HPV E6/E7mRNA association with interleukin 10 (rs1800872) polymorphism in a group of Macedonian women

Interleukin 10 (IL-10) is an immunosuppressive cytokine and its genetic variants could have an indirect impact on viral biology and human papillomavirus (HPV) E6/E7 messenger RNA (mRNA) expression as well. This study evaluates the association between IL-10-592 C/A (rs1800872) single-nucleotide polymorphism and HPV E6/E7 mRNA expression in a group of women from the Republic of North Macedonia. Using a commercial test, 272 women's cervical samples were analyzed for HPV E6/E7 mRNA and HPV DNA presence. The cases were stratified into three groups: double-positive (n = 108, positive for both tests), negative (n = 51, negative for HPV E6/E7 mRNA and HPV DNA positive), and the control group (n = 113, negative for both tests). The IL-10-592 C/A polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism. The results showed the CC genotype and the C allele frequencies of IL-10-592C/A were significantly higher in double-positive (59.3% and 78.2%) compared to negative group (39.2% and 65.7%), (p = 0.018, confidence interval [CI] = 2.25; 1.14-4.45 and p = 0.016, CI = 1.88; 1.11-3.16, respectively). The CC genotype and C allele of rs1800872 polymorphism were shown to be associated with HPV E6/E7 mRNA but not with HPV DNA positivity, which implies a possible role of this polymorphism in the course of the infection only after HPV onset, and lack of association with the susceptibility to HPV

Association of p53Pro72Arg (rs1042522) and MDM2309 (rs2279744) polymorphisms with risk for cervical intraepithelial lesions and cervical cancer development in Macedonian women

High risk Human Papillomavirus (HPV) is an important etiological factor in initiation of squamous intraepithelial lesions (SIL), but not enough for malignant progression to cervical cancer (CCa). Single nucleotide polymorphisms (SNPs): rs1042522 within the codon 72 of p53 and rs2279744 within MDM2 promoter gene are plausible factors for development of SIL or CCa conferring increased attenuation of p53 pathway. We investigated the association of these SNPs with the HPV positive SIL and CCa among women from the Republic of Macedonia. Using a multiplex PCR SNaPShot analysis we genotyped rs1042522 and rs2279744 in 131 HPV positive women with SIL or CCa and 110 HPV and cytologicaly negative controls subject. No significant difference in either genotype or allelic frequencies for rs1042522 and rs2279744 between cases and control was found. The stratification of patients on the basis of the lesion grade revealed lower frequency of CC genotype and C allele of rs1042522 in HSIL and CCa compared to LSIL [GG vs CC; p=0.001, OR=0.4; CG vs CC; p=0.04, OR=0.03 and CG+ GG vs CC; p=0.004, OR=0.2]. Additionally TT genotype and T allele of MDM2 309 showed significantly lower frequency in HSIL and CCa group then in LSIL [G vs T p=0.02, OR=0.52; GG vs TT; p=0.04, OR=0.29; ТТ vs ТG+GG; p=0.007, OR=0.34].The Arg variant of rs1042522 and T allele/TT genotype of rs2279744 are associated with progression to LSIL to HSIL or CCa and may be used as prediction markers in CCa management, but the clinical relevant warrants further validation in large and well-designed studies. Keywords: Squamous intraepithelial lesions (SIL), cervical cancer (CCa), Human Papillomavirus (HPV), single nucleotide polymorphism (SNP), cancer and SIL susceptibilit

A novel germline MLH1 mutation causing Lynch Syndrome in patients from the Republic of Macedonia

Aim To implement molecular analysis in the clinical diagnosis and management of Lynch syndrome (LS). Methods We analyzed the mutations in MLH1 and MSH2 in the selected LS families from the Republic of Macedonia. Results We performed the very first genetic identification of LS families and characterized a novel mutation. The novel nonsense germline point mutation c.392C>G in the codon 131 of MLH1(S131X) was identified as the underlying genetic cause of LS in three families. The haplotype analysis suggested a founder effect of this mutation in our population. Conclusion We expect to detect the mutation in other LS patients from the region, and recommend costeffective screening for this mutation by restriction fragment length polymorphism-polymerase chain reaction or DNA sequencing of MLH1 Exon5 prior to full genetic testing in all LS suspects of Macedonian ancestry

