Chirurgische Universitätsklinik Heidelberg

BACKGROUND: Significant regression of coronary and femoral atherosclerotic lesions has been documented by angiographic studies using aggressive lipid-lowering treatment. This study tested the applicability and effects of intensive physical exercise and low-fat diet on coronary morphology and myocardial perfusion in nonselected patients with stable angina pectoris. METHODS AND RESULTS: Patients were recruited after routine coronary angiography for stable angina pectoris; they were randomized to an intervention group (n = 56) and a control group on "usual care" (n = 57). Treatment comprised intensive physical exercise in group training sessions (minimum, 2 hr/wk), daily home exercise periods (20 min/d), and low-fat, low-cholesterol diet (American Heart Association recommendation, phase 3). No lipid-lowering agents were prescribed. After 12 months of participation, repeat coronary angiography was performed; relative and minimal diameter reductions of coronary lesions were measured by digital image processing. Change in myocardial perfusion was assessed by 201Tl scintigraphy. In patients participating in the intervention group, body weight decreased by 5% (p less than 0.001), total cholesterol by 10% (p less than 0.001), and triglycerides by 24% (p less than 0.001); high density lipoproteins increased by 3% (p = NS). Physical work capacity improved by 23% (p less than 0.0001), and myocardial oxygen consumption, as estimated from maximal rate-pressure product, by 10% (p less than 0.05). Stress-induced myocardial ischemia decreased concurrently, indicating improvement of myocardial perfusion. Based on minimal lesion diameter, progression of coronary lesions was noted in nine patients (23%), no change in 18 patients (45%), and regression in 13 patients (32%). In the control group, metabolic and hemodynamic variables remained essentially unchanged, whereas progression of coronary lesions was noted in 25 patients (48%), no change in 18 patients (35%), and regression in nine patients (17%). These changes were significantly different from the intervention group (p less than 0.05). CONCLUSIONS: In patients participating in regular physical exercise and low-fat diet, coronary artery disease progresses at a slower pace compared with a control group on usual care.

BACKGROUND: The impact of patient- and tumor-dependent factors and the postoperative course on the prognosis of patients who underwent resection for gastric carcinoma between 1986 and 1989 were analyzed in a prospective multicenter observation study. METHODS: Resection techniques, the extent of lymph node dissection, and the histopathologic assessment of the specimen were standardized at all participating centers. A total of 1654 patients were enrolled. Follow-up is complete for 99.2% of the patients, with a median follow-up time of 48 months. Prognostic factors were assessed by multivariate analysis. RESULTS: In the total patient population there was an independent prognostic effect of nodal status, a International Union Against Cancer (UICC)-R0 resection, distant metastases, the pT category, three or more risk factors on preoperative risk analysis, and the presence of postoperative complications. Multivariate analysis in the subgroup of patients who had a UICC-R0 resection confirmed the nodal status as the major independent prognostic factor. CONCLUSION: These data suggest that the prognosis of patients who undergo gastrectomy for gastric carcinoma may be improved by a complete resection of the primary tumor and its lymphatic drainage, resulting in a UICC-R0 resection. In addition, a detailed preoperative risk analysis and identification of high-risk patients and meticulous attention to the technical details of the surgical procedure to reduce the frequency of postoperative complications may improve the prognosis.

A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE's) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical-generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular function by binding to several binding sites including the receptor for AGE's, RAGE. Binding of AGE's (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo. Consistently, activation of NF-kappaB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant alpha-lipoic acid. The development of techniques allowing for a tissue culture independent measurement of NF-kappaB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation.

The experimental association psychology approach to mental associations has been the conceptual background for the concept of schizophrenia. Cognitive neuroscience methods and concepts can be used to study various forms of schizophrenic thought disorder. In particular, the concepts of semantic associative and working memory can be applied fruitfully to schizophrenia research. Semantic associative networks can be simulated with self-organizing feature maps. Dysfunctional lexical access can be modeled in terms of low signal-to-noise ratio in intra- or between-network information processing. Evidence for the crucial role of dopamine in this function is presented, and a general neurocomputational model of schizophrenic thought disorder is developed. This model capitalizes on basic aspects of neural information processing (i.e., neuromodulation and neuroplasticity) and allows a parsimonious explanation of a number of otherwise inexplicable or unrelated clinical phenomena and experimental results.

OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

OBJECTIVE: To determine the safety and efficacy of an exercise protocol designed to improve strength, mobility, and balance and to reduce subsequent falls in geriatric patients with a history of injurious falls. DESIGN: A randomized controlled 3-month intervention trial, with an additional 3-month follow-up. SETTING: Out-patient geriatric rehabilitation unit. PARTICIPANTS: Fifty-seven female geriatric patients (mean age 82 +/- 4.8 years; range 75-90) admitted to acute care or inpatient rehabilitation with a history of recurrent or injurious falls including patients with acute fall-related fracture. INTERVENTION: Ambulatory training of strength, functional performance, and balance 3 times per week for 3 months. Patients of the control group attended a placebo group 3 times a week for 3 months. Both groups received an identical physiotherapeutic treatment 2 times a week, in which strengthening and balance training were excluded. MEASUREMENTS: Strength, functional ability, motor function, psychological parameters, and fall rates were assessed by standardized protocols at the beginning (T1) and the end (T2) of intervention. Patients were followed up for 3 months after the intervention (T3). RESULTS: No training-related medical problems occurred in the study group. Forty-five patients (79%) completed all assessments after the intervention and follow-up period. Adherence was excellent in both groups (intervention 85.4 +/- 27.8% vs control 84.2 +/- 29.3%). The patients in the intervention group increased strength, functional motor performance, and balance significantly. Fall-related behavioral and emotional restrictions were reduced significantly. Improvements persisted during the 3-month follow-up with only moderate losses. For patients of the control group, no change in strength, functional performance, or emotional status could be documented during intervention and follow-up. Fall incidence was reduced nonsignificantly by 25% in the intervention group compared with the control group (RR:0.753 CI:0.455-1.245). CONCLUSIONS: Progressive resistance training and progressive functional training are safe and effective methods of increasing strength and functional performance and reducing fall-related behavioral and emotional restrictions during ambulant rehabilitation in frail, high-risk geriatric patients with a history of injurious falls.

Dexmedetomidine was evaluated for sedation of 401 post-surgical patients in this double-blind, randomized, placebo-controlled, multicenter trial. Dexmedetomidine or saline was started on arrival in the intensive care unit (ICU) (1.0 mcg/kg for 10 minutes), then titrated at 0.2 to 0.7 mcg/kg/h to effect. Patients could be given propofol if necessary. Morphine was administered for pain. Sixty percent of the dexmedetomidine patients required no other sedative to maintain an RSS > or = 3; 21% required < 50 mg propofol. In contrast, 76% of the control group received propofol; 59% required > or = 50 mg. Dexmedetomidine patients required significantly less morphine for pain relief (P <.001). Continuously given throughout the ICU stay, dexmedetomidine had no effect on respiratory rate, oxygen saturation, duration of weaning, or times to extubation. Nurses judged the dexmedetomidine patients were easier to manage. Later, fewer dexmedetomidine patients remembered pain or discomfort. The majority of dexmedetomidine patients maintained blood pressures within normal range, without rebound. Hypertension, atelectasis, and rigors occurred more frequently in the control group, while hypotension and bradycardia occurred more frequently in the dexmedetomidine group. Preoperative cardiovascular conditions were not risk factors for dexmedetomidine patients.

