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PubMed1984

Visualization of both peroxidase and acid phosphatase isozymes from flax (Linum) on the same gels.

The staining of both peroxidases (PERs) and acid phosphatases (APs) following electrophoresis on acrylamide gels is described. Scanning doubly stained gels at appropriate wavelengths reveals individual isozyme bands for both enzyme systems, giving essentially identical results to those obtained from separately run and stained gels. Collection of relative mobility (Rm) data is unaffected by such tandem staining. Few complications arise from overlapping PER and AP bands, or interactions between the two staining methods and PER or AP isozymes. Even if repeat scans of a gel at different wavelengths are needed to retrieve all isozyme information, dual staining provides distinct savings in time and sample material.

Acid Phosphatase↗
PubMedDate not supplied

Crystallization and preliminary crystal structure of the complex of 17beta-hydroxysteroid dehydrogenase with a dual-site inhibitor.

Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) catalyzes the synthesis of 17beta-estradiol (E2) from estrone, in the ovary and peripheral tissues. While the structures of 17beta-HSD1 alone and in complex with E2 have been determined (D. Ghosh, V. Pletnev, D.-W. Zhu, Z. Wawrzak, W.-L. Duax, W. Pangborn, F. Labrie, S.-X. Lin, Structure of human 17beta-hydroxysteroid dehydrogenase at 2.20 A resolution, Structure 3 (1995) 503-513), no structures of inhibitor/enzyme complex, either modeled or from crystallography, have been reported before the submission of the present paper. The best available inhibitors are among the 'dual-site inhibitors', blocking estrogenic 17beta-HSD and the estrogen receptor. These compounds belong to a family of estradiol analogues having an halogen atom at the 16alpha position and an extended alkyl-amide chain at the 7alpha position (C. Labrie, G. Martel, J.M. Dufour, G. Levesque, Y. Merand, F. Labrie, Novel compounds inhibit estrogen formation and action, Cancer Res. 52 (1992) 610-615). We now report the crystallization of this enzyme/inhibitor complex. The complex of the best available dual-site inhibitor, EM-139, with 17beta-HSD1 has been crystallized using both cocrystallization and soaking methods. Crystals are isomorphous to the native crystals grown in the presence of 0.06% beta-octyl-glucoside and polyethyleneglycol 4000, with a monoclinic space group C2. Data at 1.8 A have been collected from a synchrotron source. Even though the size of the inhibitor is greater than that of the substrate, our preliminary X-ray-diffraction study shows that EM-139 fits into the active site in a position similar to that of estrogen. The availability of such structural data will help design more potent inhibitors of estrogenic 17beta-HSD.

Apoenzymes↗
PubMed1998

Development and validation of a simple questionnaire to facilitate identification of women likely to have low bone density.

The relationship between low bone mass and risk of fracture is well documented. Although bone densitometry is the method of choice for detecting low bone mass, its use may be limited by the availability of equipment, cost, and reimbursement issues. Improved patient selection for bone densitometry might increase the cost-effectiveness of screening for osteoporosis, a goal we sought to achieve by developing and validating a questionnaire based solely on patient-derived data. Responses to the questionnaire were used to assign postmenopausal women to one of two groups: (1) those unlikely to have low bone mineral density (defined as 2 standard deviations or more below the mean bone mass at the femoral neck in young, healthy white women) and therefore probably not currently candidates for bone densitometry; and (2) those likely to have low bone mineral density and therefore probably candidates for bone densitometry. We asked community-dwelling perimenopausal and postmenopausal women attending one of 106 participating multispecialty centers (both academic and community based) to complete a self-administered questionnaire and undergo bone density measurement using dual x-ray absorptiometry. We used regression modeling to identify factors most predictive of low bone density at the femoral neck in the postmenopausal group. A simple additive scoring system was developed based on the regression model. Results were validated in a separate cohort of postmenopausal women. Data were collected from 1279 postmenopausal women in the development cohort. Using only six questions (age, weight, race, fracture history, rheumatoid arthritis history, and estrogen use), we achieved a target of 89% sensitivity and 50% specificity. The likelihood ratio was 1.78. Validation in a separate group of 207 postmenopausal women yielded 91% sensitivity and 40% specificity. Assuming population characteristics similar to those of our development cohort, use of our questionnaire could decrease the use of bone densitometry by approximately 30%. Sensitivity and specificity can be varied by changing the level for referral for densitometry to provide the most cost-effective use within a particular healthcare setting. Thus use of our questionnaire, an inexpensive prescreening tool, in conjunction with physician assessment can optimize the use of bone densitometry and may lead to substantial savings in many healthcare settings where large numbers of women require evaluation for low bone mass.

