS. Health professionals also accepted ASSESS MS, but with greater ambivalence arising from the need to alter patient interaction styles. There was little variation in results across participating centers, and no differences between neurologists and nurses. Conclusions: In typical clinical settings, ASSESS MS is usable and acceptable to both patients and health professionals, generating data of a quality suitable for clinical analysis. An iterative design process appears to have been successful in accounting for factors that permit ASSESS MS to be used by a range of health professionals in new settings with minimal training. The study shows the potential of shifting ubiquitous sensing technologies from research into the clinic through a design approach that gives appropriate attention to the clinic environment.

Leptomeningeal contrast enhancement and blood-CSF barrier dysfunction in aseptic meningitis

OBJECTIVE To investigate the blood-CSF barrier (BCSFB) dysfunction in aseptic meningitis. METHODS In our case series of 14 patients with acute aseptic meningitis, we compared MRI characteristics with CSF findings. RESULTS Contrast enhancement in the sulcal space in a leptomeningeal pattern was visualized in 7 patients with BCSFB dysfunction categorized as moderate to severe as evidenced by the CSF/serum albumin ratio (Qalb) but was not present in those with mild or no barrier disturbance (p = 0.001). The Qalb as a marker for the leakiness of the BCSFB and, more indirectly, of the blood-brain barrier (BBB) was positively correlated with the incidence of leptomeningeal contrast enhancement seen on postcontrast fluid-attenuated inversion recovery (FLAIR) MRI (p = 0.003). Patients with a more pronounced brain barrier dysfunction recovered more slowly and stayed longer in the hospital. CONCLUSIONS The severity of meningeal BBB disturbance can be estimated on postcontrast FLAIR MRI, which may be of diagnostic value in patients with aseptic meningitis.

Non-surgical treatment of pain associated with posterior tibial tendon dysfunction: study protocol for a randomised clinical trial

BACKGROUND Symptoms associated with pes planovalgus or flatfeet occur frequently, even though some people with a flatfoot deformity remain asymptomatic. Pes planovalgus is proposed to be associated with foot/ankle pain and poor function. Concurrently, the multifactorial weakness of the tibialis posterior muscle and its tendon can lead to a flattening of the longitudinal arch of the foot. Those affected can experience functional impairment and pain. Less severe cases at an early stage are eligible for non-surgical treatment and foot orthoses are considered to be the first line approach. Furthermore, strengthening of arch and ankle stabilising muscles are thought to contribute to active compensation of the deformity leading to stress relief of soft tissue structures. There is only limited evidence concerning the numerous therapy approaches, and so far, no data are available showing functional benefits that accompany these interventions. METHODS After clinical diagnosis and clarification of inclusion criteria (e.g., age 40-70, current complaint of foot and ankle pain more than three months, posterior tibial tendon dysfunction stage I & II, longitudinal arch flattening verified by radiography), sixty participants with posterior tibial tendon dysfunction associated complaints will be included in the study and will be randomly assigned to one of three different intervention groups: (i) foot orthoses only (FOO), (ii) foot orthoses and eccentric exercise (FOE), or (iii) sham foot orthoses only (FOS). Participants in the FOO and FOE groups will be allocated individualised foot orthoses, the latter combined with eccentric exercise for ankle stabilisation and strengthening of the tibialis posterior muscle. Participants in the FOS group will be allocated sham foot orthoses only. During the intervention period of 12 weeks, all participants will be encouraged to follow an educational program for dosed foot load management (e.g., to stop activity if they experience increasing pain). Functional impairment will be evaluated pre- and post-intervention by the Foot Function Index. Further outcome measures include the Pain Disability Index, Visual Analogue Scale for pain, SF-12, kinematic data from 3D-movement analysis and neuromuscular activity during level and downstairs walking. Measuring outcomes pre- and post-intervention will allow the calculation of intervention effects by 3×3 Analysis of Variance (ANOVA) with repeated measures. DISCUSSION The purpose of this randomised trial is to evaluate the therapeutic benefit of three different non-surgical treatment regimens in participants with posterior tibial tendon dysfunction and accompanying pes planovalgus. Furthermore, the analysis of changes in gait mechanics and neuromuscular control will contribute to an enhanced understanding of functional changes and eventually optimise conservative management strategies for these patients. TRIAL REGISTRATION ClinicalTrials.gov Protocol Registration System: ClinicalTrials.gov ID NCT01839669.