Hodgkin- and Reed-Sternberg (HRS) cells microdissected from 41 classical Hodgkin lymphomas (cHL) of 40 patients comprising 8 lymphocyte-rich (cHL-LR), 16 nodular sclerosis (cHL-NS), 15 mixed-cellularity (cHL-MC), and 2 lymphocyte-depletion (cHL-LD) subtypes were analyzed by comparative genomic hybridization for recurrently imbalanced chromosomal subregions. Chromosomal gains most frequently involved chromosome 2p (54%), 12q (37%), 17p (27%), 9p and 16p (24% each), and 17q and 20q (20% each), whereas losses primarily affected chromosome 13q (22%). Using fluorescence in situ hybridization, amplification of the REL oncogene was demonstrated within a distinct 2p15-p16 amplicon. The high frequency of 2p overrepresentations including REL, particularly in cHL-NS (88%), suggests that an alternative mechanism of constitutive activation of nuclear factor NF-kappaB is a hallmark of HRS cells. Hierarchical cluster analysis of chromosomal imbalances revealed a closer relationship among cHL-NS than other subtypes. Furthermore, there is a tendency for different subtypes of cHL-MC tumors characterized by different ages at the time of tumor onset and gain of chromosome 17p. The imbalance pattern of cHL subtypes suggests that different molecular pathways are activated, with REL or other genes on chromosomal band 2p15-p16 playing a fundamental role in the pathogenesis of classical Hodgkin lymphoma.

Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Insulin caused a transient increase in H2O2 accumulation in human fat cell suspensions that was observed only in the presence of an inhibitor of catalase and heme-containing peroxidases, such as azide, and reached peak levels of 30 microM within 5 min. The cells contained a plasma membrane-bound NADPH oxidase, producing 1 mol H2O2/mol of NADPH oxidation, that was activated on exposure of intact cells to insulin at contrations that are physiologically relevant (0.1-10 nM). The hormone effect was rapid and was due to a selective increase in substrate affinity. The enzyme was magnesium dependent, required a flavine nucleotide for optimal activity, and was most active at pH 5.0-6.5. In contrast to all other hormone- or cytokine-sensitive NADPH oxidases that have been characterized in sufficient detail, the human fat cell oxidase retained its hormone responsiveness after cell disruption, and only Mn2+, but no ATP, was required for a ligand-induced activation in crude plasma membranes. The results demonstrate that insulin utilizes tyrosine kinase-independent pathways for receptor signaling and strongly support the view that H2O2 contributes to the intracellular propagation of the insulin signal.

The glycophorin A transmembrane segment homo-dimerizes to a right-handed pair of alpha-helices. Here, we identified the amino acid motif mediating this interaction within a natural membrane environment. Critical residues were grafted onto two different hydrophobic host sequences in a stepwise manner and self-assembly of the hybrid sequences was determined with the ToxR transcription activator system. Our results show that the motif LIxxGxxxGxxxT elicits a level of self-association equivalent to that of the original glycophorin A transmembrane segment. This motif is very similar to the one previously established in detergent solution. Interestingly, the central GxxxG motif by itself already induced strong self-assembly of host sequences and the three-residue spacing between both glycines proved to be optimal for the interaction. The GxxxG element thus appears to be the most crucial part of the interaction motif.

AIMS: A substantial percentage of patients with mitral regurgitation (MR) in need of mitral valve repair are currently considered not suitable for conventional surgery. In Germany, the largest cohort of patients studied to date has been treated using a percutaneous, catheter-based approach. We report the acute outcomes of patients enrolled in the investigator-initiated German transcatheter mitral valve interventions (TRAMI) registry. METHODS AND RESULTS: Between January 2009 and August 2011, 486 patients [median age 75 (interquartile range 70-80) years; 200 women (41%)] were enrolled in the registry (309 retrospectively and 177 prospectively), with 481 patients (99%) having undergone percutaneous edge-to-edge therapy for MR using the MitraClip. At baseline, 93% of patients were in New York Heart Association (NYHA) functional class III or IV and 71% of patients had a left ventricular ejection fraction (LVEF) ≤50%. Two-thirds of patients presented with functional MR. Procedural success was achieved in 94% of patients, with grade III present in 93% of patients at baseline yet only 6% post-intervention. Retrospective patients were followed for a median of 183 days, prospective patients for a median of 44 days. The periprocedural complication rate was low, with only minor bleedings as the most significant event. In-hospital and post-discharge mortality was 2.5% and 12.5%, respectively. CONCLUSIONS: Data from the German TRAMI registry suggest that MitraClip therapy is a viable treatment option in daily clinical routine for high surgical risk patients with significant MR.