Bone Density↗
PubMed2000

Substance dependence. A hospital based survey.

OBJECTIVE: To collect basic data on multiple and diverse issues such as drugs of dependence, smoking, initiation age, injection related harm, nutritional status, trauma, accidents, abnormal laboratory parameters and co-morbid conditions. METHOD: Seven hundred and ninety nine subjects from a voluntary detoxification unit were studied. Four hundred and ninety seven charts from June 1995 to December 1995 were reviewed retrospectively. For the other 302 subjects admitted between September 1996 to December 1996, information regarding drug use, smoking, trauma, accidents and co-morbid conditions was recorded during the admission interview while the remaining data was later obtained from the charts. RESULTS: Sixty eight percent were under 35. Ninety seven percent were smokers and 55% started smoking before the age of 15. Sixty four percent initiated drugs before the age of 25 while 34% had been on drugs for less than 5 years. Eighty seven percent were using heroin or alcohol. Fourteen percent were dependent on more than one drug. Among heroin users 91% were injecting, 21% had injection related complications, 69% had Hepatitis C Virus and 0.40% died. Forty four percent had at least one current medical disorder, 59% had one abnormal laboratory parameter and 21% below normal Body Mass Index. Nine percent had mental disorders and 1% presented with overdose. Twenty nine percent reported unintentional injuries and 12% reported of road traffic accidents. Seventeen point five percent had family history of drug use, 4.5% had mental disorders and 87% physical disorders. CONCLUSION: More accurate and reliable data is required. Current services need to be improved. Preventative measures should focus on early detection and intervention and a central body for information collection should be established.

Accidents↗
PubMed2000

A high-throughput AFLP-based method for constructing integrated genetic and physical maps: progress toward a sorghum genome map.

Sorghum is an important target for plant genomic mapping because of its adaptation to harsh environments, diverse germplasm collection, and value for comparing the genomes of grass species such as corn and rice. The construction of an integrated genetic and physical map of the sorghum genome (750 Mbp) is a primary goal of our sorghum genome project. To help accomplish this task, we have developed a new high-throughput PCR-based method for building BAC contigs and locating BAC clones on the sorghum genetic map. This task involved pooling 24,576 sorghum BAC clones ( approximately 4x genome equivalents) in six different matrices to create 184 pools of BAC DNA. DNA fragments from each pool were amplified using amplified fragment length polymorphism (AFLP) technology, resolved on a LI-COR dual-dye DNA sequencing system, and analyzed using Bionumerics software. On average, each set of AFLP primers amplified 28 single-copy DNA markers that were useful for identifying overlapping BAC clones. Data from 32 different AFLP primer combinations identified approximately 2400 BACs and ordered approximately 700 BAC contigs. Analysis of a sorghum RIL mapping population using the same primer pairs located approximately 200 of the BAC contigs on the sorghum genetic map. Restriction endonuclease fingerprinting of the entire collection of sorghum BAC clones was applied to test and extend the contigs constructed using this PCR-based methodology. Analysis of the fingerprint data allowed for the identification of 3366 contigs each containing an average of 5 BACs. BACs in approximately 65% of the contigs aligned by AFLP analysis had sufficient overlap to be confirmed by DNA fingerprint analysis. In addition, 30% of the overlapping BACs aligned by AFLP analysis provided information for merging contigs and singletons that could not be joined using fingerprint data alone. Thus, the combination of fingerprinting and AFLP-based contig assembly and mapping provides a reliable, high-throughput method for building an integrated genetic and physical map of the sorghum genome.

Chromosomes, Bacterial↗
PubMed2025

Expanding and improving analyses of nucleotide recoding RNA-seq experiments with the EZbakR suite.

