•Almost a quarter of the worldwide population is infected with tuberculosis.•Seizures are commonly associated with central nervous system (CNS) tuberculosis, especially in children and HIV-infected ...patients.•Early treatment of CNS tuberculosis is vital to avoid complications that increase the risk of seizures.•Young age, early onset of seizures during illness, refractory seizures, tuberculoma, cortical involvement, epileptiform discharges, and residual lesions, are risk factors for the development of epilepsy in CNS tuberculosis.
Central nervous system (CNS) tuberculosis is a life-threatening condition that usually presents with seizures, particularly in children and HIV-infected patients. Tuberculous meningitis (TBM) and tuberculomas are the two forms of CNS tuberculosis that can present with seizures. Seizures usually resolve after successful treatment of the underlying infection. However, the success of the treatment is usually based on an early diagnosis. Delay in the treatment of CNS tuberculosis increases the risk of its associated complications, such as stroke. This would lead to the development of epilepsy. Early seizures may be related to meningeal irritation and cerebral edema, whereas late seizures are often associated with structural brain lesions that generally require more advanced and prolonged treatment. Risk factors associated with the development of epilepsy include young age, refractory seizures, tuberculoma, cortical involvement, epileptiform discharges, and residual lesions. Treatment of CNS tuberculosis is based on early initiation of appropriate anti-tuberculous drugs, antiseizure medications, and correction of associated predisposing factors. Finally, further research into the mechanisms of seizures and the development of epilepsy in CNS tuberculosis could help improve management of these conditions.
The psychological impact of the prolonged lockdown measures in the UK as a response to the COVID-19 pandemic is unclear. Our aim was to determine if there are significant differences in self-control, ...self-efficacy, depressive symptoms and leisure motivation between UK older adults with differing levels of physical activity, and which of these variables can be used to predict activity level after 1 year of lockdown restrictions,
521 adults aged 50-92 years completed an online survey consisting of several validated measures relating to physical activity, self-control, self-efficacy, depressive symptoms, and leisure motivation. Participant's responses were grouped into active (≥150minutes activity per week) and inactive (<150minutes activity per week). Data was analysed using ANOVA, Pearson's Correlation and Multiple Regression (forward stepwise).
We found significant differences in self-efficacy, self-control, and depressive symptoms between physically active vs inactive subjects. High levels of self-control and self-efficacy were associated with higher levels of activity and fewer depressive symptoms. Self-control, amotivation, depressive symptoms and self-efficacy were predictors of physical activity level.
Psychological variables including self-control, self-efficacy, depressive symptoms and amotivation can be used to predict physical activity levels in UK middle-aged and older adults following 1 year of Covid restrictions.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
MAC is commonly found in patients affected with MR, and it is associated with high morbidity, mortality and worse cardiac surgical outcomes. Transcatheter edge-to-edge repair could be an alternative ...treatment, although there is little evidence in this population.
The aim of this study was to analyse the safety, efficacy and durability of MitraClip implantation in patients affected with mitral regurgitation (MR) and mitral annulus calcification (MAC).
We analysed the outcomes of 61 suitable patients affected with severe MR and moderate or severe MAC (the "MAC" group) and 791 patients with no or mild MAC (the "NoMAC" group) treated with the MitraClip device.
Procedural success was similar (91.8% vs 95.1%, p=0.268, in MAC and NoMAC, respectively), with a very low rate of complications. At one-year follow-up, 90.6% of MAC and 79.5% of NoMAC patients had MR grade ≤2 (p=0.129), 80% in both groups remained in NYHA Functional Class ≤II, and a significant reduction in cardiac readmissions was observed (65% vs 78% in MAC vs NoMAC, p=0.145). One-year mortality tended to be higher in MAC patients (19.7% vs 11.3%, p=0.050), with no difference in cardiovascular mortality (15.3% vs 9.2%, p=0.129).
MitraClip use in selected patients with moderate or severe MAC is safe, feasible and achieves good clinical and echocardiographic results at one-year follow-up.
