Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests

A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT(4)) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully.

Lung-function tests in neonates and infants with chronic lung disease: tidal breathing and respiratory control

This paper is the fourth in a series of reviews that will summarize available data and critically discuss the potential role of lung-function testing in infants with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses information derived from tidal breathing measurements within the framework outlined in the introductory paper of this series, with particular reference to how these measurements inform on control of breathing. Infants with acute and chronic respiratory illness demonstrate differences in tidal breathing and its control that are of clinical consequence and can be measured objectively. The increased incidence of significant apnea in preterm infants and infants with chronic lung disease, together with the reportedly increased risk of sudden unexplained death within the latter group, suggests that control of breathing is affected by both maturation and disease. Clinical observations are supported by formal comparison of tidal breathing parameters and control of breathing indices in the research setting.

Oxygen-sensitive 3He-MRI in bronchiolitis obliterans after lung transplantation

Oxygen-sensitive 3He-MRI was studied for the detection of differences in intrapulmonary oxygen partial pressure (pO2) between patients with normal lung transplants and those with bronchiolitis obliterans syndrome (BOS). Using software developed in-house, oxygen-sensitive 3He-MRI datasets from patients with normal lung grafts (n = 8) and with BOS (n = 6) were evaluated quantitatively. Datasets were acqiured on a 1.5-T system using a spoiled gradient echo pulse sequence. Underlying diseases were pulmonary emphysema (n = 10 datasets) and fibrosis (n = 4). BOS status was verified by pulmonary function tests. Additionally, 3He-MRI was assessed blindedly for ventilation defects. Median intrapulmonary pO2 in patients with normal lung grafts was 146 mbar compared with 108 mbar in patients with BOS. Homogeneity of pO2 distribution was greater in normal grafts (standard deviation pO2 34 versus 43 mbar). Median oxygen decrease rate during breath hold was higher in unaffected patients (-1.75 mbar/s versus -0.38 mbar/s). Normal grafts showed fewer ventilation defects (5% versus 28%, medians). Oxygen-sensitive 3He-MRI appears capable of demonstrating differences of intrapulmonary pO2 between normal lung grafts and grafts affected by BOS. Oxygen-sensitive 3He-MRI may add helpful regional information to other diagnostic techniques for the assessment and follow-up of lung transplant recipients.

Lung volume reduction surgery for severe emphysema

BACKGROUND: We report mid-term results after 25 consecutive lung volume reduction operations (LVRS) for the treatment of severe dyspnea due to advanced emphysema. METHODS: Study design: patients were studied prospectively up to 12 months after surgery. Setting: preoperative evaluation, surgery and postoperative care took place in our university hospital. Patients: patient selection was based on severe dyspnea and airway obstruction despite optimal medical treatment, lung overinflation and completed rehabilitation programme. Patients with severe hypercarbia (PCO2>50 mmHg) were excluded. Nineteen rehabilitated patients who fulfilled our inclusion criteria but postponed or denied LVRS were followed up clinically. Interventions: LVRS was performed bilaterally in 22 patients (median sternotomy) and unilaterally in 3 patients (limited thoracotomy). Measures: Outcome was measured by dyspnea evaluation, 6-minute-walking distance and pulmonary function tests. RESULTS: Twelve months postoperatively dyspnea and mobility improved significantly (MRC score from 3.3+/-0.7 to 2.12+/-0.8, 6-min-walk from 251+/-190 to 477+/-189 m). These results were superior compared to the results of the conservatively treated patients. Significant improvement could also be documented in airway obstruction (FEV1 from 960+/-369 to 1438+/-610 ml) and overinflation (TLC from 133+/-14 to 118+/-21% predicted and RV from 280+/-56 to 186+/-59% predicted). CONCLUSIONS: LVRS is an effective and promising treatment option for selected patients with end-stage emphysema and could be offered as an alternative and / or bridge to lung transplantation.

Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis.

Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF.

Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis

BACKGROUND: Functional deterioration in cystic fibrosis (CF) may be reflected by increasing bronchial obstruction and, as recently shown, by ventilation inhomogeneities. This study investigated which physiological factors (airway obstruction, ventilation inhomogeneities, pulmonary hyperinflation, development of trapped gas) best express the decline in lung function, and what role specific CFTR genotypes and different types of bronchial infection may have upon this process. METHODS: Serial annual lung function tests, performed in 152 children (77 males; 75 females) with CF (age range: 6-18 y) provided data pertaining to functional residual capacity (FRCpleth, FRCMBNW), volume of trapped gas (VTG), effective specific airway resistance (sReff), lung clearance index (LCI), and forced expiratory indices (FVC, FEV1, FEF50). RESULTS: All lung function parameters showed progression with age. Pulmonary hyperinflation (FRCpleth > 2SDS) was already present in 39% of patients at age 6-8 yrs, increasing to 67% at age 18 yrs. The proportion of patients with VTG > 2SDS increased from 15% to 54% during this period. Children with severe pulmonary hyperinflation and trapped gas at age 6-8 yrs showed the most pronounced disease progression over time. Age related tracking of lung function parameters commences early in life, and is significantly influenced by specific CFTR genotypes. The group with chronic P. aeruginosa infection demonstrated most rapid progression in all lung function parameters, whilst those with chronic S. aureus infection had the slowest rate of progression. LCI, measured as an index of ventilation inhomogeneities was the most sensitive discriminator between the 3 types of infection examined (p < 0.0001). CONCLUSION: The relationships between lung function indices, CFTR genotypes and infective organisms observed in this study suggest that measurement of other lung function parameters, in addition to spirometry alone, may provide important information about disease progression in CF.

Increased uptake of 111In-octreotide in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by an uncontrolled accumulation and activation of lung fibroblasts. A modulation of fibroblast activation has been observed in various systems with octreotide, a synthetic somatostatin analog with strong affinity for the somatostatin receptor subtype 2 (sst2). One aim of our study was to evaluate the expression of somatostatin receptors in the lungs of patients with IPF. A second aim was to evaluate the relationship between 111In-octreotide uptake and the effect of pulmonary fibrosis as assessed by lung function tests and parameters and by radiologic findings. METHODS: We investigated 11 patients with IPF, 6 patients with pulmonary fibrosis associated with systemic sclerosis (SSc), and 19 patients with disease not of the lung (control patients). The expression of somatostatin receptors was evaluated in vivo using 111In-octreotide scintigraphy. We evaluated the relationship between 111In-octreotide uptake and the activity of pulmonary fibrosis as assessed by lung function tests, bronchoalveolar lavage (BAL) cellularity, and high-resolution CT (HRCT) of the chest. Planar images and thoracic SPECT (24 h) were performed after injection of 222 MBq of 111In-octreotide. Lung uptake was quantified using the lung-to-background ratio (L/B). In addition, the expression of sst2 was evaluated in vitro, in frozen lung-tissue samples using autoradiography, and in human cultures of lung fibroblasts using a ligand-binding assay. RESULTS: Compared with lung uptake in control patients (median L/B, 1.25; range, 1.14-1.49), lung uptake was increased in all 11 IPF patients (median L/B, 2.63; range, 1.59-3.13; P < 0.001) and in 4 of 6 SSc patients (median L/B, 1.68; range, 1.42-2.16). The L/B was lower in SSc patients than in IPF patients (P = 0.011). Increased uptake correlated with the alteration of lung function (carbon monoxide diffusing capacity [rho = -0.655; P = 0.038], diffusing capacity for carbon monoxide and alveolar volume ratio [rho = -0.627; P = 0.047], vital capacity [rho = -0.609; P = 0.054], and total lung capacity [rho = -0.598; P = 0.058]) and with the intensity of alveolitis (total BAL cellularity [rho = 0.756; P = 0.045], neutrophil counts [rho = 0.738; P = 0.05]), and HRCT fibrosis score (rho = 0.673; P = 0.007). Autoradiography suggested that vascular structures were a prominent binding site. Lung fibroblasts expressed somatostatin receptors in vitro as measured by binding assay. CONCLUSION: Our preliminary results identified an increased expression of sst2 in (mainly idiopathic) pulmonary fibrosis. Lung uptake correlates with the alteration of lung function and with the intensity of alveolitis.

