Proinflammatory conditions leading to activation of macrophages via interferon‐γ bear an important role in host defence against intracellular bacteria such as Mycobacterium tuberculosis (Mt). ...Interleukin‐17 plays a similar role, as it appears to be also an activator of macrophages. Recently, the TLR‐10 was identified as an anti‐inflammatory factor that exerts its action via association with the TLR‐2 chain at the cell surface of macrophages, the latter being an Mt‐binding protein. We have previously found that gene polymorphisms that either inactivate the TLR2 gene product or have a dominant‐negative role are associated with tuberculosis (TB) in Croatian population. We have now extended our survey and found that single nucleotide polymorphism (SNP) in TLR10 (rs11096957) is associated with risk for TB. Homozygotes carrying the A allele are associated with predisposition to disease as analysed by the dominant model of inheritance. In contrast, SNPs in the proinflammatory IL17A and IL17F genes (rs2275913 and rs763780, respectively), found previously to correlate with the disease occurrence in Chinese population, were not significantly associated with tuberculosis in the Croatian population.
The value of microbiological criteria in diagnosing non-tuberculous mycobacteria pulmonary disease (NTM-PD) and monitoring its epidemiology is unknown.
To correlate the rate of NTM-PD based on ...microbiological criteria (American Thoracic Society/Infectious Diseases Society of America ATS/IDSA or stricter microbiological criteria) compared with the full ATS/IDSA criteria, to assess the positive predictive value (PPV) of different microbiological criteria in predicting NTM-PD, and to evaluate the clinical relevance of different NTM species.
Retrospective study of all patients with pulmonary NTM isolates in Croatia during an 8-year period. NTM species were divided into low, intermediate and high clinical relevance groups for additional analyses.
Good correlation between both microbiological and full ATS/IDSA criteria was observed. The PPV of stricter and ATS/IDSA microbiological criteria was respectively 93.3% and 59.8%. The usefulness of microbiological criteria varied between groups. ATS/IDSA microbiological criteria had a PPV of 89.8% in the high relevance group, while in the intermediate relevance group, the PPV of stricter and ATS/IDSA microbiological criteria was respectively 94.3% and 63.4%.
Microbiological criteria are useful in detecting NTM-PD, allowing laboratory-based monitoring. Stricter criteria should be used for species of low clinical relevance, and less stringent criteria for species of high relevance in the local setting.
We have sequenced 416 Toll-like receptor-2 (TLR2) alleles in 208 subjects in a tuberculosis case-control study in Croatian Caucasian population. We found ten single nucleotide polymorphisms (SNP) ...among which three were novel (S97S, T138I and L266F). The genotype containing TLR2-P631H SNP was significantly overrepresented in patients with tuberculosis when compared to contact controls, suggesting a small yet increased risk to disease. The causative agent of tuberculosis is Mycobacterium tuberculosis, which can bind to TLR2 with its lipoprotein coat. The TLR2-P631H mutant has a dominant negative effect on the wild type TLR2 signalling in transfected HEK293 kidney cells using the NF-κB-driven luciferase as a reporter gene with ligands like M. avium extracts, Pam3CysSK4 or FSL-1 that bind TLR2/TLR1 or TLR2/TLR6 heterodimers, respectively. Studies on internalization from the Regular Madine Darby Canine Kidney cell surface into the early endosomal compartments showed a lower rate of the mutant compared to the wild type. Our data, in combination with a report by others show that the TLR2-P631H allele could be associated with protection to meningococcal meningitis, suggest that by dominantly inhibiting the response of cells important in the immune response this mutant might confer either protection or susceptibility to meningitis or tuberculosis, respectively.
Genetic susceptibility to tuberculosis includes several unknown yet different loci each contributing to a small extent. Intronic polymorphisms within the interferon‐γ (IFN‐γ) gene IFNG T+874A and ...IFNG G+2109A correlate with the IFN‐γ production in vitro, and the frequency of potential high IFN‐γ producers was previously reported by others to be lower in patients than in controls from Sicily. The aim of this study was to determine whether there is an association between polymorphisms in the IFN‐γ gene and predisposition to tuberculosis. We analysed two IFNG SNPs (T+874A and G+2109A) in patients (n = 253) hospitalized in Rijeka (Croatia) and controls (n = 519) from the same area. One‐fifth of the controls were healthy contacts of the diseased, and the rest were blood donors. IFNG alleles, their predicted haplotypes or genotypes were not associated with disease susceptibility. Thus, we could not reproduce results from Sicilian case‐control study. However, T/T+874 (possible high IFN‐γ producer) and +874A/A (putative low producer) genotypes were associated with microscopically positive–negative forms of disease. Haplotypes (T+874A and G+2109A) based on a prediction by software phase and subsequent genotype analysis corroborated these findings. Patients had significantly higher frequency of genotypes without T at +874 (AA/AA; AA/AG and AG/AG) in microscopy‐ or bacterial culture‐positive groups compared with their negative counterparts. These data suggest an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population.