Nucleotide recoding RNA sequencing methods (NR-seq; TimeLapse-seq, SLAM-seq, TUC-seq, etc.) are powerful approaches for assaying transcript population dynamics. In addition, these methods have been extended to probe a host of regulated steps in the RNA life cycle. Current bioinformatic tools significantly constrain analyses of NR-seq data. To address this limitation, we developed EZbakR (https://github.com/isaacvock/EZbakR), an R package to facilitate a more comprehensive set of NR-seq analyses, and fastq2EZbakR (https://github.com/isaacvock/fastq2EZbakR), a Snakemake pipeline for flexible preprocessing of NR-seq datasets, collectively referred to as the EZbakR suite. Together, these tools generalize many aspects of the NR-seq analysis workflow. The fastq2EZbakR pipeline can assign reads to a diverse set of genomic features (e.g., genes, exons, splice junctions), and EZbakR can perform analyses on any combination of these features. EZbakR extends standard NR-seq mutational modeling to support multi-label analyses (e.g., s4U and s6G dual labeling), and implements an improved hierarchical model to better account for transcript-to-transcript variance in metabolic label incorporation. EZbakR also generalizes dynamical systems modeling of NR-seq data to support analyses of premature mRNA processing and flow between subcellular compartments. Finally, EZbakR implements flexible and well-powered comparative analyses of all estimated parameters via design matrix-specified generalized linear modeling. The EZbakR suite will thus allow researchers to make full, effective use of NR-seq data.

Software↗
PubMed2006

The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis.

PREMISE: It has been suggested that proton pump inhibitor (PPI)-related differences in Helicobacter pylori eradication rates are partly because of CYP2C19 polymorphisms and there have been conflicting data in this area. We conducted a meta-analysis to investigate the evidence relating CYP2C19 to first-line H. pylori eradication rates. METHODS: A search of the literature was conducted up to June 2005 using Medline, EMBase, and Cochrane Register of Controlled Trials (CENTRAL). Twenty-eight arms from 17 papers were extracted for omeprazole, lansoprazole, and rabeprazole, collectively. Review Manager 4.2.8 was used for analysis. RESULTS: When all eradication rates, regardless of PPI used, were combined there was no significant difference between poor metabolizers (PM) and heterozygous extensive metabolizers (HetEMs) (odds ratio [OR]= 1.35, 95% confidence interval [CI] 0.89-2.07, p = 0.15); however, there was a significant difference between HetEM and homozygous extensive metabolizers (HomEMs) (OR = 1.90, 95% CI 1.38-2.60, p < 0.0001). Significant heterogeneity was observed in a HomEM and PM comparison, hence additional subanalysis of individual PPIs revealed that dual and triple omeprazole therapies significantly favored higher H. pylori eradication rates in PM over HomEM (OR = 4.03, 95% CI 1.97-8.28, p = 0.0001), and also over HetEM (OR = 2.24, 95% CI 1.09-4.61, p = 0.03). Dual and triple rabeprazole and triple lansoprazole therapies did not show significantly different H. pylori eradication rates between PM and HomEM (OR = 1.04, 95% CI 0.44-2.46, p = 0.25) and (OR = 1.80, 95% CI 0.67-4.85, p = 0.93), respectively. CONCLUSIONS: The impact of CYP2C19 polymorphisms on H. pylori eradication rates in studied populations appears clinically relevant in patients prescribed omeprazole as a component of their dual- or triple-drug therapy, whereas regimens that include lansoprazole or rabeprazole are unaffected. The choice of PPI and/or dose rather than CYP2C19 genotyping could be a more practical approach to assure the highest H. pylori eradication rates in clinical settings.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

A journey to becoming: the student nurse in transition.

The study reported in this paper explored the nature of the transition experienced by student nurses in their journey to becoming qualified nurses. In keeping with the developing relationship between the disciplines of anthropology and nursing, the methodology of choice was ethnography. Data were collected by open-ended questionnaires and interviews with key informants from one English College of Nursing undertaking Diploma level Project 2000 Adult Branch Studies. Thematic analysis of the data revealed an ill-defined transition for the student nurse and this lack of clarity was being perpetuated for many by their dual role as both student nurse and worker. This was also creating a potential role conflict and a blurring of the boundaries between professional nursing and skilled health care work. The data also revealed two 'in limbo' states, a ritualized transition phase, and that the rationale for 'learning to become a nurse' retains the idealized and vocational imagery of nursing as helping and caring for sick people.

