442 research outputs found
Assessment of right ventricular function at rest and during exercise by echocardiography in patients with pulmonary hypertension
Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension
<p>Abstract</p> <p>Background</p> <p>Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (<it>BMPR2</it>) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in <it>BMPR2 </it>gene have more severe disease than patients with truncating mutations.</p> <p>Methods</p> <p>We reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1<sup>st </sup>2004 and April, 1<sup>st </sup>2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a <it>BMPR2 </it>mutation, according to gender or <it>BMPR2 </it>mutation type.</p> <p>Results</p> <p>PAH patients carrying a <it>BMPR2 </it>mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 Ā± 15.4 and 47.5 Ā± 16.2 respectively, p < 0.0001). The presence of a <it>BMPR2 </it>mutation was associated with a younger age at diagnosis in females (36.4 Ā± 14.9 in <it>BMPR2 </it>mutation carriers and 47.4 Ā± 15.8 in non-carriers, p < 0.0001), and males (34.6 Ā± 16.8 in <it>BMPR2 </it>mutation carriers and 47.8 Ā± 17.1 in non-carriers, p < 0.0001). <it>BMPR2 </it>mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a <it>BMPR2 </it>mutation. No differences were observed in clinical outcomes according to the type of <it>BMPR2 </it>mutations (missense, truncating, large rearrangement or splice defect).</p> <p>Conclusion</p> <p>When compared to non-carriers, <it>BMPR2 </it>mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, <it>BMPR2 </it>mutation type had no influence on clinical phenotypes in our patient population.</p
Hypoxia and dehydroepiandrosterone in old age: a mouse survival study
BACKGROUND: Survival remains an issue in pulmonary hypertension, a chronic disorder that often affects aged human adults. In young adult mice and rats, chronic 50% hypoxia (11% FIO2 or 0.5 atm) induces pulmonary hypertension without threatening life. In this framework, oral dehydroepiandrosterone was recently shown to prevent and reverse pulmonary hypertension in rats within a few weeks. To evaluate dehydroepiandrosterone therapy more globally, in the long term and in old age, we investigated whether hypoxia decreases lifespan and whether dehydroepiandrosterone improves survival under hypoxia. METHODS: 240 C57BL/6 mice were treated, from the age of 21 months until death, by normobaric hypoxia (11% FIO2) or normoxia, both with and without dehydroepiandrosterone sulfate (25 mg/kg in drinking water) (4 groups, N = 60). Survival, pulmonary artery and heart remodeling, weight and blood patterns were assessed. RESULTS: In normoxia, control mice reached the median age of 27 months (median survival: 184 days). Hypoxia not only induced cardiopulmonary remodeling and polycythemia in old animals but also induced severe weight loss, trembling behavior and high mortality (p < 0.001, median survival: 38 days). Under hypoxia however, dehydroepiandrosterone not only significantly reduced cardiopulmonary remodeling but also remarkably extended survival (p < 0.01, median survival: 126 days). Weight loss and trembling behavior at least partially remained, and polycythemia completely, the latter possibly favorably participating in blood oxygenation. Interestingly, at the dose used, dehydroepiandrosterone sulfate was detrimental to long-term survival in normoxia (p < 0.05, median survival: 147 days). CONCLUSION: Dehydroepiandrosterone globally reduced what may be called an age-related frailty induced by hypoxic pulmonary hypertension. This interestingly recalls an inverse correlation found in the prospective PAQUID epidemiological study, between dehydroepiandrosterone blood levels and mortality in aged human smokers and former smokers
Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in human pregnancy
BACKGROUND: It is known that during normal pregnancy and after immunotherapy blocking antibodies are developed, these antibodies inhibit mixed lymphocyte reaction and are also anti-mitogenic in nature. Mixed lymphocyte reaction blocking antibodies are specific to the husband's lymphocytes. In the present study an attempt has been made to characterize the mixed lymphocyte reaction blocking antibodies in normal pregnancy and in women with recurrent spontaneous abortion after immunotherapy. METHODS: Serum was obtained from women of different gestational windows of pregnancy (Ist, IInd, IIIrd trimesters and post delivery period of normal pregnancy), recurrent spontaneous aborters from pre and post immunization. Healthy (male and females) controls were screened