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Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.
The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada.
The response of chronic inflammatory demyelinating polyneuropathy (CIDP) to intravenous immunoglobulins (IVIgs) treatment is well established. However, it remains unclear whether patients not responding to two IVIg treatments or those whose condition stabilizes (ICE trial) may benefit from additional doses. We aim to identify the time period required to reach maximal strength gains from IVIg treatment.
Retrospective chart review of 14 patients with CIDP was performed. Change in handgrip (HG), Knee extension (KE), elbow flexion, and dorsiflexion was analyzed with a dynamometer during IVIg therapy. Strength improvements in Nm or kg, cumulative grams (g) of IVIg, and time in days required for maximal strength recovery were determined per function (± standard error of the mean). Ancillary therapy was recorded for all patients.
Improvements in strength of each function were significant (p < 0.05). Earliest improvement was in HG (137.07 ± 21.23) and latest in KE (238.15 ± 38.9). Majority of patients improved by 200 days of therapy. HG required the lowest cumulative grams of IgG (561.71 ± 97.21) and KE the most (798 ± 120.7).
Our study has demonstrated the effectiveness of multiple treatments with IVIg to reach significant improvement in strength. Different muscle groups manifested different time dependency, reflecting the requirement of variable amounts of IVIg. Improvement was identified on an ongoing basis, with therapy lasting between 20.2 and 37.3 weeks, requiring between 562 and 798 g of IVIg.
The fate of field-applied herbicides, including losses in surface runoff with water and sediment, is highly dependent on herbicide properties. The two most important properties are soil adsorption and persistence. Adsorption affects the potential for a herbicide to be lost primarily with sediment, runoff water, or possibly leaching water. Solubility, often though not always inversely correlated with adsorption, is of secondary importance, although low solubility can limit transport with water. Persistence affects the time available to be lost in runoff. Studies have shown that for soil-applied herbicides; extraction into runoff water or movement with sediment takes place from a thin soil layer at the surface. In addition, for herbicides studied, there is little interaction between surface crop residue and applied herbicides, and washoff from the residue readily occurs with small amounts of rainfall. Runoff loss equals the volume of carrier (water or sediment) times the concentration in that carrier; therefore, practices that reduce either, or both, can reduce losses. Rate of application has been directly related to concentration and therefore loss. Reducing rate, such as by banding, soil incorporation, and avoidance of application to crop residue reduce losses. The choice of herbicide and herbicide formulation, in conjunction with application technology, as they affect properties, rate, and placement, play a large role in determining runoff loss. Runoff losses of herbicides that are strongly adsorbed and therefore transported mainly with sediment can be reduced by erosion control; runoff volume reduction can reduce losses with water of moderately to weakly adsorbed herbicides. Conservation tillage has potential to reduce both runoff and erosion. Timing of application relative to expected intense storms, both in the short and long term, can reduce the potential for runoff. If possible to determine thresholds, herbicide use could be avoided if weed infestation is below the economic effect level. Buffer or filter strips have the potential to reduce transport of herbicides lost from fields to surface water resources.
The statins have emerged as the dominant class of drug for the treatment of hypercholesterolemia. These medications are generally well tolerated. However, myalgias, the most frequent side-effect, occur in up to 7% of patients. Transaminitis and skeletal myotoxicity, with elevated serum creatine kinase (CK) levels (i.e., >10 times the upper limit of normal), occur with reported frequencies of 1% and 0.1%, respectively. Various hypotheses have been proposed to explain the relationship between statin therapy and the spectrum of muscle dysfunction manifested by myalgia, myopathy, and rhabdomyolysis.
Statin-mediatd inhibition of mevalonate metabolism impairs the synthesis of isoprenylated products–the most notable of which is ubiquinone. However, isoprenylation is responsible for the post-translational modification of up to 2% of cellular proteins. Therefore, numerous metabolic pathways are potentially modified by statin-mediated hypoprenylation. Subclinical defects in one or more energy-deriving pathways may be unmasked upon exposure to the pleotropic effects of statins. Such pharmacogenomic synergism may underlie the development of “statin myopathy” in a subset of patients. In this regard, we describe four patients with mutations in the myophosphorylase (PYGM; MIM 232600), myoadenylate deaminase (AMPD1; MIM 102770), and carnitine palmitoyltransferase (CPT2; MIM 600650) genes whose diagnoses became apparent during the course of investigations for statin-induced myalgias and hyperCKemia.
