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VARIJANTE U REGULATORNOJ REGIJI LCT GENA POVEZANE S ADULTNIM TIPOM INTOLERANCIJE NA LAKTOZU U HRVATSKOJ POPULACIJI
No full textLaktoza je mliječni šećer koji spada u skupinu disaharida, građena od glukoze i galaktoze
važan je izvor energije posebice kod dojenčadi. Enzim zaslužan za razgradnju laktoze u
probavnom sustavu je laktaza, a smanjena funkcionalnost enzima jedan je od ključnih razloga
nepodnošenja laktoze odnosno nemogućnosti njezine pravilne razgradnje. Ukoliko se laktaza ne
izražava na mikrovilima govorimo o laktaznoj deficijenciji koja se može manifestirati u obliku
malapsorpcije ili intolerancije. Razlikujemo četiri skupine deficijencije ovisno o vremenu
javljanja i značajkama koje ju opisuju: kongenitalna, razvojna, primarna i sekundarna intolerancija
na laktozu. Primarna intolerancija na laktozu, poznata i pod nazivom adultna hipolaktazija vezuje
se s genetskom predispozicijom. Do adultne hipolaktazije dolazi zbog opadanja aktivnosti enzima
koja vodi u laktoznu neperzistenciju. Osobe koje u odrasloj dobi zadržavaju normalnu aktivnost
laktaze smatraju se laktoza perzistentnima. Poznato je da stanovnici sjeverozapadne Europe
predstavljaju skupinu tolerantnu na laktozu dok južna Europa, Afrika te pojedine zemlje Azije čine
skupinu kod koje se javlja adultna hipolaktazija. Varijante LCT gena koje dovode do laktozne
neperzistencije nalaze se na 2. kromosomu u intronima 13 i 9 MCM6 gena. Molekularnogenetičkom metodom PCR-RFLP analizirali smo promjenu nukleotida u DNA s ciljem utvrđivanja
prisustva LCT-13190 C>T (rs4988235) i LCT-22018 G>A (rs182549) polimorfizma u 350
ispitanika (175 muškaraca i 175 žena) iz hrvatske populacije. U uzorku naših ispitanika frekvencija
T alela za LCT-13910C>T polimorfizam iznosila je 33,6%, a alela A za LCT-22018G>A
polimorfizam 35,0% pri čemu nije bilo statistički značajne razlike među spolovima. Rezultati
dobiveni za populaciju Hrvatske sukladni su rezultatima susjednih zemalja te se za alel LCT13910T uklapaju u postojeći sjever-jug gradijent u EuropLactose is a milk sugar that belongs to the group of disaccharides, composed of glucose and
galactose, and is an important energy source, especially in infants. The enzyme responsible for the
breakdown of lactose in the digestive system is lactase, and reduced enzyme functionality is one
of the key reasons for lactose intolerance, i.e., the inability to properly digest lactose. If lactase is
not expressed on the microvilli, we refer to this as lactase deficiency, which can manifest as
malabsorption or intolerance. There are four types of lactase deficiency, depending on the timing
and characteristics: congenital, developmental, primary, and secondary lactose intolerance.