Adult↗
PubMedDate not supplied

Adrenal incidentaloma (adrenaloma).

The management of adrenalomas should include the following: 1. A detailed history and physical examination to detect subtle evidence of hormonal hypersecretion or the possibility of metastatic carcinoma. 2. Hormonal studies: Short dexamethasone suppression test (2 mg of dexamethasone) followed by a high-dose dexamethasone suppression test (8 mg), CRH assay and analysis of the diurnal cortisol rhythm if serum cortisol value post dexamethasone is greater than 3 microg/dL, 24-hour (or spot) urinary catecholamine metabolites (metanephrine and normetanephrine), In the hypertensive or normotensive patient with serum potassium less than 3.9 nmol/L, the upright aldosterone level to plasma renin activity (PRA) ratio. 3. Additional studies, such as: Glucose tolerance test, Bone mineral density evaluation, Body composition and fat distribution by DEXA (Dual energy X-Ray absorptiometry). The role of FNA is limited. It may be helpful only in the patient with coexistent extradrenal carcinoma to confirm adrenal metastasis. Although genetic and molecular biology studies do not have wide clinical application, they should be encouraged and supported. Once all of these data are collected, the recommendations are: 1. All clearly nonfunctioning adrenalomas that are not suspicious for malignancy in asymptomatic patients should be observed for several years, mainly with hormonal studies, until their secretory and benign nature is confirmed. 2. All patients with adrenalomas and evidence of subclinical function, suspicion for malignancy (using size, imaging, FNA and molecular biology criteria) and symptoms, such as hypertension, obesity, impaired glucose tolerance, central fat deposition and reduced bone mineral density, should undergo laparoscopic adrenalectomy. The age, the overall medical condition and the anxiety of the patient should also be considered in the decision to operate on a patient with an adrenaloma.

Journal Article↗
PubMed2004

Epidemiology and clinical manifestation of rotavirus and norwalk-like viruses in Thai children.

Acute gastroenteritis is one of the most common diseases affecting children and rotavirus is the major etiological agent worldwide. Although the role of rotavirus as a causal agent of gastroenteritis has been previously established in Thailand, little is known about the epidemiology of Norwalk-like viruses. The present study was designed to determine the epidemiology and clinical manifestation of Norwalk-like viruses in comparison with rotavirus in Thailand. One hundred and one children with watery diarrhea between November 2002 and October 2003 were recruited into the study. The clinical data and stool specimens were collected for clinical analysis and rotavirus and Norwalk-like virus detection. Rotavirus and Norwalk-like viruses were detected viral agent by RT-PCR method. Of 101 stool samples obtained, rotavirus was detected in 25/101 (24.7%). Norwalk-like viruses were detected in 23/101 (22.7%). Dual infections were detected in 6/101 (5.9%). Rotavirus and Norwalk-like viruses peaked in the winter time. Clinical manifestations of rotavirus and Norwalk-like viruses were watery stool, nausea, vomiting, abdominal pain and fever Norwalk-like viruses and rotavirus were the most common etiologic agents in children with acute gastroenteritis in Thailand Epidemiology and clinical manifestations of rotavirus and Norwalk-like viruses were not different.

Caliciviridae Infections↗
PubMed2006

Dual blockade of angiotensin II with enalapril and losartan reduces proteinuria in hypertensive patients with type 2 diabetes.

In this study we evaluated the effect of a dual blockade with enalapril and losartan on the reduction of overt macroproteinuria and its potential mechanism(s) in hypertensive patients with type 2 diabetes. Twenty-six hypertensive patients with type 2 diabetes at the baseline were administered 5 mg of enalapril once daily for 12 weeks. At the beginning of the study, the subjects were assigned to receive an add-on of 50 mg of losartan once daily or 5 mg of enalapril once daily for another 12 weeks. Blood samples were collected at the baseline, at the beginning, and at the end of the study for the measurement of laboratory parameters, and these data, including blood pressure, were compared between the two groups. Treatment with 5 mg of enalapril significantly decreased the systolic blood pressure level in both groups, and the addition of losartan and/or enalapril further decreased the levels. There was no difference in blood pressure between the two groups. However, the addition of losartan, but not enalapril, significantly decreased the urinary protein excretion level, plasma aldosterone, and hypersensitive-C-reactive protein at the end of the study. The results established that the dual blockade of angiotensin II with enalapril and losartan has a greater clinical benefit for high-risk patients with hypertension and advanced diabetic nephropathy.