The spread of antibiotic-resistant bacteria represents a substantial health threat. Current antibiotics act on a few metabolic pathways, facilitating resistance. Consequently, novel regulatory ...inhibition mechanisms are necessary. Riboswitches represent promising targets for antibacterial drugs. Purine riboswitches are interesting, since they play essential roles in the genetic regulation of bacterial metabolism. Among these, class I (2'-dG-I) and class II (2'-dG-II) are two different 2'-deoxyguanosine (2'-dG) riboswitches involved in the control of deoxyguanosine metabolism. However, high affinity for nucleosides involves local or distal modifications around the ligand-binding pocket, depending on the class. Therefore, it is crucial to understand these riboswitches' recognition mechanisms as antibiotic targets. In this work, we used a combination of computational biophysics approaches to investigate the structure, dynamics, and energy landscape of both 2'-dG classes bound to the nucleoside ligands, 2'-deoxyguanosine, and riboguanosine. Our results suggest that the stability and increased interactions in the three-way junction of 2'-dG riboswitches were associated with a higher nucleoside ligand affinity. Also, structural changes in the 2'-dG-II aptamers enable enhanced intramolecular communication. Overall, the 2'-dG-II riboswitch might be a promising drug design target due to its ability to recognize both cognate and noncognate ligands.
Background and Purpose
Mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA mutations. There ...are no disease‐modifying therapies, and treatment remains mainly supportive. It has been shown previously that patients with MELAS syndrome have significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Glutamine has many metabolic fates in neurons and astrocytes, and the glutamate–glutamine cycle couples with many metabolic pathways depending on cellular requirements. The aim was to compare CSF glutamate and glutamine levels before and after dietary glutamine supplementation. It is postulated that high‐dose oral glutamine supplementation could reduce the increase in glutamate levels.
Method
This open‐label, single‐cohort study determined the safety and changes in glutamate and glutamine levels in CSF after 12 weeks of oral glutamine supplementation.
Results
Nine adult patients with MELAS syndrome (66.7% females, mean age 35.8 ± 3.2 years) were included. After glutamine supplementation, CSF glutamate levels were significantly reduced (9.77 ± 1.21 vs. 18.48 ± 1.34 μmol/l, p < 0.001) and CSF glutamine levels were significantly increased (433.66 ± 15.31 vs. 336.31 ± 12.92 μmol/l, p = 0.002). A side effect observed in four of nine patients was a mild sensation of satiety. One patient developed mild and transient elevation of transaminases, and another patient was admitted for an epileptic status without stroke‐like episode.
Discussion
This study demonstrates that high‐dose oral glutamine supplementation significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. These findings may have potential therapeutic implications in these patients.
Trial Registration Information
ClinicalTrials.gov Identifier: NCT04948138. Initial release 24 June 2021, first patient enrolled 1 July 2021. https://clinicaltrials.gov/ct2/show/NCT04948138.
High‐dose oral glutamine supplementation for 12 weeks significantly reduces cerebrospinal fluid (CSF) glutamate and increases CSF glutamine levels in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome. This decrease in CSF glutamate levels could reduce glutamate‐mediated excitotoxicity. These findings may have potential therapeutic implications in patients with MELAS syndrome.
Calcium phosphate (CaP)-based ceramics are the most investigated materials for bone repairing and regeneration. However, the clinical performance of commercial ceramics is still far from that of the ...native tissue, which remains as the gold standard. Thus, reproducing the structural architecture and composition of bone matrix should trigger biomimetic response in synthetic materials. Here, we propose an innovative strategy based on the use of track-etched membranes as physical confinement to produce collagen-free strontium-substituted CaP nanotubes that tend to mimic the building block of bone, i.e., the mineralized collagen fibrils. A combination of high-resolution microscopic and spectroscopic techniques revealed the underlying mechanisms driving the nanotube formation. Under confinement, poorly crystalline apatite platelets assembled into tubes that resembled the mineralized collagen fibrils in terms of diameter and structure of bioapatite. Furthermore, the synergetic effect of Sr2+ and confinement gave rise to the stabilization of amorphous strontium CaP nanotubes. The nanotubes were tested in long-term culture of osteoblasts, supporting their maturation and mineralization without eliciting any cytotoxicity. Sr2+ released from the particles reduced the differentiation and activity of osteoclasts in a Sr2+ concentration-dependent manner. Their bioactivity was evaluated in a serum-like solution, showing that the particles spatially guided the biomimetic remineralization. Further, these effects were achieved at strikingly low concentrations of Sr2+ that is crucial to avoid side effects. Overall, these results open simple and promising pathways to develop a new generation of CaP multifunctional ceramics that are active in tissue regeneration and able to simultaneously induce biomimetic remineralization and control the imbalanced osteoclast activity responsible for bone density loss.
