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Značajke neuroinflamacije tijekom kronične intermitentne hipoksije na mišjem modelu opstruktivne apneje spavanja [Characteristics of neuroinflammation during chronic intermittent hypoxia, a mouse model of obstructive sleep apnea]
Get PDFObstructive sleep apnea (OSA) is a chronic, underdiagnosed, multi-system disease characterized by intermittent hypoxia (IH) and sleep fragmentation that occurs due to periodic upper airway obstruction during sleep. OSA often presents with multiple comorbidities, the most important of which are cardiovascular diseases, stroke and Alzheimer's dementia (AD). Detailed research is needed to confirm the hypothesis that neuroinflammation is the common ethiopathogenic background for both OSA and AD. The study focused on establishing the properties of neuroinflammation in animals exposed to IH, the mouse model of OSA.
To optimize the IH model a fast and precise system was developed. Transgenic TLR2-luc-GFP mice underwent 21 days of IH (N=20) and their TLR2 expression was followed using in vivo bioluminescenc imaging (BLI), while the controls (N=6) were imaged in the same way without IH exposure. Groups of mice with and without Tlr2 gene exposed to IH (N(TLR2 IH)= 15, N(TLR2-/- IH)= 15) and their controls (N(TLR2 CTRL)= 11, N(TLR2-/- CTRL)= 8) were tested using the tail suspension test (TST), open field and Y maze. The brains were subsequently isolated and imaged ex vivo using MRI. Immunohistochemical staining for microglia (Iba1), astrocytes (GFAP) and c-Fos positive neurons was quantified.
BLI showed an acute upregulation of TLR2 after IH exposure that remained elevated throughout the 21-day protocol. Bilateral hypertrophy of the hippocampal, and left motor and cingulate cortex as well as hypotrophy of the thalamus and piriform cortex were found in the TLR2 IH group. Structural changes were less pronounced in the TLR2-/- IH group in the cerebrum, while significant hypotrophic changes were found in the midbrain, pons and medulla as well as hypertrophy of the cerebellum. Behavioral and histological testing found limited effects that warrant further investigation.
IH exposure caused an acute and chronic upregulation of TLR2 expression in the brain and induced structural changes that were more pronounced in animals with the functional TLR2 gene. IH caused limited functional and histological changes in the brain
The influence of dopamine-beta-hydroxylase and catechol O-methyltransferase gene polymorphism on the efficacy of insulin detemir therapy in patients with type 2 diabetes mellitus
Get PDFBackground:
Type II diabetes is an important health problem with a complex connection to obesity, leading to a broad range of cardiovascular complications. Insulin therapy often results in weight gain and does not always ensure adequate glycemic control. However, previous studies reported that insulin detemir is an efficient long-acting insulin with a weight sparing effect. The aim of this study was to determine the association of catechol O-methyltransferase (COMT) Val108/158Met and dopamine-beta-hydroxylase (DBH) 1021C/T polymorphisms with the effectiveness of insulin detemir in achieving glucose control and body weight control. Participants and methods: This 52-week observational study included 185 patients with inadequate glycemic control treated with premix insulin analogues, which were replaced with insulin aspart and insulin detemir, and 156 healthy controls. After DNA isolation from blood samples, genotyping of DBH-1021C/T polymorphism (rs1611115) and COMT Val108/158Met polymorphism (rs4680) was performed. -----
Results:
Our results confirmed that insulin detemir did not lead to weight gain. The most significant finding was that A carriers (the combined AG and AA genotype) of the COMT Val108/158Met achieved significantly better hemoglobin A1c (HbA1c) values compared to patients carrying GG genotype. No association between DBH-1021C/T genotypes and weight and/or glucose control was detected in diabetes patients or in healthy control subjects. -----
Conclusions:
This study showed that the presence of one or two A allele of the COMT Val108/158Met was associated with improved glycemic response, and with a better response to insulin detemir therapy in patients with type II diabetes, separating them as best candidates for detemir therapy
Combined metformin and insulin treatment reverses metabolically impaired omental adipogenesis and accumulation of 4-hydroxynonenal in obese diabetic patients
Get PDFOBJECTIVE:
Obesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype. -----
METHODS:
OM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment. -----
RESULTS:
Preadipocytes isolated from insulin resistant (IR) and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS) individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin. -----
CONCLUSION:
This study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic action of insulin and metformin. Further studies are needed to evaluate involvement of 4-HNE in metabolically impaired abdominal adipogenesis and to confirm benefits of combined metformin-insulin therapy in T2DM patients