Aged↗
PubMed2005

Passive motion characteristics of the talocrural and the subtalar joint by dual Euler angles.

The objective of this study is to validate previous descriptions of hindfoot kinematics using dual Euler angle methods in a passive cadaveric model. The dual Euler angle method was chosen so as to facilitate description of the translational and rotational movement occurring at both the ankle and subtalar joints. A non-metal experimental set-up was fabricated to generate motion in foot cadaver specimens. Three-dimensional kinematic data of the ankle joint complex was collected from ten knee-below foot cadaver specimens using a 'Flock of Birds' electromagnetic tracking device. The data correlates well with previously published kinematic descriptions of the ankle subtalar joint complex. Both the ankle and subtalar joint show 6 degree of freedom motion and multiaxial characteristics. The motions of the talocrural joint, the talocalcaneal joint, and the gross motion between the foot and the shank were analyzed. During dorsiflexion-plantarflexion the motion of the calcaneus with respect to the tibia occurs mainly at the ankle joint, with little motion at the subtalar joint. The subtalar joint contributes more than the ankle joint during inversion-eversion.

Algorithms↗
PubMed2005

Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine.

Angiogenesis, a key rate-limiting step in the growth and dissemination of malignant tumors, is regulated by the balance between positive and negative effectors. Recent studies indicate that the pleiotropic cytokine interleukin-6 (IL-6) may contribute to the vascularization of some tumors by disrupting the equilibrium between positive and negative angiogenic regulatory molecules. We determined whether IL-6 participates in the angiogenesis observed during the progression of ovarian carcinoma. We measured IL-6 production by human ovarian cancer cell lines in vitro and in vivo. Not all cell lines secreted IL-6 in vitro; however, when the cell lines were implanted into the peritoneal cavity of female nude mice, every line secreted IL-6. Most human ovarian carcinoma cell lines tested secreted significant levels of the soluble IL-6 receptor (sIL-6R). Endothelial cell lines established from the ovary and mesentery of female H-2K(b)-tsA58 mice were tested for response to IL-6. Both endothelial cell lines expressed the IL-6R and their stimulation with the exogenous ligand significantly enhanced cell migration and activated the downstream signaling molecule signal transducers and activators of transcription 3. Dual immunohistochemical staining for IL-6R and CD31 revealed IL-6R expression on human endothelial cells within normal ovary and carcinoma specimens. Gelfoam sponges containing 0.4% agarose and IL-6 or basic fibroblast growth factor and implanted into the subcutis of BALB/c mice were vascularized to the same extent. Collectively, the data indicate that ovarian tumor cells secreted IL-6, a highly angiogenic cytokine that supports progression of disease.

Animals↗
PubMed2000

Acquired chromosome 11q deletion involving the ataxia teleangiectasia locus in B-cell non-Hodgkin's lymphoma: correlation with clinicobiologic features.