The scientific basis for the statement that plants and their active constituents play an important role in the prevention of chronic and degenerative diseases is continuously advancing. In fact, the ...origin of many therapeutic substances is due to secondary metabolism in the plant. The genus
Hibiscus contains 220 species distributed around the world. It is an interesting source of potential bioactive molecules, as phenolic compounds, triterpene derivatives, phytosteroids, with antioxidant, cardioprotective, antihypertensive and antiproliferative activities. This work reviews the pharmacological evidence of extracts of plants from the genus
Hibiscus, giving an overview of the most studied biological effects and the known phytochemical composition. Although more studies are necessary,
Hibiscus spp. exhibits proven potential to become of important pharmacological interest.
Epilepsy is a complex disorder affecting the central nervous system and is characterised by spontaneously recurring seizures (SRSs). Epileptic patients undergo symptomatic pharmacological treatments, ...however, in 30% of cases, they are ineffective, mostly in patients with temporal lobe epilepsy. Therefore, there is a need for developing novel treatment strategies. Transplantation of cells releasing γ-aminobutyric acid (GABA) could be used to counteract the imbalance between excitation and inhibition within epileptic neuronal networks. We generated GABAergic interneuron precursors from human embryonic stem cells (hESCs) and grafted them in the hippocampi of rats developing chronic SRSs after kainic acid-induced status epilepticus. Using whole-cell patch-clamp recordings, we characterised the maturation of the grafted cells into functional GABAergic interneurons in the host brain, and we confirmed the presence of functional inhibitory synaptic connections from grafted cells onto the host neurons. Moreover, optogenetic stimulation of grafted hESC-derived interneurons reduced the rate of epileptiform discharges in vitro. We also observed decreased SRS frequency and total time spent in SRSs in these animals in vivo as compared to non-grafted controls. These data represent a proof-of-concept that hESC-derived GABAergic neurons can exert a therapeutic effect on epileptic animals presumably through establishing inhibitory synapses with host neurons.
Antigen B (EgAgB) is an abundant lipoprotein released by the larva of the cestode Echinococcus granulosus into the host tissues. Its protein moiety belongs to the cestode-specific family known as ...hydrophobic ligand binding protein (HLBP), and is encoded by five gene subfamilies (EgAgB8/1-EgAgB8/5). The functions of EgAgB in parasite biology remain unclear. It may play a role in the parasite's lipid metabolism since it carries host lipids that E. granulosus is unable to synthesise. On the other hand, there is evidence supporting immuno-modulating activities in EgAgB, particularly on innate immune cells. Both hypothetical functions might involve EgAgB interactions with monocytes and macrophages, which have not been formally analysed yet.
EgAgB binding to monocytes and macrophages was studied by flow cytometry using inflammation-recruited peritoneal cells and the THP-1 cell line. Involvement of the protein and phospholipid moieties in EgAgB binding to cells was analysed employing lipid-free recombinant EgAgB subunits and phospholipase D treated-EgAgB (lacking the polar head of phospholipids). Competition binding assays with plasma lipoproteins and ligands for lipoprotein receptors were performed to gain information about the putative EgAgB receptor(s) in these cells. Arginase-I induction and PMA/LPS-triggered IL-1β, TNF-α and IL-10 secretion were examined to investigate the outcome of EgAgB binding on macrophage response.
Monocytes and macrophages bound native EgAgB specifically; this binding was also found with lipid-free rEgAgB8/1 and rEgAgB8/3, but not rEgAgB8/2 subunits. EgAgB phospholipase D-treatment, but not the competition with phospholipid vesicles, caused a strong inhibition of EgAgB binding activity, suggesting an indirect contribution of phospholipids to EgAgB-cell interaction. Furthermore, competition binding assays indicated that this interaction may involve receptors with affinity for plasma lipoproteins. At functional level, the exposure of macrophages to EgAgB induced a very modest arginase-I response and inhibited PMA/LPS-mediated IL-1β and TNF-α secretion in an IL-10-independent manner.
EgAgB and, particularly its predominant EgAgB8/1 apolipoprotein, are potential ligands for monocyte and macrophage receptors. These receptors may also be involved in plasma lipoprotein recognition and induce an anti-inflammatory phenotype in macrophages upon recognition of EgAgB.
PDF
