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Zahradnikova, A., M. Dura, I. Gyorke, A. L. Escobar, I. Zahradnik, and S. Gyorke. Regulation of dynamic behavior of cardiac ryanodine receptor by [Mg.sup.2.sup.+] under simulated physiological conditions. Am J Physiol Cell Physiol 285: C1059--C1070, 2003. First published July 2, 2003; 10.1152/ ajpcell.00118.2003.--[Mg.sup.2.sup.+], an important constituent of the intracellular milieu in cardiac myocytes, is known to inhibit ryanodine receptor (RyR) [Ca.sup.2.sup.+] release channels by competing with [Ca.sup.2.sup.+] at the cytosolic activation sites of the channel. However, the significance of this competition for local, dynamic [Ca.sup.2.sup.+]-signaling processes thought to govern cardiac excitation-contraction (EC) coupling remains largely unknown. In the present study, [Ca.sup.2.sup.+] stimuli of different waveforms (i.e., sustained and brief) were generated by photolysis of the caged [Ca.sup.2.sup.+] compound nitrophenyl (NP)-EGTA. The evoked RyR activity was measured in planar lipid bilayers in the presence of 0.6-1.3 mM free [Mg.sup.2.sup.+] at the background of 3 mM total ATP in the presence or absence of 1 mM luminal [Ca.sup.2.sup.+].[Mg.sup.2.sup.+] dramatically slowed the rate of activation of RyRs in response to sustained ([greater than or equal to]10-ms) elevations in [Ca.sup.2.sup.+] concentration. Paradoxically, [Mg.sup.2.sup.+] had no measurable impact on the kinetics of the RyR response induced by physiologically relevant, brief ( excitation-contraction coupling; cardiac myocytes; magnesium; calcium signaling

An optimized NMR experiment combining the advantages of methyl-TROSY and SOFAST-HMQC is developed. The SOFAST-methyl-TROSY-based experiment has helped in studying structural and dynamic changes occurring in molecular nanomachines while they perform their biological function in vitro.

The structure of DR1199 protein isolated from the radio-resistant bacterium Deinococcus radiodurans was determined to gain insight into its function and the role in response to irradiation and oxidative stress. The results revealed that DR1199 might function as a general stress protein involved in the detoxification of the cell from oxygen reactive species rather than as a peptidase in D. radiodurans.

Analytical ultracentrifugation and electron microscopy studies have showed that the PH1527 protein from Pyrococcus horikoshii encodes a 39014 Da protein and shares the characteristic tetrahedral shape of Haloarcula marismortui TET (HmTET) and PhDAP in solution. The specificity, the mode of action, and the enzymatic activity of the PhTET2 complex from Pyrococcus horikoshii are discussed.

Objectives: The Paediatric Throat Disorders Outcome Test (T‐14) is a disease‐specific questionnaire that parents are requested to complete; it aimed to assess the quality of life related to tonsil and adenoid disease or its treatment in children with throat disorders. The aim of this study was to validate the Spanish adaptation of the T‐14, thus allowing comparison across studies and facilitating international multicentre projects. Design, setting and participants: This was a multicentre prospective instrument validation study. Guidelines for the cross‐cultural adaptation process from the original English‐language scale into a Spanish‐language version were followed. The psychometric properties (reproducibility, reliability, validity, responsiveness) of the Spanish version (“T‐14‐s” for “T‐14‐Spanish”) were assessed in 50 consecutive children undergoing adeno/tonsillectomy (both before and 6 months after surgery) and in a separate cohort of 50 unaffected children in a comparable age range. Main outcome measures and results: Test‐retest reliability (γ = 0.83) and internal consistency reliability (α = 0.94) were adequate. The T‐14‐s demonstrated satisfactory construct validity (r > 0.40). The instrument showed excellent between‐group discrimination (P < .0001) and a high responsiveness to change (effect size = 2.09). Conclusions: The Spanish version of the T‐14 (T‐14‐s) is a valid tool for measuring the subjective severity of throat disorders, and its use is recommended. [ABSTRACT FROM AUTHOR]

