Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids are extremely effective anti-inflammatory therapies, but their clinical use is limited due to severe side effects, including osteoporosis, muscle wasting, fat redistribution, and skin thinning. Here we use heavy water labeling and mass spectrometry to measure fluxes through metabolic pathways impacted by glucocorticoids. We combine these methods with measurements of body composition in corticotropin-releasing hormone (CRH)-transgenic (Tg)(+) mice that have chronically elevated, endogenously produced corticosterone and a phenotype that closely mimics Cushing's disease in humans. CRH-Tg(+) mice had increased adipose mass, adipose triglyceride synthesis, and greatly increased triglyceride/fatty acid cycling in subcutaneous and abdominal fat depots and increased de novo lipogenesis in the abdominal depot. In bone, CRH-Tg(+) mice had decreased bone mass, absolute collagen synthesis rates, and collagen breakdown rate. In skin, CRH-Tg(+) mice had decreased skin thickness and absolute collagen synthesis rates but no decrease in the collagen breakdown rate. In muscle, CRH-Tg(+) mice had decreased muscle mass and absolute protein synthesis but no decrease in the protein breakdown rate. We conclude that chronic exposure to endogenous glucocorticoid excess in mice is associated with ongoing decreases in bone collagen, skin collagen, and muscle protein synthesis without compensatory reduction (coupling) of breakdown rates in skin and muscle. Both of these actions contribute to reduced protein pool sizes. We also conclude that increased cycling between triglycerides and free fatty acids occurs in both abdominal and subcutaneous fat depots in CRH-Tg(+) mice. CRH-Tg mice have both increased lipolysis and increased triglyceride synthesis in adipose tissue.
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PMID:Large increases in adipose triacylglycerol flux in Cushingoid CRH-Tg mice are explained by futile cycling. 2321 15

Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to -a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1-/-), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1-/- mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1-/- mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1-/- mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1-/- and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1-/- mice.
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PMID:The lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice. 2497 50

Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome.
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PMID:Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia. 2658 3

SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the 'ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature.
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PMID:Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia. 2731 63

We herein report the case of a 54-year-old man who abused toluene for 25 years and gradually developed gait disturbance. Neurological findings showed mild cognitive impairment, hearing impairment, dysarthria, marked hyperreflexia of the limbs, spastic paraplegia, slight impairment of deep sensation, and urinary disturbance; however, there was no muscular atrophy. Serum antibodies against human T-lymphocytic virus 1 and aquaporin 4 were negative. Biochemical analysis did not show an increase in very-long-chain fatty acids. The cerebrospinal fluid was normal for the cell number and protein level but positive for oligoclonal IgG band, with a mildly increased IgG index. Brain MRI showed marked high intensity in the bilateral periventricular, deep cerebral and subcortical white matter as well as atrophy of the cerebrum, cerebellum and brainstem, and thinning of the corpus callosum. Spinal MRI showed marked atrophy of the lower cervical spinal cord, thoracic spinal cord, and conus medullaris. Spinal cord lesions are extremely rare in chronic toluene intoxications, and there are no reports of spinal cord atrophy. Lateral and ventral columns of the spinal cord are responsible for pyramidal tract signs, and insidious ongoing inflammation related to chronic toluene intoxication in the central nervous system is predicted to underlie the pathogenesis.
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PMID:[Generalized spinal cord atrophy and oligoclonal IgG band in the cerebrospinal fluid due to chronic toluene intoxication: a case report]. 3223 42

Inadequate thickness of subcutaneous tissue, pectoralis muscle wasting, and/or a lack of availability of subpectoral space can become significant issues in patients with or requiring cardiovascular implantable electronic devices (CIEDs). This is particularly concerning but not exclusive in the elderly population, who may experience discomfort and hypersensitivity of the site as well as the potential for erosion and an increased risk of infection. Thus, the use of an alternative location, the axillary fossa, offers several advantages that make it a suitable option. Specifically, it usually has a preserved fat pad (even in thin patients); is unperturbed by arm movement; is not directly exposed to contact; is easily accessed with no significant compromise of neurovascular structures; and is near the conventional subclavicular sites, with enough lead length to reach in case of the need for generator replacement. Here, we present a series of five patients, including details of their anatomy and the implant techniques used. Two underwent device replacements, with one of them presenting with significant ongoing site discomfort and the other with extreme tissue thinning, respectively. Two patients with no significant fat layer or pectoral muscle wasting had new pacemakers implanted. Lastly, a biventricular implantable cardioverter-defibrillator generator was reimplanted in a younger patient who had issues with protrusion and discomfort in the setting of thin subcutaneous tissue and the subpectoral space being occupied by a large breast implant. In conclusion, the use of the axillary fossa as a new alternative CIED implantation site, using the proposed implant technique, appears feasible and safe and demonstrated excellent results related to patient comfort and adequate device cover in five cases.
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PMID:The Axillary Fossa: An Uncovered Hidden Site as a New Alternative for Cardiac Pacemaker and Defibrillator Implantation. 3249 79

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology. This article is protected by copyright. All rights reserved.
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PMID:Advanced cancer is also a heart failure syndrome - an hypothesis. 3324 8


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