Background & Aims Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver ...disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. Methods This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N = 50) and after leptin replacement (N = 27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy. Results In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 ± 3.7 months (mean ± SE, p = 0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score ( p <0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. Conclusions The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients.
•We propose a data-driven framework to analyze cerebro-spinal fMRI signals.•This approach disentangles activity into well-delineated, functionally relevant signatures.•We demonstrate its potential in ...the context of motor sequence learning.•We uncover cerebral and spinal networks that can be used to accurately decode learning stages.•This versatile approach can be readily extended to other facets of human behavior.
Mapping the neural patterns that drive human behavior is a key challenge in neuroscience. Even the simplest of our everyday actions stem from the dynamic and complex interplay of multiple neural structures across the central nervous system (CNS). Yet, most neuroimaging research has focused on investigating cerebral mechanisms, while the way the spinal cord accompanies the brain in shaping human behavior has been largely overlooked. Although the recent advent of functional magnetic resonance imaging (fMRI) sequences that can simultaneously target the brain and spinal cord has opened up new avenues for studying these mechanisms at multiple levels of the CNS, research to date has been limited to inferential univariate techniques that cannot fully unveil the intricacies of the underlying neural states. To address this, we propose to go beyond traditional analyses and instead use a data-driven multivariate approach leveraging the dynamic content of cerebro-spinal signals using innovation-driven coactivation patterns (iCAPs). We demonstrate the relevance of this approach in a simultaneous brain-spinal cord fMRI dataset acquired during motor sequence learning (MSL), to highlight how large-scale CNS plasticity underpins rapid improvements in early skill acquisition and slower consolidation after extended practice. Specifically, we uncovered cortical, subcortical and spinal functional networks, which were used to decode the different stages of learning with a high accuracy and, thus, delineate meaningful cerebro-spinal signatures of learning progression. Our results provide compelling evidence that the dynamics of neural signals, paired with a data-driven approach, can be used to disentangle the modular organization of the CNS. While we outline the potential of this framework to probe the neural correlates of motor learning, its versatility makes it broadly applicable to explore the functioning of cerebro-spinal networks in other experimental or pathological conditions.
Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO ...synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow, but the molecular mechanisms that transduce mechanical force to eNOS activation are not well understood. In this study, we found that laminar flow (shear stress=12 dyne/cm2) rapidly activates vascular endothelial growth factor receptor 2 (VEGFR2) in a ligand-independent manner and leads to eNOS activation in cultured endothelial cells. Flow-stimulated VEGFR2 recruits phosphoinositide 3-kinase and mediates activation of Akt and eNOS. Inhibiting VEGFR2 kinase with selective inhibitors blocks flow-induced activation of Akt and eNOS and production of NO. Decreasing VEGFR2 expression with antisense VEGFR2 oligonucleotides significantly attenuates activation of Akt and eNOS. Furthermore, Src kinases are involved in flow-stimulated VEGFR2 because inhibiting Src kinases by PP2, a selective inhibitor for Src kinases, abolishes flow-induced VEGFR2 tyrosine phosphorylation and downstream signaling. Finally, we show that inhibiting VEGFR2 kinase significantly reduces flow-mediated NO-dependent arteriolar dilation in vivo. These data identify VEGFR2 as a key mechanotransducer that activates eNOS in response to blood flow.
•Behavioral determinants and neural correlates of motor sequence learning.•Advances in methodological approaches and neuroimaging data analyses.•Motor sequence acquisition and consolidation in ...healthy and clinical populations.•Current challenges in the development of non-invasive clinical interventions.
The learning of sequential motor behaviors involves the integration of separate movements into a unified and coordinated sequence of actions through practice. Neuroimaging studies in humans strongly suggest that this form of procedural memory relies on the progressive reorganization of motor-related neural networks over the course of learning. This experience-driven reorganization of internal task representations is also subserved by consolidation processes that require time, and sometimes sleep, to become effective, hence constituting the mechanism by which long-term memory of the skill is achieved. In this review, we present the current understanding of the behavioral determinants, brain functional plasticity and neurophysiological processes related to the formation and long-term retention of motor sequence knowledge. Insights from clinical research and their practical implications, with the development of non-invasive and patient-oriented interventions, are also discussed.
AIMS: Rice (Oryza sativa L.), wheat (Triticum aestivum L.) and common bean (Phaseolus vulgaris L.) are major staple food crops consumed worldwide. Zinc (Zn) deficiency represents a common ...micronutrient deficiency in human populations, especially in regions of the world where staple food crops are the main source of daily calorie intake. Foliar application of Zn fertilizer has been shown to be effective for enriching food crop grains with Zn to desirable amounts for human nutrition. For promoting adoption of this practice by growers, it is important to know whether foliar Zn fertilizers can be applied along with pesticides to wheat, rice and also common bean grown across different soil and environmental conditions. METHODS: The feasibility of foliar application of zinc sulphate (ZnSO₄.7H₂O) to wheat, rice and common bean in combination with commonly used five fungicides and nine insecticides was investigated under field conditions at the 31 sites-years of seven countries, i.e., China, India, Pakistan, Thailand, Turkey, Brazil and Zambia. RESULTS: Significant increases in grain yields were observed with foliar Zn/foliar Zn + pesticide (5.2–7.7 % of wheat and 1.6–4.2 % of rice) over yields with no Zn treatment. In wheat, as average of all experiments, higher grain Zn concentrations were recorded with foliar Zn alone (41.2 mg kg⁻¹) and foliar Zn + pesticide (38.4 mg kg⁻¹) as compared to no Zn treatment (28.0 mg kg⁻¹). Though the magnitude of grain Zn enrichment was lesser in rice than wheat, grain Zn concentrations in brown rice were significantly higher with foliar Zn (24.1 mg kg⁻¹) and foliar Zn + pesticide (23.6 mg kg⁻¹) than with no Zn (19.1 mg kg⁻¹). In case of common bean, grain Zn concentration increased from 68 to 78 mg kg⁻¹ with foliar Zn alone and to 77 mg kg⁻¹ with foliar Zn applied in combination with pesticides. Thus, grain Zn enrichment with foliar Zn, without or with pesticides, was almost similar in all the tested crops. CONCLUSIONS: The results obtained at the 31 experimental site-years of seven countries revealed that foliar Zn fertilization can be realized in combination with commonly-applied pesticides to contribute Zn biofortification of grains in wheat, rice and common bean. This agronomic approach represents a useful practice for the farmers to alleviate Zn deficiency problem in human populations.
