Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31

OBJECTIVES: The aim of our study was to identify genetic causes of primary pulmonary hypertension (PPH), to estimate the proportion of families with mutations in the BMPR2 (bone morphogenetic protein receptor type 2) gene, and to examine whether genetic heterogeneity might play a role. BACKGROUND: The BMPR2 mutations have been identified in a substantial portion of patients with familial or sporadic PPH. However, the genetic cause of PPH remains unclear in at least 45% of families. METHODS: We investigated 130 members of 10 families with at least 1 PPH patient, recruited without selection for familial disease. Manifest PPH was documented in 21 individuals. An increase in pulmonary artery systolic pressure (PASP) above 40 mm Hg during supine bicycle exercise was found in 46 healthy individuals. Their PASP increased from 21.0 +/- 4.6 mm Hg at rest to 54.0 +/- 9.8 mm Hg during exercise. In 51 relatives, PASP values were normal at rest and during exercise, and 12 members were classified as status unknown. RESULTS: Two families showed a mutation in the BMPR2 gene. Three families with no BMBR2 mutation showed evidence for linkage to a more proximal location on chromosome 2q31 (odds ratio [OR] for linkage 1.1.10(6):1). This locus, designated PPH2, maps in-between the markers D2S335 and D2S2314. We obtained significant support for heterogeneity in PPH with an OR of 2.8.10(11). CONCLUSIONS: We conclude that PPH may be a genetically heterogeneous disorder with at least two-and possibly more-causative genes.     

Computerized Vectorcardiography Telemetry: A New Device for Continuous Multilead ST‐Segment Monitoring of Ambulatory Patients. A Preliminary Report

Background: Continuous vectorcardiography ST‐segment monitoring has become a well‐established method in the surveillance of patients with acute myocardial ischemia. However, immobility of the vectorcardiography technique prevents monitoring of patients during ambulatory activities. Computerized vectorcardiography telemetry (CVT) with the capacity of real‐time ST‐segment analysis has been developed in an attempt to overcome this shortcoming. Recent data, however, indicate that changes in body position occasionally lead to pseudo‐ischemic ST‐segment changes during continuous ST‐segment monitoring. Aims: This report describes the technical features of the CVT system, presents clinical examples using CVT, and assesses the influence of changes in body position on ST‐vector magnitude (ST‐VM) during CVT, respectively. Methods: Clinical cases involving CVT are presented. The influence of changing body position during CVT monitoring was evaluated on 24 patients with suspected acute coronary syndromes, i.e., unstable angina or acute myocardial infarction. Each patient performed a specific body positional schedule. Results: We present three discrete clinical cases where CVT provided early and valuable evidence of ongoing myocardial ischemia. The consequences of different recumbent and ambulatory body positions on ST‐VM during CVT monitoring appear to be limited. Conclusion: Computerized vectorcardiography telemetry is a promising new tool for disclosing residual myocardial ischemic activity during the mobilization phase of patients with acute coronary syndromes. The clinical value of CVT needs further investigation in future trials. A.N.E. 2002;7(3):204–210     

Do statins influence the prognostic impact of non-sustained ventricular tachycardia after ST-elevation myocardial infarction?

AIMS: The study evaluates the effect of statin therapy on the prognostic impact of non-sustained ventricular tachycardia (NSVT) occurring after acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: From the German Acute Coronary Syndrome Registry (ACOS), 3137 patients with STEMI and in-hospital Holter monitoring were analysed. Three hundred and forty-six (11.0%) patients had NSVT. When compared with patients with no documented NSVT, patients with NSVT were older, more often had myocardial infarction in their history, diabetes mellitus, and an ejection fraction <40%. Regarding frequency of drug application, medication at discharge did not (beta-blockers, ACE-inhibitors, amiodarone) or only slightly (acetylsalicylic acid, statins, and sotalol) differ between both groups. Multivariable analysis of 1 year mortality, adjusted for age, gender, diabetes, reperfusion therapy, ejection fraction <40%, and beta-blocker therapy showed the following results: In patients without statin treatment and no NSVT, 1 year mortality after STEMI was 9.2%, but increased to 25.0% [odds ratio (OR) 3.02; 95% confidence interval (CI) 1.47-6.20], if NSVT were present. In patients on statin treatment and no NSVT, 1 year mortality was only 3.2%, and in the presence of NSVT 1 year mortality was not significantly increased anymore (5.3%; OR 1.03; 95% CI 0.55-1.92). CONCLUSION: After STEMI, only in patients not on statin treatment, the occurrence of NSVT is associated with a significant and marked increase in 1 year mortality.     

