Cholesterol : its regulation and role in central nervous system disorders

Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer's disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions

Familial association of genetic generalised epilepsy with limb-girdle muscular dystrophy through a mutation in CAPN3

Muscular dystrophies are a heterogeneous group of inherited dis-eases that cause progressive muscle weakness. The association of epi-lepsy with some of these diseases has been previously described andhas most commonly been found for Fukuyama-type muscular dystro-phy due to alterations in cerebral neuronal migration[1]. Among mus-cular dystrophies, limb-girdle muscular dystrophies (LGMDs)represent the fourth most common group, with a prevalence of 1.63per 100, 000 individuals[2]. The diseases in this group share a commonphenotype involving progressive weakness of the scapular and pelvicgirdles that starts after 2 years of age and can be accompanied by differ-ent degrees of elevation in blood creatine kinase (CK) levels and by var-ious anatomic pathologicalfindings. LGMDs are subdivided into LGMD1and LGMD2 depending on whether the inheritance is dominant or re-cessive, respectively. LGMD2A, which is caused by deficiency of thecalpain 3 protein owing to mutations in theCAPN3gene, is the mostcommon form of LGMD in Europe and America[2]. Its associationwith epilepsy has been described in only two isolated cases[1, 3], bothof them on the spectrum of genetic generalised epilepsies (GGEs). Thelatter are the most common group of epilepsies with genetic aetiology, accounting for 15–20% of all epilepsy cases[4]. Nonetheless, none of thegenes usually involved in monogenic epilepsies seem to play a majorrole in GGE, probably indicating a polygenic predisposition to GGE andtherefore a complex inheritance pattern[5]. Here, we describe a family..

Cost-effectiveness of two dry needling interventions for plantar heel pain: A secondary analysis of an rct

Plantar heel pain is a common cause of foot pain that affects patients’ quality of life and represents a significant cost for the healthcare system. Dry needling and percutaneous needle electrolysis are two minimally invasive treatments that were shown to be effective for the management of plantar heel pain. The aim of our study was to compare these two treatments in terms of health and economic consequences based on the results of a published randomized controlled trial. For this, we evaluated the costs from the point of view of the hospital and we carried out a cost-effectiveness study using quality of life as the main variable according to the Eq-5D-5L questionnaire. The cost of the complete treatment with dry needling (DN) was €178.86, while the percutaneous needle electrolysis (PNE) was €200.90. The quality of life of patients improved and was translated into +0.615 quality-adjusted life years (QALYs) for DN and +0.669 for PNE. PNE presented an average incremental cost-effectiveness ratio (ICER) of €411.34/QALY against DN. These results indicate that PNE had a better cost-effectiveness ratio for the treatment of plantar heel pain than DN

Smooth Muscle Cell Phenotypic Switch Induced by Traditional Cigarette Smoke Condensate: A Holistic Overview

Cigarette smoke (CS) is a risk factor for inflammatory diseases, such as atherosclerosis. CS condensate (CSC) contains lipophilic components that may represent a systemic cardiac risk factor. To better understand CSC effects, we incubated mouse and human aortic smooth muscle cells (SMCs) with CSC. We evaluated specific markers for contractile [i.e., actin, aortic smooth muscle (ACTA2), calponin-1 (CNN1), the Kruppel-like factor 4 (KLF4), and myocardin (MYOCD) genes] and inflammatory [i.e., IL-1 beta, and IL-6, IL-8, and galectin-3 (LGALS-3) genes] phenotypes. CSC increased the expression of inflammatory markers and reduced the contractile ones in both cell types, with KLF4 modulating the SMC phenotypic switch. Next, we performed a mass spectrometry-based differential proteomic approach on human SMCs and could show 11 proteins were significantly affected by exposition to CSC (FC >= 2.7, p <= 0.05). These proteins are active in signaling pathways related to expression of pro-inflammatory cytokines and IFN, inflammasome assembly and activation, cy-toskeleton regulation and SMC contraction, mitochondrial integrity and cellular response to oxidative stress, proteostasis control via ubiquitination, and cell proliferation and epithelial-to-mesenchymal transition. Through specific bioinformatics resources, we showed their tight functional correlation in a close interaction niche mainly orchestrated by the interferon-induced double-stranded RNA-activated protein kinase (alternative name: protein kinase RNA-activated; PKR) (EIF2AK2/PKR). Finally, by combining gene expression and protein abundance data we obtained a hybrid network showing reciprocal integration of the CSC-deregulated factors and indicating KLF4 and PKR as the most relevant factors

Human Cancer Cells Signal Their Competitive Fitness Through MYC Activity

MYC-mediated cell competition is a cell-cell interaction mechanism known to play an evolutionary role during development from Drosophila to mammals. Cells expressing low levels of MYC, called losers, are committed to die by nearby cells with high MYC activity, called winners, that overproliferate to compensate for cell loss, so that the fittest cells be selected for organ formation. Given MYC's consolidated role in oncogenesis, cell competition is supposed to be relevant to cancer, but its significance in human malignant contexts is largely uncharacterised. Here we show stereotypical patterns of MYC-mediated cell competition in human cancers: MYC-upregulating cells and apoptotic cells were indeed repeatedly found at the tumour-stroma interface and within the tumour parenchyma. Cell death amount in the stromal compartment and MYC protein level in the tumour were highly correlated regardless of tumour type and stage. Moreover, we show that MYC modulation in heterotypic co-cultures of human cancer cells is sufficient as to subvert their competitive state, regardless of genetic heterogeneity. Altogether, our findings suggest that the innate role of MYC-mediated cell competition in development is conserved in human cancer, with malignant cells using MYC activity to colonise the organ at the expense of less performant neighbours

