Propagating population activity patterns during spontaneous slow waves in the thalamus of rodents.

Slow waves (SWs) represent the most prominent electrophysiological events in the thalamocortical system under anesthesia and during deep sleep. Recent studies have revealed that SWs have complex spatiotemporal dynamics and propagate across neocortical regions. However, it is still unclear whether neuronal activity in the thalamus exhibits similar propagation properties during SWs. Here, we report propagating population activity in the thalamus of ketamine/xylazine-anesthetized rats and mice visualized by high-density silicon probe recordings. In both rodent species, propagation of spontaneous thalamic activity during up-states was most frequently observed in dorsal thalamic nuclei such as the higher order posterior (Po), lateral posterior (LP) or laterodorsal (LD) nuclei. The preferred direction of thalamic activity spreading was along the dorsoventral axis, with over half of the up-states exhibiting a gradual propagation in the ventral-to-dorsal direction. Furthermore, simultaneous neocortical and thalamic recordings collected under anesthesia demonstrated that there is a weak but noticeable interrelation between propagation patterns observed during cortical up-states and those displayed by thalamic population activity. In addition, using chronically implanted silicon probes, we detected propagating activity patterns in the thalamus of naturally sleeping rats during slow-wave sleep. However, in comparison to propagating up-states observed under anesthesia, these propagating patterns were characterized by a reduced rate of occurrence and a faster propagation speed. Our findings suggest that the propagation of spontaneous population activity is an intrinsic property of the thalamocortical network during synchronized brain states such as deep sleep or anesthesia. Additionally, our data implies that the neocortex may have partial control over the formation of propagation patterns within the dorsal thalamus under anesthesia.

Analysis of necroptosis and its association with pyroptosis in organ damage in experimental pulmonary arterial hypertension.

In this study, a role of cell loss due to necroptosis and its linkage with pyroptosis in organ damage under the conditions of pulmonary arterial hypertension (PAH) was examined. Monocrotaline (MCT) was used to induce PAH in Wistar rats, and depending on the severity of the disease progression, they were further divided into two subgroups: MCT group-sacrificed 4 weeks after MCT administration and ptMCT group-prematurely sacrificed due to rapid deterioration in vital functions (on Day 24,11 ± 0,7). The elevation of respiratory rate and right ventricular (RV) hypertrophy were more evident in ptMCT group, while the heart rate and cardiac haemodynamic stress markers were comparably higher in both diseased groups. Detailed immunoblotting analysis revealed that the upregulation of pThr231 /Ser232 -RIP3 proceeded into necroptosis execution in the RVs, unlike in the lungs of both PAH stages. The elevated pulmonary pThr231 /Ser232 -RIP3 levels in both PAH subgroups were associated rather with GSDMD-mediated pyroptosis. On the contrary, other inflammasome forms, such as AIM2 and NLRC4, were higher in the RV, unlike in the lungs, of diseased groups. The PAH-induced increase in the plasma RIP3 levels was more pronounced in ptMCT group, and positively correlated with RV hypertrophy, but not with haemodynamic stress. Taken together, we indicated for the first time that pThr231 /Ser232 -RIP3 upregulation resulting in two different necrosis-like cell death modes might underlie the pathomechanisms of PAH and that the plasma RIP3 might serve as an additional diagnostic and prognostic marker of cardiac injury under these conditions.

Subacute Reperfusion in Ischemic Hearts: Study of Autophagy and its Possible Interconnection with Receptor-Interacting Protein Kinase 3.

Background: The role of cardiac autophagy during ischemia and reperfusion (I/R) remains controversial. Furthermore, whether this cell death during I/R is also interconnected with other cell damaging event, such as necroptosis, is insufficiently known. Thus, the aim of this study was to investigate possible links between autophagy and necroptosis in the hearts under conditions of acute I/R injury. Methods: Langendorff-perfused male Wistar rat hearts were subjected to 30-min global ischemia followed by 10-min reperfusion in the presence of either vehicle or a drug inhibiting the pro-necroptotic receptor-interacting protein kinase 3 (RIP3). Hemodynamic parameters and lactate dehydrogenase (LDH) release were measured to assess heart function and non-specific cell death due to the disruption of plasma membrane. Results: Immunoblot analysis of left ventricles revealed that early reperfusion suppressed the activation of autophagy as evidenced by the decreased protein expression of Beclin-1, pSer555-ULK1, pSer555-ULK1/ULK1 ratio, and LC3-II/LC3-I ratio. On the other hand, the molecular signalling responsible for autophagy inhibition did not appear to be affected in these I/R settings. RIP3 inhibition during reperfusion significantly mitigated the loss of the plasma membrane integrity but did not improve cardiac function. This pharmacological intervention targeting necroptosis-mediating protein decreased LC3-II expression in I/R hearts, suggesting some effect on autophagosome processing, but it did not significantly alter other signalling pathways involved in autophagy activation or inhibition. Conclusions: In summary, we showed for the first time that an early reperfusion phase does not promote autophagy and that there may be an interplay between pro-necroptotic protein RIP3 and autophagy with respect to the regulation of autophagosome processing.