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Methylprednisolone Fails to Preserve Pulmonary Surfactant and Blood-Air Barrier Integrity in a Porcine Cardiopulmonary Bypass Model

BACKGROUND: Pulmonary inflammation after cardiac surgery with cardiopulmonary bypass (CPB) has been linked to respiratory dysfunction and ultrastructural injury. Whether pretreatment with methylprednisolone (MP) can preserve pulmonary surfactant and blood-air barrier, thereby improving pulmonary function, was tested in a porcine CPB-model. MATERIALS AND METHODS: After randomizing pigs to placebo (PLA; n = 5) or MP (30 mg/kg, MP; n = 5), animals were subjected to 3 h of CPB with 1 h of cardioplegic cardiac arrest. Hemodynamic data, plasma tumor necrosis factor-alpha (TNF-alpha, ELISA), and pulmonary function parameters were assessed before, 15 min after CPB, and 8 h after CPB. Lung biopsies were analyzed for TNF-alpha (Western blot) or blood-air barrier and surfactant morphology (electron microscopy, stereology). RESULTS: Systemic TNF-alpha increased and cardiac index decreased at 8 h after CPB in PLA (P < 0.05 versus pre-CPB), but not in MP (P < 0.05 versus PLA). In both groups, at 8 h after CPB, PaO(2) and PaO(2)/FiO(2) were decreased and arterio-alveolar oxygen difference and pulmonary vascular resistance were increased (P < 0.05 versus baseline). Postoperative pulmonary TNF-alpha remained unchanged in both groups, but tended to be higher in PLA (P = 0.06 versus MP). The volume fraction of inactivated intra-alveolar surfactant was increased in PLA (58 +/- 17% versus 83 +/- 6%) and MP (55 +/- 18% versus 80 +/- 17%) after CPB (P < 0.05 versus baseline for both groups). Profound blood-air barrier injury was present in both groups at 8 h as indicated by an increased blood-air barrier integrity score (PLA: 1.28 +/- 0.03 versus 1.70 +/- 0.1; MP: 1.27 +/- 0.08 versus 1.81 +/- 0.1; P < 0.05). CONCLUSION: Despite reduction of the systemic inflammatory response and pulmonary TNF-alpha generation, methylprednisolone fails to decrease pulmonary TNF-alpha and to preserve pulmonary surfactant morphology, blood-air barrier integrity, and pulmonary function after CPB.

[Unilateral vs. bilateral lung transplantation in obstructive pulmonary disease]

BACKGROUND: The question whether patients suffering from end-stage emphysema who are candidates for lung transplantation should be treated with a single lung or with a double lung transplantation is still unanswered. METHODS: We reviewed 24 consecutive lung transplant procedures, comparing the results of 6 patients with an unilateral and 17 with a bilateral transplantation. PATIENTS AND RESULTS: After bilateral transplantation the patients showed a trend towards better blood gas exchange with shorter time on ventilator and intensive care compared patients after unilateral procedure. Three-year-actuarial survival was higher in the group after bilateral transplantation (83% versus 67%). There was a continuous improvement in pulmonary function in both groups during the first months after transplantation. Vital capacity and forced exspiratory ventilation therapies during the first second were significantly higher in the bilateral transplant group. CONCLUSION: Both unilateral and bilateral transplantation are feasible for patients with end-stage emphysema. Bilateral transplantation results in better pulmonary reserve capacity and faster rehabilitation.

SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice

Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in α1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema.

Can infant lung function predict respiratory morbidity during the first year of life in preterm infants?

Compared with term-born infants, preterm infants have increased respiratory morbidity in the first year of life. We investigated whether lung function tests performed near term predict subsequent respiratory morbidity during the first year of life and compared this to standard clinical parameters in preterms.The prospective birth cohort included randomly selected preterm infants with and without bronchopulmonary dysplasia. Lung function (tidal breathing and multiple-breath washout) was measured at 44 weeks post-menstrual age during natural sleep. We assessed respiratory morbidity (wheeze, hospitalisation, inhalation and home oxygen therapy) after 1 year using a standardised questionnaire. We first assessed the association between lung function and subsequent respiratory morbidity. Secondly, we compared the predictive power of standard clinical predictors with and without lung function data.In 166 preterm infants, tidal volume, time to peak tidal expiratory flow/expiratory time ratio and respiratory rate were significantly associated with subsequent wheeze. In comparison with standard clinical predictors, lung function did not improve the prediction of later respiratory morbidity in an individual child.Although associated with later wheeze, noninvasive infant lung function shows large physiological variability and does not add to clinically relevant risk prediction for subsequent respiratory morbidity in an individual preterm.

