Stipan Janković

A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample

Rationale Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers. Conclusions Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.

Removal of tracheobronchial foreign bodies in adults using flexible bronchoscopy: experience 1995–2006

BackgroundTracheobronchial foreign body (TFB) removal in adult patients using the combined technique of flexible bronchoscopy (FBSC) through the endotracheal tube as well as using the simple FBSC has not often been described. This study reports our experience with FBSC for removal of TFBs and describes diagnosis, techniques of removal, and types of TFBs.MethodsWe retrospectively examined bronchoscopic records of adult patients performed between 1995 and 2006 and collection of foreign bodies in Clinical Department for Respiratory Diseases, University Hospital Split, Croatia.ResultsTFBs were found in 86 (0.33%) out of 26,124 patients who were submitted to bronchoscopy. The majority of the patients (90%) had some risk factor for aspiration, among which stroke (30%) was the most frequent. Patients with different neurologic and neuromuscular diseases together accounted for 58% of all patients with TFB aspiration. Medical history was suggestive of foreign body aspiration in 38.4% of the patients, while chest X-ray was indicative in 7% of the patients. TFBs were most often found in the right bronchial tree (75.6%). The most common TFBs were animal and fish bones (39.5%). In 90.7% of the patients they were successfully removed under FBSC, whereas in 8.1% of the patients a TFB was extracted with flexible bronchoscope through endotracheal tube. Surgery was needed in only one case.ConclusionsAlthough foreign bodies in the tracheobronchial tree are rare in adults, the clinician must be aware of their likelihood. Foreign body aspiration should be considered especially in the etiology of recurrent lung diseases and in the presence of risk factors for aspiration, in particular with different neurologic and neuromuscular diseases. They can be successfully and safely removed in the majority of patients under local anesthesia by using FBSC. In cases when repeated procedure is needed, endotracheal tube is recommended.

Anti-CD20 Monoclonal Antibody (Rituximab) for Therapy of Mediastinal CD20-Positive Large B-Cell Non-Hodgkin Lymphoma with a Local Tumor Extension into the Lung of a 10-Year-Old Girl

Intravenous therapy with the anti-CD20 antibody Rituximab has been recently approved for the treatment of CD20 positive non-Hodgkins lymphoma (NHL) in adults but not in children. The authors present the benefits of its application for mediastinal NHL CD 20+ with a local extension into the lung of a 10-year-old-girl. Receiving the chemotherapy according to study NHL-BFM-95 for high-risk lymphoma the girl did not reach complete remission. Before the last chemotherapy block was started, a computed tomography scan of the thorax showed residue in the right lung. Twenty-five days after the last chemotherapy she received Rituximab at a dose of 375 mg/m 2 by intravenous infusion once a week for a total of four doses without the adverse reactions. Complete remission was achieved. The patient was high risk with lung involvement of lymphoma suggesting a pure prognosis. The results suggest that Rituximab may improve the outcome in high-risk patients and appeared to be safe and effective in children also.

Cardiac magnetic resonance imaging during pulmonary hyperinflation in apnea divers.