for the presence of mixed lymphocyte reaction blocking antibodies. The standard mixed lymphocyte reaction technique was used to evaluate the inhibitory effect of serum in the mixed lymphocyte reaction. Each serum was tested for cytotoxic antibodies. Immunoglobulin G and its isotypes were isolated according to the standard protocol. RESULTS: In the present study we have observed that there was significant inhibition of proliferation response when immunoglobulin G from different trimesters of pregnancy were added to one way mixed lymphocyte reaction or to phytohemagglutinin activated lymphocyte proliferation assay. Similar pattern was seen when immunoglobulin G isolated from adequately immunized women with recurrent spontaneous abortion was used. It was further confirmed that amongst all the isotypes of immunoglobulin G, only immunoglobulin G-3 was found to be positive for the inhibitory effect. CONCLUSIONS: Present study indicates that mixed lymphocyte reaction blocking antibodies are immunoglobulin G-3 in nature. It is developed during pregnancy and also after immunotherapy in women with recurrent spontaneous abortion who subsequently have the successful pregnancy
Health-related quality of life and long-term prognosis in chronic hypercapnic respiratory failure: a prospective survival analysis
<p>Abstract</p> <p>Background</p> <p>Health-related quality of life (HRQL) is considered as an important outcome parameter in patients with chronic diseases. This study aimed to assess the role of disease-specific HRQL for long-term survival in patients of different diagnoses with chronic hypercapnic respiratory failure (CHRF).</p> <p>Methods</p> <p>In a cohort of 231 stable patients (chronic obstructive pulmonary disease (COPD), n = 98; non-COPD (obesity-hypoventilation syndrome, restrictive disorders, neuromuscular disorders), n = 133) with CHRF and current home mechanical ventilation (HMV), HRQL was assessed by the disease-specific Severe Respiratory Insufficiency (SRI) questionnaire and its prognostic value was prospectively evaluated during a follow-up of 2ā4 years, using univariate and multivariate regression analysis.</p> <p>Results</p> <p>HRQL was more impaired in COPD (mean Ā± SD SRI-summary score (SRI-SS) 52.5 Ā± 15.6) than non-COPD patients (67.6 Ā± 16.4; p < 0.001). Overall mortality during 28.9 Ā± 8.8 months of follow-up was 19.1% (31.6% in COPD, 9.8% in non-COPD). To identify the overall role of SRI, we first evaluated the total study population. SRI-SS and its subdomains (except attendance symptoms and sleep), as well as body mass index (BMI), leukocyte number and spirometric indices were associated with long-term survival (p < 0.01 each). Of these, SRI-SS, leukocytes and forced expiratory volume in 1 s (FEV<sub>1</sub>) turned out to be independent predictors (p < 0.05 each). More specifically, in non-COPD patients SRI-SS and most of its subdomains, as well as leukocyte number, were related to survival (p < 0.05), whereas in patients with COPD only BMI and lung function but not SRI were predictive.</p> <p>Conclusion</p> <p>In patients with CHRF and HMV, the disease-specific SRI was an overall predictor of long-term survival in addition to established risk factors. However, the SRI predominantly beared information regarding long-term survival in non-COPD patients, while in COPD patients objective measures of the disease state were superior. This on one hand highlights the significance of HRQL in the long-term course of patients with CHRF, on the other hand it suggests that the predictive value of HRQL depends on the underlying disease.</p
Tyrphostins that suppress the growth of human papilloma virus 16āimmortalized human keratinocytes
ABSTRACT Human papilloma virus 16 (HPV16) is considered to be the causative agent for cervical cancer, which ranks second to breast cancer in women's malignancies. In an attempt to develop drugs that inhibit the malignant transformation of HPV16-immortalized epithelial cells, we examined the effect of tyrphostins on such cells. We examined the effect of tyrphostins from four different families on the growth of HPV16-immortalized human keratinocytes (HF-1) cells. We found that they alter their cell cycle distribution, their morphology, and induce cell death by apoptosis. The effects of tyrphostins on HF-1 cells are different from their effects on normal keratinocytes. Growth suppression by AG555 and AG1478 is accompanied by 30% apoptosis in HF-1 cells, but this is not observed in normal keratinocytes. Tyrphostin treatment produces distinctive morphological changes in HF-1 cells and in normal keratinocytes; however, the