Utilizing Graphical Analysis of Chest Radiographs for Primary Screening of Osteoporosis.

Background and Objectives: Osteoporosis is a major risk of fractures, harming patients' quality of life. Dual-energy X-ray absorptiometry (DXA), which can detect osteoporosis early, is too expensive to be conducted on a regular basis. Therefore, we aimed to evaluate a screening method using chest radiographs developed in Japan applied to another population. Materials and Methods: Fifty-five patients who had a chest radiograph and DXA and applied within three months of each test were recruited from the patient database of Semmelweis University (Budapest, Hungary). Graphical analysis of the chest radiographs was conducted to identify the ratio of the cortical bone in the clavicle of each patient. Two researchers performed the analysis, and multiple regression was conducted to determine the bone mineral density of each patient provided by DXA. Results: The Pearson correlation between two examiners' determinations of the cortical bone ratio was 0.769 (p < 0.001). The multiple regression model proved to be statistically significant in identifying osteoporosis, but the model adopted for the Hungarian population was different compared to the Japanese population. Conclusions: This simple, economic Japanese graphical analysis method for chest radiographs may be feasible in detecting osteoporosis. Further studies with a larger population of patients with greater variety of ethnicity would be of value in improving the accuracy of this model.

Peripheral quantitative computed tomography in the assessment of bone mineral density in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients.

INTRODUCTION: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. METHODS: Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. RESULTS: We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p<0.017 after Bonferroni's correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. CONCLUSIONS: BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Midterm Follow-Up and Assessment of Cartilage Thickness by Arthro-Magnetic Resonance Imaging After Arthroscopic Cam Resection, Labral Repair, and Rim Trimming Without Labral Detachment.

PURPOSE: To evaluate the clinical and radiological outcome, sum of acetabular and femoral cartilage thickness, and rate of failure in the midterm after arthroscopic treatment of femoroacetabular impingement (FAI) syndrome with femoral osteoplasty, labral repair, and rim trimming without labral detachment. METHODS: This retrospective case series included patients with FAI syndrome who had undergone hip arthroscopy from January 2009 to December 2010 by a single surgeon, with a minimum follow-up of 55 months. Data from patients who had undergone arthroscopic hip procedures with labral repair, rim trimming, and femoral osteoplasty were analyzed pre- and postoperatively. Clinical outcome (nonarthritic hip score [NAHS], Short Form 36 [SF-36]), range of motion, progression of osteoarthritis (Tönnis grade), radiological parameters (α angle, lateral center-edge angle [LCEA], Tönnis angle), femoral and acetabular cartilage thickness (using magnetic resonance imaging [MRI]), and intraoperative findings were evaluated. RESULTS: Of 148 hip arthroscopies performed, 97 included rim trimming, labral refixation, and femoral osteoplasty. Ten cases were lost to follow-up, leaving 87 hips. Arthroscopic revision was performed on 4 hips and total hip replacement on 4 hips, and 1 hip underwent both arthroscopic revision and total hip replacement. Excluding these 9 cases of revision, for which follow-up was not possible (retrospective study), the remaining 78 hips were followed up for a minimum of 55 months (77 ± 11.4, mean ± SD; range 55 to 124). Mean NAHS (65 to 88, P < .001), SF-36 physical subscale (65 to 85, P < .001), and the numerical pain rating scale (NRS) (5 to 1, P < .001) improved significantly. Outcome scores of minimal clinical importance (NAHS) were achieved in 67.6% of the patients. Mean range of movement improved significantly in flexion (109 to 122, P < .001) and internal rotation (10 to 22.7, P < .001). NAHS was positively associated with flexion of the hip postoperatively (r = 0.307, P = .011). In 16 cases, microfracture was performed (15 acetabular and 1 femoral). Preoperative α angles (anteroposterior and modified Dunn) were significantly higher in this cohort (P < .001, 95% confidence interval 8.9 to 25.2, P = .001). Twenty hips (28 %) progressed to worse Tönnis grades. Initial Tönnis grades were grade 0, 38; grade 1, 48; grade 2, 8. Pre- or postoperative Tönnis grades did not show any correlation with pre- or postoperative NAHS and NRS. MRI measurements at the latest follow-up (69 patients) of the femoral and acetabular cartilage thickness did not reveal any significant reduction at the 12 o'clock position. CONCLUSION: Arthroscopic cam resection, rim trimming, and labral repair without detachment of the labrum provides good or excellent outcome in 77.1% of hips based on NAHS in the midterm. Higher range of motion in flexion is associated with higher NAHS postoperatively. Arthroscopic cam resection, rim trimming and labral repair without detachment of the labrum is a successful method for the treatment of FAI syndrome in the midterm. LEVEL OF EVIDENCE: IV, retrospective case series.

Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling.

Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress; however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3-MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ-mPTP (calcium/calmodulin-dependent protein kinase IIδ-mitochondrial permeability transition pore), PGAM5-Drp1 (phosphoglycerate mutase 5-dynamin-related protein 1) and JNK-BNIP3 (c-Jun N-terminal kinase-BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis.

Strong Genetic Effects on Bone Mineral Density in Multiple Locations with Two Different Techniques: Results from a Cross-Sectional Twin Study.

Background and Objectives: Previous studies have demonstrated that risk of hip fracture is at least partly heritable. The aim of this study was to determine the magnitude of the genetic component of bone mineral density (BMD), using both X-ray and ultrasound assessment at multiple sites. Materials and Methods: 216 adult, healthy Hungarian twins (124 monozygotic, MZ, 92 dizygotic, DZ; mean age 54.2 ± 14.3 years), recruited from the Hungarian Twin Registry with no history of oncologic disease underwent cross-sectional BMD studies. We measured BMD, T- and Z-scores with dual energy X-ray absorptiometry (DEXA) at multiple sites (lumbar spine, femoral neck, total hip and radius). Quantitative bone ultrasound (QUS) was also performed, resulting in a calculated value of estimated bone mineral density (eBMD) in the heel bone. Heritability was calculated using the univariate ACE model. Results: Bone density had a strong genetic component at all sites with estimates of heritability ranging from 0.613 to 0.838 in the total sample. Lumbar BMD and calcaneus eBMD had major genetic components with estimates of 0.828 and 0.838 respectively, and least heritable (0.653) at the total hip. BMD of the radius had also a strong genetic component with an estimate of 0.806. No common environmental effect was found. The remaining variance was influenced by unique environment (0.162 to 0.387). In females only, slightly higher additive genetic estimates were found, especially in the case of the femoral neck and total hip. Conclusion: Bone mineral density is strongly heritable, especially in females at all locations using both DEXA and QUS, which may explain the importance of family history as a risk factor for bone fractures. Unshared environmental effects account for the rest of the variance with slight differences in magnitude across various bone regions, supporting the role of lifestyle in preventing osteoporotic fractures with various efficacy in different bone regions.

Different signalling in infarcted and non-infarcted areas of rat failing hearts: A role of necroptosis and inflammation.

Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1ß axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.

Determination of Novel Highly Effective Necrostatin Nec-1s in Rat Plasma by High Performance Liquid Chromatography Hyphenated with Quadrupole-Time-of-Flight Mass Spectrometry.

Necrostatins have been shown to retard necroptosis, a programmed necrotic-like cell death, which has been shown to underlie pathophysiology of various diseases. Nec-1s, a novel highly effective necrostatin, overcomes some drawbacks of former necrostatin analogues. The determination of Nec-1s in biological system, however, has not been carried out so far. Therefore, this study was undertaken to optimize and validate the HPLC-DAD-Q-TOF method for the assessment of Nec-1s levels in the plasma what is the necessity for designing its proper dosing regimen for in vivo studies. Benefits of the proposed analytical protocol include: (i) simple sample preparation (precipitation of plasma proteins, evaporation of acetonitrile, reconstitution in mobile phase), (ii) fast, selective and sensitive analysis due to a highly orthogonal LC-MS system providing less than 8 min analysis time, (iii) detection of Nec-1s without any matrix interferences, and quantitation of very low concentration levels of Nec-1s (LLOQ ~ 20 ng/mL), (iv) high reliability of Nec-1s determination with precision and accuracy values meeting the FDA criteria for biomedical analysis. The proposed analytical protocol is suitable for routine use in relevant biological studies, and, in this work, it was successfully applied for monitoring of Nec-1s plasma levels in rats providing reproducible and consistent results. Based on pharmacokinetic features, which can also be assessed due to the results of this study, there will be efforts to perform both acute and chronic in vivo studies and potential clinical safety studies first.