Mg[sup 2+], an important constituent of the intracellular milieu in cardiac myocytes, is known to inhibit ryanodine receptor (RyR) Ca[sup 2+] release channels by competing with Ca[sup 2+] at the cytosolic activation sites of the channel. However, the significance of this competition for local, dynamic Ca[sup 2+]-signaling processes thought to govern cardiac excitation-contraction (EC) coupling remains largely unknown. In the present study, Ca[sup 2+] stimuli of different waveforms (i.e., sustained and brief) were generated by photolysis of the caged Ca[sup 2+] compound nitrophenyl (NP)-EGTA. The evoked RyR activity was measured in planar lipid bilayers in the presence of 0.6-1.3 mM free Mg[sup 2+] at the background of 3 mM total ATP in the presence or absence of i mM luminal Ca[sup 2+]. Mg[sup 2+] dramatically slowed the rate of activation of RyRs in response to sustained (≥10-ms) elevations in Ca[sup 2+] concentration. Paradoxically, Mg[sup 2+] had no measurable impact on the kinetics of the RyR response induced by physiologically relevant, brief (<1-ms) Ca[sup 2+] stimuli. Instead, the changes in activation rate observed with sustained stimuli were translated into a drastic reduction in the probability of responses. Luminal Ca[sup 2+] did not affect the peak open probability or the probability of responses to brief Ca[sup 2+] signals; however, it slowed the transition to steady state and increased the steady-state open probability of the channel. Our results indicate that Mg[sup 2+] is a critical physiological determinant of the dynamic behavior of the RyR channel, which is expected to profoundly influence the fidelity of coupling between L-type Ca[sup 2+] channels and RyRs in heart cells. [ABSTRACT FROM AUTHOR]

Background: Operative treatment of fragility fractures of the pelvis has become a gold standard. Preoperative planning, including the assessment of the pathway for iliosacral screws, is crucial. The anchorage of the screw depends on the bone quality. Some recent studies have concentrated on assessing bone mineral density (BMD) with the use of Hounsfield unit (HU) values obtained from CT scans. The aim of the present study is to determine the best sacral levels of S1-S3 on the pathway of iliosacral screws for sacroiliac joint fixation. Methods: Patients admitted to the Independent Public Healthcare Center in Rypin between 1 of September and 1 of December in 2023, who had CT scans of the pelvis performed on them for different reasons, were included in this study. In total, 103 patients-56 men and 47 women-were enrolled in the study and consecutively separated into two groups of different ages: 18-60 years old (group A) and above 60 years old (group B). The volumetric bone density expressed in HU values was measured with sacral levels of S1, S2 and S3. Apart from the bodies of sacral vertebrae S1-S3, our measurements involved the ala of the ilium in the vicinity of the sacroiliac joint and the wing of the sacrum. All the measurements were performed on the pathway of presumptive iliosacral screws to stabilize the sacroiliac joint. Results: In group A (58 patients) the highest bone density in sacral bodies was found in S1 that gradually decreased to S3, while the opposite tendency was demonstrated in the ala of ilium. The HU values in the wing of the sacrum did not display statistical significance. In group B (45 patients), the highest bone density was also found in the sacral body S1 that decreased toward S3 but in the ala of ilium, the highest bone density was found with level S1 and lowest with level S2. In both groups, the highest bone density referred to the wing of the sacrum. Conclusion: While the perfect construct for posterior pelvic ring fixation remains unclear, our findings may imply that sacroiliac joint screws inserted into the wing of the sacrum of greater bone density could provide much more successful fixation in comparison to those anchored in the body of sacral vertebra of lesser bone density.