PURPOSE: To study the clinicobiologic significance of acquired 11q deletions involving the ataxia teleangiectasia locus (ATM+/-) in B-cell non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Fifty-three indolent lymphomas and 82 aggressive lymphomas were studied by conventional cytogenetic analysis and by fluorescence in situ hybridization using an 11q22-23 probe recognizing ATM sequences. Pertinent clinical data were collected. RESULTS: A hemizygous ATM deletion was seen in 44% to 88% of the interphase cells in 15 cases (11.1%); four patients had an indolent lymphoma (follicular center cell lymphoma), and 11 patients had an aggressive lymphoma (five mantle-cell lymphomas [MCLs] and six diffuse large-cell lymphomas). Dual-color hybridization studies showed ATM deletion to be possibly a secondary aberration in three patients with MCL. Ten out of 15 ATM+/- patients had a complex karyotype, 11 out of 15 had more than 90% abnormal metaphases (AA karyotype status), and +12, 13q14 deletion, and 17p13 deletion were seen in seven, four, and five cases, respectively. Patients with ATM+/- more frequently had a complex karyotype (P =.01) and the AA karyotype (P =.04) compared with patients without ATM+/-. With the exception of a poor performance status (P =.001), no correlation was found between ATM+/-, initial clinical variables, and complete remission rate; whereas a highly significant association was found with shorter survival (P <.0001). This cytogenetic lesion maintained its prognostic importance in multivariate analysis (P =.0004), along with performance status (P =.0006), serum lactate dehydrogenase level (P =.03), splenomegaly (P =.01), and histologic grade (P =.03). When analyzing indolent lymphomas and aggressive lymphomas separately, ATM+/- maintained its prognostic importance as an independent variable in both histologic groups (P =.0001 and P =.016, respectively). CONCLUSION: Though possibly not representing a primary genetic lesion in the majority of cases, the acquired ATM+/- status has clinicobiologic importance in NHL, possibly representing a major cytogenetic determinant of outcome.

Ataxia Telangiectasia↗
PubMed1997

A role for the VLA-4 integrin in the activation of human memory B cells.

It is generally recognized that activation through membrane effector molecules such as CD40 or the B cell receptor (BCR) is mandatory to allow B cells to proliferate and differentiate into antibody (Ab)-secreting cells in response to cytokines. We show here that purified tonsillar B cells can be stimulated directly by a cytokine combination to proliferate and secrete immunoglobulins when cultures are performed at high cell density. The contact-mediated activation of B cells in this experimental system is strongly inhibited both by anti-very late antigen (VLA)-4 monoclonal Ab and by a peptide containing the LDV sequence specifically recognized by the alpha 4 integrin binding site. These reagents also significantly suppressed the B cell responses elicited by engagement of the BCR or CD40. Our data reveal that memory B cells but not virgin or germinal center B cells are sensitive to the direct stimulatory effect of cytokines in high-density cultures. Finally, we found that the dual expression of the alpha and beta chains of VLA-4 is a distinctive feature of the memory B cell population. Collectively, our findings support the notion that VLA-4-dependent homotypic B cell interactions can mediate a co-stimulatory signal to human memory B cells and might participate in the B cell activation triggered through the BCR and CD40.

B-Lymphocytes↗
PubMed1996

Evaluation of respirometric data: identification of features that preclude data fitting with existing kinetic expressions.

The use of respirometric for from the evaluation of intrinsic biodegradation kinetic parameters for single organic compounds is discussed. Emphasis is placed on the preliminary assessment of the data set to determine whether it is suitable for kinetic parameter estimation. Careful preliminary examination of the data avoids attempting parameter estimation with unacceptable data. Furthermore, the use of unbiased respirometric data helps ensure that the estimated parameters truly reflect the intrinsic kinetics for biodegradation of a single substrate by the culture tested. Both experimental and theoretical oxygen uptake curves are used to illustrate how various conditions can limit the utility of a given data set. The effect of substrate inhibition, dual or multiple substrate limited growth, inaccuracies in the initial conditions assumed for curve fitting, and the use of poorly acclimated cultures are discussed. Techniques are presented which allow identification of whether a data set is unsuitable and should not be used for parameter estimation. In addition, experimental procedures which can help avoid the collection of aberrant data are discussed.

Biodegradation, Environmental↗
PubMed2003

Parents' perspectives on homelessness and its effects on the educational development of their children.

This qualitative study explored parents' perceptions of how their homelessness affected the development and academic achievement of their children. Grounded theory with symbolic interactionism was the framework for this study. Data were collected through semistructured interviews with 34 homeless families in a variety of settings. Multiple factors were found, including unstable relationships, abuse and violence, abdication of parental responsibility, poor parenting models, and resilient children. The findings present a case for supportive educational services for homeless school-age children. School nurses play a dual role. They can ensure that school personnel and resource providers understand the culture of homelessness, and they can develop and implement innovative programs for parents and school personnel to help homeless children.

Adolescent↗
PubMed2005

Survival with first-line bosentan in patients with primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

Adolescent↗