Airway remodelling and its relationship to inflammation in cystic fibrosis

Pulmonary disease is the most important cause of morbidity and mortality in cystic fibrosis (CF). Most patients with CF die from respiratory failure with extensive airway destruction. Airway remodelling, defined as structural airway wall changes, begins early in life in CF but the sequence of remodelling events in the disease process is poorly understood. Airway remodelling in CF has traditionally been thought to be solely the consequence of repeated cycles of inflammation and infection. However, new evidence obtained from developmental, physiological and histopathological studies suggests that there might instead be multiple mechanisms leading to airway remodelling in CF including (1) changes related to infection and inflammation; (2) changes specific to CF as a result of CF transmembrane conductance regulator (CFTR) dysfunction in the airway wall, independent of infection and inflammation; and (3) protective responses to (1) and/or (2). Recent advances in bronchoscopic techniques have allowed airway mucosal (endobronchial) biopsies to be taken in children and even infants. Endobronchial biopsy studies may provide insight into the role and relative contribution of the different mechanisms of airway remodelling in CF, with the main limitation that they assess only changes in proximal large airways and not in peripheral small airways from where CF disease is thought to originate. Findings from biopsy studies could encourage the development of novel therapeutic strategies targeting structural changes in addition to infection and inflammation.

Associations between fluctuations in lung function and asthma control in two populations with differing asthma severity

Lung function is a major criterion used to assess asthma control. Fluctuation analyses can account for lung function history over time, and may provide an additional dimension to characterise control. The relationships between mean and fluctuations in lung function with asthma control, exacerbation and quality of life were studied in two independent data sets.

Multiple-breath washout measurements can be significantly shortened in children

Multiple-breath washout (MBW)-derived lung clearance index (LCI) is a sensitive measure of ventilation inhomogeneity in patients with cystic fibrosis (CF), but LCI measurement is time consuming. We systematically assessed ways to shorten LCI measurements. In 68 school-aged children (44 with mild CF lung disease) three standard nitrogen (N2) MBWs were applied. We assessed repeatability and diagnostic performance of (1) LCI measured earlier from three MBW runs and (2) LCI measured at complete MBW (1/40th of starting N2 concentration) from two runs only. Compared with the standard LCI from three complete MBW runs, the new LCI based on three N2MBW runs until 1/20th, or two complete runs until 1/40th, provided similar or better repeatability as well as sensitivity and specificity for CF lung disease. Alternative ways to measure LCI reduced test duration in children with CF by 30% and 41%, respectively. LCI measurements can be reliably shortened in children. These new MBW protocols may advance the transition of LCI from research into clinical settings.

[Case report: an exceptional case of a monozygotic thoracopagus parasiticus in a German Holstein calf]

A black and white German Holstein calf displayed a complex double malformation in shape of a thoracopagus parasiticus. By means of a molecular genetic investigation the genesis of the malformation from one zygote could be demonstrated. Both vertebral columns showed a pronounced lordosis, with the vertebral column of one animal ending in a rudimentary head. Close to this rudiment two derivates of branchial arches were found. The two thoracic cavities merged into one "thorax". In the shared thoracic cavity one heart was found. In its right atrium, a cherry-sized structure was found in which heart- and vascular smooth muscles were demonstrated histologically. The aorta split shortly after its origin to provide both animals with one aorta each. The larger pair of lungs was connected with a trachea leading to the head while the smaller pair of lungs originated from a trachea deriving from the rudimentary head. The diaphragm jejunum and split afterwards. The pedigree of the affected animal showed neither inbreeding nor any other affected animal.

The relationship between coagulation and the extend of surgery and postoperative infection in surgical infants below 6 months of age

AIM: First to assess coagulation changes after surgery in children below 6 months of age. Second to detect differences attributable to the extent of surgery and postoperative infection. MATERIALS AND METHODS: Blood counts, haemoglobin concentration (Hb), haematocrit (Ht), prothrombine time (PT), activated partial thromboplastine time (aPTT) and thrombelastography (TEG) were studied pre- and 2+/-1/2 d postoperatively. Patients were divided in 3 groups. I: minor surgery without access to the abdomen or thorax (n=51); II: abdominal or thoracic interventions (n=24); III: abdominal surgery with postoperative sepsis (n=11). RESULTS: Preoperative values of Hb, Ht and INR were related to the age of the infant. Postoperatively clot strength and formation rate increased in gr. I (p<0.05). In gr. II, clot formation was initiated earlier (p<0.05) even though PT decreased (p<0.05). In group III, patients postoperatively developed a tendency for hypocoagulability in all TEG-parameters, but not in plasmatic coagulation. Postoperative TEG measurements were significantly inferior in gr. III when compared to gr. I and II. CONCLUSION: Our findings suggest activation of whole blood coagulation in the uncomplicated postoperative period despite of a decrease in plasmatic coagulation. In sepsis, only thrombelastography, but not plasmatic coagulation was affected.