Sympathomimetic-related intracerebral hemorrhage is well-documented. Most cases are associated with phenylpropanolamine use.
We report a case of intracerebral hemorrhage occurring in a middle-aged man who suffered from chronic sinusitis and had been ingesting pseudoephedrine daily for one year. This patient was previously well with no known cardiovascular risk factors. Clinical examination revealed no evidence of vasculitis nor coagulopathy and initial neuroimaging (i.e., computed tomography, angiography, magnetic resonance imaging) demonstrated no features consistent with aneurysm, arteriovenous malformation (AVM), cavernoma, nor cerebral metastases. A follow-up cerebral angiogram demonstrated a small AVM arising off a branch of the pericallosal artery and a small arteriovenous fistula arising off the costal marginal branch. The AVM was embolized without incident, however, the AVF was not accessible.
Sympathomimetics have long been associated with intracerebral hemorrhage. Since 1979, over 30 published case reports have documented the relationship between phenylpropanolamine and stroke. Only one report links phenylpropanolamine consumption to an intracerebral hemorrhage in a patient with an AVM. There is a paucity of literature etiologically inculpating other ephedra alkaloids in the causation of intracerebral hemorrhage. This is a case of pseudoephedrine-induced intracerebral hemorrhage in a patient with an underlying vascular malformation.
Approximately 95% of statin-treated patients tolerate this form of cholesterol management without any adverse effects. However, given their efficacy in reducing low density lipoproteins and cardiovascular events large numbers of patients are selected for statin therapy. Therefore muscle complications are, in fact, quite common. Limited understanding of the underlying pathophysiology has hampered physicians' ability to identify patients at risk for developing statin myotoxicity. A growing number of published case reports/series have implicated statins in the exacerbation of both acquired and genetic myopathies. A clinical management algorithm is presented which outlines a variety of co-morbidities which can potentiate the adverse effects of statins on muscle. In addition, a rational approach to the selection of those patients most likely to benefit from skeletal muscle biopsy is discussed. Ongoing work will define the extent to which statin-intolerant patients represent carriers of recessive metabolic myopathies or pre-symptomatic acquired myopathies. The expanding importance of pharmacogenomics will undoubtedly be realized in the field of statin myopathy research within the next few years. Such critical information is needed to establish more definitive management and diagnostic strategies.
Statins have recently been reported to cause a rare autoimmune inflammatory and/or necrotic myopathy that begins or persists after drug cessation.
We report on 26 patients seen at a neuromuscular centre between 2005 and 2011 who demonstrated muscle weakness/myalgias and creatine kinase elevations during or after statin treatment with continuation of signs and symptoms despite statin withdrawal.
All patients were treated with immunosuppressive therapy with good response; all improved biochemically and 86% improved clinically. Sixty-five percent of patients who attempted to taper off immunosuppressive therapy relapsed. We report on a novel finding whereby five of the seven patients who underwent multiple biopsies throughout their disease demonstrated a transformation of their histological diagnosis, with four progressing from having myofibre necrosis with minimal or no inflammation to a diagnosis of polymyositis.
This study offers preliminary evidence that statin-associated necrotizing myopathy and statin-associated polymyositis may not be separate entities but are part of the same pathophysiological spectrum. Both entities respond well to immunosuppression.
Dihydrohpoamide acetyl transferase (E2), a catalytic and structural component of a multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate, forms the central core to which the other components are bound. We have utilized protein engineering and 3-D electron microscopy to study the structural organization of the largest multienzyme complex known (Mr ∼ 107). The structures of the truncated 60-mer core (tE2) and complexes of the tE2 associated with a binding protein (BP), and the BP associated with its dihydrohpoamide dehydrogenase (BP'E3) and the intact E2 associated with BP and the pyruvate dehydrogenase (E1) were determined (Figs. 1 and 2). The tE2 core is a pentagonal dodecahedron consisting of 20 cone-shaped trimers interconnected by 30 bridges.
Previous studies have given rise to the generally accepted belief that BP and BP'E3 components are bound on the outside of the E2 scaffold and that E1 is similarly bound to the core in variable positions by flexible tethers.
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