Biomedical subjects
Maija Halme
Publications and source records attributed to Maija Halme.
BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension.
In a nationwide study, we identified a total of 59 patients diagnosed with primary pulmonary hypertension (PPH) in Finland between the years 1987 and 1999. These data support a minimum estimate for a PPH population prevalence of 5.8 cases/million with an incidence of 0.2-1.3 cases/million/year. The male-to-female ratio among the patients was 1:4, while 7% (4/59) of the PPH probands had a known family history of the disorder. Familial or sporadic PPH showed no geographic clustering to any region of Finland. Sequencing of the coding regions and exon-intron boundaries of the bone morphogenetic protein receptor type 2 (BMPR2) identified heterozygous BMPR2 mutations in 12% (3/26) of the sporadic and 33% (1/3) of the familial patients. All four mutations were different, and two of those have been previously reported in other populations. Pathogenic defects in BMPR2 include a novel missense mutation (c.2696G>C encoding R899P), located within the receptor intracellular cytoplasmic domain whose function has been poorly characterized. Our analysis demonstrates that this mutant, while localizing to the cell surface, does not impact on SMAD-mediated (mothers against decapentaplegic homolog) intracellular signaling, but leads to constitutive activation of the p38(MAPK) pathway. The absence of a founder mutation in a genetically homogeneous population, such as the Finns, suggests that all identified BMPR2 mutations have to be rather young while the ancestral (if any) mutations have been lost either due to repetitive genetic bottlenecks or due to significant negative selection. Hum Mutat 26(2), 1-6, 2005. (c) 2005 Wiley-Liss, Inc.
Leukotriene E(4)-induced persistent eosinophilia and airway obstruction are reversed by zafirlukast in patients with asthma.
BACKGROUND: We have shown that inhalation of leukotriene (LT) E 4 contributes to specific recruitment of eosinophils to the airway mucosa in patients with asthma at the time of maximal decrease in airway-specific conductance. OBJECTIVE: We examined the ability of the cysteinyl LT 1 receptor antagonist, zafirlukast, to improve or prevent LT-mediated eosinophilia and airway obstruction in asthma. METHODS: Bronchial biopsies were taken and pulmonary function was measured before and 4 to 6 hours after the dose of inhaled LTE 4 causing a > or =15% fall in FEV 1 at baseline both at week 0 and after 6-week randomly assigned treatment with a high dose of zafirlukast, 80 mg twice daily. RESULTS: Leukotriene E 4 inhalation at week 0 doubled the number of eosinophils in the airway mucosa in 21 of 25 patients with mild asthma, increased the numbers of neutrophils and lymphocytes, and decreased FEV 1 (-17%). Zafirlukast reduced both airway eosinophilia and obstruction in FEV 1 , whereas with a double-blind placebo treatment, the effect of LTE 4 on both parameters persisted for 6 weeks. On repeat LTE 4 inhalation challenge after 6 weeks, zafirlukast treatment prevented further airway eosinophilia and decrease in FEV 1 seen in the placebo group. CONCLUSION: Persistent LTE 4 -induced airway eosinophilia may form the basis of an amplification mechanism for further eosinophil recruitment. Zafirlukast prevents LTE 4 -induced eosinophilic airway inflammation in mild asthma.
Bronchoscopy in the diagnosis and surveillance of respiratory infections in lung and heart-lung transplant recipients.
Fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) is a widely used method to detect respiratory infections and to differentiate them from other postoperative complications in lung transplant (LTX) recipients, but the usefulness of surveillance FOBs is not yet established. The aim of this study was to evaluate the usefulness of FOB in the diagnosis and surveillance of infections in LTX recipients. We reviewed all the consecutive 609 FOBs performed on 40 lung or heart-LTX recipients between February 1994 and November 2002. The overall diagnostic yield was 115/190 (61%) and 43/282 (15%) for clinically indicated and surveillance FOBs respectively (P < 0.001). Infection was established by bronchoscopic samples in 96/190 (50.5.%) of the clinically indicated FOBs and 34/282 (12.1%) of the surveillance FOBs (P < 0.001). The diagnostic yield of the clinically indicated FOBs was highest (72%) from 1 to 6 months post-transplant (P = 0.04). Pneumocystis carinii was detected in 23 (4.9%) of the bronchoscopic specimens and 15 (65%) of the P. carinii infections were detected during adequate chemoprophylaxis. To conclude, in LTX recipients clinically indicated FOB has a good diagnostic yield in detecting infections and other postoperative complications, whereas the information received from surveillance FOB has remained less significant. With current prophylaxis and screening strategies FOB is still required to detect P. carinii infections.
A prospective study comparing cytomegalovirus antigenemia, DNAemia and RNAemia tests in guiding pre-emptive therapy in thoracic organ transplant recipients.