[Role of the diet in urinary stone formation and prevalence]. / Az étrend szerepe a húgyúti kövek kialakulásában és megelozésében.

In Hungary and in the developed countries urinary stones occur more often due to nutritional habits, obesity and sedentary lifestyle beside the endocrine and metabolic causes. In the daily urological and family doctor practice prevention should have an important role. Prevention is based not only on body weight control, physical exercise and medical treatment, but on proper diet as well. The nutritional components can change the consistence of urine, causing supersaturation, which is essential in stone formation. Specific nutritional components can either prevent stone formation (increased fluid intake, citrate, magnesium, fruits and vegetables) or either increase stone formation (decreased fluid intake, proteins, carbohydrates, oxalate, salt, increased calcium intake, ascorbic-acid etc). We summarized evidence-based practical dietary suggestions on the primary and secondary prevention of urinary stones. Orv Hetil. 2017; 158(22): 851-855.

Acetabular Labral Debridement/Segmental Resection Versus Reconstruction in the Comprehensive Treatment of Symptomatic Femoroacetabular Impingement: A Systematic Review.

PURPOSE: To perform a systematic review comparing outcomes of labral debridement/segmental resection with labral reconstruction as part of a comprehensive treatment strategy for femoroacetabular impingement. METHODS: A systematic review was conducted according to established PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines using defined inclusion and exclusion criteria. The study groups were divided into labral debridement/segmental resection (group 1) and labral reconstruction (group 2). Multiple search engines were queried (PubMed, Medline) for this analysis. RESULTS: After an exhaustive search of the available literature, 20 publications were included. Twelve studies explored outcomes after labral debridement/resection in a total of 400 hips, whereas 7 studies reported on outcomes after labral reconstruction in a total of 275 hips. One additional matched-pair control study compared labral resection (22 hips) with reconstruction (11 hips). The surgical intervention was a revision in 0% to 100% for group 1 versus 5% to 55% for group 2. A direct anterior approach was not performed in group 2, and cam-type impingement appeared to make up a larger percentage of group 1. The Tönnis grade ranged from 0 to 1 for group 1 versus 0.3 to 1.1 for group 2. Joint replacements were performed in 0% to 30% and 0% to 25%, respectively. The modified Harris Hip Score was the most widely used patient-reported outcome measure and suggested that labral reconstruction was not inferior to labral debridement/segmental resection. CONCLUSIONS: Clinical outcomes after labral debridement/segmental resection versus labral reconstruction were found to be comparable. In the setting of unsalvageable labral pathology, labral reconstruction was used more frequently as a revision option whereas debridement may be more commonly used in the index setting. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, III, and IV studies.

[Ten-year fracture risk by FRAX(®) of women with osteoporosis attending osteoporosis care in Hungary]. / A szakellátásban megjeleno osteoporosisos nok 10 éves csonttöréskockázata a FRAX(®) alapján.

INTRODUCTION: Identification of patients with high fracture risk is a key-point in osteoporosis care. AIM: To assess the fracture risk among osteoporotic women attending osteoporosis care in Hungary. METHOD: A cross-sectional survey was conducted in 2009 in 11 centres among women with osteoporosis aged ≥50 years. Main risk factors were recorded and 10-year fracture risk was calculated using the FRAX(®) for Hungary. Health status was assessed by EQ VAS. RESULTS: 1301 patients with mean age of 68.5 (SD = 8.3) years and EQ VAS of 62.0 (SD = 17.2) participated, of whom 690 (53.0%) have already had previous fracture. Major osteoporotic and hip fracture FRAX(®) scores were 20.1 (SD = 13.9) and 10.6 (SD = 12.5), respectively (by 10-year age groups, mean: 18.5/9.3; 16.2/6.7; 23/13.5; 28.9/18.3). Patients with previous fracture had significantly higher scores (p<0.05). CONCLUSIONS: Similar rate of patients attend osteoporosis care for primary and secondary prevention. FRAX(®) score was higher than 7% in the majority of patients. The findings provide inputs for cost-effectiveness analyses and development of intervention thresholds in Hungary.

Using the anatomical tibial axis for total knee arthroplasty alignment may lead to an internal rotation error.

