Primary and acquired drug resistance of tuberculosis bacilli in Poland

Information about resistant pattern of Mycobacterium tuberculosis isolates against antituberculon drugs is a very important part of tuberculosis control and indicates the directions of TB policy in each country. Poland joined WHO/IUATLD global project on drug resistance surveillance, and carried out the first prospective survey, simultaneously on primary and acquired drug resistance of tuberculosis patients according WHO/IUATLD recommendations. The programme covered the whole country, basing on cooperation between the National Reference Laboratory (NRL) with regional TB laboratories. Questionnaires and cultures were obtained from patients who excreted TB bacilli during the period from 1 November 1996 to 1 November 1997 (12 months). Drug susceptibility testing to INH, SM, EMB and RMP were performed on Lowenstein-Jensen medium according to the proportion method or/and radiometric Bactec 460 TB system. 3970 TB patients bacteriologically confirmed by culture were included in a one-year study. The male to female ratio was 2.6:1. Patients were at the age of 6 to 83 years. Majority of patients (86% males and 77% of females) was older than 35 years. Primary resistance to any drug was found in 3.6% of new cases and 2.4% of those patients who excreted monoresistant strains. No monoresistance to EMB was found. 18 patients (0.6%) were infected by MDR strains. Total resistance in new cases was for INH--2.6%, for SM--1.8%, for RMP--0.7% and for EMB--0.1%. Acquired resistance to any drug was found in 17.0% of treated. Majority of patients--7.7% excreted monoresistant strains. 7.0% were infected by MDR strains. Total resistance to INH was 14.8%, to SM--9.2%, to RMP--7.8%, and to EBM--2.5%. No correlation was found between sex and primary resistance rates. Among new cases, 3.7% of males and 3.3% of females were infected with resistant strains. However, among treated patients, males (20%) excreted resistant strains twice as much as females (9.1%). Mean age of women and men infected with primary and acquired resistant strains was similar.     

Health literacy and public health: A systematic review and integration of definitions and models

Background  

Health literacy concerns the knowledge and competences of persons to meet the complex demands of health in modern society. Although its importance is increasingly recognised, there is no consensus about the definition of health literacy or about its conceptual dimensions, which limits the possibilities for measurement and comparison. The aim of the study is to review definitions and models on health literacy to develop an integrated definition and conceptual model capturing the most comprehensive evidence-based dimensions of health literacy.     

Recurrent monocular exudative retinal detachment as the first manifestation of squamous cell lung cancer: A case report

Rationale:In this report, we present an extremely rare case of recurrent monocular exudative retinal detachment without concomitant ocular metastases. This turned out to be the first symptom of squamous cell lung cancer.Patient concerns:A 63-year-old woman was referred to our ophthalmology clinic by her primary care physician with a complaint of deteriorating vision in her right eye that had started four months prior, without concomitant pain.Diagnoses:We observed a detachment in the lower part of the retina during her ophthalmoscopy. We did not find any tears, holes, or degenerative changes in the periphery of the retina of the right eye during the surgery. In addition, plaques, tumor masses, and metastases were absent. Therefore, we diagnosed her with unilateral paraneoplastic exudative retinal detachment. Imaging tests performed before surgery revealed perihilar density with a visible air bronchogram in the middle field of the left lung. This turned out to be squamous cell carcinoma.Interventions:Patient underwent pars plana vitrectomy and routine laboratory and imaging tests before the procedure that utilized 20-gauge instrumentation. The subretinal fluid and was drained and a tamponade using Densiron (Fluoron Co, Neu-Ulm, Germany) was applied. After ophthalmic treatment, patient underwent complex oncological treatment based on chemotherapy and radiotherapy.Outcomes:Despite the application of heavy silicone oil (Densiron) into the vitreous chamber, we observed a recurrence of retinal detachment in the right eye during the follow-up visit, 13 months after the first ophthalmic surgery. Following subsequent pars plana vitrectomy, the Densiron and subretinal membranes were removed. Despite oncological treatment, the patient died, twenty months after the appearance of the first ocular symptoms.Lessons:Exudative retinal detachment without tumor metastasis to the eyeball can be one of the first signs of lung cancer in rare cases. Multidisciplinary care and imaging methods with greater accuracy will provide comprehensive care to the patients. It will not only facilitate timely detection and treatment of lung tumors but also for a plethora of oncological diseases.     

A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency

Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.     

Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway

Nonhomologous end-joining (NHEJ) DNA factors maintain genomic stability through their DNA double-strand break (DSB) repair and telomere-associated activities. Unrepaired or misrepaired DSBs can lead to apoptotic death or chromosomal damage. The B cells of some B-chronic lymphocytic leukemia (B-CLL) patients are resistant to radiation-induced apoptosis in vitro. We show here that the novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the phosphatidylinositol 3 (PI-3) kinase inhibitor, wortmannin, restored sensitivity to DNA damage-induced apoptosis of otherwise resistant cells. These resistant malignant B cells also escaped DSB-induced apoptosis following exposure to etoposide or neocarzinostatin. We found that at 15 minutes after irradiation, the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PK catalytic subunit (DNA-PKcs) activity were, respectively, 2-fold and 4-fold higher in radio-resistant than in radio-sensitive B-CLL cells or Epstein-Barr virus (EBV)-transformed B cells. Ku70/Ku80 heterodimer DNA end-binding activity was also 2- to 3-fold higher in the resistant B-CLL cell subset compared with the sensitive B-CLL cell subset. Our results provide the first evidence that overactivating the NHEJ DNA repair pathway impairs DNA damage-induced apoptosis in malignant B cells and that this may contribute to their resistance to current chemotherapy.     

