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Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-Î³ Disrupts Vascular Wall Structure and Function. - PloS one
Activation of the nuclear hormone receptor, PPARÎ³, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARÎ³-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARÎ³ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARÎ³ overexpression (smPPARÎ³OE). Our results demonstrate that smPPARÎ³OE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPARÎ³OE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPARÎ³ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARÎ³ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARÎ³ activity is essential for vascular smooth muscle homeostasis.
Mutations causing mitochondrial disease: What is new and what challenges remain? - Science (New York, N.Y.)
Mitochondrial diseases are among the most common and most complex of all inherited genetic diseases. The involvement of both the mitochondrial and nuclear genome presents unique challenges, but despite this there have been some remarkable advances in our knowledge of mitochondrial diseases over the past few years. A greater understanding of mitochondrial genetics has led to improved diagnosis as well as novel ways to prevent transmission of severe mitochondrial disease. These and other advances have had a major impact on patient care, but considerable challenges remain, particularly in the areas of therapies for those patients manifesting clinical symptoms associated with mitochondrial dysfunction and the tissue specificity seen in many mitochondrial disorders. This review highlights some important recent advances in mitochondrial disease but also stresses the areas where progress is essential.Copyright Â© 2015, American Association for the Advancement of Science.
Discrimination, mental health, and leukocyte telomere length among African American men. - Psychoneuroendocrinology
African American men in the US experience disparities across multiple health outcomes. A common mechanism underlying premature declines in health may be accelerated biological aging, as reflected by leukocyte telomere length (LTL). Racial discrimination, a qualitatively unique source of social stress reported by African American men, in tandem with poor mental health, may negatively impact LTL in this population. The current study examined cross-sectional associations between LTL, self-reported racial discrimination, and symptoms of depression and anxiety among 92 African American men 30-50 years of age. LTL was measured in kilobase pairs using quantitative polymerase chain reaction assay. Controlling for sociodemographic factors, greater anxiety symptoms were associated with shorter LTL (b=-0.029, standard error [SE]=0.014; p<0.05). There were no main effects of racial discrimination or depressive symptoms on LTL, but we found evidence for a significant interaction between the two (b=0.011, SE=0.005; p<0.05). Racial discrimination was associated with shorter LTL among those with lower levels of depressive symptoms. Findings from this study highlight the role of social stressors and individual-level psychological factors for physiologic deterioration among African American men. Consistent with research on other populations, greater anxiety may reflect elevated stress associated with shorter LTL. Racial discrimination may represent an additional source of social stress among African American men that has detrimental consequences for cellular aging among those with lower levels of depression.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Telomere Fragment Induced Amnion Cell Senescence: A Contributor to Parturition? - PloS one
Oxidative stress (OS)-induced senescence of the amniochorion has been associated with parturition at term. We investigated whether telomere fragments shed into the amniotic fluid (AF) correlated with labor status and tested if exogenous telomere fragments (T-oligos) could induce human and murine amnion cell senescence. In a cross-sectional clinical study, AF telomere fragment concentrations quantitated by a validated real-time PCR assay were higher in women in labor at term compared to those not in labor. In vitro treatment of primary human amnion epithelial cells with 40 Î¼M T-oligos ([TTAGGG]2) that mimic telomere fragments, activated p38MAPK, produced senescence-associated (SA) Î²-gal staining and increased interleukin (IL)-6 and IL-8 production compared to cells treated with complementary DNA sequences (Cont-oligos, [AATCCC]2). T-oligos injected into the uteri of pregnant CD1 mice on day 14 of gestation, led to increased p38MAPK, SA-Î²-gal (SA Î²-gal) staining in murine amniotic sacs and higher AF IL-8 levels on day 18, compared to saline treated controls. In summary, term labor AF samples had higher telomere fragments than term not in labor AF. In vitro and in situ telomere fragments increased human and murine amnion p38MAPK, senescence and inflammatory cytokines. We propose that telomere fragments released from senescent fetal cells are indicative of fetal cell aging. Based on our data, these telomere fragments cause oxidative stress associated damages to the term amniotic sac and force them to release other DAMPS, which, in turn, provide a sterile immune response that may be one of the many inflammatory signals required to initiate parturition at term.
