Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin (ET) produced by endothelial cells has recently been found to be a potent vasoconstricting hormone. In this report, ET is shown to be a potent stimulator of interleukin-6 (IL-6) production by rat bone marrow (BM)-derived stromal cells. It was also shown that ET increased the level of mRNA for IL-6 in these cells. The two types of ET receptor (R), ETAR and ETBR, were shown to be expressed on both BM-derived stromal cells in culture and ex vivo in BM tissue, suggesting that ET works as a physiologic stimulator of IL-6 production in the BM. It was shown that ETAR is coupled to phospholipase C activation, leading to the production of inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG) as second messengers in BM-derived stromal cells. This was corroborated by data showing that IL-6 production in these cells was induced by combined stimulation with ionomycin and phorbol myristate acetate, thereby bypassing the effects of IP3 and DAG, respectively. This is the first report on the hormonal regulation of IL-6 production by BM stromal cells, indicating that hematopoiesis is subject to endocrinologic regulation under physiologic conditions. ET has recently been reported to be produced by macrophages in response to bacterial lipopolysaccharide and human immunodeficiency virus-1 glycoprotein 120. These facts, taken together with our findings, raise the possibility that ET shares the same role of IL-1 as a local cytokine, mediating an intercellular signal between macrophages and BM stromal cells in response to bacterial or viral stimulation.
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PMID:Stimulation of interleukin-6 production by endothelin in rat bone marrow-derived stromal cells. 791 71

Clinical studies have shown the importance of endothelin as a pathogenic mediator in pulmonary arterial hypertension (PAH). We describe the effects of bosentan, an oral dual endothelin receptor antagonist, in patients with PAH associated with human immunodeficiency virus (HIV) infection. In this prospective study, 16 patients with PAH associated with HIV infection in stable condition received bosentan for 16 weeks. Efficacy endpoints included exercise capacity, cardiopulmonary hemodynamics, Doppler echocardiography, New York Heart Association functional class, and quality of life (SF-36 and EQ-5D). Safety was assessed by laboratory tests, vital signs, and adverse events. Improvements were observed from baseline to Week 16 in all efficacy parameters: 6-minute walk distance (+91 +/- 60 m, p < 0.001), New York Heart Association class (14 patients improved), hemodynamics (cardiac index: +0.9 +/- 0.7 L/minute/m(2), p < 0.001), Doppler echocardiographic variables, and quality of life. During the study, no patient died and none required epoprostenol treatment. Hepatic tolerability was similar to that reported in patients with PAH. Bosentan had no negative impact on control of HIV infection. Although limited by uncontrolled design, small sample size and short duration, this study suggests that bosentan may benefit patients with PAH associated with HIV infection, and that endothelin is an important pathogenic mediator in this disease.
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PMID:Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. 1531 66

Although extensively investigated, the complete repertoire of genes associated with and causative of metastasis remain largely unknown. We developed an efficient approach for identifying differentially expressed genes that involves rapid subtraction hybridization (RaSH) of cDNA clones prepared from two cell populations, a driver and a tester. This RaSH approach has previously documented high sensitivity and effectiveness in identifying genes that are differentially expressed as a function of induction of terminal differentiation in human melanoma cells, resistance or sensitivity to human immunodeficiency virus-1 (HIV-1) infection of human T cells and perturbation in gene expression in normal human fetal astrocytes infected with HIV-1 or treated with HIV-1 gp120 viral envelope glycoprotein or tumor necrosis factor-alpha (TNF-alpha). In the present study, RaSH has been applied to a metastatic melanoma model, which mimics the early events of metastasis in humans, comprising weakly metastatic vs. immunosuppressed newborn rat-selected highly metastatic variants. This has now resulted in the identification of eight genes displaying elevated expression in the high metastatic variants vs. normal immortal melanocytes or weakly metastatic parental clones. These include six known genes, 67-kDa laminin receptor (67LR), endothelin receptor B (ENDRB), Na+/K+-ATPase, Ku antigen, interleukin-receptor-associated kinase-1 (IRAK-1) and ribosomal protein RPLA, which may contribute to the complex process of melanoma metastasis. Additionally, two unknown genes (not reported in current databases) that may also impact on the metastatic phenotype have also been identified. These studies provide additional support of the use of the RaSH approach, in this application in the context of closely related variant cell lines with different metastatic potential, for effective differential gene identification and elucidate eight previously unrecognized genes whose role in melanoma progression to metastatic competence can now be scrutinized.
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PMID:Identification and cloning of genes displaying elevated expression as a consequence of metastatic progression in human melanoma cells by rapid subtraction hybridization. 1556 45