Primary lactose intolerance, also known as adult hypolactasia, is associated with a genetic
predisposition. Adult hypolactasia occurs due to a decline in enzyme activity and is linked to
lactose non-persistence. Individuals who retain normal lactase activity in adulthood are considered
lactose persistent. It is known that the population of Northwestern Europe is generally lactose
tolerant, while Southern Europe, Africa, and certain Asian countries have a higher prevalence of
adult hypolactasia. Variants of the LCT gene that lead to lactose non-persistence are located on
chromosome 2 in introns 13 and 9 of the MCM6 gene. Using the molecular-genetic method PCRRFLP, we analyzed nucleotide changes in DNA to determine the presence of LCT-13190 C>T
(rs4988235) and LCT-22018 G>A (rs182549) polymorphisms in 350 subjects (175 men and 175
women) from the Croatian population. In our sample, the frequency of the T allele for the LCT13910C>T polymorphism was 33.6%, and the A allele for the LCT-22018G>A polymorphism was
35.0%, with no statistically significant difference between genders. The results obtained for the
Croatian population are consistent with those of neighboring countries and align with the existing
north-south gradient in Europe for the LCT-13910T allele
Quetiapine-Related Deaths: In Search of a Surrogate Endpoint
No full textQuetiapine is a second-generation antipsychotic drug available for two and half decades. Due to increased misuse, prescription outside the approved indications, and availability on the black market, it is being encountered in medicolegal autopsies more frequently. For instance, it has been linked to increased mortality rates, most likely due to its adverse effects on the cardiovascular system. Its pharmacokinetic features and significant postmortem redistribution challenge traditional sampling in forensic toxicology. Therefore, a systematic literature review was performed, inclusive of PubMed, the Web of Science—core collection, and the Scopus databases; articles were screened for the terms “quetiapine”, “death”, and “autopsy” to reevaluate each matrix used as a surrogate endpoint in the forensic toxicology of quetiapine-related deaths. Ultimately, this review considers the results of five studies that were well presented (more than two matrices, data available for all analyses, for instance). The highest quetiapine concentrations were usually measured in the liver tissue. As interpreted by their authors, the results of the considered studies showed a strong correlation between some matrices, but, unfortunately, the studies presented models with poor goodness of fit. The distribution of quetiapine in distinct body compartments/tissues showed no statistically significant relationship with the length of the postmortem interval. Furthermore, this study did not confirm the anecdotal correlation of peripheral blood concentrations with skeletal muscle concentrations. Otherwise, there was no consistency regarding selecting an endpoint for analysis
Protective Effect of EBF Transcription Factor 1 (EBF1) Polymorphism in Sporadic and Familial Spontaneous Preterm Birth: Insights from a Case-Control Study
No full textThis study investigated the potential role of specific single-nucleotide polymorphisms (SNPs) in the genes Astrotactin 1 (ASTN1), EBF Transcription Factor 1 (EBF1), Eukaryotic Elongation Factor, Selenocysteine-tRNA Specific (EEFSEC), Microtubule-Associated Serine/Threonine Kinase 1 (MAST1), and Tumor Necrosis Factor Alpha (TNF-α) to assess whether these genetic variants contribute to the risk of spontaneous preterm birth (sPTB). A case-control study was conducted involving 573 women from Croatia and Slovenia: 248 with sporadic sPTB (positive personal and negative family history of sPTB before 37 weeks’ gestation), 44 with familial sPTB (positive personal and family history of sPTB before 37 weeks’ gestation), and 281 control women. The analysis of ASTN1 rs146756455, EBF1 rs2963463, EBF1 rs2946169, EEFSEC rs201450565, MAST1 rs188343966, and TNF-α rs1800629 SNPs was performed using TaqMan real-time PCR. p-values were Bonferroni-adjusted for multiple comparisons. EBF1 SNP rs2963463 was significantly associated with sPTB (p adj = 0.03). Women carrying the CC genotype had a 3–4-times lower risk of sPTB (p adj < 0.0001). In addition, a significant difference in the frequency of the minor C allele was observed when comparing familial sPTB cases with controls (p adj < 0.0001). All other associations were based on unadjusted p-values. The minor T allele of EBF1 SNP rs2946169 was more frequent in sPTB cases overall than in controls, especially in sporadic sPTB (p = 0.045). Similarly, the CC genotype of ASTN1 SNP rs146756455 was more frequent in sporadic sPTB cases compared to controls (p = 0.019). Finally, the TNF-α SNP rs1800629 minor A allele and AA genotype were more common in the familial sPTB group compared to sporadic sPTB and controls (p < 0.05). The EBF1 SNP rs2963463 polymorphism showed a protective effect in the pathogenesis of sPTB, particularly in women carrying the CC genotype. Moreover, EBF1 SNP rs2946169 and ASTN1 SNP rs146756455, as well as TNF-α SNP rs1800629, were associated with an increased risk of sPTB, representing suggestive potential risk factors for sporadic and familial sPTB, respectively