The effect of alpha-linolenic acid on glycemic control in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized controlled clinical trials
Get PDFBACKGROUND:
Polyunsaturated fats (PUFAs) have been shown to reduce type 2 diabetes (T2DM) risk and improve insulin responsiveness in T2DM subjects, but whether the plant sources of omega-3 PUFA (alpha-linolenic acid [ALA]) have an effect on glycemic control requires further investigation. -----
METHODS:
The parameters of interest were glycated hemoglobin (HbA1c), fasting blood glucose (FBG), fasting blood insulin (FBI), homeostatic model assessment for insulin resistance (HOMA-IR), fructosamine, and glycated albumin. A comprehensive search was conducted with MEDLINE, Embase, CINAHL, and Cochrane. Eligible studies included randomized controlled trials (RCTs) ≥1 month in duration that compared diets enriched in ALA with usual diets on glycemic parameters. For each study, the risk of bias as well as the study quality was assessed. Using the statistical software RevMan (v5.3), data were pooled using the generic inverse method with random effects model, and final results were expressed as mean differences (MD) with 95% confidence intervals (CI). Heterogeneity was assessed by the Cochran Q statistic and quantified by the I statistic. -----
RESULTS:
A total of 8 trials (N = 212) were included in the meta-analysis. Compared to a control diet, a median dose of 4.4 g/day of ALA intake for a median duration of 3 months did not affect HbA1c (%) (MD = -.01; [95%: -.32, .31], P = .96). A median ALA dose of 5.4 g/day did not lower FBG (MD = .07; [95% CI: -.61, .76], P = .84) or FBI (MD = 7.03, [95% CI: -5.84, 19.89], P = .28). Summary effect estimates were generally compromised by considerable and unexplained heterogeneity (I ≥75%). In the subgroup analysis of continuous predictors, a reduction in HbA1c (%) and FBG (mmol/L) was significantly associated with an increased intake of ALA. Further adjustment for Publication Bias using Duval and Tweedie's trim-and-fill analysis provided an adjusted, significant MD of -.25 (95% CI: -.38, -.12; P <.001) for HbA1c (%). -----
CONCLUSIONS:
ALA-enriched diets did not affect HbA1c, FBG, or FBI. The scarce number of existing RCTs and the presence of heterogeneity in our meta-analysis limit the ability to make firm conclusions about ALA in T2DM management. The potential for ALA to have dose-dependent effects warrants further research in this area
Role of MYC in B cell lymphomagenesis
Get PDFB cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations
Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: the role of PCSK9 inhibitors
Get PDFFamilial hypercholesterolaemia is an autosomal dominant inherited disorder characterised by elevated low-density lipoprotein cholesterol levels and consequently an increased risk of atherosclerotic cardiovascular disease (ASCVD). Familial hypercholesterolaemia is relatively common, but is often underdiagnosed and undertreated. Cardiologists are likely to encounter many individuals with familial hypercholesterolaemia; however, patients presenting with premature ASCVD are rarely screened for familial hypercholesterolaemia and fasting lipid levels are infrequently documented. Given that individuals with familial hypercholesterolaemia and ASCVD are at a particularly high risk of subsequent cardiac events, this is a missed opportunity for preventive therapy. Furthermore, because there is a 50% chance that first-degree relatives of individuals with familial hypercholesterolaemia will also be affected by the disorder, the underdiagnosis of familial hypercholesterolaemia among patients with ASCVD is a barrier to cascade screening and the prevention of ASCVD in affected relatives. Targeted screening of patients with ASCVD is an effective strategy to identify new familial hypercholesterolaemia index cases. Statins are the standard treatment for individuals with familial hypercholesterolaemia; however, low-density lipoprotein cholesterol targets are not achieved in a large proportion of patients despite treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce low-density lipoprotein cholesterol levels considerably in individuals with familial hypercholesterolaemia who are concurrently receiving the maximal tolerated statin dose. The clinical benefit of PCSK9 inhibitors must, however, also be considered in terms of their cost-effectiveness. Increased awareness of familial hypercholesterolaemia is required among healthcare professionals, particularly cardiologists and primary care physicians, in order to start early preventive measures and to reduce the mortality and morbidity associated with familial hypercholesterolaemia and ASCVD
The modification of rotation - advancement flap made in 1950