We evaluated the usefulness of DNAemia and mRNAemia tests in guiding the pre-emptive therapy against cytomegalovirus (CMV) infections in thoracic organ transplant recipients using antigenemia test as the reference. Seven lung (LTR) and 14 heart (HTR) transplant recipients were prospectively monitored for CMV by antigenemia, DNAemia (Cobas Amplicor PCR Monitor) and pp67-mRNAemia (NASBA) tests. However, only the antigenemia test guided pre-emptive therapy with cut-off levels of >or=2 and >or=5-10 pp65-positive leukocytes/50 000 leukocytes in the LTRs and HTRs, respectively. CMV DNAemia was detected in 26/28 (93%) and RNAemia in 17/28 (61%) of the CMV antigenemias requiring antiviral therapy (P = 0.01). Optimal DNAemia levels (sensitivity/specificity) estimated from receiver-operating characteristic curve to achieve maximal sum of sensitivity and specificity were 400 (75.9/92.7%), 850 (91.3/91.3%) and 1250 (100/91.5%) copies/ml for the antigenemia of 2, 5 and 10 pp65-positive leukocytes, respectively. The sensitivities of nucleic acid sequence-based amplification (NASBA) were 25.9%, 43.5% and 56.3% in detecting the same cut-off levels of antigenemia. In thoracic organ transplant recipients, the Cobas PCR assay is comparable with the antigenemia test in guiding pre-emptive therapy against CMV infections when threshold levels of over 5 pp65-antigen-positive leukocytes are used as the reference. In contrast, the low sensitivity of NASBA limits its usefulness in the guidance of pre-emptive therapy.
Clinical usefulness of bronchoalveolar lavage in heart transplant recipients with suspected lower respiratory tract infection.
BACKGROUND: Bronchoscopy with bronchoalveolar lavage (BAL) is the recommended initial invasive diagnostic procedure when lower respiratory tract infection is suspected in solid-organ transplant recipients. In this study, we evaluated the clinical impact and safety of bronchoscopy with BAL in heart transplant recipients. METHODS: We reviewed all 44 consecutive diagnostic bronchoscopies with BAL that were performed in 35 heart transplant recipients at Helsinki University Central Hospital between May 1988 and December 2001. RESULTS: Bronchoscopy findings established specific microbiologic diagnoses in 18 of 44 (41%) cases, and 14 of 44 (32%) bronchoscopic findings led to changes in therapy. The diagnostic yield of bronchoscopy from 1 to 6 months after transplantation was 73%, significantly better (p = 0.002) than diagnostic yield during the first month (18%) and after 6 months (28%). Pneumocystis carinii and cytomegalovirus were the most frequently detected pathogens in the BAL fluid. Cytomegalovirus pneumonia carried a high mortality rate (44%), whereas all patients with P carinii pneumonia recovered. Fourteen episodes were diagnosed as bacterial pneumonia, but because of empiric antibiotic therapy that was started widely before bronchoscopy, a microbiologic diagnosis was established in only 1 case. However, all patients with community-acquired pneumonia responded to empiric therapy. Four cases of major complications occurred after bronchoscopy, all cardiovascular but none fatal. CONCLUSIONS: Bronchoscopy with BAL is a useful diagnostic tool in heart transplant recipients, especially between 1 and 6 months after transplantation.
Salmeterol resolves airway obstruction but does not possess anti-eosinophil efficacy in newly diagnosed asthma: a randomized, double-blind, parallel group biopsy study comparing the effects of salmeterol, fluticasone propionate, and disodium cromoglycate.
BACKGROUND: Salmeterol (SLM) is a long-acting beta(2)-receptor agonist that produces bronchodilatation for 12 hours in asthmatic subjects. The effects of the regular use of long-acting beta(2)-agonists on airway inflammation are largely unknown. OBJECTIVES: We examined the effects of 16 weeks of treatment with 50 microg SLM bid, 250 microg fluticasone propionate (FP) bid,5 mg disodium cromoglycate (DSCG) qid, or placebo on airway inflammation in bronchial mucosa. METHODS: Airway inflammation was assessed in bronchial biopsy specimens before and after treatments and bronchial hyperresponsiveness (BHR) in 80 patients with newly diagnosed asthma. Inflammatory cells and tenascin in the basement membrane were studied with immunohistochemical methods. Peak expiratory flow rate (PEF), symptoms, and need for rescue medication were recorded. RESULTS: SLM, FP, and DSCG reduced symptoms and need for rescue medication (P <.04). Both SLM and FP improved PEF and increased PD15FEV(1) to histamine by 2.8 and 5.2 doubling dose units, respectively. Both compounds reduced BHR more than placebo (P <.05). Both SLM and placebo had no effect on any inflammatory cell type. In both FP-treated and DSCG-treated patients, the number of EG2-positive eosinophils in the airway mucosa decreased (P =.002 and P <.05, respectively). CONCLUSIONS: SLM showed no anti-eosinophil properties in this study, but it provided good symptom control. FP provided the best anti-eosinophil properties and symptom relief of the studied compounds.