We analysed frequencies of two single‐nucleotide polymorphisms (SNP) in the interferon‐γ (IFN‐γ) receptor‐1 (IFNGR1) gene promoter (G‐611A, T‐56C) in tuberculosis patients (n = 244) and compared them ...with controls (n = 521). These frequencies were not significantly different, whether analysed independently or as haplotypes. Because these SNP affect transcription, the results suggest that the expression of the IFNGR1 gene does not confer susceptibility to disease in patients from Croatia. Further analysis revealed a significant association between the protective (CA)n polymorphism (22 repeats, 192 FA1), located in the fifth intron of the IFNGR1 gene (+16682), and GT promoter haplotype (−611; −56) that showed the strongest expression capacity. In addition to this cis relationship, the (CA)22 allele was correlated in trans with an IFN‐γ SNP (IFNG G + 2109A), which might affect the transcription of the IFNG gene. These results suggest that a particular combination of IFNG and IFNGR1 SNP might offer a better protection against tuberculosis in this population.
Recent studies have indicated that the interleukin‐12/interferon‐γ (IFN‐γ) axis is important in mycobacterial infection susceptibility. Using an intronic (CA)n polymorphic microsatellite marker ...within the IFN‐γ receptor‐1 (IFNGR1) gene, we have compared the allelic frequencies of this marker in hospitalized tuberculosis patients (n = 120) with that of controls (n = 87) from Rijeka, Croatia. We identified 13 (CA)n alleles in the tuberculosis patients, whereas only 10 were found in the controls. A significant difference between one allelic marker and the control group was observed (P = 0.02, 95% confidence interval 0.14–0.94), suggesting a possible protective association. In contrast, several other allelic markers showed a trend towards association with the disease. We also found a trend towards an increased frequency in homozygosity of one allelic marker in patients (11.7%) as compared with controls (4.6%). We conclude that there is no evidence for disease association of the IFNGR1 gene marker in Mendelian‐type (single‐allele) inheritance. However, our results also suggest that unidentified allelic variations in the IFNGR1 gene might elevate or decrease the risk in this ethnic population, as a part of the multigenic predisposition to tuberculosis.
Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) lead to poor outcomes and increased burden for patients and healthcare systems. The Global Initiative for COPD (GOLD) includes ...specific recommendations for AECOPD interventions, discharge criteria, and follow-up. Aligning the AECOPD discharge letters (DL) with GOLD guidelines could facilitate dissemination of recommendations among general practitioners (GPs).
This study was conducted to assess the compliance of DL with the GOLD recommendations in Croatia.
Pre-pandemic DL of patients presenting for AECOPD to emergency room (ER) were analyzed and stratified by clinical decision to hospitalize (HDL) or discharge patients for outpatient treatment (ERDL). Experienced pulmonologists checked the information from DL against guidelines by using online study-specific questionnaires.
In total, 225 HDL and 368 ERDL were analyzed. In most cases, the GOLD ABCD categories (85% HDL, 92% ERDL) or the spirometry-based degree of severity (90% HDL, 91% ERDL) were not included. The number of AEs in the previous year was recorded, but the specific frequent exacerbator phenotype not explicitly stated. The AE phenotype was included in two thirds of HDL and one third of ERDL. The blood eosinophil count was frequently available, but not considered decision-relevant information. Adjustments of previous maintenance therapy, mostly escalation, were recommended in 58.4% HDL and 27.9% ERDL, respectively. Education on proper use of inhalers was recommended only in 15.6% of HDL. Smoking cessation measures were advised in 23.1% HDL and 7.9% ERDL; pulmonary rehabilitation in 35.6% HDL and 0.8% ERDL. Early follow-up was frequently advised (>50%), but rarely appointed.
Significant deficiencies in compliance with the GOLD guidelines were identified, translating into a missed opportunity for GPs to become acquainted with GOLD recommendations. These findings emphasize the necessity to increase compliance with guidelines first at specialist level and consequent standardization of DL.
Ascites, pseudocyst, necrosis of the retroperitoneal fat tissue and pancreatopleural fistula with left sided pleural effusion may complicate pancreatitis. However, steatonecrosis of the mediastinum ...and right side pleural effusion are rather rare complications of pancreatitis. We present a case of a patient with alcohol induced pancreatitis. Chest x-ray showed right sided pleural effusion. Although high levels of amylase in pleural fluid made the diagnosis of pancreatopleural fistula most likely, necrosis of the mediastinal fat tissue with right side pleural effusion was found postmortem.
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