Subclinical Thyroid Dysfunction and Depressive Symptoms among Elderly: A Prospective Cohort Study

BACKGROUND Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. METHODS In the Leiden sub-study of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) among adults aged 70-82 years with pre-existing cardiovascular disease or known cardiovascular risk factors, TSH and free T4 levels were measured at baseline and repeated after 6 months to define persistent thyroid function status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS) at baseline and after 3 years. All analyses were adjusted for age, gender and education. RESULTS Among 606 participants (41% women, mean age 75 years) without anti-depressant medication, GDS scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS 1.75, 95% CI 1.29-2.20, p = 0.50) or subclinical hyperthyroidism (n = 13; GDS 1.64 [0.78-2.51], p = 1.00) compared to euthyroid participants (n = 546, mean GDS 1.60 [1.46-1.73]). After 3 years, compared to euthyroid participants, change in GDS scores did not differ for participants with subclinical hypothyroidism (ΔGDS -0.03 [-0.50-0.44], p = 0.80), while subclinical hyperthyroidism was associated with an increase in GDS scores (ΔGDS 1.13 [0.32-1.93] p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. CONCLUSIONS In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study. © 2015 S. Karger AG, Basel.

Thyroid dysfunction and anemia in a large population-based study.

OBJECTIVE AND BACKGROUND Anemia and thyroid dysfunction are common and often co-occur. Current guidelines recommend the assessment of thyroid function in the work-up of anemia, although evidence on this association is scarce. PATIENTS AND METHODS In the "European Prospective Investigation of Cancer" (EPIC)-Norfolk population-based cohort, we aimed to examine the prevalence and type of anemia (defined as hemoglobin <13 g/dl for men and <12 g/dl for women) according to different thyroid function groups. RESULTS The mean age of the 8791 participants was 59.4 (SD 9.1) years and 55.2% were women. Thyroid dysfunction was present in 437 (5.0%) and anemia in 517 (5.9%) participants. After excluding 121 participants with three most common causes of anemia (chronic kidney disease, inflammation, iron deficiency), anemia was found in 4.7% of euthyroid participants. Compared with the euthyroid group, the prevalence of anemia was significantly higher in overt hyperthyroidism (14.6%, P < .01), higher with borderline significance in overt hypothyroidism (7.7%, P = .05) and not increased in subclinical thyroid dysfunction (5.0% in subclinical hypothyroidism, 3.3% in subclinical hyperthyroidism). Anemia associated with thyroid dysfunction was mainly normocytic (94.0%), and rarely macrocytic (6.0%). CONCLUSION The prevalence of anemia was higher in overt hyperthyroidism, but not increased in subclinical thyroid dysfunction. Systematic measurement of thyroid-stimulating hormone in anemic patients is likely to be useful only after excluding common causes of anemia.

Subclinical Thyroid Dysfunction and Frailty Among Older Men

CONTEXT Both subclinical thyroid dysfunction and frailty are common among older individuals, but data on the relationship between these 2 conditions are conflicting. OBJECTIVE The purpose of this study was to assess the cross-sectional and prospective associations between subclinical thyroid dysfunction and frailty and the 5 frailty subdomains (sarcopenia, weakness, slowness, exhaustion, and low activity). SETTING AND DESIGN The Osteoporotic Fractures in Men Study is a prospective cohort study. PARTICIPANTS Men older than 65 years (n = 1455) were classified into 3 groups of thyroid status: subclinical hyperthyroidism (n = 26, 1.8%), subclinical hypothyroidism (n = 102, 7.0%), and euthyroidism (n = 1327, 91.2%). MAIN OUTCOME MEASURES Frailty was defined using a slightly modified Cardiovascular Health Study Index: men with 3 or more criteria were considered frail, men with 1 to 2 criteria were considered intermediately frail, and men with no criteria were considered robust. We assessed the cross-sectional relationship between baseline thyroid function and the 3 categories of frailty status (robust/intermediate/frail) as well as the prospective association between baseline thyroid function and subsequent frailty status and mortality after a 5-year follow-up. RESULTS At baseline, compared with euthyroid participants, men with subclinical hyperthyroidism had an increased likelihood of greater frailty status (adjusted odds ratio, 2.48; 95% confidence interval, 1.15-5.34), particularly among men aged <74 years at baseline (odds ratio for frailty, 3.63; 95% confidence interval, 1.21-10.88). After 5 years of follow-up, baseline subclinical hypothyroidism and hyperthyroidism were not consistently associated with overall frailty status or frailty components. CONCLUSION Among community-dwelling older men, subclinical hyperthyroidism, but not subclinical hypothyroidism, is associated with increased odds of prevalent but not incident frailty.