MTHFR Gene Polymorphisms and DNA Methylation in Idiopathic Spontaneous Preterm Birth
No full textBackground and Objectives: Preterm birth (PTB) is a complex condition with various contributing factors, including genetic and epigenetic influences such as DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in DNA methylation and the remethylation of homocysteine. This study aimed to investigate the association between maternal MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation levels, and the risk of idiopathic spontaneous preterm birth (SPTB) in Caucasian women from Croatia and Slovenia. Materials and Methods: A total of 50 women with SPTB
Methimazole-Related Substances: Structural Characterization and In Silico Toxicity Assessment
No full textThe continuous tightening of pharmaceutical regulations forces drug manufacturers to unambiguously characterize the substances related to the active pharmaceutical ingredients (API). Here, we report the synthesis, complete spectroscopic, chromatographic, thermal and computational characterization, as well as in silico prediction of bacterial mutagenicity for two previously reported but never fully characterized impurities of methimazole. Additionally, their structures were analyzed by single-crystal X-ray diffraction. 1-Methyl-(2-methylthio)-1H-imidazole also known as methimazole impurity C, was obtained mainly in the form of the iodide salt (C5H9IN2S) crystallizing in monoclinic space group P21/c. The disulfide (2,2′-disulphanylbis(1-methyl-1H-imidazole)), C8H10N4S2) was obtained in yellow form crystallizing in the monoclinic C2/c space group
Second Case of Gonadal Mosaicism and a Novel Nonsense NR2F1 Gene Variant as the Cause of Bosch–Boonstra–Schaaf Optic Atrophy Syndrome
No full textABSTRACT Bosch–Boonstra–Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disease characterized by developmental delay, intellectual disability, and optic atrophy with a variable expression of other clinical features (dysmorphic features, autistic behaviour, corpus callosum hypoplasia and seizures). To date, approximately a hundred cases of the syndrome have been described, with an estimated prevalence of 1 in 100 000–250 000. BBSOAS is caused by the loss of function of the NR2F1 gene (nuclear receptor subfamily 2 group F member 1), which encodes the COUP‐TFI (Chicken ovalbumin upstream promotor‐transcription factor 1). COUP‐TFI functions as a homodimer and is one of the major transcriptional regulators directing cortical arealization, cell differentiation and maturation. Most cases of BBSOAS occur de novo, and one case was previously described in which the disease resulted from gonadal mosaicism. In the present case, we report two sisters with BBSOAS, a novel nonsense mutation in the NR2F1 gene and potential gonadal mosaicism as the cause of this rare disease, making it the second such case described in the literature
The Role of SHBG as a Marker in Male Patients with Metabolic-Associated Fatty Liver Disease: Insights into Metabolic and Hormonal Status
No full textBackground: Metabolic-associated fatty liver disease (MAFLD) is a spectrum of liver diseases linked to insulin resistance (IR), type 2 diabetes, and metabolic disorders. IR accelerates fat accumulation in the liver, worsening MAFLD. Regular physical activity and weight loss can improve liver function, reduce fat, and lower cardiovascular risk. This study examines the role of sex hormone-binding globulin (SHBG) in MAFLD, focusing on its potential as a biomarker and its relationship with insulin resistance. Methods: The study included 98 male patients (ages 30–55) with MAFLD, identified through systematic examinations, and 74 healthy male controls. All participants underwent abdominal ultrasound and blood tests after fasting, assessing markers such as glucose, liver enzymes (AST, ALT, γGT), lipids (cholesterol, triglycerides), insulin, SHBG, estradiol, and testosterone. SHBG levels were analyzed in relation to body mass index (BMI) and age. Results: A significant association was found between low SHBG levels and the presence of fatty liver. Individuals with MAFLD had lower SHBG levels compared to controls. BMI and age were key factors influencing SHBG, with higher BMI linked to lower SHBG in younger men, while SHBG remained stable in older individuals regardless of BMI. Conclusion: SHBG may serve as a valuable biomarker for early detection and risk assessment of MAFLD. The complex relationship between SHBG, BMI, and age highlights the importance of considering both hormonal and metabolic factors when assessing fatty liver risk. Our findings support the need for comprehensive metabolic evaluations in clinical practice
Mehanizmi dugotrajnog preživljavanja Francisella unutar ameba : Plan upravljanja istraživačkim podacima
No full textObinutuzumab in Combination with Alternative Chlorambucil Schedules in Front-Line Treatment of Chronic Lymphocytic Leukemia: A Study by KroHem, the Croatian Cooperative Group for Hematologic Diseases
No full textBackground/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks