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SARS-CoV-2 viral load in feces does not have a prognostic benefit in outcome of COVID-19: Clinical and immunological study
No full textThis study explores the correlation between immunological and clinical characteristics in coronavirus disease 2019 (COVID-19) patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in feces, analyzing data from 251 patients admitted to Mostar University Clinical Hospital from December 2021 to January 2022. Methods involved reverse transcription quantitative polymerase chain reaction RT-qPCR from nasopharyngeal swabs and feces, alongside serological tests for anti-SARS-CoV-2 spike IgGs. Demographic and clinical data were collected through questionnaires and medical records. The data analyses were performed using SPSS statistical software. Death occurred in 53 patients (21.1%, P < 0.001), mostly in the elderly (47/53, 88.7%, P = 0.001) and immunocompromised (19/53, 35.8%, P = 0.05), particulary those developing acute respiratory insufficiency (ARI) (46/53, 86.8%, P = 0.004), and severe/critical disease (46/53, 86.8%, P = 0.002). Among the patients with positive anti-SARS-CoV-2 IgG antibodies (86/251, 34.3%, P < 0.001), 41 (47.7%) were vaccinated and 45 (52.3%) unvaccinated (P = 0.666), showing no significant differences in clinical outcomes or mortality. Unvaccinated patients with a negative antibody titer had a higher incidence of ARI (96/123, 78%, P = 0.029) and intensive care unit admission (22/123, 17.9%, P = 0.026), than those with a positive antibody titer. Forty-seven (62.7%) patients, out of the 75 hospitalized who provided a feces sample, were positive for SARS-CoV-2 RNA (P = 0.028), without statistical differences between fecal SARS-CoV-2 positive and negative groups regarding vaccination status (15/47, 31.9%, P = 0.493), antibody status (18/47, 38.3%, P = 0.628) or death outcome (5/47, 10.6%, P = 0.706). In conclusion, unvaccinated hospitalized patients with a severe COVID-19 presentation and a negative anti-spike SARS-CoV-2 IgG titer have more frequent adverse outcomes. This suggests cautious consideration for the diagnostic use of fecal samples compared to nasopharyngeal swabs
Indirect influence of microRNA‐146a on the association of IL‐6 and TNF‐α genetic polymorphisms with the increased risk of hip osteoarthritis
No full textAbstract Primary osteoarthritis (POA) is a complex hereditary disease that involves the interplay between genetics and epigenetics. MicroRNA molecules play important roles in epigenetic mechanisms. MicroRNA‐146a (miR‐146a) is a negative regulator of the immune response in osteoarthritis (OA). So, variations in the miR‐146a gene could affect OA risk. The aim of this study was to investigate the relationships between single nucleotide polymorphisms (SNPs) in the miR‐146a, interleukin‐6 (IL‐6), Toll‐like receptor 10 (TLR10), and tumor necrosis factor‐alpha (TNFA) genes and the risk for development of advanced‐stage primary hip osteoarthritis (PHOA) and primary knee osteoarthritis (PKOA) in the Croatian population. A total of 609 POA patients and 656 healthy donors were genotyped for SNPs in the miR‐146a (rs2910164, G>C). Since we used same patients and controls as two studies before us, we already had information about IL‐6 (rs1800795, C>G), TLR10 (rs11096957, C>T), and TNFA (rs1800629, C>T) genotypes of our subjects. None of the differences were statistically significant comparing either allelic or genotypic frequencies of miR‐146a SNP rs2910164 (G>C) between the PHOA and PKOA patients and controls. However, we found a significant association with risk to PHOA for the combination of genotypes (stratified miR‐146a genotype with the IL‐6, and stratified miR‐146a genotype with the TNFA). In a multifactorial disease such as POA, we have shown the indirect relevance of a second modifying factor (miR‐146a), which apparently contributes to the overall risk of PHOA. There was no risk association with the PKOA, indicating that these two localities (hip and knee) might have different risk‐modifying factors
The interplay of mitophagy, autophagy, and apoptosis in cisplatin-induced kidney injury: involvement of ERK signaling pathway
No full textAKI induced by CP chemotherapy remains an obstacle during patient treatments. Extracellular signal-regulated protein kinases 1/2 (ERK), key participants in CP-induced nephrotoxicity, are suggested to be involved in the regulation of mitophagy, autophagy, and apoptosis. Human renal proximal tubular cells (HK-2) and BALB/cN mice were used to determine the role of ERK in CP-induced AKI. We found that active ERK is involved in cell viability reduction during apoptotic events but exerts a protective role in the early stages of treatment. Activation of ERK acts as a maintainer of the mitochondrial population and is implicated in mitophagy initiation but has no significant role in its conduction. In the late stages of CP treatment when ATP is deprived, general autophagy that requires ERK activation is