Home parenteral nutrition is beneficial in systemic sclerosis patients with gastrointestinal dysfunction

OBJECTIVES To assess 12-month changes in nutritional status and quality of life (QoL) in systemic sclerosis (SSc) patients requiring home parenteral nutrition (HPN). METHOD We conducted a retrospective, single-centre database analysis of SSc patients regarding a 12-month period of HPN at an interdisciplinary University Unit/team for nutrition and rheumatic diseases. Nutritional status was analysed by nutritional risk screening (NRS) and body mass index (BMI). QoL was evaluated using Short-Form Health Survey (SF-36) questionnaires. RESULTS Between 2008 and 2013, daily nocturnal HPN was initiated in five consecutive SSc patients (four females and one male, mean age 62.2 years) suffering severe malnutrition due to gastrointestinal tract (GIT) involvement. After 12 months of HPN, the mean NRS score decreased from 4.4 (range 4-5) to 1.4 (range 1-2), the mean BMI increased from 19.1 (range 17.4-20.3) to 21.0 kg/m(2) (range 18.3-23.4). QoL improved in all patients, reflected by the summary of physical components with 33.92 points before vs. 67.72 points after 12 months of HPN, and the summary of mental components with 49.66 points before vs. 89.27 points after 12 months of HPN. Two patients suffered one catheter-related infection each with subsequent surgical removal and reinsertion. CONCLUSIONS HPN is a feasible method for improving anthropometric parameters and QoL in SSc patients severely affected by GIT dysfunction. We recommend HPN in malnourished, catabolic SSc patients unable to otherwise maintain or improve their nutritional status.

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg(-/-) mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg(-/-) foetal hearts. CPCs harvested from Speg(-/-) mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg(-/-) mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg(-/-) mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases.

Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.

BACKGROUND Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking. OBJECTIVES To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. PATIENTS Elderly participants with VTE. METHODS In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid stimulating hormone levels (TSH=4.50-19.99 mIU/l), and subclinical hyperthyroidism (SHyper) as TSH<0.45, both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling. RESULTS Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. rVTE incidence rate was 7.2 (95% confidence interval:2.7-19.2) per 100 patient-years in SHypo, 0.0 (0.0-7.6) in SHyper and 5.9 (4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio [SHR] for rVTE was 0.00 (0.00-0.58) in SHyper and 1.50 (0.52-4.34) in SHypo compared to euthyroids, without increased thrombophilic biomarkers. SHyper (HR 0.80,0.23-2.81) and SHypo (HR 0.99,0.30-3.29) were not associated with mortality. CONCLUSION In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers. This article is protected by copyright. All rights reserved.

Magnetic Resonance Imaging of the Pituitary Gland of Horses With Pituitary Pars Intermedia Dysfunction

Magnetic Resonance Imaging of the Pituitary Gland of Horses With Pituitary Pars Intermedia Dysfunction

ER strikes again: Proteostasis Dysfunction In ALS

The precise contribution of endoplasmic reticulum (ER) chaperone protein disulfide isomerase (PDI) variants in human amyotrophic lateral sclerosis (ALS) patients to the pathogenesis of ALS remained unclear. In the present study, Woehlbier et al (2016) demonstrated that these PDI variants are capable of altering motor neuron morphology, impairing the expression of synaptic proteins, and compromising neuromuscular junction (NMJ) integrity.