Hydrogen Motion in Magnesium Hydride by NMR

In coarse-grained MgH2, the diffusive motion of hydrogen remains too slow (<10^5 hops s^−1) to narrow the H NMR line up to 400 °C. Slow-motion dipolar relaxation time T1D measurements reveal the motion, with hopping rate ωH from 0.1 to 430 s^−1 over the range of 260 to 400 °C, the first direct measurement of H hopping in MgH2. The ωH data are described by an activation energy of 1.72 eV (166 kJ/mol) and attempt frequency of 2.5 × 10^15 s^−1. In ball-milled MgH2 with 0.5 mol % added Nb2O5 catalyst, line-narrowing is evident already at 50 °C. The line shape shows distinct broad and narrow components corresponding to immobile and mobile H, respectively. The fraction of mobile H grows continuously with temperature, reaching ∼30% at 400 °C. This demonstrates that this material’s superior reaction kinetics are due to an increased rate of H motion, in addition to the shorter diffusion paths from ball-milling. In ball-milled MgH2 without additives, the line-narrowed component is weaker and is due, at least in part, to trapped H2 gas. The spin−lattice relaxation rates T1^−1 of all materials are compared, with ball-milling markedly increasing T1^−1. The weak temperature dependence of T1^−1 suggests a mechanism with paramagnetic relaxation centers arising from the mechanical milling

Immersive virtual reality and antigravity treadmill training for gait rehabilitation in Parkinson’s disease: A pilot and feasibility study

Introduction. Treadmill training is considered an effective intervention to improve gait ability in patients with Parkinson’s disease (PD). In parallel, virtual reality shows promising intervention with several applications in the inpatient medical setting. Aim. To evaluate the feasibility and preliminary efficacy of mechanical gait assistance combined with immersive virtual reality in patients with PD. Patients and methods. This pilot and feasibility study followed a pre-post study design. The intervention consisted of 12 sessions of 30 minutes, distributed regularly over four consecutive weeks. Participants walked on a treadmill with a body- weight support system set at approximately 20% of body weight and equipped with a virtual reality helmet controlled by a two-handed joystick. Feasibility and intervention outcomes were collected at baseline and after four weeks of intervention. Results. Twelve participants of 60 patients were finally enrolled. Nine of them (75%) completed the treatment intervention with an adherence rate of 97%. Two participants left the study, one of them due to sickness associated with virtual reality and another because of a lack of motivation. There were significant differences associated with small-medium effect sizes when comparing the pre and post values for walk distance, walk speed, balance, and quality of life. Conclusions. The present study provided preliminary evidence supporting the feasibility of the combination of antigravity treadmill and immersive virtual reality system for the rehabilitation of patients with PD

Methylene blue? Therapeutic alternative in the management of septic shock refractory to norepinephrine

Introduction: Methylene blue is receiving special interest in perioperative and intensive care of patients with distributive shock due to its ability to block the action of nitric oxide and to antagonize deep vasodilation. Objective: The objective is to illustrate the use of the methylene blue, summarizing the perioperative management of a case with secondary vasoplegic syndrome due to a norepinephrine refractory septic shock and the response to methylene blue, reviewing the latest evidence of this therapeutic alternative. In practice:We describe the case of a 60-year-old man, paraplegic, with septic shock due to a long evolution decubitus pressure ulcer. After two hours of surgery, the patient remained with hemodynamic deterioration despite high doses of vasopressin (3 IU/hour) and norepinephrine (2 µg/kg /min), therefore methylene blue was administered with two intravenous bolus doses of 50 mg without adverse effects. After half an hour hemodynamic improvement was evidenced, allowing to decrease norepinephrine infusion and normalizing blood pressure. Finally, debridement of necrotic tissue, amputation and disarticulation of left coxofemoral joint was performed with subsequent transfer to the ICU and discharge to the spinal cord injury ward twenty eight days later. Conclusions: As it has been demonstrated in our patient, methylene blue is a therapeutic alternative to manage patients with persistent hypotension despite the use of various vasopressors during the management of vasoplegic syndrome secondary to septic shock

Epilepsy in elderly patients: does age of onset make a difference?

Introduction: Epilepsy is most frequent in children and elderly people. Today\u27s population is ageing and epilepsy prevalence is increasing. The type of epilepsy and its management change with age. Methods: We performed a retrospective, observational study comparing patients aged ≥ 65 years with epilepsy diagnosed before and after the age of 65, and describing epilepsy characteristics and comorbidities in each group. Results: The sample included 123 patients, of whom 61 were diagnosed at \u3c 65 years of age (group A), 62 at ≥ 65 of age (group B). Sex distribution was similar in both groups, with 39 men (62.9%) in group A and 37 (60.7%) in group B. Mean age was 69.97 ± 5.6 years in group A and 77.29 ± 6.73 in group B. The most common aetiology was unknown in group A (44.3%, n = 27) and vascular in group B (74.2%, n = 46). History of stroke was present in 12 patients from group A (19.7%) and 32 (51.6%) in group B. Antiepileptic drugs were prescribed at lower doses in group A. Statistically significant differences were found between groups for history of ischaemic stroke, cognitive impairment, psychiatric disorders, and diabetes mellitus; degree of dependence; and number of antiepileptic drugs. Conclusion: Age of onset ≥ 65 years is closely related to cardiovascular risk factors; these patients require fewer antiepileptic drugs and respond to lower doses. Some cases initially present as status epilepticus