Antihuman Immunodeficiency Virus Type 1 (HIV-1) Activity of Rare Earth Metal Complexes of 4-Hydroxycoumarins in Cell Culture

The cerium Ce(III), lanthanum La(III), and neodymium Nd(III) complexes with 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (warfarin) (W) and 3,3′-benzylidenebis[4-hydroxycoumarin] (1) were synthesized and studied for the first time for cytotoxicity (on MT-2 cells) and as anti-HIV agents under acute and chronic infection. The complexes were characterized by different physicochemical methods: mass spectrometry, (1)H NMR, (13)C NMR, and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligands. Anti-HIV effect of the complexes/ligands was measured in MT-2 cells by microtiter infection assay. Detection of endogenous reverse transcriptase (RT) activity and RT processivity by PCR indicative for proviral DNA synthesis demonstrated that anti-HIV activity has not been linked to early stages of viral replication. No effect on late steps of viral replication has been found using cells chronically producing HIV-1(LAI) virus. La(W) demonstrated anti-HIV activity (IC50=21.4 μM) close to maximal nontoxic concentration. Nd(W), Ce(1), and Nd(1) demonstrated limited anti-HIV potency, so none of the complexes seems appropriate to be used in clinic. Further targeting of HIV-1 inhibition by La(W) is under progress

Association Study between Idiopathic Scoliosis and Polymorphic Variants of VDR, IGF-1, and AMPD1 Genes

Idiopathic scoliosis (IS) is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine with unknown etiology. For the aims of the current study we selected 3 single nucleotide polymorphisms with a low incidence of the polymorphic allele in Bulgarian population, AMPD1 (rs17602729), VDR (rs2228670), and IGF-1 (rs5742612), trying to investigate the association between these genetic polymorphisms and susceptibility to and progression of IS. The polymorphic regions of the genes were amplified by polymerase chain reaction (PCR). The PCR products were cleaved with the appropriate restriction enzymes. The statistical analysis was performed by Pearson's chi-squared test. A value of < 0.05 was considered to be statistically significant. In conclusion, this case-control study revealed no statistically significant association between the VDR, IGF-1, and AMPD1 polymorphisms and the susceptibility to IS or curve severity in Bulgarian patients. Replication case-control studies will be needed to examine the association between these candidate-genes and IS in different populations. The identification of molecular markers for IS could be useful for early detection and prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures

IL-1RN VNTR Polymorphism in Adult Dermatomyositis and Systemic Lupus Erythematosus

Polymorphisms in the cytokine genes and their natural antagonists are thought to influence the predisposition to dermatomyositis (DM) and systemic lupus erythematosus (SLE). A variable number tandem repeat (VNTR) polymorphism of 86 bp in intron 2 of the interleukin-1 receptor antagonist (IL-1RN) gene leads to the existence of five different alleles which cause differences in the production of both IL-1RA (interleukin-1 receptor antagonist) and IL-1 . The aim of this case-control study was to investigate the association between the IL-1RN VNTR polymorphism and the susceptibility to DM and SLE in Bulgarian patients. Altogether 91 patients, 55 with SLE and 36 with DM, as well as 112 unrelated healthy controls, were included in this study. Only three alleles were identified in both patients and controls ((1) four repeats, (2) two repeats, and (3) five repeats). The IL-1RN * 2 allele ( = 0.02, OR 2.5, and 95% CI 1.2-5.4) and the 1/2+2/2 genotypes were found prevalent among the SLE patients ( = 0.05, OR 2.6, and 95% CI 1-6.3). No association was found between this polymorphism and the ACR criteria for SLE as well as with the susceptibility to DM. Our results indicate that the IL-1RN VNTR polymorphism might play a role in the susceptibility of SLE but not DM

A therapeutic conundrum: pregnant lady with thrombophilia and recurrent cystic-fibrosis-related haemoptysis

