Prevalence of FA-D2 Rare Complementation Group of Fanconi Anemia in Serbia

Objective

To investigate genetic subtypes of inherited bone marrow failure syndrome Fanconi anemia (FA) in Sebia. FA-D2 subtype was found to be the most frequent genetic subtype among investigated FA patients; specific observations of FA-D2 phenotype are pointed out.

Methods

Several biological endpoints of FA cells in vitro such as radiation-induced level of lymphocyte micronuclei (radiosensitivity), base line and radiation induced level of the DNA double strand breaks (DSBs), leukocyte apoptosis, and telomere capping function were assessed.

Results

The results indicate that all FA-D2 patients display radioresistant in vitro response, which is seen as significantly reduced yield of radiation-induced micronuclei. On the contrary, FA-A patients display radiosensitive in vitro response seen as increased number of radiation-induced micronuclei (MN). A massive elimination of irradiated cells via apoptosis is found in both FA-A and FA-D2 subtypes. In FA-A subtype apoptosis positively relates with the yield of radiation-induced MN, whereas in FA-D2 subtype apoptosis relates with a high percentage of cells carrying dysfunctional telomeres. The present results unequivocally demonstrate that cytokinesis-block micronucleus (CBMN) assay and analyses of telomere capping function can be used to distinguish FA-D2 and FA-A complementation groups.

Conclusions

Considering all biological endpoints were analyzed, it can be concluded that all FA patients are radiosensitive, regardless of their complementation group. Thus, using CBMN test and telomere capping function analysis can discriminate FA-A from FA-D2 complementation groups, which could be important for assessment the conditioning regimens prior to bone marrow transplantation.     

Adipokines and proinflammatory cytokines,the key mediators in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The “two-hit“ hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.     

Survivin gene promoter polymorphism -31G/C as a risk factor for keratocystic odontogenic tumor development

Several single nucleotide polymorphisms in survivin gene promoters, notably -31G/C, have been shown to modulate the expression and activity of the survivin protein. Consequently, the -31G/C polymorphism has been identified as a risk factor for the development of several types of tumors. The aim of this study was to investigate a possible association between the -31G/C polymorphism and the risk for keratocystic odontogenic tumor (KCOT) development. DNA from 52 biopsy specimens of KCOTs and from 82 buccal swabs of healthy individuals was subjected to PCR restriction fragment length polymorphism analysis to identify individual genotypes. The distribution of genotypes in KCOT and control groups, respectively, was: GG: 30 (57.7%) vs. 26 (31.7%); CG: 17 (32.7%) vs. 45 (54.9%); and CC: 5 (9.6%) vs. 11 (13.4%), respectively. These differences were statistically significant. The G allele was more common in the KCOT group than in the control group: 76 (74%) vs. 96 (59%), respectively. Logistic regression analysis showed that GC heterozygotes had a considerably decreased susceptibility for KCOTs compared with GG homozygotes. The same was true for GC+CC vs. GG. The GG genotype of the -31G/C polymorphism might be a risk factor for KCOT development.     

Short pain-provoked head-up tilt test for the confirmation of vasovagal syncope

We investigated a short pain-provoked head-up tilt (PP-HUT) and the Calgary Syncope Symptom Score in a group of patients with clinically diagnosed vasovagal syncope and group of neurological patients without transient loss of consciousness. We included 127 consecutive patients who were investigated in our laboratory. The group 1 included 56 patients who after appropriate investigations were diagnosed with vasovagal syncope. The group 2 included 70 neurological patients without transient loss of consciousness. The subjects were tilted to 70° for a maximum period of 10 min or until symptoms occurred. If there were no symptoms after initial 10 min, a painful stimulus with the insertion of 0.7 mm needle into the dorsum of hand subcutaneously for 30 s was performed with the patient in the tilted for further 5 min. Calgary Syncope Symptom Score was calculated for all patients. In the group 1, significantly higher number of patients had positive results on PP-HUT (36 vs. 6 patients, respectively; p < 0,001). There was no difference in the presence of orthostatic hypotension (8 vs. 15 patients, respectively; p = 0.36) or postural orthostatic tachycardia syndrome (3 vs. 1 patient, respectively; p = 0.32) between groups. PP-HUT had sensitivity of 65.9 % (95 % CI 0.49–0.79) and specificity of 89.7 % (95 % CI 0.75–0.97). The CSSS had sensitivity of 58.5 % (95 % CI 0.42–0.73) and specificity of 46.1 % (95 % CI 0.30–0.63). PP-HUT has a higher diagnostic rate than the CSSS and provides a rapid alternative to conventional methods.     

Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis

It is unknown what proportion of long-term lung function decline in cystic fibrosis (CF) is explained by pulmonary exacerbations. The aim of this study was to determine how exacerbations requiring hospitalisation contribute to the course of CF lung disease. This was a retrospective cohort study. The primary outcome was the rate of decline of forced expiratory volume in 1 s (FEV(1)) % predicted. Out of 851 subjects, 415 (48.8%) subjects had ≥ 1 exacerbation. After adjustment for confounders, the annual rate of FEV(1) decline in those without an exacerbation was 1.2% per yr (95% CI 1.0-1.5), compared with 2.5% per yr (95% CI 2.1-2.8) in those with an exacerbation. The proportion of overall FEV(1) decline associated with ≥ 1 exacerbation was 52% (95% CI 35.0-68.9). For a given number of exacerbations, the annual rate of FEV(1) decline was greatest in subjects with ≤ 6 months between exacerbations. Half of FEV(1) decline seen in CF patients was associated with pulmonary exacerbations. Time between exacerbations, specifically ≤ 6 months between exacerbations, plays an important contribution to overall lung function decline. These findings support using time to next exacerbation as a clinical end-point for CF trials.