Comparative genomic hybridization (CGH) has been used widely for the molecular cytogenetic analysis of tumors. Until now, the spatial resolution of this technique for diagnosing deletions of chromosomal sequences has not been assessed in detail. In the present study, we performed CGH analyses on five DNA samples derived from B-cell leukemias with 11q deletions, the sizes of which ranged from 3 Mbp to 14–18 Mbp. CGH experiments were evaluated by two established commercial analysis systems. Deletions down to a size of 10–12 Mbp were diagnosed based on a diagnostic threshold value of 0.8, if the vast majority of cells carried the deletion. For cases with smaller deletions, the ratio profiles were shifted toward underrepresentation at the respective chromosomal bands; however, the diagnostic threshold value was not reached. In all five cases, there was complete agreement between the two image analysis systems. Genes Chromosomes Cancer 21:172–175, 1998. © 1998 Wiley-Liss, Inc.

Although known for almost 80 years, the physiological role of plasmalogens (PLs), the major mammalian ether lipids (ELs), is still enigmatic. Humans that lack ELs suffer from rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder usually resulting in death in early childhood. In order to learn more about the functions of ELs, we generated a mouse model for RCDP by a targeted disruption of the dihydroxyacetonephosphate acyltransferase gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract and optic nerve hypoplasia, some of which were also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain PLs and the occurrence of PLs in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, PLs were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 and F3/contactin were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin 43, known to be recruited to LRMs and essential for lens development and spermatogenesis, was down-regulated in embryonic fibroblasts of the EL-deficient mice. Free cholesterol, an important constituent of LRMs, was found in these fibroblasts to be accumulated in a perinuclear compartment. These data suggest that the EL-deficient mice allow the identification of new phenotypes not related so far to EL-deficiency (male sterility, defects in myelination and optic nerve hypoplasia) and indicate that PLs are required for the correct assembly and function of LRMs.

Skin biopsies were collected from 15 patients with cutaneous tumors morphologically similar to Ki-1+ anaplastic large cell (ALC) lymphoma of the lymph nodes, including Ki-1+ ALC lymphoma of childhood. The histology and immunophenotype of these cutaneous tumors are reported and follow-up data on the patients are given. The tumorous infiltrates were composed of large, sometimes very bizarre cells with one nucleolus or multiple nucleoli. All tumor cells expressed the lymphoid cell activation antigen Ki-1 (CD30) in conjunction with CD25 and the beta-chain of the T cell receptor. In 11 patients, Ki-1+ cutaneous tumors developed primarily in the skin. In nine patients, these were restricted to the skin in follow-up periods ranging from 3 months to 6 years. Two patients developed lymph node involvement after 2 months and 2 years, indicating the spreading potential of these cutaneous tumors. Morphologic and immunophenotypical identity of the atypical cells found in primary cutaneous ALC lymphoma, in regressing atypical histiocytosis (RAH), and in lymphomatoid papulosis (LyP) of type A, together with the protracted clinical course in all three conditions, suggests that primary cutaneous ALC lymphoma, RAH, and LyP of type A represent clinical variants of the same lymphoma entity. Secondary development of Ki-1+ ALC skin tumors was observed in two patients with cutaneous T cell lymphomas of mycosis fungoides type. These secondary Ki-1+ ALC lymphomas of the skin showed rapid systemic progression similar to the primary lymphonodal Ki-1+ ALC lymphomas. Concomitant or subsequent occurrence of Ki-1+ ALC tumors in cutaneous T cell lymphomas thus may be a bad prognostic sign.