[Pulmonary microscopic tumor embolism syndrome]

HISTORY: A 76-year-old woman and a 62-year-old man were both referred to our clinic because of an unexplained weight loss, increasing dry cough and shortness of breath. INVESTIGATIONS: Investigations revealed an adenocarcinoma of the colon with retroperitoneal, mediastinal and supraclavicular lymph node metastasis and poorly differentiated carcinoma of the prostate with extensive bone metastases. During their hospital stay both patients developed increasing shortness of breath and clinical signs of right heart failure. Echocardiography confirmed severe pulmonary hypertension and dilatation of the right ventricle in both patients. Despite the high degree of clinical suspicion CT scans of the thorax could not demonstrate pulmonary embolism. DIAGNOSIS, TREATMENT AND COURSE: During the following days the patients condition deteriorated further and both patients' died from irreversible right heart failure. Both autopsies showed extensive metastatic adenocarcinoma with marked angiosis carcinomatosa of the lungs with numerous occlusions of small arteries and arterioles and resulting cor pulmonale. Thrombotic pulmonary embolism could not be detected. CONCLUSION: In patients with malignant neoplasms, especially adenocarcinomas, dyspnea and signs of increasing pulmonary artery pressure, the possibility of a microscopic pulmonary tumor embolism should be considered after exclusion of more usual causes especially thrombotic pulmonary embolism. In selected cases a cytologic examination of blood aspirated from a wedged pulmonary artery catheter can be performed to prove angiosis is carcinomatosa.

Alterations of the thoracic spine in Marfan's syndrome

OBJECTIVE: The purpose of this study was to determine if the thoracic vertebral elements are altered in patients with Marfan's syndrome. MATERIALS AND METHODS: Thirty patients underwent helical CT of the thorax because of suspected thoracic aortic dilatation and acute dissection. Thirteen had Marfan's syndrome and 17 did not. Two reviewers, unaware of the final diagnosis, evaluated the images by consensus for laminar thickness, foraminal width, dural sac ratios, and vertebral scalloping for T2-T12. RESULTS: At T9-T12, dural sac ratios at the midcorpus level (p = 0.031) and foraminal width (p = 0.0124) were significantly greater in the patients with Marfan's syndrome than in the patients without. Dural sac ratios at lower endplate levels (p = 0.0685), laminar thickness (p = 0.951), and vertebral scalloping (p = 0.24) were not significantly greater in the patients with Marfan's syndrome than in the patients without. CONCLUSION: Because the phenotypic expression of Marfan's syndrome is variable, information on the spine from thoracic studies in combination with major criteria may be helpful clinically.

Locally generated particulate pollution and respiratory symptoms in young children

BACKGROUND: Particulate matter <10 mum (PM(10)) from fossil fuel combustion is associated with an increased prevalence of respiratory symptoms in children and adolescents. However, the effect of PM(10) on respiratory symptoms in young children is unclear. METHODS: The association between primary PM(10) (particles directly emitted from local sources) and the prevalence and incidence of respiratory symptoms was studied in a random sample cohort of 4400 Leicestershire children aged 1-5 years surveyed in 1998 and again in 2001. Annual exposure to primary PM(10) was calculated for the home address using the Airviro dispersion model and adjusted odds ratios (ORS) and 95% confidence intervals were calculated for each microg/m(3) increase. RESULTS: Exposure to primary PM(10) was associated with the prevalence of cough without a cold in both 1998 and 2001, with adjusted ORs of 1.21 (1.07 to 1.38) and 1.56 (1.32 to 1.84) respectively. For night time cough the ORs were 1.06 (0.94 to 1.19) and 1.25 (1.06 to 1.47), and for current wheeze 0.99 (0.88 to 1.12) and 1.28 (1.04 to 1.58), respectively. There was also an association between primary PM(10) and new onset symptoms. The ORs for incident symptoms were 1.62 (1.31 to 2.00) for cough without a cold and 1.42 (1.02 to 1.97) for wheeze. CONCLUSION: In young children there was a consistent association between locally generated primary PM(10) and the prevalence and incidence of cough without a cold and the incidence of wheeze which was independent of potential confounders.

Postmortem noninvasive virtual autopsy: extrapleural hemorrhage after blunt thoracic trauma

A 19-year-old man speeding recklessly along a highway caused a left-frontal crash with another car. After his vehicle came to a standstill, he climbed out of the wreck and crawled across the tarmac to the other side of the road, where he died several minutes after the accident and before the arrival of an ambulance. Postmortem multislice computed tomography (MSCT) demonstrated fractures of the first, second, and third ribs and scapula on the left, an extrapleural hemorrhage in the apical region of the left thorax, as well as a large amount of blood in the left thoracic cavity. These radiologic findings were indicative of a delayed rupture of a traumatic extrapleural hematoma into the pleural space. A traditional autopsy confirmed the very rare diagnosis of a traumatic extrapleural hemorrhage with a delayed rupture.