INTRODUCTION: Despite intensive research, current total knee arthroplasty (TKA) designs do not always provide the correct kinematics for the native joint and thus further optimisation is necessary. Several studies support the importance of malrotation of the tibial components in the failure of TKA. We hypothesise that using the anatomical tibial axis (ATA) to align tibial component rotation on the resected tibial surface may lead to an internal rotation error due to relative anterior shift of the lateral articular surface centre compared to the medial one. The aim of this study was to compare the anatomical tibial axis of the physiological tibial joint surface to the resected one. METHOD: Twenty formalin-fixed cadaveric knees were obtained for study. After computed tomography scanning the data of each specimen were entered into a standardised coordinate system and virtual bone cuts were performed with 6, 8 and 10 mm resection depths. The positions of the articular surface centres were determined at each resection depth. RESULTS: The lateral articular surface centre had moved anteriorly after the resection by a mean 1.475 mm, while the medial one had not changed significantly. Resecting the tibia at a 6-mm cut and using the transverse tibial axis to align the prosthetic tibial plateau will result in a mean 4.0° (95 % confidence interval, 2.5-5.5°) of internal rotation compared to the uncut tibia. DISCUSSION: The ATA lies in 6 degrees of external rotation compared to the perpendicular to the posterior tibial condylar axis (PTCA). Graw et al. suggest aligning the tibial component in 10 degrees of external rotation to the latter. Thus, if we accept the above suggestion, the ATA is 4 degrees internally rotated compared to the same line on the resected proximal tibia. These prior studies appear to be in accordance with our findings. CONCLUSIONS: We conclude that using the ATA on the resected tibial surface may contribute to an internal rotation error.

[Assessment of risk factors for fractures in postmenopausal women with osteoporosis]. / A csonttörés kockázati tényezoinek vizsgálata postmenopausás, osteoporosisos nobetegek körében.

INTRODUCTION: The main consequence of osteoporosis is bone fracture. Bone fracture risk is determined by several risk factors beyond osteodensitometric results. Some of these factors could be estimated by simple clinical questionnaires. AIM: The aim of the present study (Score-HU) was to investigate the risk factors of bone fracture among osteoporotic postmenopausal women (n = 11,221), who were examined in an osteologic outpatient departments. METHOD: Risk factors of each patient were recorded with the use of a simple identical data sheet. RESULTS: The incidence of risk factors were the following: previous bone fracture (79.4%), medication (except antiporotic treatment, antihypertensive drugs 67.9%, sleeping pills 36%, antidepressants 26.5%, corticosteroids 13.5%), decreased mobility (44.6%), early menopause (31.9%), smoking (31.2%), frequent falls (29.1%), and poor health status (more than 3 chronic diseases; 24.1%). CONCLUSIONS: Estimating the above mentioned risk factors we could assess the bone fracture risk more accurately than taking alone the bone mineral density results into consideration.

Analysis of the serum levels of RIP3 and Drp1 in patients with heart failure.

AIMS: As necroptosis involving receptor-interacting protein kinase 3 (RIP3) and dynamin-related protein 1 (Drp1)-mediated signalling is a crucial mechanism of cell loss in heart failure (HF), we aimed to determine the potential diagnostic use of these molecules. METHODS AND RESULTS: The serum samples of the healthy subjects (n = 8) and patients with HF with reduced ejection fraction (n = 31), being subdivided according to the aetiology and New York Heart Association (NYHA) class, were used to measure RIP3 and Drp1 levels by enzyme-linked immunosorbent assay. Although the serum levels of Drp1 in the patients with HF were comparable with those seen in healthy individuals, we found a trend of increase in the levels of RIP3 (P = 0.0697) in the diseased group. These changes were unlikely dependent on the HF aetiology or NYHA class. The circulating RIP3 correlated with neither the main parameters assessing cardiac function (left ventricular ejection fraction, left ventricular end-diastolic diameter, and N-terminal pro-brain natriuretic peptide) nor the marker of inflammation (C-reactive protein). CONCLUSIONS: In this pilot study, findings on serum RIP3 supported the importance of necroptosis in HF pathomechanisms. The potential diagnostic use of circulating RIP3, unlike Drp1, as an additional biomarker of HF has also been indicated; however, further large studies are needed to prove this concept.

Genetic and environmental determinants of bone quality: a cross-sectional analysis of the Hungarian Twin Registry.