Secondary pulmonary arterial hypertension (SPAH) is an adverse outcome of a variety of systemic disorders. These include collagen vascular diseases, chronic thromboembolism, human immunodeficiency virus, portopulmonary hypertension, and other diseases. Progression of SPAH may persist despite stabilization of the causative disease, thereby contributing to the poor quality of life and unfavorable survival in these patients. Treatment of the underlying cause and oxygen supplementation may alleviate symptoms, but no specific therapy to treat SPAH currently exists. Endothelin receptor blockade with bosentan has been shown to be beneficial in the treatment of primary pulmonary hypertension, but efficacy of this therapy in SPAH has not been established. We describe a case series of 6 patients with disparate causes of SPAH, who benefited from endothelin receptor blockade therapy. The causes of SPAH included collagen vascular disease (scleroderma) (1); systemic lupus erythematosus (2); chronic thromboembolic disease (2); and granulomatous vasculitis from sarcoidosis (1). Therapy with bosentan led to improvements in symptoms, New York Heart Association functional class, and walking distance in all patients. Distance walked in 6 minutes increased from a mean of 151.67 +/- 69.30 m at baseline to 314.83 +/- 89.09 m after an average of 14 months of bosentan treatment. Pulmonary arterial pressure decreased in most but not all 6 patients on follow-up echocardiography. This case series suggests a role for endothelin receptor blockade therapy in SPAH and should generate further interest in pharmacologic management of SPAH. A prospective controlled clinical trial of bosentan in SPAH is urgently needed.
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PMID:Secondary pulmonary arterial hypertension: treated with endothelin receptor blockade. 1639 31

Viral breakthroughs (VB), defined as having detectable HCV VL while on anti-HCV therapy after achieving maximal suppression, have not yet been characterized with the use of PEG-IFN in HIV/HCV-coinfected patients. We evaluated possible mechanisms for VB among HIV/HCV-coinfected patients receiving PEG-IFN/RBV. Thirty HIV/HCV coinfected patients were treated with PEG-IFN (1.5 mug/kg sc qwk) and RBV (1-1.2 g daily) for 48 weeks. Liver chemistry, HCV VL, genotyping, DNA microarray, and sequencing of HCV E-2 envelope were performed before and during treatment. VB had lower baseline HCV VL but higher ALT and AST than relapsers (ETR) (p < 0.05) and lower CD4+ T lymphocytes (%) than patients with sustained virological responses (SVR), but similar first and second phase HCV viral kinetics (vs. ETR and SVR; p > 0.05). HCV genotypes and envelope sequences were similar for patients with VB pretreatment and at break-through. VB had higher levels of interferon-induced gene (IFIG) expression pretreatment than patients with ETR (p < 0.01). HIV/HCV-coinfected patients have a high rate of VB on PEG-IFN/RBV therapy characterized by higher levels of IFIG expression, immunodeficiency, and hepatic inflammation. Novel strategies are required for the treatment of persons with VB.
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PMID:Immunodeficiency and intrinsic IFN resistance are associated with viral breakthrough to HCV therapy in HIV-coinfected patients. 1818 77

The present study reports on the chromosomal expression and localization of aphidicolin-induced fragile sites in the standard karyotype of river buffalo (Bubalus bubalis, 2n = 50) with the aim of establishing a 'fragile site map' of the species. Totally, 400 aphidicolin-induced breakages were analyzed from eight young and clinically healthy animals, four males and four females; these breakages were localized in 106 RBG-negative chromosome bands or at the band-interband regions. The number of breakages per chromosome did not vary statistically 'among' the animals investigated but the differences among individual chromosomes were highly significant thus indicating that the chromosomal distribution of the breakages is not random and appears only partially related to chromosome length. Fragile sites were statistically determined as those chromosomal bands showing three or more breakages. In the river buffalo karyotype, 51 fragile sites were detected and localized on the standardized ideogram of the species. The most fragile bands were as follows: 9q213 with 24 breakages out of 400; 19q21 with 16, 17q21 and inacXq24 with 15, 15q23 with 13 and 13q23 with 12 breaks, respectively. Previous gene mapping analysis in this species has revealed that the closest loci to these fragile sites contain genes such as RASA1 and CAST (9q214), NPR3 and C9 (19q19), PLP and BTK (Xq24-q25), OarCP09 (15q24), and EDNRB (13q22) whose mutations are responsible for severe phenotypic malformations and immunodeficiency in humans as well as in mice and meat quality in pigs. Further cytogenetic and molecular studies are needed to fully exploit the biological significance of the fragile sites in karyotype evolution of domestic animals and their relationships with productive and reproductive efficiency of livestock.
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PMID:Chromosomal expression and localization of aphidicolin-induced fragile sites in the standard karyotype of river buffalo (Bubalus bubalis). 1846 45

