A gyermekkorban diagnosztizált 2-es típusú diabetes mellitus klasszifikációjának, epidemiológiájának és pathofiziológiájának, valamint a szövődmények rizikó faktorainak és pathomechanizmusának vizsgálata = Investigation of classification, epidemiology and pathophysiology, as well as that of risk factors and pathomechanism of complications in children with type 2 diabetes mellitus

Egészséges gyermekekben végzett szűrővizsgálat során az obezitás prevalenciáját 15,3%-nak, ezen belül a metabólikus szindróma (MS) előfordulását 46,4 %-nak találtuk. Az obezus gyermekek között a 2-es típusú diabetesz (2TDM) prevalenciája 4 %, a csökkent glukóz tolerancia (IGT) előfordulása 38,2% volt. Vizsgálataink alapján a vizelet nitrogén monoxid (NO) végtermék koncentrációjának, illetve a fehérvérsejtek NO szintáz (NOS) II mennyiségének vizsgálata nem jelzi előre a diabetesz mellitusz kialakulását. Kövér gyermekekben az interferon-gamma+/ Interleukin-4+ CD4+ sejtek aránya emelkedett, ami a citokinek összetételének obezitásban tapasztalt Th1 túlsúlyára utal. Elhízott gyermekekben az emelkedett tumor nekrózis faktor (TNF)-α és a szolubilis TNF receptor (sTNFR)-2 szintek szerepet játszhatnak az inzulinrezisztencia kialakulásában. A Toll-like receptor-4 és a peroxiszóma proliferátor-aktiválta receptor-gamma gén polimorfizmusai az inzulinrezisztencia mellett a citokinszinteket is befolyásolják. Az IGT-ben szenvedő kövér gyermekekben a kardiovaszkuláris autonóm neuropátia (KVAN)) kifejezettebb jeleit észleltük, mint a normál szénhidrát anyagcseréjű társaikban. Az obezitás és a szénhidrát anyagcserezavar együttes fennállása tehát fokozott KV rizikót jelent, 2TDM-ben szenvedő fiatalokban már kimutathatók a késői szövődmények korai jelei, mint a relatív éjszakai hipertónia, a KVAN és a bal kamra hipertrófia. | During screening, the prevalence of obesity among healthy children appeared to be 15.3%. Within the obese group the prevalence of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM) and that of impaired glucose tolerance (IGT) was 46,4 %, 4 %, and 38,2%, respectively. According to our study, neither the concentration of urinary nitric oxide (NO) end products, nor leukocyte NOS II content predict the manifestation of diabetes. The ratio of IFN-?+/ IL-4+ CD4+ cells is increased in obese children, which points at the skewness of Th1/Th2 toward Th1 direction in obesity. Elevated tumor necrosis factor (TNF)-alpha and soluble TNF receptor (sTNFR)-2 levels may contribute to insulin resistance in obese children. In obesity, cytokine concentrations and insulin resistance might be influenced by TLR4 and PPAR- gamma allelic polymorphisms. Signs of cardiac autonomic neuropathy were more pronounced in obese children with IGT, than in those with normal glucose tolerance. Simultaneous occurrence of obesity and glucose intolerance confer a higher cardiovascular risk. Early signs of late complications can be traced already in children and adolescents with T2DM, such as relative nocturnal hypertension, cardiac autonomic neuropathy and left ventricular hypertrophy

Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies

Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases

Dynamic interaction of genetic risk factors and cocaine abuse in the background of Parkinsonism - a case report.

