Ingramhoward7460
Plants and microbes coinhabit the earth and have coevolved during environmental changes over time. Root metabolites are the key to mediating the dynamic association between plants and microbes, yet the underlying functions and mechanisms behind this remain largely illusive. Knowledge of metabolite-mediated alteration of the root microbiota in response to environmental stress will open avenues for engineering root microbiotas for improved plant stress resistance and health. Here, we synthesize recent advances connecting environmental stresses, the root metabolome and microbiota, and propose integrated synthetic biology-based strategies for tuning the plant root metabolome in situ for microbe-assisted stress resistance, offering potential solutions to combat climate change. The current limitations, challenges and perspectives for engineering the plant root metabolome for modulating microbiota are collectively discussed.
QT prolongation and intracellular Ca
loading with diastolic Ca
release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia-induced ventricular arrhythmia. We investigated the antiarrhythmic actions of two RyR2 inhibitors dantrolene and VK-II-86, a carvedilol analogue lacking antagonist activity at β-adrenoceptors, in hypokalaemia.
Surface ECG and ventricular action potentials (APs) were recorded from whole-heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K
], and those pretreated with dantrolene or VK-II-86. Whole-cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK-II-86 on AP parameters in low [K
] and effects of VK-II-86 on the inward rectifier current (I
), late sodium current (I
) and the L-type Ca
current (I
). Effects of VK-II-86 on I
were investigated in transfected HEK-293 cells. A fluorogenic probe quantified the effectload.The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non-pharmacological pain relief is advocated by the US-NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation-induced analgesia is also discussed.In the retina, the mineralocorticoid receptor is expressed in retinal and choroidal vessels and in cells from neural and glial origins. Like in the brain, the major ligand of the mineralocorticoid receptor is cortisol, and the mineralocorticoid/glucocorticoid receptor balance regulates the activation of the MR pathway. Experimental mineralocorticoid receptor pathway activation using either pharmacological agents or transgenic manipulation favours retinal and choroidal pathology. In various models of retinal diseases, such as glaucomatous neuropathy, retinopathy of prematurity, ischaemic retinopathies, diabetic retinopathy and choroidal neovascularization, mineralocorticoid receptor antagonism exerts beneficial effects, demonstrating its potential in the treatment of major blinding retinal diseases. But specific formulations are required to optimize the bioavailability of mineralocorticoid receptor antagonists in various compartments of the eye, and molecular biomarkers of mineralocorticoid receptor pathway activation remain to be identified in humans to select patients amenable to clinical trials.
To evaluate the changes in prescription patterns in the treatment of idiopathic generalized epilepsy (IGE) due to updated treatment recommendations and to assess seizure outcomes of valproate compared to other antiseizure medications (ASMs), with emphasis on women with epilepsy (WWE).
Records of IGE patients treated at Tampere University Hospital between 1January 2009 and 31 December 2018 were retrospectively inspected. Data were analysed for two subgroups based on age and sex. Seizure control with reference to the efficacy of different ASMs and their combinations was examined for each subgroup.
The study compiled 263subjects (166 females and 97males). Of all patients, 72.6% remained seizure free. There was no difference in seizure control between sexes (OR 1.25, p=.48). Males used valproate more often than females while females used lamotrigine and levetiracetam more often than males. Lamotrigine and levetiracetam were used especially as monotherapy in WWE, and mostly as part of combination therapy in py.
Mitochondrial DNA (mtDNA)-associated Leigh syndrome (LS) is characterized by maternal inheritance, and the heteroplasmic mutant load of mtDNA pathogenic variants is known to affect clinical phenotypes. Among mtDNA pathogenic variants, variants of the MT-ATP6gene account for most of reported cases. In this report, we aimed to describe the clinical and genetic findings of MT-ATP6-associated LS patients diagnosed at a single tertiary institution in Korea.
Thirteen patients with genetically confirmed MT-ATP6-associated LS were selected. We reviewed each patient's clinical findings, including general characteristics, biochemical parameters, brain MR images, muscle biopsy results, and heteroplasmic mutant load over a long-term follow-up period.
MT-ATP6-associated LS was of predominantly early onset (age <2years), although we identified 2late-onset (>60months) LS patients. The heteroplasmic mutant load estimated by next-generation sequencing was 96%-100% in all nucleotide change groups. Compared with other forms of MT-ATP6-associated LS, the m.8993T>G point mutation elicited a significantly higher rate of symptom onset before 2years of age. Brain MRI showed bilateral basal ganglia involvement in all patients, followed by cerebral atrophy, brainstem and thalamus involvement, and cerebellar atrophy. After follow-up (median 7.2years, range 1.4 to 11.5years), LS with m.8993T>G point mutations had a slightly more severe clinical progression compared with other forms of MT-ATP6-associated LS.