Pulmonary arterial hypertension (PAH) is a rare but life-threatening complication of human immunodeficiency virus (HIV) infection. PAH can complicate the course of HIV infection regardless of the route of HIV transmission, the stage of HIV infection, and the degree of immunosuppression. The clinical presentation and underlying pathology of PAH associated with HIV infection (PAH-HIV) are similar to those encountered in other forms of PAH, although there are data suggesting a greater inflammatory component in the HIV-related form. Given the good long-term prognosis of HIV patients with highly active antiretroviral treatments and the severity of PAH in HIV-infected patients, screening for pulmonary hypertension according to a precise algorithm is warranted in HIV-infected patients presenting with dyspnea not explained by another cause. In all cases, right heart catheterization must be performed to establish the diagnosis of PAH. Beneficial effects of antiretroviral treatments on PAH-HIV still remain to be proven. Patients with PAH-HIV appear to respond well to treatment with the prostacyclin epoprostenol, although continuous intravenous infusion is associated with a range of potential complications. Treatment with the oral dual endothelin receptor antagonist bosentan has been shown to benefit patients with PAH-HIV without adversely affecting the control of HIV infection, and resulted in functional and hemodynamic normalization in approximately 20% of patients. Other PAH therapies, including prostacyclin analogs, type 5 phosphodiesterase inhibitors, and single endothelin receptor antagonists, have yet to be evaluated in PAH-HIV.
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PMID:Pulmonary arterial hypertension and HIV infection. 1963 83

Because of the improvement in survival rates of human immunodeficiency virus (HIV)-infected patients after the introduction of combined antiretroviral therapy, pulmonary arterial hypertension (PAH) has become an important cause of morbidity. As the awareness of PAH has increased, it is more likely that this condition will be diagnosed more frequently and earlier in the course of the disease and HIV infection. The etiopathogenesis is not clear; no evidence of direct infection of the pulmonary vascular tree has been found and the current evidence seems to favor a role of dysregulated cytokine response to HIV infection. The pathological changes of plexiform arteriopathy are indistinguishable from the pathological changes of idiopathic pulmonary arterial hypertension (IPAH). Dyspnea is the most common presenting symptom. Echocardiography, though always not accurate in diagnosing PAH and estimating its severity, remains the main screening tool. Right heart catheterization is the gold standard investigation for diagnosis. New therapies like prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors have improved the outcome of patients with HIV-associated PAH. However, the overall prognosis of HIV-infected patients who develop PAH still remains poor.
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PMID:Pulmonary arterial hypertension in human immunodeficiency virus infection. 1982 Feb 75

Pulmonary arterial hypertension (PAH), which can be a complication of human immunodeficiency virus (HIV) infection, is characterized by increased pulmonary arterial pressure and peripheral vascular resistance, subsequently leading to right heart failure. In HIV-infected patients, the management of PAH is challenging given the potential drug interactions between PAH-specific vasodilators and antiretroviral drugs. We describe a 51-year-old female with acquired immunodeficiency syndrome (AIDS) and HIV-associated PAH. She was treated with the oral endothelin receptor antagonist bosentan while taking a nevirapine (a nonnucleoside reverse transcriptase inhibitor)-based antiretroviral regimen. Due to concerns about potential drug interactions with the antiretroviral therapy, her nevirapine plasma concentration, as well as CD4(+) cell count and viral load, were continuously monitored. We observed no interaction between bosentan and nevirapine during a 4-year period. To our knowledge, this report is the first to demonstrate successful, long-term coadministration of bosentan and a nonnucleoside reverse transcriptase inhibitor.
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PMID:Successful bosentan and nonnucleoside reverse transcriptase inhibitor-based therapy in a patient with acquired immunodeficiency syndrome and pulmonary arterial hypertension. 2033 65

In recent years, the pathogenic role of human immunodeficiency virus (HIV) and the clinical manifestations of HIV-associated pulmonary arterial hypertension (HIV-PAH), which currently represents one of the most severe complications of HIV infection, have received more attention HIV-PAH occurs at all stages of the disease, and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HIV-PAH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnoea that will progress to the point of breathlessness at rest. Echocardiography is an extremely useful tool for the diagnosis of HIV-PAH, and Doppler echocardiography can be used to estimate systolic pulmonary artery pressure. Assessment of haemodynamic measures by catheterization remains, however, the best test for evaluating the response to therapy. Cardiac catheterization is mandatory to definitively diagnose the disease and exclude any underlying cardiac shunt as the aetiology. Recently, effective therapies for pulmonary arterial hypertension (PAH) have been available, including prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, allowing amelioration of symptoms and a better prognosis. However, HIV-PAH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new efficient antiretroviral treatment is introduced, clinicians should expect to encounter an increasing number of cases of PAH in HIV-infected patients in the future.
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PMID:Pulmonary hypertension and human immunodeficiency virus infection: epidemiology, pathogenesis, and clinical approach. 2054 62


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