PURPOSE Apnea divers hyperinflate the lung by taking a deep breath followed by glossopharyngeal insufflation. The maneuver can lead to symptomatic arterial hypotension. We tested the hypotheses that glossopharyngeal insufflation interferes with cardiac function further reducing cardiac output (CO) using cardiac magnetic resonance imaging (MRI) to fully sample both cardiac chambers. METHODS Eleven dive athletes (10 men, 1 woman; age = 26 ± 5 yr, body mass index = 23.5 ± 1.7 kg·m(-2)) underwent cardiac MRI during breath holding at functional residual capacity (baseline), at total lung capacity (apnea), and with submaximal glossopharyngeal insufflation. Lung volumes were estimated from anatomic images. Short-axis cine MR images were acquired to study biventricular function. Dynamic changes were followed by long-axis cine MRI. RESULTS Left and right ventricular end-diastolic volumes (LVEDV, RVEDV) decreased during apnea with and without glossopharyngeal insufflation (baseline: LVEDV = 198 ± 19 mL, RVEDV = 225 ± 30 mL; apnea: LVEDV = 125 ± 38 mL, RVEDV = 148 ± 37 mL, P < 0.001; glossopharyngeal insufflation: LVEDV = 108 ± 26 mL, RVEDV = 136 ± 29 mL, P < 0.001 vs baseline). CO decreased during apnea (left = -29 ± 4 %, right = -29 ± 4 %) decreasing further with glossopharyngeal insufflation (left = -38% ± 4%, right = -39% ± 4%, P < 0.05). HR increased 16 ± 4 bpm with apnea and 17 ± 5 bpm with glossopharyngeal insufflation (P < 0.01). Ejection fraction moderately decreased (apnea: left = -5% ± 2%, right = -7% ± 2%, glossopharyngeal insufflation: left = -6% ± 2%, right = -10% ± 2%, P < 0.01). With continued apnea with and without glossopharyngeal insufflation, LVEDV and CO increased over time by a similar but small amount (P < 0.01). CONCLUSIONS The major finding of our study was that submaximal glossopharyngeal insufflation decreased CO further albeit by a small amount compared to maximal inspiratory apnea. The response was not associated with severe biventricular dysfunction.

Plasma and cerebrospinal fluid endogenous digoxin-like immunoreactivity in patients with aneurysmal subarachnoid haemorrhage.

Summary Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, presumed to be endogenous hormones regulating the biological activity of the NA+/K+-ATPase and its isoforms. This substance has been postulated to enhance renal tubular sodium excretion and to increase peripheral vascular resistance. Digoxin-like immunoreactive substance (DLIS) was observed in plasma of some patients with spontaneous subarachnoid haemorrhage (SSAH). Accumulating evidence suggests the central nervous system as a site of synthesis, but also as a site of hypertensinogenic action of endogenous cardioglycosides. The present study intends to establish the ratio of the DLIS in plasma to that in cerebrospinal fluid (CSF) in patients with SSAH and to investigate possible connection of this substance with development of arterial vasospasm. A prospective analysis of DLIS levels was performed on plasma and CSF samples obtained in 40 patients who had suffered a recent SSAH. DLIS levels were determined by the fluorescence polarisation immuno-assay method immediately after the admission to the Ward, and again seven days later. The comparison of CSF and plasma DLIS levels did not show statistically significant differences between the results – neither for the first (Z=0.530; P=0.591) nor for the seventh day after the disease onset (Z=0.448; P=0.654). Three possible hypothetical explanations of these results are offered: a) substance determined by digoxin immuno-assay has no essential likeness to digoxin; b) loss of the haemato-encephalic barrier integrity enabling free substance exchange between plasma and central nervous system; c) digoxin-like substance production within the central nervous system. Further, comparison of DLIS plasma levels (7th day from onset of SSAH) with angiography results showed that patients with multiple vasospasm had essentially higher plasma DLIS levels compared to patients with no vasospasms (Z=2.59; P=0.0097). The amount of extravasated blood, assessed on the basis of cranial CT scanning, was also connected with higher plasma DLIS levels (X2=3.29; P=0.0305). The enhanced arterial narrowing which occurs in SSAH may be in part mediated by increased digitalis-like factor activity.

Successful management of bleeding with recombinant factor VIIa (NovoSeven®) in a patient with Burkitt lymphoma and thrombosis of the left femoral and left common iliac veins

We present the case of an 18‐year‐old female with Burkitt lymphoma involving the intra‐abdominal and inguinal lymph nodes. The tumor had invaded the left femoral and common iliac veins causing secondary thrombosis and vessel occlusion. Chemotherapy and anticoagulant treatment resulted in mild thrombocytopenia and a prolonged prothrombin time, respectively, which exacerbated postoperative bleeding following surgical removal of a deep inguinal necrosis. After 6 days, bleeding combined with epistaxis was considered to be life threatening and anticoagulant reversal with recombinant factor VIIa was successfully performed. The patient has since achieved complete remission and subsequent antithrombotic therapy has resolved the vascular occlusion. Pediatr Blood Cancer 2007;49:332–335.