Introduction: Haemoptysis is a common complication of cystic fibrosis (CF) with a 5-year incidence of around 9.1%. The pathophysiology of haemoptysis in CF is poorly understood but characteristical­ly involves the development of tortuous, dilated vessels in the bronchial circulation. Treatment has been the subject of consensus guidance and centres on appropriate antibiotic therapy with bronchi­al artery embolization recommend it as the treatment of choice for massive haemoptysis. Concern has previously been raised over an increased risk of venous thromboembolism with tranexamic acid, but this has not been resolved conclusively as of yet. Pregnancy is a hypercoagulable state. It was con­firmed that severe pregnancy complications, such as severe preeclampsia intrauterine growth retar­dation, abruptio placentae and stillbirth, as well as recurrent miscarriage has been shown to be as­sociated with thrombophilia. Thromboembolism in pregnancy as in the non-pregnant state is also linked to thrombophilia. Main prophylaxis is using fractionated heparins.Materials and methods: A case report of a 30-year-old patient with genetically confirmed CF with re­current cystic-fibrosis-related haemoptysis, with chronic Pseudomonas aeruginosa and Staphylococ­cus aureus infection is presented. Due to a very robust antibiotic therapeutic scheme Aspergillus fu­migatus was also grown from her sputum samples. Six years ago she had a miscarriage and in the di­agnostic follow up thrombophilia was also genetically confirmed.Results: The patient was given antibiotics for the infection. At the moment her lung health is relative­ly stable (with FEV1 (forced expiratory volume) of 90%) and is currently pregnant in her 12th week (at the time of the abstract submission).Conclusion: Pointing out the impossible dilemma of using heparins or not, as well as of the possible treatment options in the patient and the management plan, followed by the team during the pregnan­cy with an optimism for successful accomplishment in the end - a healthy baby

STK11 gene mutations among patients with sporadic breast cancer

Germline mutations affecting STK11 (LRG_319) are profoundly studied in relation to Peutz-Jeghers syndrome, predisposing to the development of various cancers at multiple sites. Though somatic mutations in STK11 are found to be present in several cancers, limited data on its involvement in sporadic breast cancer are available. The present study aims to evaluate the frequency and spectrum of genetic alterations in STK11 in a group of Bulgarian patients with sporadic breast cancer. A total of 73 tumor and 22 corresponding blood specimens derived from the patients, and 10 blood samples from clinically healthy controls were analyzed. High Resolution Melting analysis followed by Sanger sequencing and bioinformatic prediction tools were utilized. Seven patients (9.58%) harbored STK11 alterations, only two (2.74%) of which are exonic: one nonsense c.322A>T; p.K108X (deleterious) and one missense c.440G>A; p.Arg147His (of unknown significance). Two intronic variants were also observed: c.290+36G>T and c. *16+18C>A (novel). To our knowledge the results represent the first data indicating presence of STK11 alterations in patients with sporadic breast cancer. The limited number of the detected deleterious mutations indicates that mutational inactivation of the gene is a rare event and probably plays a minor role in sporadic breast carcinogenesis

Positive Association between TGFB1 Gene and Susceptibility to Idiopathic Scoliosis in Bulgarian Population

Idiopathic scoliosis (IS) is a common medical condition beginning in childhood and characterized by strong evidence for a genetic susceptibility to three-dimensional spinal deformity. The primary goal of the current case-control study is to examine the association between the TGFB1 (-509C/T) functional polymorphic variant and genetic predisposition to IS in the Bulgarian population and the genotype-phenotype correlations in distinct case-control subgroups based on age at onset, family history, and gender. A total of 127 patients with primary scoliosis and 254 gender-matched control subjects were recruited. The mean Cobb angle was 53.8 ± 21.2°. Genotyping of cases and controls was performed using the TaqMan real-time amplification technique. The results were processed statistically using Pearson’s Chi-squared test and Fisher’s exact test with a value of p less than 0.05 as statistically significant. The polymorphic T allele and TT genotype were associated with a greater incidence of IS and can be considered as predisposing factors with a moderate effect on deformity development. The current results suggested that there was a genetic predisposition in early and late onset IS and familial, sporadic, and female cases. Nevertheless, replication studies are needed to reveal the relationship between the TGFB1 locus and certain subtypes of IS in different populations