A triglyceride lipase different from lipoprotein lipase, but measurable only after intravenous heparin injection, has been isolated from human plasma by sequential use of heparin-Sepharose and concanavalin A-Sepharose affinity chromatography. Using these procedures, phospholipase A1 activity was found to chromatograph identically with the triglyceride lipase. The constancy of the ratio of activities after isoelectric focusing (pI 4.1) and during thermal deactivation indicates that this enzyme has hydrolase activity against both triglycerides and phospholipids. This conclusion was supported further by the homogeneity of the protein as indicated by sodium dodecyl sulfate polyacrylamide gel electrophoresis.

This study of 70 schizophrenic patients used a lexical decision task involving the recognition of words that were preceded (primed) either by meaningfully or phonologically associated or by nonassociated words to study the intrusion of contextually inappropriate associations in thought disorder (TD). The patients were split into subgroups of TD and non-TD patients, and the data from these two groups were compared with data from 44 normal control participants. TD schizophrenic patients exhibited more semantic priming than non-TD patients and controls, and differences in phonological priming dependent on stimulus onset asynchrony (SOA) were obtained. Results support the hypotheses of an increase in activation or a decrease in inhibition in the spreading of semantic and phonological associations in TD schizophrenic patients.

BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

BACKGROUND: Longer dialysis session length (treatment time, TT) has been associated with better survival among hemodialysis (HD) patients. The impact of TT on clinical markers that may contribute to this survival advantage is not well known. METHODS: Using data from the international Dialysis Outcomes and Practice Patterns Study, we assessed the association of TT with clinical outcomes using both standard regression analyses and instrumental variable approaches. The study included 37,414 patients on in-center HD three times per week with prescribed TT from 120 to 420 min. RESULTS: Facility mean TT ranged from 214 min in the USA to 256 min in Australia-New Zealand. Accounting for country effects, mortality risk was lower for patients with longer TT {hazard ratio for every 30 min: all-cause mortality: 0.94 [95% confidence interval (CI): 0.92-0.97], cardiovascular mortality: 0.95 (95% CI: 0.91-0.98) and sudden death: 0.93 (95% CI: 0.88-0.98)}. Patients with longer TT had lower pre- and post-dialysis systolic blood pressure, greater intradialytic weight loss, higher hemoglobin (for the same erythropoietin dose), serum albumin and potassium and lower serum phosphorus and white blood cell counts. Similar associations were found using the instrumental variable approach, although the positive associations of TT with weight loss and potassium were lost. CONCLUSIONS: Favorable levels of a variety of clinical markers may contribute to the better survival of patients receiving longer TT. These findings support longer TT prescription in the setting of in-center, three times per week HD.

BACKGROUND: As there is controversy about changes in lung function in primary pulmonary hypertension (PPH), lung mechanics were assessed with a focus on expiratory airflow in relation to pulmonary haemodynamics. METHODS: A cross sectional study was performed in 64 controls and 171 patients with PPH (117 women) of mean (SD) age 45 (13) years, pulmonary artery pressure (PAPmean) 57 (15) mm Hg, and pulmonary vascular resistance 1371 (644) dyne.s/cm(5). RESULTS: Mean (SD) total lung capacity was similar in patients with PPH and controls (98 (12)% predicted v 102 (17)% predicted, mean difference -4 (95% confidence interval (CI) -7.89 to -0.11); residual volume (RV) was increased (118 (24)% predicted v 109 (27)% predicted, mean difference 9 (95% CI 1.86 to 16.14); and vital capacity (VC) was decreased (91 (16)% predicted v 102 (10)% predicted, mean difference -11 (95% CI 15.19 to -6.80). RV/TLC was increased (117 (27)% predicted v 97 (29)% predicted, mean difference 20 (95% CI 12.3 to 27.8)) and correlated with PAPmean (r=0.31, p<0.001). In patients with PAPmean above the median of 56 mm Hg, RV/TLC was further increased (125 (32)% predicted v 111 (22)% predicted, mean difference -14 (95% CI -22.2 to -5.8)). Expiratory flow-volume curves were reduced and curvilinear in patients with PPH. CONCLUSIONS: Peripheral airway obstruction is common in PPH and is more pronounced in severe disease. This may contribute to symptoms. Reversibility of bronchodilation and relation to exercise capacity need further evaluation.