Cell-associated HIV DNA measured early during infection has prognostic value independent of serum HIV RNA measured concomitantly

Using data from the Danish AIDS Cohort of HIV-infected homosexual men established in the 1980s, the prognostic value of early HIV DNA loads was evaluated. In addition to DNA measurements, concomitant serum HIV RNA levels, CD4 cell counts and CCR5 genotypes were determined. The patients were divided into 3 groups, according to whether their cell-associated HIV DNA load was < or = 100, 500 or > or = 2,500 DNA copies/10(6) peripheral blood mononuclear cells. Clinical progression rates differed significantly between the groups (p < 0.005). Cell-associated HIV DNA load had prognostic value independent of serum HIV RNA (p < 0.02). However, when HIV DNA, HIV RNA and CD4 cell counts were all included in a Cox model, only serum HIV RNA had independent prognostic value. Patients heterozygous for the CCR5 delta 32 allele had significantly lower HIV DNA loads than those homozygous for the normal allele (p < 0.05). The interplay between HIV RNA and DNA levels is discussed, together with the possibility that cell-associated HIV DNA load is a marker of the HIV RNA peak seen shortly after primary HIV infection.     

Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.     

The pharmacokinetic profile of plasma-derived mannan-binding lectin in healthy adult volunteers and patients with Staphylococcus aureus septicaemia

Mannan-binding lectin (MBL) is a member of the innate immune system, and MBL-deficiency affects 10-15% of Caucasians. With development of a plasma-derived MBL, substitution has become a therapeutic option in diseases associated with MBL insufficiency. The pharmacokinetics of injected MBL is weakly described, particularly in patients with infectious diseases. The pharmacokinetic profile of MBL following administration of 0.08 mg/kg to 20 healthy MBL-deficient volunteers and 0.2 mg/kg to 2 patients with Staphylococcus aureus septicaemia was established. In the volunteers, the maximal concentration was 2849 microg/l; the mean half-life (T(1/2)) was 69.6 h (14.6-114.9 h). The normalized clearance was 9x10(-6) l/minxkg, and the mean residence time was 82 h. In the patients the serum-MBL versus time curves were similar to those in the volunteers, and T(1/2) values were 36 and 40 h. In conclusion, MBL is distributed into a median volume of 3.4 l similar to the plasma volume, and the elimination in septicaemic patients was within the range of the controls. Due to the large individual variation in T(1/2), we recommend that MBL therapy, with respect to dose and infusion intervals, is based on the chosen therapeutic target (> or =1000 microg/l) and MBL serum determinations following the first infusion.     

Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2. METHODS: Balance studies were performed before and after treatment with GLP-2, 400 microg subcutaneously twice a day for 35 days, in 8 patients (4-17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Treatment with GLP-2 improved the intestinal absorption of energy 3.5% +/- 4.0% (mean +/- SD) from 49.9% to 53.4% (P = 0.04), wet weight 11% +/- 12% from 25% to 36% (P = 0.04), and nitrogen 4.7% +/- 5.4% from 47.4% to 52.1% (P = 0.04). Body weight increased 1.2 +/- 1.0 kg (P = 0.01), lean body mass increased 2.9 +/- 1.9 kg (P = 0.004), fat mass decreased 1.8 +/- 1.3 kg (P = 0.007), and 24-hour urine creatinine excretion increased (P = 0.02). The time to 50% gastric emptying of solids increased 30 +/- 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively. CONCLUSIONS: Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.     

Typing of 30 insertion/deletions in Danes using the first commercial indel kit--Mentype® DIPplex

In this study, we tested the first commercial kit with insertion/deletion (indel) polymorphisms, the Mentype(?) DIPplex PCR Amplification Kit (DIPplex kit). A total of 30 biallelic autosomal indels and Amelogenin were amplified with the DIPplex kit. All loci were amplified in one PCR multiplex and all amplicon lengths were shorter than 160 bp. Full indel profiles were generated from as little as 100 pg of DNA. A total of 117 individuals from Danish paternity cases were successfully typed. No deviation from Hardy-Weinberg equilibrium was observed for any of the indels. The combined mean match probability was 3.3 × 10(-13), the mean paternity exclusion probability was 99.7% and the typical paternity indices for trios and duos were 2350 and 165, respectively. Furthermore, we typed five highly degraded DNA samples with the DIPplex kit, the AmpFlSTR(?) SGM Plus kit and the AmpFlSTR(?) SEfiler Plus kit. Full indel profiles were obtained with the DIPplex kit, whereas only partial profiles were obtained with the STR kits. In general, the DIPplex kit performed well and it would be a valuable assay for forensic genetic testing, especially in crime cases with partially degraded DNA or low amounts of template DNA. However, some difficulties with pull-ups were observed at DNA concentrations of 1000 pg. Rearrangement of the allele windows by changing the lengths of some of the PCR primers would greatly improve the assay, and more robustness towards higher amounts of DNA would allow the use of the DIPplex kit without prior quantification of the samples.