In the course of psoriatic arthritis (PsA), depression occurs much more often than in the general population. Depression can be considered a poor prognostic factor. The aim of the study was to assess the relationships between the occurrence of depression and the levels of proinflammatory cytokines in patients with PsA. The study included 86 (47F/39M) patients with PsA. Only patients with high disease activity (DAPSA > 28) were enrolled in the study. The severity of depressive symptoms was assessed using the Beck Depression Inventory II (BDI-II) for all patients. Additionally, sociodemographic data were collected. All patients were also assessed for the levels of interleukins (IL): IL-1, IL-6, IL-17A, IL-23, and tumor necrosis factor alpha (TNF-α) using the enzyme-linked immunosorbent assay (ELISA) test. In the study group, depression (BDI-II ≥ 14) was diagnosed in 45 patients (52%). Patients with coexisting depression reported higher levels of pain and disease activity on the visual analogue scale compared to patients without depression (8.5 vs. 7.7, p < 0.001 and 9.3 vs. 8.4, p < 0.001, respectively). The mean levels of proinflammatory cytokines [pg/ml], IL-1 and IL-6, were also higher in the group of patients with depression (46.4 vs. 4.7, p < 0.001 and 10.5 vs. 4.9, p < 0.001, respectively). The coexistence of depression in the course of Psoriatic Arthritis (PsA) is associated with higher levels of IL-1 and IL-6. Depression has a negative impact on the perception of the underlying disease and is linked to reduced social and occupational activity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background : There are three main methods of mechanical thrombectomy (MT): using a stent retriever (SR) only (SO), aspiration catheter (AC) only (AO) and the combined method (CM) using both the SR and AC. This paper describes a real-life, single-center experience using SO, AO and CM during 276 consecutive MTs. Methods : The primary endpoint was the frequency of first-pass complete (FPE TICI3). The secondary endpoints were final mTICI 2b-3, procedure duration, clinical outcome and the total number of device passes. The third aim of this study was to test the association between the clinical outcomes in patients treated with each method and various factors. Results : There was a significant difference ( p = 0.016) between the groups' FPE TICI3 rates with 46% mTICI 3 in the AO group, 41% in the CM group and 21% in the SO group. AO resulted in procedure time shortening to a mean duration of 43 min, and the scores were 56 min for CM and 63 min for SO ( p < 0.0001). There were no significant differences in clinical outcomes or in-hospital mortality. The analysis showed a correlation between good clinical outcomes and the administration of IVT: OR 1.71 (1.03-2.84) p = 0.039. Patients ≥66 years old had higher odds of a bad outcome compared to younger patients in general (OR, 1.99 95% CI, 1.17-3.38; p = 0.011). FPE TICI3 was associated with good functional outcomes in the whole treated cohort (OR, 1.98; 95% CI, 1.21-3.25; p = 0.006). Conclusions : In our series, AO proved to be the best starting point in most cases. It demonstrates good technical efficacy regarding FPE, it is fast and clinical outcomes seem to be the least age- and FPE TICI3-dependent. It can be easily converted into the combined method, which had the second-best outcomes in our cohort.