Prevalence and predictors of kaposi sarcoma herpes virus seropositivity: a cross-sectional analysis of HIV-infected adults initiating ART in Johannesburg, South Africa

Background Kaposi sarcoma (KS) is the most common AIDS-defining tumour in HIV-infected individuals in Africa. Kaposi sarcoma herpes virus (KSHV) infection precedes development of KS. KSHV co-infection may be associated with worse outcomes in HIV disease and elevated KSHV viral load may be an early marker for advanced HIV disease among untreated patients. We examined the prevalence of KSHV among adults initiating antiretroviral therapy (ART) and compared immunological, demographic and clinical factors between patients seropositive and seronegative for KSHV. Results We analyzed cross-sectional data collected from 404 HIV-infected treatment-naïve adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa between November 2008 and March 2009. Subjects were screened at ART initiation for antibodies to KSHV lytic K8.1 and latent Orf73 antigens. Seropositivity to KSHV was defined as positive to either lytic KSHV K8.1 or latent KSHV Orf73 antibodies. KSHV viremia was determined by quantitative PCR and CD3, 4 and 8 lymphocyte counts were determined with flow cytometry. Of the 404 participants, 193 (48%) tested positive for KSHV at ART initiation; with 76 (39%) reactive to lytic K8.1, 35 (18%) to latent Orf73 and 82 (42%) to both. One individual presented with clinical KS at ART initiation. The KSHV infected group was similar to those without KSHV in terms of age, race, gender, ethnicity, smoking and alcohol use. KSHV infected individuals presented with slightly higher median CD3 (817 vs. 726 cells/mm3) and CD4 (90 vs. 80 cells/mm3) counts than KSHV negative subjects. We found no associations between KSHV seropositivity and body mass index, tuberculosis status, WHO stage, HIV RNA levels, full blood count or liver function tests at initiation. Those with detectable KSHV viremia (n = 19), however, appeared to present with signs of more advanced HIV disease including anemia and WHO stage 3 or 4 defining conditions compared to those in whom the virus was undetectable. Conclusions We demonstrate a high prevalence of KSHV among HIV-infected adults initiating ART in a large urban public-sector HIV clinic. KSHV viremia but not KSHV seropositivity may be associated with markers of advanced HIV disease.

Steroid-responsive encephalopathy associated with Hashimoto thyroiditis

An 11-year-old girl presented with sudden sensory disturbance and left-sided muscle weakness. MRI revealed ischaemic change in the right lateral thalamus and the right internal capsule. During sonographic work-up of the cervical arteries, inflammation of the thyroid gland was noted. The results of the thyroid function tests and antibody titers confirmed Hashimoto thyroidits. Under high-dose corticosteroids, the girl had a full neurological recovery.

[Non-alcoholic steatohepatitis - from NAFLD to MAFLD]

Non-alcoholic steatohepatitis (NASH) as one entity of non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and accompanies the rise in the prevalence of obesity, diabetes mellitus, hypertension and hyperlipidemia in the western world. It is not known why some patients progress in the disease and develop inflammation in the liver, whereas others remain in the stage of simple steatosis, which generally has a benign course. However, NASH can progress to fibrosis and cirrhosis as well as hepatocellular carcinoma. Therefore, it is important to determine the stage of the disease in patients presenting with the metabolic syndrome and abnormal liver function tests, suggesting NAFLD. Liver biopsy is the only tool that allows for reliable detection, grading and staging of liver disease. The main strategies in the treatment of NASH are correction of risk factors (lifestyle modifications, insuline sensitizer) and anti-oxidants (ursodeoxycholic acid, vitamin E) which both have been shown to improve liver histology as well as liver enzymes. Patients wih alcoholic fatty liver disease (AFLD) present the same liver histology and often also metabolic alterations similar to metabolic syndrome. Therefore, MAFLD (metabolic syndrome-associated fatty liver disease) might describe both patient populations more accurately and also describes the pathophysiological characteristics.