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M. Malenica

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Aim To assess the association of single nucleotide polymorphisms (SNPs) in the ACE2 and TMPRSS2 genes with COVID-19 severity and key biomarkers. Methods The study involved 750 COVID-19 patients from Bosnia and Herzegovina, divided into three groups: mild, moderate, and severe cases. Genetic variations within the ACE2 (rs2285666) and TMPRSS2 (rs2070788) genes were examined with real-time polymerase chain reaction. Biochemical markers were determined with standard procedures. Results There was a significant difference in the rs2070788 genotype distribution between patients with mild and moderate symptoms, but not between other groups. For the rs2285666 polymorphism, no significant difference in genotype distribution was found. In patients with mild symptoms, carriers of the GG genotype of rs2070788 had significantly higher total bilirubin levels than carriers of the AA genotype. Similarly, carriers of the TT genotype of rs2285666 had significantly higher activated partial thromboplastin time and international normalized ratio, and lower lactate dehydrogenase levels compared with the CC genotype. Among patients with severe symptoms, carriers of the GG genotype showed significantly higher potassium levels than carriers of the AA genotype, while carriers of the TT genotype showed significantly higher erythrocyte count as well as hemoglobin and hematocrit levels compared with the CC genotype. Conclusion This study highlights the role of genetic factors, particularly SNPs in the ACE2 and TMPRSS2 genes, in determining COVID-19 severity, aiding patient risk assessment and prognosis.

M. Malenica, A. Klisić, N. Meseldžić, T. Dujic, T. Bego, J. Kotur-Stevuljević

Background The aim of the study was to explore the mutual relationship between oxidative stress, inflammation and metabolic biomarkers in subjects with prediabetes (PRE), newly diagnosed type 2 diabetes patients (NT2D) and overt type 2 diabetes (T2D) using principal component analysis (PCA) as a thorough statistical approach. Methods Glycated hemoglobin, lipid parameters, inflammation (IL-6, CRP and fibrinogen) and oxidative stress markers pro-oxidants (AOPP, PAB, TOS) and antioxidants (PON1, tSHG, TAS) were measured. PCA was applied to explore the factors that the most strongly influenced glucoregulation. Results A total of 278 subjects were (i.e., 37 PRE, 42 NT2D and 99 T2D) were compared with 100 healthy subjects as a control group (CG). PCA emphasized 4 different factors explaining 49% of the variance of the tested parameters: oxidative stress-dyslipidemia related factor (with positive loading of TG and tSHG, and with negative loading of HDL-c and TAS), dyslipidaemia related factor (i.e., total cholesterol and LDL-c, both with positive loading), Anthropometric related factor (i.e., waist and hip circumference, both with positive loading) and oxidative stressInflammation related factor (i.e., PAB, fibrinogen, and CRP all with positive loading). Out of these 4 factors, only oxidative stress - dyslipidaemia related factor showed a significant predictive capability towards poor glucoregulation. An increase in this factor by one unit showed a 1.6 times higher probability for poor glucoregulation. Conclusions Redox imbalance (determined with lower TAS and higher tSHG), in addition to higher TG and lower HDLc was associated with poor glucoregulation.

A. Klisić, M. Malenica, J. Kostadinović, G. Kocic, A. Ninić

Background Given the fact that the studies that examined oxidative stress in relation to obesity that included late adolescents are scarce and show inconclusive results we aimed to investigate a wide spectrum of nitro-oxidative stress biomarkers i.e., malondialdehyde (MDA), xanthine oxidase (XO), xanthine oxidoreductase (XOD), xanthine dehydrogenase (XDH), advanced oxidation protein products (AOPP) and nitric oxide products (NOx), as well as an antioxidative enzyme, i.e., catalase (CAT) in relation with obesity in the cohort of adolescent girls ages between 16 and 19 years old. Methods A total of 59 teenage girls were included in this cross-sectional study. Binary logistic regression analysis was performed to examine possible associations between biochemical and nitro-oxidative stress markers and body mass index (BMI). Results There were not significant differences between oxidative stress markers between normal weight and overweight/obese girls (i.e., AOPP, XOD, XO, XDH) and CAT, except for MDA (p<0.001) and NOx (p=0.010) concentrations which were significantly higher in overweight/obese adolescent girls. Positive associations were evident between BMI and high sensitivity C-reactive protein (hsCRP) (OR=2.495), BMI and uric acid (OR=1.024) and BMI and MDA (OR=1.062). Multivariable binary regression analysis demonstrated significant independent associations of BMI and hsCRP (OR=2.150) and BMI and MDA (OR=1.105). Even 76.3% of the variation in BMI could be explained with this Model. Conclusions Inflammation (as measured with hsCRP) and oxidative stress (as determined with MDA) independently correlated with BMI in teenage girls.

Obesity is a disease of excessive accumulation of adipose tissue due to an increased energy intake which is disproportionate to the energy expenditure in the body. The visceral adipose tissue in the obese accumulated in that way increases the risk of developing a number of metabolic and cardiovascular diseases. Disorders such as diabetes, dyslipidemia, inflammation, endothelial dysfunction and mitochondria can contribute to the development of oxidative stress, which is especially pronounced in the abdominal type of obesity. Obesity can induce systemic oxidative stress through a variety of biochemical mechanisms. Although ROS is generated in a large number of cells, mitochondria play a significant role in their intracellular production through the process of oxidative phosphorylation of the respiratory chain, and in fatty acid oxidation reactions. Oxidative stress is a unique link between the various molecular disorders present in the development of insulin resistance that plays a key role in the pathogenesis and progression of chronic metabolic, proinflammatory diseases. The progression of insulin resistance is also affected by inflammation. Both of these can be the cause and the consequence of obesity. The synthesis of the inflammatory mediators is induced by oxidative stress, thus bringing the inflammation and the oxidative stress into a very significant relation. This review aims to highlight recent findings on the role of oxidative stress in the pathogenesis of obesity, with special reference to the mechanisms that explain its occurrence.

B. Prnjavorac, A. Mujaković, Lejla Prnjavorac, T. Bego, E. Jusufovic, E. Begić, Vildana Torlak-Arnaut, Meliha Mutapčić, H. Škiljo et al.

Aim To analyse the resolution of chest X-ray findings in relation to laboratory parameters in patients infected with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a two- month followup. Analysis of chest X-ray findings in the first few months after the disease is the main goal of our work. Methods Out of the total of 343 patients chest X-ray findings were followed in 269 patients. Patients were divided into groups according to the severity of findings. D-dimer, inflammatory markers, blood cell count, neutrophil lymphocyte ratio (NLR) were analysed. Chest X-ray was analysed during the hospitalization on the day of admission, on the third, the seventh and the fourteenth day (scoring method was used). After discharge chest X-ray was performed in a two-week follow-up, then after one and two months, and after three months if necessary. Results Incomplete chest X-ray resolution was identified in 24 (39.34%) patients with severe, 27 (22.31 %) patients with moderate and in three (3.91%) patients with mild findings. Statistical significance was established in overall score by comparison between all groups (p<0.001), and in the moderate compared to the mild group (p=0.0051). The difference of NLR in the severe compared to the moderate group was observed (p=0.0021) and in the severe group compared to the mild group (p=0.00013). Conclusion Chest X-ray findings persisted mostly in the severe group followed by the moderate and mild ones. Long-term followup is necessary for the appropriate treatment and prevention of fibrosis, and reduction of symptoms.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

Background Altered levels of many hematological parameters have been directly associated with diabetes in adults, while studies on children with type 1 diabetes mellitus are lacking. The aim of this study was to determine hematological indices in diabetic Bosnian children in comparison to healthy controls as well as to correlate their levels to blood glucose and hemoglobin A1c. Methods 100 healthy and 100 children with type 1 diabetes mellitus (age 1-18) were included in this study. Complete blood count, hemoglobin A1c, and glucose were tested. Results were analysed by IBM SPSS Statistics version 23. Results Significant differences (p<0.05) between healthy and diabetic children were found in relation to HbA1c, glucose, mean platelet volume, the number of white blood cells and erythrocytes, hematocrit, hemoglobin and MCH values. No gender differences or significant age differences were seen for hemoglobin, hematocrit, and MCV, while platelets, MPV, and MCH differed by age only in healthy children. When diabetic children were classified according to HbA1c levels, significant differences were seen for erythrocyte count and hematocrit value (p=0.013 and 0.019, respectively). The number of erythrocytes and white blood cells correlated significantly with HbA1c (p=0.037 and 0.027, respectively). Conclusions Lower levels of erythrocytes, hematocrit, and hemoglobin in diabetic compared to healthy children indicate possible development of anemia, while higher MCV, MCH, and MPV values indicate an alteration in erythrocyte morphology. Hematological indices could be a useful inexpensive tool in the diagnosis and follow up of type 1 diabetes in children.

The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C>T within the transcription factor 7 like 2 gene (TCF7L2) is the strongest genetic risk factor associated with T2D to date. In this study we explored the effects of TCF7L2 rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of TCF7L2 rs7903146 was performed by the Sequenom MassARRAY® iPLEX® platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (p = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9-38.3%, p = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1-44.1%, p = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1-12.0%, p = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0-25.6%, p = 0.002) compared to the patients with CC genotype. Our results suggest that TCF7L2 rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.

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