•Three months of aerobic exercise training (AET) improves fitness in PD patients.•Effects of AET on cognitive and motor skills in PD were evaluated concurrently.•Some executive functions and ...procedural learning capacity improved after AET.•AET can be used as a non-pharmacological intervention to improve functioning in PD.
Background: Aerobic exercise training (AET) has been shown to provide health benefits in individuals with Parkinson’s disease (PD). However, it is yet unknown to what extent AET also improves cognitive and procedural learning capacities, which ensure an optimal daily functioning. Objective: In the current study, we assessed the effects of a 3-month AET program on executive functions (EF), implicit motor sequence learning (MSL) capacity, as well as on different health-related outcome indicators. Methods: Twenty healthy controls (HC) and 19 early PD individuals participated in a supervised, high-intensity, stationary recumbent bike-training program (3 times/week for 12weeks). Exercise prescription started at 20min (+5min/week up to 40min) based on participant’s maximal aerobic power. Before and after AET, EF tests assessed participants’ inhibition and flexibility functions, whereas implicit MSL capacity was evaluated using a version of the Serial Reaction Time Task. Results: The AET program was effective as indicated by significant improvement in aerobic capacity in all participants. Most importantly, AET improved inhibition but not flexibility, and motor learning skill, in both groups. Conclusion: Our results suggest that AET can be a valuable non-pharmacological intervention to promote physical fitness in early PD, but also better cognitive and procedural functioning.
Aerobic exercise training (AET) has been shown to provide general health benefits, and to improve motor behaviours in particular, in individuals with Parkinson's disease (PD). However, the influence ...of AET on their motor learning capacities, as well as the change in neural substrates mediating this effect remains to be explored.
In the current study, we employed functional Magnetic Resonance Imaging (fMRI) to assess the effect of a 3-month AET program on the neural correlates of implicit motor sequence learning (MSL).
20 healthy controls (HC) and 19 early PD individuals participated in a supervised, high-intensity, stationary recumbent bike training program (3 times/week for 12 weeks). Exercise prescription started at 20 min (+ 5 min/week up to 40 min) based on participant's maximal aerobic power. Before and after the AET program, participants' brain was scanned while performing an implicit version of the serial reaction time task.
Brain data revealed pre-post MSL-related increases in functional activity in the hippocampus, striatum and cerebellum in PD patients, as well as in the striatum in HC individuals. Importantly, the functional brain changes in PD individuals correlated with changes in aerobic fitness: a positive relationship was found with increased activity in the hippocampus and striatum, while a negative relationship was observed with the cerebellar activity.
Our results reveal, for the first time, that exercise training produces functional changes in known motor learning related brain structures that are consistent with improved behavioural performance observed in PD patients. As such, AET can be a valuable non-pharmacological intervention to promote, not only physical fitness in early PD, but also better motor learning capacity useful in day-to-day activities through increased plasticity in motor related structures.
Background: Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe ...acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success.
Methods: We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment.
Results: All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events.
Conclusions: In seven patients with type B insulin resistance, standardized treatment with rituximab, cyclophosphamide, and pulse steroids results in remission of the disease. Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.
A standardized therapeutic protocol of rituximab, cyclophosphamide, and pulse steroids results in remission from type B insulin resistance.
Cyclophilin A (CyPA) is an abundant intracellular protein that is considered to be the main target of the immunosuppressive drug cyclosporine A. We and others showed that CyPA is secreted from smooth ...muscle cells and macrophages in response to oxidative stress and lipopolysaccharide, suggesting a role for CyPA in inflammation. We therefore studied the proinflammatory effects of CyPA on vascular endothelium.
Because atherosclerosis is an inflammatory disease, we studied expression of CyPA in atherosclerotic plaques from the ApoE-/- mouse. Using immunohistochemistry, we showed that CyPA was highly expressed in these plaques. Because endothelial cells (EC) are important mediators of inflammation, we next studied the ability of CyPA to activate EC. Human recombinant CyPA activated mitogen-activated protein kinases, including ERK1/2, JNK, and p38 in cultured human umbilical vein EC. CyPA also stimulated IkappaB-alpha phosphorylation and NF-kappaB activation, and induced expression of adhesion molecules including E-selectin and vascular cell adhesion molecule-1. Furthermore, the combination of CyPA and cycloheximide induced EC apoptosis similar to the proapoptotic effect of tumor necrosis factor-alpha.
Our data indicate that CyPA has proinflammatory effects on EC and may play an important role in the pathogenesis of inflammatory diseases, such as atherosclerosis.
Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO ...synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae. Exposure of cultured bovine aortic endothelial cells to 1 mum CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress=dynes/cm2). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A, because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo, CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect was similar to that of beta-cyclodextrin, a cholesterol-binding molecule, and beta-cyclodextrin had a similar inhibitory effect on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 mug/ml cholesterol blocked the CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension.
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