Parkinsonism is a complex multifactorial neurodegenerative disorder, in which genetic and environmental risk factors may both play a role. Among environmental risk factors cocaine was earlier ambiguously linked to Parkinsonism. Former single case reports described Parkinsonism in chronic cocaine users, but an epidemiological study did not confirm an increased risk of Parkinson's disease. Here we report a patient, who developed Parkinsonism in young age after chronic cocaine use, in whom a homozygous LRRK2 risk variant was also detected.The patient was investigated because of hand tremor, which started after a 1.5-year period of cocaine abuse. Neurological examination suggested Parkinsonism, and asymmetrical pathology was confirmed by the dopamine transporter imaging study. The genetic investigations revealed a homozygous risk allele in the LRRK2 gene. After a period of cocaine abstinence, the patient's symptoms spontaneously regressed, and the dopamine transporter imaging also returned to near-normal.This case report suggests that cocaine abuse indeed might be linked to secondary Parkinsonism and serves as an example of a potential gene-environmental interaction between the detected LRRK2 risk variant and cocaine abuse. The reversible nature of the DaTscan pathology is a unique feature of this case, and needs further evaluation, whether this is incidental or can be a feature of cocaine related Parkinsonism

Definition of hidden drug cardiotoxicity

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments

Evaluation of transorbital sonography measures of optic nerve diameter in the context of global and regional brain volume in multiple sclerosis

Transorbital sonography (TOS) could be a swift and convenient method to detect the atrophy of the optic nerve, possibly providing a marker that might reflect other quantitative structural markers of multiple sclerosis (MS). Here we evaluate the utility of TOS as a complementary tool for assessing optic nerve atrophy, and investigate how TOS-derived measures correspond to volumetric brain markers in MS. We recruited 25 healthy controls (HC) and 45 patients with relapsing-remitting MS and performed B-mode ultrasonographic examination of the optic nerve. Patients additionally underwent MRI scans to obtain T1-weighted, FLAIR and STIR images. Optic nerve diameters (OND) were compared between HC, MS patients with and without history of optic neuritis (non-ON) using a mixed-effects ANOVA model. The relationship between within-subject-average OND and global and regional brain volumetric measures was investigated using FSL SIENAX, voxel-based morphometry and FSL FIRST. OND was significantly different between HC-MS (HC = 3.2 ± 0.4 mm, MS = 3 ± 0.4 mm; p < 0.019) and we found significant correlation between average OND and normalised whole brain (β = 0.42, p < 0.005), grey matter (β = 0.33, p < 0.035), white matter (β = 0.38, p < 0.012) and ventricular cerebrospinal fluid volume (β = - 0.36, p < 0.021) in the MS group. History of ON had no impact on the association between OND and volumetric data. In conclusion, OND is a promising surrogate marker in MS, that can be simply and reliably measured using TOS, and its derived measures correspond to brain volumetric measures. It should be further explored in larger and longitudinal studies

Ca2+/calmodulin-dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model

Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression.Therefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to develop VO-induced hypertrophy. The animals were subdivided into four different groups, two sham operated animals served as age-matched controls and two groups with aortocaval fistula. Echocardiography was performed prior termination after 4- and 8-month. Functional and molecular changes of several sarcomeric proteins and their signalling pathways involved in the regulation and modulation of cardiomyocyte function were investigated.The model was characterized with preserved ejection fraction in all groups and with elevated heart/body weight ratio, left/right ventricular and atrial weight at 4- and 8-month, which indicates VO-induced hypertrophy. In addition, 8-months groups showed increased left ventricular internal diameter during diastole, RV internal diameter, stroke volume and velocity-time index compared with their age-matched controls. These changes were accompanied by increased Ca2+ sensitivity and titin-based cardiomyocyte stiffness in 8-month VO rats compared with other groups. The altered cardiomyocyte mechanics was associated with phosphorylation deficit of sarcomeric proteins cardiac troponin I, myosin binding protein C and titin, also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric proteins in 8-month VO rats compared with age-matched control group. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in the oxidative status of both kinases CaMKII and PKG explaining by this the elevated Ca2+ sensitivity and titin-based cardiomyocyte stiffness and perhaps the development of hypertrophy.Our findings showed VO-induced cardiomyocyte dysfunction via deranged phosphorylation of myofilament proteins and signalling pathways due to increased oxidative state of CaMKII and PKG and this might contribute to the development of hypertrophy