Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and ...antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of
and
that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
In pulmonary arterial hypertension (PAH), antiapoptotic, proliferative, and inflammatory diatheses converge to create an obstructive vasculopathy. A selective down-regulation of the Kv channel Kv1.5 ...has been described in human and animal PAH. The resultant increase in intracellular free Ca²⁺ (Ca²⁺i) and K⁺ (K⁺i) concentrations explains the pulmonary artery smooth muscle cell (PASMC) contraction, proliferation and resistance to apoptosis. The recently described PASMC hyperpolarized mitochondria and increased bcl-2 levels also contribute to apoptosis resistance in PAH. The cause of the Kv1.5, mitochondrial, and inflammatory abnormalities remains unknown. We hypothesized that these abnormalities can be explained in part by an activation of NFAT (nuclear factor of activated T cells), a Ca²⁺/calcineurin-sensitive transcription factor. We studied PASMC and lungs from six patients with and four without PAH and blood from 23 PAH patients and 10 healthy volunteers. Compared with normal, PAH PASMC had decreased Kv current and Kv1.5 expression and increased Ca²⁺i, K⁺i, mitochondrial potential (ΔΨm), and bcl-2 levels. PAH but not normal PASMC and lungs showed activation of NFATc2. Inhibition of NFATc2 by VIVIT or cyclosporine restored Kv1.5 expression and current, decreased Ca²⁺i, K⁺i, bcl-2, and ΔΨm, leading to decreased proliferation and increased apoptosis in vitro. In vivo, cyclosporine decreased established rat monocrotaline-PAH. NFATc2 levels were increased in circulating leukocytes in PAH versus healthy volunteers. CD3-positive lymphocytes with activated NFATc2 were seen in the arterial wall in PAH but not normal lungs. The generalized activation of NFAT in human and experimental PAH might regulate the ionic, mitochondrial, and inflammatory remodeling and be a therapeutic target and biomarker.
Sildenafil was recently approved for the treatment of pulmonary arterial hypertension. The beneficial effects of phosphodiesterase type 5 (PDE5) inhibitors in pulmonary arterial hypertension are ...thought to result from relatively selective vasodilatory and antiproliferative effects on the pulmonary vasculature and, on the basis of early data showing lack of significant PDE5 expression in the normal heart, are thought to spare the myocardium.
We studied surgical specimens from 9 patients and show here for the first time that although PDE5 is not expressed in the myocardium of the normal human right ventricle (RV), mRNA and protein are markedly upregulated in hypertrophied RV (RVH) myocardium. PDE5 also is upregulated in rat RVH. PDE5 inhibition (with either MY-5445 or sildenafil) significantly increases contractility, measured in the perfused heart (modified Langendorff preparation) and isolated cardiomyocytes, in RVH but not normal RV. PDE5 inhibition leads to increases in both cGMP and cAMP in RVH but not normal RV. Protein kinase G activity is suppressed in RVH, explaining why the PDE5 inhibitor-induced increase in cGMP does not lead to inhibition of contractility. Rather, it leads to inhibition of the cGMP-sensitive PDE3, explaining the increase in cAMP and contractility. This is further supported by our findings that, in RVH protein kinase A, inhibition completely inhibits PDE5-induced inotropy, whereas protein kinase G inhibition does not.
The ability of PDE5 inhibitors to increase RV inotropy and to decrease RV afterload without significantly affecting systemic hemodynamics makes them ideal for the treatment of diseases affecting the RV, including pulmonary arterial hypertension.
Background Isolated loss-of-function single nucleotide polymorphisms (SNPs) for
(a mitochondrial deacetylase) and
(an atypical uncoupling protein enabling mitochondrial calcium entry) have been ...associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both
and
along with several clinical features (including invasive hemodynamic data) and outcomes. We found
and
SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10-year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for
and
and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose-dependent manner), along with insulin resistance, compared with wild-type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild-type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.
Psychological assessment can play an important role in informing the intervention process with child and adolescent victims of maltreatment. This study investigated the validity of the Rorschach in ...assessing aggressive drive derivatives using a profile-based approach, with a sample of 108 children and adolescents in foster care. Aggression indicators were derived from the work of Gacono and Meloy (
1994
). Latent class analysis yielded a 4-class model including gender and age as covariates. The first 2 classes were characterized by low prevalence rates across all indicators of aggression, and were distinguished primarily on the basis of participant's age. The 3rd class was characterized by the presence of Aggressive Vulnerability (AgV) responses, whereas the 4th showed higher occurrence of all markers except AgV. Modest associations were found between characteristics of abuse, select classes, and behavior problems. The 4th class showed the strongest link with behavior problems, albeit only in the presence of ego impairment. These findings support a contextualized, developmentally informed use of aggression markers on the Rorschach in the context of child maltreatment.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Research Findings: This study examined the moderating role of parenting style in the relations between different dimensions of parental involvement and their children's school readiness. A total of ...311 Chinese parents (Mean age = 35.74, SD = 4.61) and their kindergarten children (Mean age = 5.53, SD = .50) participated in this study. Parents completed questionnaires about their demographic information, parenting styles and parental involvement practices and teachers rated children's school readiness levels. Results indicated that parents' home-based, school-based and home-school conferencing involvement were all positively related to children's school readiness. Home-based involvement showed stronger relationship to children's school readiness than the other two types of parental involvement. In addition, authoritative parenting moderated the effects of both school-based involvement and home-school conferencing on children's school readiness. The effect of school-based involvement was enhanced in the context of high authoritative parenting style. In contrast, the effect of home-school conferencing was decreased in the context of low authoritative parenting style. Practice or Policy. The results suggest that programs designed for enhancing parents' involvement in children's school readiness need to consider the emotional context that parents create through their parenting style. Implications for practice and suggestions for further research are offered.
