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The study is focused on the analysis and statistical evaluation of the joint probability of the occurrence of hydrological variables such as peak discharge (Q), volume (V) and duration (t). In our case study, we focus on the bivariate statistical analysis of these hydrological variables of the Danube River in Bratislava gauging station, during the period of 1876-2013. The study presents the methodology of the bivariate statistical analysis, choice of appropriate marginal distributions and appropriate copula functions in representing the joint distribution. Finally, the joint return periods and conditional return periods for some hydrological pairs (Q-V, V-t, Q-t) were calculated. The approach using copulas can reproduce a wide range of correlation (nonlinear) frequently observed in hydrology. Results of this study provide comprehensive information about flood where a devastating effect may be increased in the case where its three basic components (or at least two of them) Q, V and t have the same significance.

Many sickle cell disease (SCD) patients lack matched family donors (MFD) or matched unrelated donors (MUD), implying haploidentical donors (MMFD) as a logical donor choice. We used a reduced toxicity protocol for all donor types. We included 31 patients (2-22 years) with MFD (n = 15), MMFD (10), or MUD (6) HSCT and conditioning with alemtuzumab/ATG, thiotepa, fludarabine and treosulfan, and post-transplant cyclophosphamide for MMFD. After the initial six patients, treosulfan was replaced by targeted busulfan (AUC 65-75 ng*h/ml). After a median follow-up of 26 months (6-123), all patients are alive and off immunosuppression. Two MMFD patients experienced secondary graft failure with recurrence of SCD, both after treosulfan conditioning. Neither acute GVHD ≥ °III nor moderate/severe chronic GVHD was observed. The disease-free, severe GVHD-free survival was 100%, 100%, and 80% in the MFD, MUD, and MMFD groups, respectively (p = 0.106). There was a higher rate of virus reactivation in MMFD (100%) and MUD (83%) compared to MFD (40%; p = 0.005), but not of viral disease (20% vs 33% vs 13%; p = 0.576). Six patients had treosulfan-based conditioning, two of whom experienced graft failure (33%), compared to 0/25 (0%) after busulfan-based conditioning (p = 0.032). Donor chimerism was ≥ 80% in 28/31 patients (90%) at last follow-up. Reduced toxicity myeloablative conditioning resulted in excellent overall survival, negligible GVHD, and low toxicity among all donor groups in pediatric and young adult patients with SCD., Competing Interests: Declarations. Competing interests: MA reports travel support from medac and Neovii and consulting fees from bluebird bio. The remaining authors have no competing interests to declare., (© 2023. The Author(s).)

Endurance training prior to spinal cord injury (SCI) has a beneficial effect on the activation of signaling pathways responsible for survival, neuroplasticity, and neuroregeneration. It is, however, unclear which training-induced cell populations are essential for the functional outcome after SCI. Adult Wistar rats were divided into four groups: control, six weeks of endurance training, Th9 compression (40 g/15 min), and pretraining + Th9 compression. The animals survived six weeks. Training alone increased the gene expression and protein level of immature CNP-ase oligodendrocytes (~16%) at Th10, and caused rearrangements in neurotrophic regulation of inhibitory GABA/glycinergic neurons at the Th10 and L2 levels, known to contain the interneurons with rhythmogenic potential. Training + SCI upregulated markers for immature and mature (CNP-ase, PLP1) oligodendrocytes by ~13% at the lesion site and caudally, and increased the number of GABA/glycinergic neurons in specific spinal cord regions. In the pretrained SCI group, the functional outcome of hindlimbs positively correlated with the protein levels of CNP-ase, PLP1, and neurofilaments (NF-l), but not with the outgrowing axons (Gap-43) at the lesion site and caudally. These results indicate that endurance training applied before SCI potentiates the repair in damaged spinal cord, and creates a suitable environment for neurological outcome.

Oscillating field stimulation (OFS) with regular alterations in the polarity of electric current is a unique, experimental approach to stimulate, support, and potentially guide the outgrowth of both sensory and motor nerve fibers after spinal cord injury (SCI). In previous experiments, we demonstrated the beneficial effects of OFS in a 4-week survival period after SCI. In this study, we observed the major behavioral, morphological, and protein changes in rats after 15 minutes of T9 spinal compression with a 40 g force, followed by long-lasting OFS (50 µA), over a 8-week survival period. Three groups of rats were analyzed: rats after T9 spinal compression (SCI group); SCI rats subjected to implantation of active oscillating field stimulator (OFS + SCI group); and SCI rats subjected to nonfunctional OFS (nOFS + SCI group). Histopathological analysis of spinal tissue indicated a strong impact of epidural OFS on the reduction of tissue and myelin loss after SCI in the segments adjacent to the lesion site. Quantitative fluorescent analysis of the most affected areas of spinal cord tissue revealed a higher number of spared axons and oligodendrocytes of rats in the OFS + SCI group, compared with rats in the SCI and nOFS + SCI groups. The protein levels of neurofilaments (NF-l), growth-associated protein-43 (marker for newly sprouted axons), and myelin basic protein in rats were signifiantly increased in the OFS + SCI group than in the nOFS + SCI and SCI groups. This suggests a supporting role of the OFS in axonal and myelin regeneration after SCI. Moreover, rats in the OFS + SCI group showed great improvements in sensory and motor functions than did rats in the nOFS + SCI and SCI groups. All these findings suggest that long-lasting OFS applied immediately after SCI can provide a good microenviroment for recovery of damaged spinal tissue by triggering regenreative processes in the acute phase of injury., Competing Interests: None