initiated as a response, in addition to apoptosis activation. Furthermore, activation of ERK is responsible for the decrease in reserve respiratory capacity and controls glycolysis regulation during CP treatment. Additionally, we found that ERK activation is also required for the induction of NOXA gene and protein expression as well as FoxO3a nuclear translocation, but not for the regular ERK-induced phosphorylation of FoxO3a on Ser294. In summary, this study gives detailed insight into the involvement of ERK activation and its impact on key cellular processes at different time points during CP-induced kidney injury. Inhibitors of ERK activation, including Mirdametinib, are important in the development of new therapeutic strategies for the treatment of AKI in patients receiving CP chemotherapy
Parenteral iron therapy in children with iron deficiency anemia: A single‐institution experience
No full textType 2 Diabetes Mellitus in 11-Year-Old Boy - a Case Report
No full textCilj: Prikazati jedanaestogodišnjeg bolesnika sa šećernom bolešću tipa 2 s ciljem podizanja svijesti o porastu incidencije šećerne bolesti tipa 2 u pedijatrijskoj populaciji. Prikaz slučaja: Tijekom neurološke obrade devetogodišnjeg dječaka ustanovljeno je da je dječak preuhranjen i ima akantozu na vratu. Laboratorijskim pretragama utvrđeni su povišeni jetreni enzimi, a ultrazvučnim pregledom abdomena difuzno ehogenija jetra homogenih odjeka. Iz obiteljske anamneze saznalo se da oba roditelja boluju od šećerne bolesti tipa, a sestra je tijekom trudnoće imala gestacijski dijabetes. Tek dvije godine kasnije, dječak dolazi na pregled kod gastroenterologa zbog povišenih vrijednosti aktivnosti jetrenih enzima. Zbog pretilosti je upućen endokrinologu. Nakon učinjenih laboratorijskih pretraga zaprima se zbog novootkrivene šećerne bolesti - glukoza u krvi natašte je bila povišena (11,3 mmol/L), kao i glikozilirani hemoglobin (HbA1c) (9,3 %). Negirali su simptome poliurije, polidipsije i gubitak na tjelesnoj masi. Na temelju dobi, pretilosti, akantoze i pozitivne obiteljske anamneze postavljenja je dijagnoza šećerne bolesti tipa 2. Naknadno pristigla negativna protutijela na šećernu bolest tipa 2 - ICA (engl. Islet cell antibodies), GAD (engl. glutamic acid decarboxylase) i IA2 (engl. Islet antigen 2), potvrdila su dijagnozu šećerne bolesti tipa 2. Tijekom hospitalizacije utvrđene su hipertrigliceridemija i hipertenzija. Uvedena mu je terapija metforminom te su dječak i roditelji educirani o važnosti promjene načina života - o balansiranoj prehrani i svakodnevnoj tjelesnoj aktivnosti. Metabolička kontrola bolesti je loša, a na kontrole dolazi neredovito. Zaključak: Diferencijalno-dijagnostički o šećernoj bolesti tipa 2 treba razmišljati u one djece i adolescenata s dijabetesom koja su pretila i imaju pozitivnu obiteljsku anamnezu na šećernu bolest tipa 2. Pri postavljanju dijagnoze šećerne bolesti tipa 2 od pomoći može biti činjenica da ovi bolesnici u trenutku postavljanja dijagnoze obično već imaju jedan ili više komorbiditeta.Aim: To present a patient with a diagnosis of Type 2 diabetes mellitus (T2DM) in childhood and to raise awareness of the increasing incidence of T2DM in the pediatric population and the importance of early detection and treatment. Case report: During the neurological treatment of a nine-year-old boy, it was found that the boy was overfed and had acanthosis on the neck. Laboratory tests revealed elevated liver enzymes, and ultrasound examination of the abdomen revealed diffuse echogenicity of the liver with homogeneous echoes. From the family history, it was learned that both parents suffer from T2DM, and the sister had gestational diabetes during pregnancy. Only two years later, the boy comes to see a gastroenterologist because of elevated liver enzymes. Due to obesity, he was referred to an endocrinologist. According to laboratory tests, he was admitted for newly diagnosed diabetes - fasting blood glucose was elevated (11.3 mmol/L) as well as glycosylated hemoglobin (HbA1c) (9.3%). They denied symptoms of polyuria, polydipsia and weight loss. Based on age, obesity, acanthosis and positive family history, a diagnosis of T2DM was made. Negative antibodies to T1DM - ICA (Islet cell antibodies), GAD (glutamic acid decarboxylase), IA2 (Islet antigen 2) - confirmed the diagnosis of T2DM. During hospitalization, hypertriglyceridemia and hypertension were diagnosed. Metformin therapy was introduced and the boy and his parents were educated about the importance of lifestyle changes, a balanced diet and daily physical activity. Metabolic control of the disease is poor, and check-ups are irregular. Conclusion: The differential diagnosis of T2DM should be considered in those children and adolescents with diabetes who are obese and have a positive family history of T2DM. The fact that these patients usually already have one or more comorbidities at the time of diagnosis can be helpful in making a diagnosis of T2DM
ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?