Get PDFThe early techniques of cleft lip repair involved the straight-line technique, the triangular flap technique or some kind of geometric line (triangular, quadrangular closure). A turning point in cleft lip surgery was in 1955 when doctor. Millard presented his method: the rotation-advancement technique or flap, at the First International Congress of Plastic Surgery in Stockholm. Today, the technique, with or without some modifications, is used by more than 85% of cleft surgeons around the world. We are presenting a patient with complete unilateral cleft lip and palate who underwent surgery sixty-five years ago. The scar on his lip was similar to rotation advancement line. Cheiloplasty was performed by Professor Šercer in 1950, five years before Millard's publication. Professor Ante Šercer was an internationally recognized Croatian scholar in the area of ear, nose and throat diseases. He also gave a significant contribution to surgical management of velopharyngeal insufficiency and plastic surgery of the nose and ear
First case of imported chikungunya infection in Croatia, 2016
Get PDFIn recent years, several European countries reported cases of imported chikungunya infection. We present the first imported clinically manifested chikungunya fever in Croatia. A 27-year-old woman returned to Croatia on 21 March 2016, after she stayed in Costa Rica for two months where she had noticed a mosquito bite on her left forearm. Five days after the mosquito bite she developed severe arthralgias, fever and erythematous papular rash. In next few days symptoms gradually subsided. After ten days she felt better, but arthralgias re-appeared accompanied with morning stiffness. Two weeks after the onset of the disease she visited the infectious diseases outpatient department. The physical examination revealed rash on the trunk, extremities, palms and soles. Laboratory findings showed slightly elevated liver transaminases. Serological tests performed on day 20 after disease onset showed a high titer of chikungunya virus (CHIKV) IgM and IgG antibodies which indicated CHIKV infection. CHIKV-RNA was not detected. Serology to dengue and Zika virus was negative. The patient was treated with nonsteroid anti-inflammatory drugs and paracetamol. Her symptoms ameliorated, however, three months later she still complaint of arthralgias. The presented case highlights the need for inclusion of CHIKV in the differential diagnosis of arthralgia in all travelers returning from countries with documented CHIKV transmission
Povezanost intenziteta aktivnosti i biljega oksidacijskoga stresa u nogometaša [Association between activity intensity and oxidative stress biomarkers in football players]
Get PDFThe aim of this research was to analyse the changes in the values of oxidative stress markers caused by a soccer game (malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD) and total antioxidant status (TAS)) in adolescent soccer players in order to determine the correlation between oxidative stress markers and player positions, as well as with the intensity of the activities during a soccer match.
44 examinees, aged 16.8, played two soccer matches. The examinees were equipped with pulse meters and GPS devices which were used to estimate the intensity during the games, while blood samples were taken for analysis of markers right before and immediately after the games.
A statistically significant correlation was determined only in the changes of TAS and MDA concentrations with regard to the percentage of the average heart rate during the game in relation to the heart rate measured at the lactate threshold, as well as between the changes of GPx activity and the percentage of time spent by running at a speed between 5–8 km/h . There were no statistically significant differences determined in the changes of concentrations of any other measured markers between various player positions.
Based on the obtained results, the conclusion can be made that the intensity during a soccer game is not the only factor in the creation and occurrence of oxidative stress
Molekularna analiza gena nim i inducibilne rezistencije na metronidazol u kliničkih izolata grupe Bacteroides fragilis [Molecular analysis of nim genes and inducible metronidazole resistance in Bacteroides fragilis clinical isolates]
Get PDFThe study is essentially based on detection of nim genes in B. fragilis group strains, in vitro induction of resistance to metronidazole in strains which are phenotypically sensitive to metronidazole and measurement of LDH activity in strains with induced resistance to metronidazole.
All strains were nim-gene negative, as well as sensitive to metronidazole.
In-vitro induction of metronidazole resistance is selected in nim-negative strains, after repeated exposure to subinhibitory concentrations of metronidazole incorporated into growth medium. The MIC values for metronidazole of the induced strains ranged from 8 to 96 mg/L.
Only one B. fragilis strain with induced resistance to metronidazole demonstrated an emergent increase in LDH activity. We believe that genetic mutations were responsible for the increased activity. A significant decrease in LDH activity of the most other strains was contrary to previous findings in which, underlying higher metronidazole MICs, an increase in LDH activity compensated for the decreased activity of PFOR complex. These findings could be explained if the induction caused only physiologic and not genetic changes.
These results provide the first insights into the mechanisms of metronidazole resistance during the exposure of nim-negative strains to antibiotic, that have been observed, but not investigated in detail, by other authors