Disseminated BCG infection resembling langerhans cell histiocytosis in an infant with severe combined immunodeficiency: A case report

We present a very rare congenital immunologic disease, severe combined immunodeficiency syndrome (SCID) in 6-months-old-boy with prolonged mucocutaneous candidiasis, severe anaemia, skin rash similar to the infiltrative eczema of Langerhans cell histiocytosis (LCH) and subcutaneous nodules with histiocytic infiltration. Laboratory findings show profound absence of humoral and cell-mediated immunity. Pathology specimens analysis of subcutaneous nodule revealed numerous S-100 protein and Cd1a negative histiocytes, occupied by BCG intracellular growth. Histopathology and immunohistochemistry confirmed the diagnosis of BCG dissemination. BCG vaccination in infants with SCID can lead to life threatening dissemination, resembling to the infiltrative eczema of LCH and may mislead the clinician.

Endoluminal Stenting for Subclavian Artery Stenosis in Takayasu’s Arteritis

We describe a patient with Takayasu’s arteritis (type I): occlusion of all large vessels of the aortic arch except the left subclavian artery which was, however, almost completely occluded, resulting in a characteristic subclavian steal syndrome. Elective left main subclavian artery balloon angioplasty followed by endoluminal stenting was performed with excellent results. After prolonged immunosuppressive treatment, at the 12-month follow-up there was no evidence of restenosis. In selected patients with Takayasu’s arteritis and subclavian stenosis, elective endoluminal stenting can be used as a definitive procedure or as a bridge to surgical revascularization.

Interobserver Variations in Diagnosing Asbestosis According to the ILO Classification

Interobserver Variations in Diagnosing Asbestosis According to the ILO Classification Inhalation of asbestos fibres leads to asbestosis of the pleura and the lung, with possible progression to lung cancer and malignant pleural or peritoneal mesothelioma. Asbestosis remains difficult to diagnose, especially in its early stages. The most important role in its diagnosis is that of chest radiographs. The aim of this cross-sectional study was to address interobserver variations in interpreting chest radiographs in asbestos workers, which remain to be an issue, despite improvements in the International Labour Office (ILO) classification system. In our ten-year study, we investigated 318 workers occupationally exposed to asbestos, and in 210 workers with diagnosed asbestos-related changes we compared interpretations of chest radiographs according to ILO by two independent radiologists. The apparent degree of interobserver variation in classifying lung fibrosis was 26.66% for the diameter of changes and 42.2% for the profusion of the changes. In cases with diffuse pleural thickening, the interobserver variation using ILO procedures was 34.93%. This investigation raises the issue of standardisation and objectivity of interpretation of asbestosis according to the ILO classification system. This study has revealed a significant disagreement in the estimated degree of pleural and parenchymal asbestos pulmonary disease. This is why we believe high-resolution computed tomography (HRCT) should also be used as a part of international classification. Interopservacijske razlike u dijagnosticiranju azbestoze prema klasifikaciji ILO

From biography to osteobiography: an example of anthropological historical identification of the remains of St.Paul

In the identification process of historical figures, and especially in cases of Saints bodies or mummified remains, any method that includes physical encroachment or sampling is often not allowed. In these cases, one of the few remaining possibilities is the application of nondestructive radiographical and anthropological methods. However, although there have been a few attempts of such analyses, no systematic standard methodology has been developed until now. In this study, we developed a methodological approach that was used to test the authenticity of the alleged body of Saint Paul the Confessor. Upon imaging the remains on MSCT and post‐processing, the images were analyzed by an interdisciplinary team to explore the contents beneath the binding media (e.g., the remains) and to obtain osetobiographical data for comparison with historical biological data. Obtained results: ancestry, sex, age, occupation, and social status were consistent with historical data. Although the methodological approach proved to be appropriate in this case, due to the discrepancy in the amount of data, identity could not be fully confirmed. Nonetheless, the hypothesis that the remains do not belong to St. Paul was rejected, whilst positive identification receives support. Anat Rec, 300:1535–1546, 2017.