The effect of enamel matrix proteins and deproteinized bovine bone mineral on heterotopic bone formation

To evaluate the osteoinductive potential of deproteinized bovine bone mineral (DBBM) and an enamel matrix derivative (EMD) in the muscle of rats. Sixteen rats were used in this study. The animals were divided in three groups. Group A: a pouch was created in one of the pectoralis profundis muscles of the thorax of the rats and DBBM particles (Bio-Oss) were placed into the pouch. Healing: 60 days. Group B: a small pouch was created on both pectoralis profundis muscles at each side of the thorax midline. In one side, a mixture of EMD (Emdogain) mixed with DBBM was placed into one of the pouches, whereas in the contralateral side of the thorax the pouch was implanted with DBBM mixed with the propylene glycol alginate (PGA--carrier for enamel matrix proteins of EMD). Healing: 60 days. Group C: the same procedure as group B, but with a healing period of 120 days. Qualitative histological analysis of the results was performed. At 60 days, the histological appearance of the DBBM particles implanted alone was similar to that of the particles implanted together with EMD or PGA at both 60 and 120 days. The DBBM particles were encapsulated into a connective tissue stroma and an inflammatory infiltrate. At 120 days, the DBBM particles implanted together with EMD or PGA exhibited the presence of resorption lacunae in some cases. Intramuscular bone formation was not encountered in any group. The implantation of DBBM particles alone, combined with EMD or its carrier (PGA) failed to exhibit extraskeletal, bone-inductive properties.

Prevalence of heart disease in symptomatic cats: an overview from 1998 to 2005

A total of 408 cats with various cardiovascular problems has been presented to two investigational clinics during the last 8 years. The number of yearly examinations has steadily increased during this period. Definitive cardiovascular disease was diagnosed in 287 cats, whereby hypertrophic cardiomyopathy (HCM) was the most common diagnosis with 67.6%. Congenital cardiovascular malformations were found in 11.8% of the cases. Ventricular septal defect (VSD) was the most frequent anomaly, in contrast to previously published studies. The ECG was found to be relatively non-specific and insensitive for the diagnosis of heart disease: Its usefulness lies in the recognition and diagnosis of cardiac arrhythmias. The radiographically recognized changes were also non-specific for certain heart diseases. Radiographs of the thorax are especially useful in the evaluation of cardiomegaly, and secondary signs of congestion.

Assessment of bronchodilator responsiveness in preschool children using forced oscillations

BACKGROUND: The forced oscillation technique (FOT) requires minimal patient cooperation and is feasible in preschool children. Few data exist on respiratory function changes measured using FOT following inhaled bronchodilators (BD) in healthy young children, limiting the clinical applications of BD testing in this age group. A study was undertaken to determine the most appropriate method of quantifying BD responses using FOT in healthy young children and those with common respiratory conditions including cystic fibrosis, neonatal chronic lung disease and asthma and/or current wheeze. METHODS: A pseudorandom FOT signal (4-48 Hz) was used to examine respiratory resistance and reactance at 6, 8 and 10 Hz; 3-5 acceptable measurements were made before and 15 min after the administration of salbutamol. The post-BD response was expressed in absolute and relative (percentage of baseline) terms. RESULTS: Significant BD responses were seen in all groups. Absolute changes in BD responses were related to baseline lung function within each group. Relative changes in BD responses were less dependent on baseline lung function and were independent of height in healthy children. Those with neonatal chronic lung disease showed a strong baseline dependence in their responses. The BD response in children with cystic fibrosis, asthma or wheeze (based on both group mean data and number of responders) was not greater than in healthy children. CONCLUSIONS: The BD response assessed by the FOT in preschool children should be expressed as a relative change to account for the effect of baseline lung function. The limits for a positive BD response of -40% and 65% for respiratory resistance and reactance, respectively, are recommended.

Airway remodelling in children with cystic fibrosis

BACKGROUND: The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls. METHODS: Bronchoalveolar lavage and endobronchial biopsy were performed in a cross-sectional study of 43 children with CF (aged 0.3-16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy. RESULTS: Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase-9 (MMP-9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = -0.45, p<0.05; MMP-9:TIMP-1 ratio: r = -0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 microm vs 4.0 microm, p<0.01) and correlated positively with levels of transforming growth factor-beta(1) (TGF-beta(1); r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function. CONCLUSIONS: This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF-beta(1) concentration but independent of other markers of inflammation.