No full textThere is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75–0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.
Comprehensive molecular and clinical insights into non-small cell lung cancer transformation to small cell lung cancer with an illustrative case report
No full textHistologic transformation to small cell lung cancer (tSCLC) is a rare but increasingly recognised mechanism of acquired resistance to tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Beyond its acknowledged role in TKI resistance, histologic transformation to SCLC might be an important, yet under-recognised, mechanism of resistance in NSCLC treated with immunotherapy. Our review identified 32 studies that investigated tSCLC development in patients with EGFR-mutated NSCLC treated with TKI therapy and 16 case reports of patients treated with immunotherapy. It revealed the rarity of tSCLC, with a predominance of EGFR exon 19 mutations and limited therapeutic options and outcomes. Across all analysed studies in EGFR-mutated NSCLC treated with TKI therapy, the median time to tSCLC development was similar to 17 months, with a median overall survival of 10 months. Histologic transformation of EGFR-mutated NSCLC to SCLC is a rare, but challenging clinical problem with a poor prognosis. A small number of documented cases of tSCLC after immunotherapy highlight the need for rebiopsies at progression to diagnose this potential resistance mechanism. Further research is needed to better understand the mechanisms underlying this phenomenon and to develop more effective treatment strategies for patients with tSCLC
APPLICATION OF WHOLE-EXOME SEQUENCING IN GENETIC RESEARCH OF PARKINSON’S DISEASE
No full textCiljevi istraživanja: Parkinsonova bolest je česti neurodegenerativni poremećaj koji
zahvaća do 1% populacije iznad 65 godina, uz predviđanja postepenog porasta
prevalencije do 2% u idućih nekoliko desetljeća. Genetska osnova bolesti se može
pronaći kod 15% do 30% pacijenata, uz sve rastući broj zahvaljujući novim tehnologijama
sekvenciranja. U dosadašnjim istraživanjima nije bila zastupljena južnoslavenska
populacija, te je specifični cilj ovog istraživanja utvrditi učestalost poznatih genetičkih
varijanti kod hrvatskih pacijenata.
Materijali i metode: Uključni kriteriji za ispitivanje su potvrđena Parkinsonova bolest,
koristeći najrelevatnije kliničke dijagnostičke kriterije. Svi ispitanici su dali informirani
pristanak i ispunili genetski upitnik prije uzorkovanja krvi te su bili podijeljeni u tri grupe
ovisno o vrsti nastanka (rani, obiteljski i sporadični) Postupak sekvenciranja cijelog
egzoma se učinio po dosadašnjim primjerima dobre prakse.
Rezultati: 152 pacijenta su uključena u ispitivanje. Kod ukupne kohorte je otkriveno 14
uzročnih mutacija po kriterijima proglašenim kao patogene i vjerojatno patogene (GBA,
n=11; PRKN, n=2; ITM2B n=1). Nadalje, u cijeloj kohorti od 152 pacijenata, njih 41 je
imalo barem jednu varijantu nejasnog značaja (n=41, 26,97%). Patogene su bile prisutne
u svim grupama, uz razlike u učestalosti: rani nastup - 12,2%, obiteljski nastup - 12,5%,
sporadični nastup - 5,63%. Kod varijanti nejasnog značaja bila sljedeća učestalost unutar
grupa: rani nastup – 29,27%, obiteljski nastup - 15%, sporadični nastup – 32,39%
Zaključak: Sekvenciranje cijelog egzoma ima primjenu u istraživanju genetske osnove
Parkinsonove bolesti. Patogene varijante su pronađene u sve tri skupine ispitanika,
najčešće u GBA genu, što odgovara dosadašnjim spoznajama za europske populacije.
Uz to, otkriveno je nekoliko varijanti nejasnog značaja, koje zahtijevaju daljnju analizu.