Downregulation of Apelin in the Human Placental Chorionic Villi from Preeclamptic Pregnancies. - American journal of physiology. Endocrinology and metabolism
The role of the endogenous apelin system in pregnancy is not well understood. Apelin's actions in pregnancy are further complicated by the expression of multiple forms of the peptide. Using radioimmunoassay (RIA) alone, we established the expression of apelin content in the chorionic villi of preeclamptic (PRE) and normal pregnant women (NORM) at 36-38 weeks of gestation. Total apelin content was lower in PRE compared to NORM chorionic villi (49.7Â±3.4 vs.72.3Â±9.8 fmol/mg protein, n=20-22) and was associated with a trend for lower preproapelin mRNA in the PRE. Further characterization of apelin isoforms by HPLC-RIA was conducted in pooled samples from each group. The expression patterns of apelin peptides in NORM and PRE villi revealed little or no apelin-36 or apelin-17. Pyroglutamate apelin-13 [(Pyr(1))-apelin-13] was the predominant form of the peptide in NORM and PRE villi. ACE2 activity was higher in PRE villi (572.0Â±23.0 vs. 485.3Â±24.8 pmol/mg/min, n=18-22). Low dose of Ang II (1nM; 2 hours) decreased apelin release in NORM villous explants that was blocked by the AT1 receptor antagonist losartan. Moreover, losartan enhanced apelin release above the 2-hour baseline levels in both NORM and PRE villi (p<0.05). In summary, these studies are the first to demonstrate the lower apelin content in human placental chorionic villi of PRE subjects using quantitative RIA. (Pyr(1))-apelin-13 is the predominant form of endogenous apelin in the chorionic villi of NORM and PRE. The potential mechanism of lower apelin expression in the PRE villi may involve a negative regulation of apelin by Ang II.Copyright Â© 2015, American Journal of Physiology - Endocrinology and Metabolism.
Perspectives on Intravenous Oxycodone for Control of Postoperative Pain. - Pain practice : the official journal of World Institute of Pain
Intravenous (IV) analgesia has particular advantages in the immediate postoperative period. For example, IV administration results in a faster onset of pain relief and results in more predictable pharmacokinetics than does administration by other routes. It also allows for convenient dosing before or during surgery, permitting the initiation of effective analgesia in the early phase of the postoperative period. In addition, when patients are able to tolerate oral intake, they can be switched from IV to oral dosing based on maintaining the predictable analgesia established by the IV route. IV morphine is widely used for the control of postoperative pain, but there is a trend toward the use of oxycodone. Oxycodone (which may be mediated partly through kappa- as well as mu-opioid receptors) offers several potential advantages. Published studies comparing IV oxycodone to other IV opioids for postsurgical pain report that oxycodone is a safe and effective analgesic. Some studies show that IV oxycodone may be associated with greater pain control, fewer or less severe adverse events, and faster onset of action, although the results are not consistent across all studies. Oxycodone has been reported to be safe in the geriatric and other special populations when adequate clinical adjustments are made. Thus, the clinical reports and oxycodone's pharmacologic profile make intravenous oxycodone a potentially important "new" old drug for postoperative pain control.Â© 2015 World Institute of Pain.
Epilepsy in adults with mitochondrial disease: A cohort study. - Annals of neurology
To determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between Jan 1(st) 2005 and Jan 1(st) 2008. We then followed this cohort over a 7 year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death.The overall prevalence of epilepsy in the cohort was 23.1%. The mean age of epilepsy onset was 29.4 years. The prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke-like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83).Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease, and in the case of the m.3243A>G mutation often presents in the context of a stroke-like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. This article is protected by copyright. All rights reserved.Â© 2015 American Neurological Association.
Support of Joint Function, Range of Motion, and Physical Activity Levels by Consumption of a Water-Soluble Egg Membrane Hydrolyzate. - Journal of medicinal food
This study evaluated the effects of consumption of hydrolyzed water-soluble egg membrane (WSEM) on joint function in an otherwise healthy population experiencing chronic pain. A randomized, double-blind, placebo-controlled crossover study included two 4-week periods of placebo and WSEM consumption, separated by a 4-week washout period. Twenty-five study participants were randomized to either the "placebo-first" or "WSEM first" sequence in the crossover trial, and 22 participants completed the study requirements. Range of motion (ROM) was assessed using digital inclinometry for joints associated with vertical weight bearing from neck to knees and for shoulders. Pain at rest and when physically active was scored for the same anatomical areas using visual analog scales (VAS). Physical functioning was tracked using questionnaires with VAS. Consumption of WSEM was associated with improved ROM for neck, spine, hips, and knees, with ROM for the neck and right knee being significantly improved during WSEM consumption compared to placebo (Pâ€‰<â€‰.05). ROM improvement for the dominant shoulder was highly significant during WSEM consumption (Pâ€‰<â€‰.01). Physical activity levels were significantly higher after WSEM than after placebo consumption (Pâ€‰<â€‰.05). Many aspects of physical functioning as part of daily living improved. Subgroup analysis showed rapid improvement of lower back pain after 5 days of WSEM consumption compared to placebo consumption (Pâ€‰<â€‰.05) in subjects who participated in the study during the winter season. Daily consumption of 450â€‰mg WSEM was associated with improved joint function, comfort during daily activities, and increased physical activity.
The presence of highly disruptive 16S rRNA mutations in clinical samples indicates a wider role for mutations of the mitochondrial ribosome in human disease. - Mitochondrion
Mitochondrial DNA mutations are well recognized as an important cause of disease, with over two hundred variants in the protein encoding and mt-tRNA genes associated with human disorders. In contrast, the two genes encoding the mitochondrial rRNAs (mt-rRNAs) have been studied in far less detail. This is because establishing the pathogenicity of mt-rRNA mutations is a major diagnostic challenge. Only two disease causing mutations have been identified at these loci, both mapping to the small subunit (SSU). On the large subunit (LSU), however, the evidence for the presence of pathogenic LSU mt-rRNA changes is particularly sparse. We have previously expanded the list of deleterious SSU mt-rRNA mutations by identifying highly disruptive base changes capable of blocking the activity of the mitoribosomal SSU. To do this, we used a new methodology named heterologous inferential analysis (HIA). The recent arrival of near-atomic-resolution structures of the human mitoribosomal LSU, has enhanced the power of our approach by permitting the analysis of the corresponding sites of mutation within their natural structural context. Here, we have used these tools to determine whether LSU mt-rRNA mutations found in the context of human disease and/or ageing could disrupt the function of the mitoribosomal LSU. Our results clearly show that, much like the for SSU mt-rRNA, LSU mt-rRNAs mutations capable of compromising the function of the mitoribosomal LSU are indeed present in clinical samples. Thus, our work constitutes an important contribution to an emerging view of the mitoribosome as an important element in human health.Copyright Â© 2015 The Authors. Published by Elsevier B.V. All rights reserved.
Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease. - Neuropathology and applied neurobiology
Cerebellar ataxia is common in patients with mitochondrial disease, and despite previous neuropathological investigations demonstrating vulnerability of the olivocerebellar pathway in patients with mitochondrial disease, the exact neurodegenerative mechanisms are still not clear. We use quantitative quadruple immunofluorescence to enable precise quantification of mitochondrial respiratory chain protein expression in Purkinje cell bodies and their synaptic terminals in the dentate nucleus.We investigated NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 protein expression in 12 clinically and genetically defined patients with mitochondrial disease and ataxia and 10 age-matched controls. Molecular genetic analysis was performed to determine heteroplasmy levels of mutated mitochondrial DNA in Purkinje cell bodies and inhibitory synapses.Our data reveal that complex I deficiency is present in both Purkinje cell bodies and their inhibitory synapses which surround dentate nucleus neurons. Inhibitory synapses are fewer and enlarged in patients which could represent a compensatory mechanism. Mitochondrial DNA heteroplasmy demonstrated similarly high levels of mutated mitochondrial DNA in cell bodies and synapses.This is the first study to use a validated quantitative immunofluorescence technique to determine complex I expression in neurons and presynaptic terminals, evaluating the distribution of respiratory chain deficiencies and assessing the degree of morphological abnormalities affecting synapses. Respiratory chain deficiencies detected in Purkinje cell bodies and their synapses and structural synaptic changes are likely to contribute to altered cerebellar circuitry and progression of ataxia.Â© 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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301 E. Carmel Drive Ste. #H-100 Carmel, IN 46032
10101 Ditch Rd
11900 N Pennsylvania St Ste 202