Nephrotoxicity of NSAIDs and MTX

Headache is one of the most common symptoms encountered in the general population as well as in medical practice worldwide. Migraine is the most frequent cause of headache and a common disabling neurological disorder with a serious socio-economical burden. Despite the introduction more than a decade ago of a new class of migraine-specific drugs with superior efficacy, the triptans, NSAIDs remain the most commonly used therapies for the migraine attack. Some are available over the counter and likely to be abused. Nonsteroidal anti-inflammatory drugs (NSAIDs) are capable of inducing a variety of renal function abnormalities. The adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are mediated via inhibition of prostaglandin synthesis by non-specific blocking cycloxygenase, leading to vasoconstriction and reversible mild renal impairment in hypoperfusion. When unopposed, this may lead to acute kidney injury (AKI). Although this presents as AKI, chronic use of NSAIDs may result in chronic kidney disease (CKD). The standard metrics to follow the progression of AKI, like serum creatinine and blood urea levels, are inconvenient and depend on kidney injury. That’s why we must use specific markers for early detection. In the present review,we will follow the levels of specific urinar biomarkers which we can use as signals for early detection of nephrotoxicity. There has not been prespective study for nefrotoxicity of NSAID used in long term by a pacient with chronic pain

Molecular profile of the Lynch Syndrome in the Republic of Macedonia

The most frequent type of hereditary colorectal cancer, the one occurring in the setting of the Lynch syndrome (LS) is considered a phenotypic manifestation of a germline defect in the mismatch repair mechanism i.e. in the MLH1, MSH2, MSH6 or PMS2 gene. Aiming towards establishment of a standardized protocol involving molecular analyses for diagnosis of this syndrome and developing a unique national register of families with hereditary colorectal cancer syndromes in the Republic of Macedonia, we began a prospective study to reveal the genetic defects among Macedonian patients with colorectal cancer (CRC) and identifying families with hereditary CRC. A total of 53 patients fulfilling the revised Bethesda criteria for MSI-genetic testing were compared to 350 patients with sporadic CRC. The results reveal significant differences in age at diagnosis (p=0.03), involvement of microsatellite instability (p<0.0001) and localization of the tumor in respect to flexura lienalis (p=0.009) and suggest affiliation of the majority of the “Bethesda+” CRCs to the so called Familial Colorectal cancer Type X group. The molecular characterization of LS suspects identified the novel MLH1 c.392C>G nonsense mutation with a possible founder effect in the Macedonian population, the MLH1 ex.3-12 deletion, as well as the c.244A>G mutation, IVS14- 19A>G and IVS4+65A>C changes in MLH1 without confirmed pathological significance. The observed high frequency (87.5%) of the Ile219Val (c.655A>G) variant in MLH1 among the LS suspects prompts further analyses to evaluate its involvement in the development of hereditary CRC by itself or as a risk modifying factor among the patients from the Republic of Macedonia

A new case with 10q23 interstitial deletion encompassing both PTEN and BMPR1A narrows the genetic region deleted in juvenile polyposis syndrome

International audienc

Short history of just mentorship and support

Since its foundation in 1992, the Croatian Medical Journal (CMJ) has followed the strict standards of quality in the scientific publishing. However, the Journal has been aware that its specific position demands more than just following the already established rules. From the very beginning, the Journal declared an “author-helpful policy,” stating that “journal editors should have a major role in training authors in science communication, especially in smaller and developing scientific communities. Journal authors usually send scientifically acceptable but poorly prepared articles and it is a pity to lose valid data because of their poor presentation.” (1,2). In brief, the editors and editorial staff of the CMJ have been well aware that the skills of scientific reporting and publishing in our academic community are not developed and that valuable research results and valid data are being lost because of poor presentation. To be perfectly honest, ten years ago this statement looked like a nice promise, one of the many we in academic medicine learnt not to take too seriously