Ovakav pristup ima i istraživačku i kliničku vrijednost, te se omogućuje individualno
predviđanje specifičnih faktora rizika.Research objectives: Parkinson's disease is a common neurodegenerative disorder that
affects up to 1% of the population over 65 years of age, with predictions of a gradual
increase in prevalence up to 2% in the next few decades. The genetic basis of the disease
can be found in 15% to 30% of patients, with the number increasing thanks to new
sequencing technologies. In previous research, the South Slavic population was not
represented, so the specific goal of this research is to determine the frequency of known
genetic variants in Croatian patients.
Materials and methods: Inclusion criteria for the trial were confirmed Parkinson's
disease, using the most relevant clinical diagnostic criteria. All subjects gave informed
consent and filled out a genetic questionnaire before blood sampling and were divided
into three groups depending on the type of origin (early, familial, and sporadic). The entire
exome sequencing procedure was done according to established methods.
Results: 152 patients were included in the study. In the total cohort, 14 causative
mutations were detected according to the criteria declared as pathogenic and probably
pathogenic (GBA, n=11; PRKN, n=2; ITM2B n=1). Furthermore, in the entire cohort of
152 patients, 41 of them had at least one variant of unclear significance (n=41, 26.97%).
Pathogens were present in all groups, with differences in frequency: early onset - 12.2%,
familial onset - 12.5%, sporadic onset - 5.63%. For variants of unclear significance, the
frequency within the groups was as follows: early onset - 29.27%, familial onset - 15%,
sporadic onset - 32.39%
Conclusion: Whole-exome sequencing has applications in research into the genetic
basis of Parkinson's disease. Pathogenic variants were found in all three groups of
subjects, most often in the GBA gene, which corresponds to current knowledge for
European populations. In addition, several interesting variants of unclear significance
were discovered, which require further analysis. This approach has both research and
clinical value since individual prediction of specific risk factors is possible
Nanotechnology-Driven Therapeutic Innovations in Neurodegenerative Disorders: A Focus on Alzheimer’s and Parkinson’s Disease
No full textNeurodegenerative disorders entail a progressive loss of neurons in cerebral and peripheral tissues, coupled with the aggregation of proteins exhibiting altered physicochemical properties. Crucial to these conditions is the gradual degradation of the central nervous system, manifesting as impairments in mobility, aberrant behaviors, and cognitive deficits. Mechanisms such as proteotoxic stress, neuroinflammation, oxidative stress, and programmed cell death contribute to the ongoing dysfunction and demise of neurons. Presently, neurodegenerative diseases lack definitive cures, and available therapies primarily offer palliative relief. The integration of nanotechnology into medical practices has significantly augmented both treatment efficacy and diagnostic capabilities. Nanoparticles, capable of traversing the blood–brain barrier, hold considerable potential for diagnosing and treating brain pathologies. By combining gene therapy with nanotechnology, the therapeutic effectiveness against neurodegenerative diseases can be substantially enhanced. Recent advancements in nano-biomaterial-based methodologies have fortified existing approaches to neural stem cell (NSC) differentiation therapies. NSC-targeting technologies offer a promising, potentially safe method for treating neurodegenerative diseases. This review endeavors to summarize current insights and perspectives on nanotechnology-driven therapeutic innovations in neurodegenerative disorders, with a particular emphasis on Alzheimer’s and Parkinson’s disease
Gender Differences in the Relationship between Physical Activity, Postural Characteristics and Non-Specific Low Back Pain in Young Adults
No full textBackground/Aim: University students are a particularly vulnerable population, as they spend increasing amounts of time sitting, which poses a major threat to their musculoskeletal health and posture. The aim of this cross-sectional study was to investigate gender differences in the relationships between physical activity (PA) and sedentary behavior, spinal curvatures and mobility, the endurance and balance of the trunk muscles, and the possible presence of non-specific low back pain (NS-LBP) in young adults aged 18–25 years. Methods: A total of 139 students completed all required tests. Results: Male students engaged in significantly more PA related to recreation, sports and leisure and were significantly more likely to be hyperkyphotic than female students. The more the male students participated in sports, the more pronounced the thoracic kyphosis. Female students had significantly more pronounced lumbar lordosis and anterior pelvic tilt that correlated with lumbar lordosis. Female students generally had significantly higher trunk extensor endurance and more balanced trunk musculature than males. NS-LBP correlated with PA in female students who generally had higher levels of NS-LBP than male students, with a statistically significant difference between those who practiced the most PA. Conclusions: Our results suggest that female students practice less PA and have pronounced lordosis and trunk extensor endurance, in contrast to males who practice more PA and have pronounced trunk flexor endurance and hyperkyphosis. Our findings suggest that more PA should be encouraged but implemented with caution and as an individualized gender-specific approach to prevent postural deformities and chronic musculoskeletal disorders, including NS-LBP