We aimed to investigate the effects of endurance training on expression of growth factors (GFs) and stimulation of neurotrophin-dependent signaling pathways (PI3k/Akt, PLCγ/PKC, PLCγ/CAMKII, Ras-Erk1/2 and Rac1-Cdc42) responsible for neuroplasticity, neuroregeneration, survival and growth after spinal cord injury (SCI). Wistar rats were divided into four groups: (i) intact controls; (ii) 6 weeks of endurance training; (iii) SCI; (iv) pre-training + SCI. The animals survived for 6 weeks after SCI. Firstly, endurance training markedly upregulated mRNA expression and protein levels (up to four times) of growth factors (BDNF, GDNF) and their receptors (TrkB, Gfrα) in low thoracic segments (Th8-Th10) compared to levels in untrained animals. Secondly, we found that spontaneous neuroplasticity seen in the SCI alone group was GF-specific and was activated through both PLCγ-PKC and PLC-CAMKII signaling pathways. In addition, training prior to SCI markedly increased the activity of PLCγ-PKC signaling at both transcript and protein levels at and around the lesion site. Similar effects were seen in expression of PI3k/Akt and Ras/Erk1/2 signaling responsible for cell survival and regeneration. Thirdly, rats which underwent physical activity prior to SCI were more active and had significantly better neurological scores at the 14th and 42nd days of survival. These results suggest that regular physical activity could play an important role after SCI, as it maintains increased expression of GFs in spinal cord tissue 6 weeks post-SCI. The BDNF- and/or BDNF + GDNF-dependent signaling pathways were significantly affected in pre-trained SCI animals. In contrast, GDNF-dependent Rac1-Cdc42 signaling was not involved in training-affected SCI response., (© 2021. The Author(s).)

Turner syndrome (TS) is a rare chromosomal disease with increased cardiovascular morbidity and mortality. The aim of this study was to investigate the influence of physical activity and diet quality on cardiovascular morbidity in German TS women. An anonymous online questionnaire was established. The questionnaire was based on the 2020 WHO recommendations on physical activity and sedentary behaviour and included the 14-Item Mediterranean Diet Assessment Tool. In addition, TS patients were asked about existing cardiovascular conditions. In total, 83 TS women were included in the final analysis. The achievement of <600 Metabolic Equivalent-minutes per week for recreational activities was significantly associated with the presence of arterial hypertension ( p = 0.006). High adherence to the Mediterranean diet was achieved by only 20.5% of TS subjects and tended to be inversely associated with the presence of lipid metabolism disorders ( p = 0.063). Only 37.3% of TS participants received nutritional counselling. Given the increased cardiovascular risk, specific counselling for lifestyle optimisation may play an important role in the management of TS. Further studies are required to evaluate the effects of regular aerobic physical training and different nutritional programs on cardiovascular morbidity in TS.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs. anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlights the time-dependent transformation of reactive microglia and astrocytes into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide suggestions on how to modulate the inflammation and discuss key therapeutic approaches leading to better functional outcome after SCI.