Introduction: Some of the obstacle Course Race (OCR) competitions are co-organized by military units that are seeking candidates for service in special operations forces (SOFs). The aim of the study was to compare psycho-physical characteristics between Polish OCR athletes and SOF soldiers, in order to assess the possibility of recruiting future SOF soldiers from the OCR community., Materials and Methods: The study included 23 OCR competitors, and 17 soldiers from JW Formoza were used as the comparative group. The psychological measure of resilience was assessed using the Connor-Davidson Resilience Scale. Participants also completed a survey in which they had to rank character strengths. Physical fitness was assessed on the basis of a 3000-m run and the maximum number of sit-ups and straight pull-ups., Results: There were significant differences between OCR participants and JW Formoza soldiers: body mass index, 24.1 ± 1.5 vs. 25.9 ± 1.9 (P = .002); 3000-m run, 11:59 ± 0:49 vs. 12:11 ± 0:28 (P = .024); and straight pull-ups, 19 ± 3 vs. 15 ± 3 (P = .001). The most commonly chosen character strengths in both groups were self-control, team worker, and optimism., Conclusions: OCR competitors show psychophysical characteristics similar to those expected from actual SOF personnel., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with rheumatic diseases suffer depression at a far greater rate than the general population. Aside from evident mental health degradation, in this group of patients depression can often lead to failures in the treatment of the basic disease. The aim of the study was to assess the concentration of advanced glycation end-products (AGE) in the skin autofluorescence (SAF) exam in patients with select rheumatic diseases depending on depression concomitance. 139 patients with rheumatic diseases were enrolled into the study-43 (39F/4 M) patients with RA, 31 (24F/7 M) patients with PsA, 27 (22F/5 M) patients with SLE and 38 (33F/5 M) patients with SSc. In all patients, the concentration of AGE was assessed using the AGE Reader device (DiagnOptics BV Groningen, The Netherlands). The Beck Depression Inventory II was used to assess depression in the patients. Patients who scored 14 points or more in the BDI-II were diagnosed with depression. In the studied group, depression was identified in 73 (53%) patients-25 with RA, 21 with PsA, 11 with SLE and 16 with SSc. Mean SAF in patients with depression was 2.8 ± 0.4, and in the group with no depression-2.2 ± 0.5 (p < 0.001). The study results indicate that in the course of rheumatic diseases, the presence of depression may influence the increase in AGE concentration in the skin. Therefore, evaluating AGE levels in the skin may be clinically relevant as it can help identify patients who may be at risk of developing depression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The current official model of training in Intensive Care Medicine (ICM) in Spain is based on exposure to experiences through clinical rotations. The main objective was to determine the level of competency (I novice to V independent practitioner) achieved by the residents at the end of the 3rd year of training (R3) in ICM through a simulation-based OSCE. Secondary objectives were: (1) To identify gaps in performance, and (2) To investigate the reliability and feasibility of conducting simulation-based assessment at multiple sites., Design: Observational multicenter study., Setting: Thirteen Spanish ICU Departments., Participants: Thirty six R3., Intervention: The participants performed on five, 15-min, high-fidelity crisis scenarios in four simulation centers. The performances were video recorded for later scoring by trained raters., Main Variables of Interest: Via a Delphi technique, an independent panel of expert intensivists identified critical essential performance elements (CEPE) for each scenario to define the levels of competency., Results: A total of 176 performances were analyzed. The internal consistency of the check-lists were adequate (KR-20 range 0.64-0.79). Inter-rater reliability was strong [median Intraclass Correlation Coefficient across scenarios: 0.89 (0.65-0.97)]. Competency levels achieved by R3 were: Level I (18.8%), II (35.2%), III (42.6%), IV/V (3.4%). Overall, a great heterogeneity in performance was observed., Conclusion: The expected level of competency after one year in the ICU was achieved only in half of the performances. A more evidence-based educational approach is needed. Multiple center simulation-based assessment showed feasibility and reliability as an evaluation method of competency., Trial Registration: COBALIDATION. NCT04278976. (https://register., Clinicaltrials: gov)., (Copyright © 2022 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Despite the existence of an effective live-attenuated vaccine, measles can appear in vaccinated individuals. We investigated breakthrough measles cases identified during our surveillance activities within the measles/rubella surveillance network (MoRoNet) in Milan and surrounding areas (Northern Italy). Between 2017 and 2021, we confirmed measles virus (genotypes B3 or D8) infections in 653 patients and 51 of these (7.8%) were vaccinees. Among vaccinated individuals whose serum was available, a secondary failure was evidenced in 69.4% (25/36) of cases while 11 patients (30.6%) were non-responders. Non-responders were more frequently hospitalized and had significantly lower Ct values in both respiratory and urine samples. Median age and time since the last immunization were similar in the two groups. Importantly, we identified onward transmissions from vaccine failure cases. Vaccinees were involved in 20 outbreaks, in 10 of them they were able to transmit the virus, and in 8 of them, they were the index case. Comparing viral hemagglutinin sequences from vaccinated and non-vaccinated subjects did not show a specific mutation pattern. These results suggest that vaccination failure was likely due to the poor immune response of single individuals and highlights the importance of identifying breakthrough cases and characterizing their clinical and virologic profiles.