Objective: Appropriate laboratory testing practices are a critical part of sexually transmitted disease (STD) control. Goal: The goal of this study was to describe the type and volume of STD tests ...performed in public health laboratories in the United States in 2004. Study Design: A web-based survey was made available to 144 members of the Association of Public Health Laboratories. Results: One hundred fourteen laboratories responded (79%). Overall, 3,553,196 chlamydia tests and 3,461,151 gonorrhea tests were performed; 64.4% of chlamydia tests and 60.8% of gonorrhea tests were nucleic acid amplification tests. Ninety-four percent of laboratories performed syphilis testing. Few laboratories used type-specific tests for herpes simplex virus or used new tests for trichomoniasis, bacterial vaginosis, or human papillomavirus. Conclusions: This survey collected important data that can be used to monitor trends in STD testing practices in public health laboratories.
Suppression of mitochondrial function promoting proliferation and apoptosis suppression has been described in the pulmonary arteries and extrapulmonary tissues in pulmonary arterial hypertension ...(PAH), but the cause of this metabolic remodeling is unknown. Mice lacking sirtuin 3 (SIRT3), a mitochondrial deacetylase, have increased acetylation and inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial function. Sirt3KO mice develop spontaneous PAH, exhibiting previously described molecular features of PAH pulmonary artery smooth muscle cells (PASMC). In human PAH PASMC and rats with PAH, SIRT3 is downregulated, and its normalization with adenovirus gene therapy reverses the disease phenotype. A loss-of-function SIRT3 polymorphism, linked to metabolic syndrome, is associated with PAH in an unbiased cohort of 162 patients and controls. If confirmed in large patient cohorts, these findings may facilitate biomarker and therapeutic discovery programs in PAH.
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•Sirt3−/− and Sirt3+/− mice develop PAH in a gene dose-dependent manner•SIRT3 is downregulated in the moncrotaline rat model of PAH and human PAH tissues•Sirt3 gene therapy reverses PAH in rats in vivo and human vascular cells in vitro•A SIRT3 loss-of-function polymorphism is associated with idiopathic PAH in humans
Pulmonary arterial hypertension (PAH) is a serious form of high blood pressure in the lung arteries. Paulin et al. show that SIRT3 deficiency is associated with the underlying suppressed mitochondrial function resulting in the development of PAH in rodents and humans.
A range of assessment methodologies pertaining to attachment in children have been developed and validated during the past decades. The present study examined the validity of a sequential, ...profile-centered approach to the assessment of attachment disorganization using a doll play methodology developed by George and Solomon (
1990
). The sample was composed of sixty-two children between the age of 5 and 12 who had been removed from their family of origin due to abuse or neglect. Latent Markov Models performed on markers of defensive dysregulation (Frightening, Chaos, Constriction) yielded three distinct states, characterized respectively by themes of fear or chaos, presence of at least partial constriction, and absence of segregated system markers across doll play stories. The states generally showed a high degree of stability across scenarios. The Frightening-Chaotic state was positively associated with sexual abuse, placement in a specialized setting and caregiver-reported externalizing problems whereas the Constricted state was associated with placement in a specialized setting and self-reported hyperactivity and attention problems. These results provide support for the validity and clinical utility of this approach to assessing attachment disorganization on the doll play.
This study preliminarily examined the multiple dimensions of Chinese family involvement in early childhood education across demographic variables through a pilot translation and validation of a ...revised 36-item measure of the Family Involvement Questionnaire (FIQ; Fantuzzo, J., E. Tighe, and S. Childs. 2000. "Family Involvement Questionnaire: A Multivariate Assessment of Family Participation in Early Childhood Education." Journal of Educational Psychology 92 (2): 367-376) for use in Chinese kindergartens. Participants were 311 parents or caregivers (Mean age = 35.74) of children (Mean age = 5.53) enrolled in kindergartens in Shanghai, China. Exploratory factor analysis revealed a three-factor structure similar to the original (non-Chinese) FIQ: school-based involvement, home-based involvement, and home-school conferencing. However, 12 items were removed because they either had cross loadings or did not load onto any factors. As expected, based on prior research with the original FIQ, differences in the Chinese Family Involvement Questionnaire (FIQ-C, hereafter) dimension scores across subgroups based on parents' educational levels and monthly family income were found using MANOVA. Implications for future research and cross-cultural studies on family involvement are discussed.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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