Background: Traumatic spinal cord injury (SCI) causes partial or total loss of sensory and motor functions. Despite enormous efforts, there is still no effective treatment which might improve patients' neurological status.The application of electric current to the injured spinal cord is known to promote healing and tissue regeneration. The use of this modality in treating the injured spinal cord to improve neurological recovery has been introduced as a potential treatment., New Method: Here we describe the method of epidural implantation of a miniature oscillating field (OF) stimulator designed in our laboratory immediately after Th9 spinal compression in Wistar rats. Three groups of animals were analyzed (intact; SCI only; OFS + SCI; n = 8 each). Histological, immunohistological and behavioral analysis were used to show the favorable effect of epidural OF stimulation on axonal regeneration and modulation of astrogliosis., Results: Our study revealed considerable differences in white matter integrity in animals with an implanted OF stimulator. Moreover, we detected significantly increased numbers of neurofilaments and massive reduction in activated forms of astrocytes in the group of stimulated animals compared to the animals without stimulation., Comparison With Existing Method(s): Compared with previous research, our study revealed that epidural implantation of an OF stimulator immediately after spinal compression effectively reduced the expression of inflammatory response and suppressed activated astrocyte formation., Conclusions: Our finding confirms that implanting an OF stimulator is safe, stable and suitable for future combined therapy which could effectively promote and accelerate regeneration and functional restoration after spinal trauma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of the present study was to investigate the therapeutic efficacy of local hypothermia (beginning 30 min post-injury persisting for 5 h) on tissue preservation along the rostro-caudal axis of the spinal cord (3 cm cranially and caudally from the lesion site), and the prevention of injury-induced functional loss in a newly developed computer-controlled compression model in minipig (force of impact 18N at L3 level), which mimics severe spinal cord injury (SCI). Minipigs underwent SCI with two post-injury modifications (durotomy vs. intact dura mater) followed by hypothermia through a perfusion chamber with cold (epidural t≈15°C) saline, DMEM/F12 or enriched DMEM/F12 (SCI/durotomy group) and with room temperature (t≈24°C) saline (SCI-only group). Minipigs treated with post-SCI durotomy demonstrated slower development of spontaneous neurological improvement at the early postinjury time points, although the outcome at 9 weeks of survival did not differ significantly between the two SCI groups. Hypothermia with saline (t≈15°C) applied after SCI-durotomy improved white matter integrity in the dorsal and lateral columns in almost all rostro-caudal segments, whereas treatment with medium/enriched medium affected white matter integrity only in the rostral segments. Furthermore, regeneration of neurofilaments in the spinal cord after SCI-durotomy and hypothermic treatments indicated an important role of local saline hypothermia in the functional outcome. Although saline hypothermia (24°C) in the SCI-only group exhibited a profound histological outcome (regarding the gray and white matter integrity and the number of motoneurons) and neurofilament protection in general, none of the tested treatments resulted in significant improvement of neurological status. The findings suggest that clinically-proven medical treatments for SCI combined with early 5 h-long saline hypothermia treatment without opening the dural sac could be more beneficial for tissue preservation and neurological outcome compared with hypothermia applied after durotomy.

The aim of our study was to limit the inflammatory response after a spinal cord injury (SCI) using Atorvastatin (ATR), a potent inhibitor of cholesterol biosynthesis. Adult Wistar rats were divided into five experimental groups: one control group, two Th9 compression (40 g/15 min) groups, and two Th9 compression + ATR (5 mg/kg, i.p.) groups. The animals survived one day and six weeks. ATR applied in a single dose immediately post-SCI strongly reduced IL-1β release at 4 and 24 h and considerably reduced the activation of resident cells at one day post-injury. Acute ATR treatment effectively prevented the excessive infiltration of destructive M1 macrophages cranially, at the lesion site, and caudally (by 66%, 62%, and 52%, respectively) one day post-injury, whereas the infiltration of beneficial M2 macrophages was less affected (by 27%, 41%, and 16%). In addition, at the same time point, ATR visibly decreased caspase-3 cleavage in neurons, astrocytes, and oligodendrocytes. Six weeks post-SCI, ATR increased the expression of neurofilaments in the dorsolateral columns and Gap43-positive fibers in the lateral columns around the epicenter, and from day 30 to 42, significantly improved the motor activity of the hindlimbs. We suggest that early modulation of the inflammatory response via effects on the M1/M2 macrophages and the inhibition of caspase-3 expression could be crucial for the functional outcome., Competing Interests: The authors declare no conflicts of interest.

This study investigated the neuroprotective efficacy of local hypothermia in a minipig model of spinal cord injury (SCI) induced by a computer-controlled impactor device. The tissue integrity observed at the injury epicenter, and up to 3 cm cranially and caudally from the lesion site correlated with motor function. A computer-controlled device produced contusion lesions at L3 level with two different degrees of tissue sparing, depending upon pre-set impact parameters (8N- and 15N-force impact). Hypothermia with cold (4°C) saline or Dulbecco's modified Eagle's medium (DMEM)/F12 culture medium was applied 30 min after SCI (for 5 h) via a perfusion chamber (flow 2 ml/min). After saline hypothermia, the 8N-SCI group achieved faster recovery of hind limb function and the ability to walk from one to three steps at nine weeks in comparison with non-treated animals. Such improvements were not observed in saline-treated animals subjected to more severe 15N-SCI or in the group treated with DMEM/F12 medium. It was demonstrated that the tissue preservation in the cranial and caudal segments immediately adjacent to the lesion, and neurofilament protection in the lateral columns may be essential for modulation of the key spinal microcircuits leading to a functional outcome. Tissue sparing observed only in the caudal sections, even though significant, was not sufficient for functional improvement in the 15N-SCI model.