Ankylosing spondylitis (AS) patients have a high risk of osteoporotic fractures. The aim of this study was to evaluate the usefulness of trabecular bone score (TBS) in assessing fracture risk in patients with AS. 67 patients meeting the ASAS classification criteria were enrolled in the study. Fracture risk for each patient was assessed based on a lumbar spine exam encompassing bone mineral density (BMD), and TBS through a dual-energy X-ray absorptiometry (DXA) exam. In addition, each patient had an X-ray taken of their lumbar and thoracic spine to determine the presence of syndesmophytes and bony bridges, as well as spinous process and vertebral body fractures. Moreover, each patient's medical history was analyzed for other osteoporotic fractures. A major osteoporosis fracture (MOF) was found in 11 (16%) patients in total, of which 7 (10%) were vertebral body fractures. The mean TBS in patients with MOF and no MOF were, respectively, 1.12 and 1.29 (p < 0.001). No significant differences were found in BMD scores between the two groups. Syndesmophytes and bony bridges occurred more frequently in patients with MOF (p = 0.02). Age of 50 or more (RR = 9.86, p = 0.002), TBS score ≤ 1.31 (RR = 2.07, p < 0.0001), and presence of syndesmophytes and bony bridges (RR = 2.14, p = 0.04) were considered a relative risk (RR) increasing factors. TBS is a markedly more sensitive method of identifying patients with a high fracture risk compared to BMD measurement in a DXA exam in patients with AS., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

DNA methylation plays a critical role in spermatogenesis, as evidenced by the male sterility of DNA methyltransferase (DNMT) mutant mice. Here, we report a division of labor in the establishment of the methylation landscape of male germ cells and its functions in spermatogenesis. Although DNMT3C is essential for preventing retrotransposons from interfering with meiosis, DNMT3A broadly methylates the genome (with the exception of DNMT3C-dependent retrotransposons) and controls spermatogonial stem cell (SSC) plasticity. By reconstructing developmental trajectories through single-cell RNA sequencing and profiling chromatin states, we found that Dnmt3A mutant SSCs can only self-renew and no longer differentiate in association with spurious enhancer activation that enforces an irreversible stem cell gene program. Our findings therefore highlight a key function of DNA methylation in male fertility: the epigenetic programming of SSC commitment to differentiation and lifelong spermatogenesis supply., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: 1. To determine the satisfaction of tutors and residents with a specific methodology used to implement CoBaTrICE. 2. To determine the reliability and validity of the global rating scales designed ad hoc to assess the performance of the residents for training purposes., Design: Prospective cohort study., Participants: All the residents and tutors of the ICU Department of the Hospital Universitario y Politécnico la Fe de Valencia., Intervention: CoBaTrICE implementation started in March 2016, it was based on: (1) Training the tutors in feedback techniques; (2) Performing multiple objective and structured work based assessments to achieve the competences of the program; and (3) The use of an electronic portfolio to promote learning reflection and to collect the evidence that learning was taking place., Methods: The acceptance of CoBaTrICE was explored through a satisfaction survey conducted after 9 months of implementation of the training program. The 15 residents and 5 tutors of the ICU Department were asked about the methodology of the formative assessments, the quality of the feedback, self-learning regulation and the electronic portfolio usefulness. The validity of the global rating scales was assessed through the tests alfa de Cronbach, reliability and generalizability indexes, and intraclass correlation coefficient., Results: The implementation of CoBaTrICE was satisfactory in all the dimensions studied. The global rating scales used for formative purposes showed reliability and validity., Conclusions: The methodology used to implement CoBaTrICE was highly valued by tutors and residents. The global rating scales used for formative purposes showed reliability and validity., (Copyright © 2019 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.)