MT-ATP6-associated LS patients presented with a broad spectrum of clinical diagnoses and had a very high heteroplasmic mutant load. This study provides valuable data on MT-ATP6-associated LS that will inform subsequent studies on LS.
MT-ATP6-associated LS patients presented with a broad spectrum of clinical diagnoses and had a very high heteroplasmic mutant load. This study provides valuable data on MT-ATP6-associated LS that will inform subsequent studies on LS.
We are living in the time of greatest dissemination of information in the history of the human race, and this excess of information has resulted in considering human attention as a scarce resource. selleck chemical Information overload is the situation in which the amount or intensity of information exceeds the individual's limited capacity for cognitive processing.
To describe the concept of information overload, its possible neurocognitive substrates, associated symptoms, causes, measures to avoid it, as well as its possible relationship with the internet and electronic devices.
People respond differently to information overload, and this depends on individual factors as well as on the amount and characteristics of the informative stimulation. Some symptoms of information overload are inefficient work, confusion, delay in making decisions, lack of critical evaluation of information, loss of control over information, refusal to receive communication, lack of general perspective, greater tolerance for error, anxiety, stress, etc. The limits of information processing capacity are probably conditioned by the limited metabolic energy that is distributed in the brain and remains constant regardless of the difficulty of the tasks.
Attention is a limited cognitive function. In order to reduce the adverse effects of information overload, it is necessary to improve the personal management of our own cognitive resources and to understand their relationship with technology. Likewise, it is necessary to improve the handling of information through the organization, filtering and application of cognitive ergonomics design guidelines.
Attention is a limited cognitive function. In order to reduce the adverse effects of information overload, it is necessary to improve the personal management of our own cognitive resources and to understand their relationship with technology. Likewise, it is necessary to improve the handling of information through the organization, filtering and application of cognitive ergonomics design guidelines.
Rituximab (RTX) is an anti-CD20 monoclonal antibody that has been used in cases of refractory myasthenia gravis (MG). The aim of this work is to analyse the efficacy and safety of RTX in MG in real clinical practice in a tertiary hospital.
A retrospective study was conducted with patients with MG treated with RTX in our centre from March 2014 to September 2020. Demographic and serological data, together with information about previous immunomodulatory treatment, clinical response and adverse effects are collected.
Twenty patients with MG - 100% generalised 70% late-onset MG (LOMG) and 30% early-onset MG (EOMG) - were given RTX (mean age 66.8 years; 70% male). A total of 90% are seropositive, 16 of them with positive anti-acetylcholine receptor antibodies and two with positive muscle-specific tyrosine kinase (anti-MuSK) antibodies. All had failed previous treatments 100% with steroids, 100% with intravenous immunoglobulins and/or plasmapheresis, 55% with other immunosuppressants (25% with one previous immunosuppressant, 10% with two, 15% with three and 5% with four) and 35% with thymectomy. After RTX, 75% of patients showed a clinical response (12 patients with complete remission and the possibility of steroid withdrawal without recurrence; and three patients with partial remission and the possible reduction of steroid dosage) and 25% therapeutic failure; in all these cases RTX was withdrawn. All the anti-MuSK+ patients (100%) and 92.8% of the LOMG patients responded to RTX, while 66% of EOMG patients failed. Only three patients reported adverse effects, all of which were mild and did not require RTX withdrawal.
In our experience, rituximab is a safe and effective treatment in aggressive generalised MG with anti-MuSK or late-onset MG (LOMG).
In our experience, rituximab is a safe and effective treatment in aggressive generalised MG with anti-MuSK or late-onset MG (LOMG).
There is currently no cure for dementia and its prevention is considered to be crucial. The aim is to analyse the association between risk factors and dementia, and how this varies according to age and sex.
This cross-sectional study includes 1,048,956 people aged 65 and over. Data were obtained from the SIDIAP pseudonymised clinical database. The response variable was dementia and cases were identified using a validated algorithm. Exposure to the following risk factors was assessed smoking, coronary heart disease, cerebrovascular disease, heart failure, peripheral arterial disease, alcoholism, high blood pressure, hyperlipidaemia, diabetes, hyperthyroidism, Parkinson's disease, depressive disorder and rurality. Logistic regression models were estimated to assess the association between risk factors and dementia, and they were stratified by age, sex and both jointly.
The association between a medical history of cerebrovascular disease, Parkinson, depressive disorder or hyperthyroidism and dementia was more pronounced in men.