There is abundant evidence that bone mineral content is highly heritable, while the heritability of bone quality (i.e. trabecular bone score [TBS] and quantitative ultrasound index [QUI]) is rarely investigated. We aimed to disentangle the role of genetic, shared and unique environmental factors on TBS and QUI among Hungarian twins. Our study includes 82 twin (48 monozygotic, 33 same-sex dizygotic) pairs from the Hungarian Twin Registry. TBS was determined by DXA, QUI by calcaneal bone ultrasound. To estimate the genetic and environmental effects, we utilized ACE-variance decomposition. For the unadjusted model of TBS, an AE model provided the best fit with > 80% additive genetic heritability. Adjustment for age, sex, BMI and smoking status improved model fit with 48.0% of total variance explained by independent variables. Furthermore, there was a strong dominant genetic effect (73.7%). In contrast, unadjusted and adjusted models for QUI showed an AE structure. Adjustments improved model fit and 25.7% of the total variance was explained by independent variables. Altogether 70-90% of the variance in QUI was related to additive genetic influences. We found a strong genetic heritability of bone quality in unadjusted models. Half of the variance of TBS was explained by age, sex and BMI. Furthermore, the adjusted model suggested that the genetic component of TBS could be dominant or an epistasis could be present. In contrast, independent variables explained only a quarter of the variance of QUI and the additive heritability explained more than half of all the variance.

Novel, non-conventional pathways of necroptosis in the heart and other organs: Molecular mechanisms, regulation and inter-organelle interplay.

Necroptosis, a cell death modality that is defined as a necrosis-like cell death depending on the receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL), has been found to underlie the injury of various organs. Nevertheless, the molecular background of this cell loss seems to also involve, at least under certain circumstances, some novel axes, such as RIPK3-PGAM5-Drp1 (mitochondrial protein phosphatase 5-dynamin-related protein 1), RIPK3-CaMKII (Ca2+/calmodulin-dependent protein kinase II) and RIPK3-JNK-BNIP3 (c-Jun N-terminal kinase-BCL2 Interacting Protein 3). In addition, endoplasmic reticulum stress and oxidative stress via the higher production of reactive oxygen species produced by the mitochondrial enzymes and the enzymes of the plasma membrane have been implicated in necroptosis, thereby depicting an inter-organelle interplay in the mechanisms of this cell death. However, the role and relationship between these novel non-conventional signalling and the well-accepted canonical pathway in terms of tissue- and/or disease-specific prioritisation is completely unknown. In this review, we provide current knowledge on some necroptotic pathways being not directly associated with RIPK3-MLKL execution and report studies showing the role of respective microRNAs in the regulation of necroptotic injury in the heart and in some other tissues having a high expression of the pro-necroptotic proteins.

Intermittent Hypoxic Preconditioning Plays a Cardioprotective Role in Doxorubicin-Induced Cardiomyopathy.

Intermittent hypoxic preconditioning (IHP) is a well-established cardioprotective intervention in models of ischemia/reperfusion injury. Nevertheless, the significance of IHP in different cardiac pathologies remains elusive. In order to investigate the role of IHP and its effects on calcium-dependent signalization in HF, we employed a model of cardiomyopathy induced by doxorubicin (Dox), a widely used drug from the class of cardiotoxic antineoplastics, which was i.p. injected to Wistar rats (4 applications of 4 mg/kg/week). IHP-treated group was exposed to IHP for 2 weeks prior to Dox administration. IHP ameliorated Dox-induced reduction in cardiac output. Western blot analysis revealed increased expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) while the expression of hypoxia inducible factor (HIF)-1-α, which is a crucial regulator of hypoxia-inducible genes, was not changed. Animals administered with Dox had further decreased expression of TRPV1 and TRPV4 (transient receptor potential, vanilloid subtype) ion channels along with suppressed Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation. In summary, IHP-mediated improvement in cardiac output in the model of Dox-induced cardiomyopathy is likely a result of increased SERCA2a expression which could implicate IHP as a potential protective intervention in Dox cardiomyopathy, however, further analysis of observed effects is still required.

Open photoacoustic cell for concentration measurements in rapidly flowing gas.

High temporal resolution concentration measurements in rapid gas flows pose a serious challenge for most analytical instruments. The interaction of such flows with solid surfaces can generate excessive aero-acoustic noise making the application of the photoacoustic detection method seemingly impossible. Yet, the fully open photoacoustic cell (OC) has proven to be operable even when the measured gas flows through it at a velocity of several m/s. The OC is a slightly modified version of a previously introduced OC based on the excitation of a combined acoustic mode of a cylindrical resonator. The noise characteristics and analytical performance of the OC are tested in an anechoic room and under field conditions. Here we present the first successful application of a sampling-free OC for water vapor flux measurements.