culture organization of normal keratinocytes is less disrupted. These differential effects of the tyrphostins on HPV16-immortalized keratinocytes compared with their effects on normal keratinocytes suggests that these compounds are suitable candidates for the treatment of papilloma. Previous and present results indicate that group 1 tyrphostins, which inhibit Cdk2 activation, and group 2 tyrphostins, represented by AG1478, a potent epidermal growth factor receptor kinase inhibitor, induce cell cycle arrest; and, in the case of HF-1 cells, apoptosis and differentiation. Cells accumulate in the G 1 phase of the cell cycle at the expense of S and G 2 Ļ© M. These compounds block the growth of normal keratinocytes without inducing apoptosis or differentiation, causing them to accumulate in G 1 . AG17, which belongs to group 4, exerts its antiproliferative effect mainly by increasing the fractions of cells in G 1 with a concomitant decrease in the fraction of cells in S and G 2 Ļ© M
The increase in pulmonary arterial pressure caused by hypoxia depends on iron status
Hypoxia is a major cause of pulmonary hypertension. Gene expression activated by the transcription factor hypoxia-inducible factor (HIF) is central to this process. The oxygen-sensing iron-dependent dioxygenase enzymes that regulate HIF are highly sensitive to varying iron availability. It is unknown whether iron similarly influences the pulmonary vasculature. This human physiology study aimed to determine whether varying iron availability affects pulmonary arterial pressure and the pulmonary vascular response to hypoxia, as predicted biochemically by the role of HIF. In a controlled crossover study, 16 healthy iron-replete volunteers undertook two separate protocols. The āIron Protocolā studied the effects of an intravenous infusion of iron on the pulmonary vascular response to 8 h of sustained hypoxia. The āDesferrioxamine Protocolā examined the effects of an 8 h intravenous infusion of the iron chelator desferrioxamine on the pulmonary circulation. Primary outcome measures were pulmonary artery systolic pressure (PASP) and the PASP response to acute hypoxia (ĪPASP), assessed by Doppler echocardiography. In the Iron Protocol, infusion of iron abolished or greatly reduced both the elevation in baseline PASP (P < 0.001) and the enhanced sensitivity of the pulmonary vasculature to acute hypoxia (P = 0.002) that are induced by exposure to sustained hypoxia. In the Desferrioxamine Protocol, desferrioxamine significantly elevated both PASP (P < 0.001) and ĪPASP (P = 0.01). We conclude that iron availability modifies pulmonary arterial pressure and pulmonary vascular responses to hypoxia. Further research should investigate the potential for therapeutic manipulation of iron status in the management of hypoxic pulmonary hypertensive disease
Case report 511
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46790/1/256_2004_Article_BF00364055.pd
Comprehensive expression analysis of prostanoid enzymes and receptors in the human endometrium across the menstrual cycle
Prostanoids are well-described primary mediators of inflammatory processes and are essential for the normal physiological function of the female reproductive system. The aim of this study was to determine the temporal expression of the prostanoid biosynthetic enzymes (PTGS1, PTGS2, PTGES, PTGES2, PTGES3, AKR1B1, AKR1C3, CBR1, HPGDS, PTGDS, PTGIS, TBXAS1 and HPGD) and the prostanoid receptors (PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGDR, GPR44, PTGIR and TBXA2R) in the human endometrium throughout the menstrual cycle. The analysis identified PTGFR to have a distinct expression profile compared with other components of the prostanoid system, as expression is maximal during the proliferative phase. Immunohistochemical analysis for PTGER1 suggests a dual function for this receptor depending on its temporal (proliferative versus secretory) and spatial (nuclear versus cell membrane) expression. The expression profiles of the PGF2Ī± synthases identified AKR1B1 and CBR1 as the likely regulators of PGF2Ī± production during the menstrual phase. Immunohistochemical analysis for AKR1B1, CBR1 and AKR1C3 suggest expression to be in the glandular epithelium and vasculature. This study represents the first comprehensive analysis of the components of prostanoid biosynthetic and signalling pathway in the human endometrium. The expression profiles described have the potential to identify specific prostanoid components that may be dysregulated in inflammatory-associated disorders of the endometrium
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