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd.     

CD38 gene polymorphisms and genetic predisposition to multiple myeloma

Single nucleotide polymorphisms (SNPs) of adhesion and signaling genes may influence the etiopathogenesis of multiple myeloma (MM). CD38 molecule and its ligand CD31 are expressed and interact in malignant plasma cells and MM microenvironment. In this study we evaluated allele frequencies and distribution of two potentially functional CD38 SNPs, intronic rs6449182 (184C>G) and missense rs1800561 (418C>T, Arg¹⁴⁰Trp) in 175 Caucasian patients with MM and 207 healthy blood donors. The carriers of variant G allele of the rs6449182 SNPs were found to have significantly elevated risk of MM as compared to non-carriers; odds ratio = 5.69 (95% confidence interval = 3.7–8.7), p < 0.0001. In contrast, rs1800561 SNP minor T allele was detected at very low and comparable frequencies in patients and controls groups. In conclusion, our data suggest that inherited genetic variation in CD38 gene may impact on the risk of MM development.     

Frequency of DRB1-DQB1 two-locus haplotypes in tuberculosis: preliminary report

Analysis of correlation between tuberculosis (TB) and human leukocyte antigen (HLA) in populations from Asia and Latin America has shown conflicting results. The aim of this study was to evaluate the frequency of HLA-DRB1-DQB1 two-locus haplotypes of 61 TB patients and 125 healthy volunteers in the same ethnic group in Poland. DRB1 and DQB1 alleles were determined by PCR-SSP "low-resolution" and "high-resolution" methods. Our study showed that DRB1*1601 and DQB1*0502 alleles were more frequent, whereas DQB1*0201 was rarer in TB than in controls. DRB1*16-DQB1*05, DRB1*04-DQB1*03 and DRB1*1601-DQB1*0502 haplotype were more common, and DRB1*11-DQB1*03 less frequent in TB in comparison to controls. Positive linkage disequilibrium (LD) for DRB1*01-DQB1*05, DRB1*03-DQB1*02, DRB1*11-DQB1*03, DRB1*13-DQB1*06 and DRB1*15-DQB1*06 was found in controls. A trend towards the positive LD for DRB1*01-DQB1*05, DRB1*03-DQB1*02, DRB1*11-DQB1*03, DRB1*15-DQB1*06 and DRB1*16-DQB1*05 was shown in TB. The trend towards the positive LD for DRB1*16-DQB1*05 haplotype in TB patients was not observed in the control group. It seems likely that the presence of DRB1*1601, DQB1*0502 alleles and DRB1*1601-DQB1*0502, DRB1*04-DQB1*03, DRB1*14-DQB1*05 haplotypes may be related to a higher risk of developing TB, whereas low frequency of DQB1*0201 and DRB1*11-DQB1*03 haplotype may be linked to the resistance to TB.     

Coronary computed tomographic angiography for prediction of procedural and intermediate outcome of bypass grafting to left anterior descending artery occlusion with failed visualization on conventional angiography

Conventional coronary angiography (CCA) has considerable limitations regarding visualization of distal vessel segments in chronic total occlusion. We assessed the ability of coronary computed tomographic angiography (CCTA) to predict the success of coronary artery bypass grafting (CABG) to the chronically occluded left anterior descending coronary artery (LAD) incompletely visualized on CCA. Thirty symptomatic patients rejected for CABG on the basis of the CCA findings underwent preoperative CCTA before intended transmyocardial laser revascularization. The LAD was explored operatively in all patients, and CABG to the LAD was attempted if the distal vessel was suitable for anastomosis. The procedural outcome of CABG and the 6-month patency of the left internal mammary artery graft at follow-up CCTA were defined as the primary and secondary end point, respectively. The primary and secondary end points were achieved in 80% and 77% of patients, respectively. We found a significant correlation between the intraoperative and computed tomographic measurement of distal LAD diameter (R = 0.428, p = 0.037). On multivariate analysis, the maximum diameter of the distal LAD by CCTA (odds ratio 8.16, p = 0.043) was the only independent correlate of procedural success of CABG. A cutoff value of 1.5 mm for the mean distal LAD diameter predicted left internal mammary artery graft patency with 100% specificity and 83% sensitivity. Successful CABG resulted in significant improvements in angina class and left ventricular function in LAD segments at 6 months of follow-up. In conclusion, CCTA predicted both the procedural and the intermediate outcome of CABG to chronic LAD occlusion with failed visualization on CCA.     

Comprehensive investigation of genetic variation in the 8q24 region and multiple myeloma risk in the IMMEnSE consortium

Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.