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Diabetic neuropathy includes various types of nerve damage associated with diabetes mellitus. The most common form,diabetic peripheral neuropathy,affects 30% of all diabetic patients. Symptoms depend on the site of nerve damage and can include motor changes such as weakness;sensory symptoms such as numbness,tingling,or pain;or autonomic changes such as urinary symptoms. These changes are thought to result from a microvascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic neuropathy include distal symmetric polyneuropathy;third,fourth,or sixth cranial nerve palsy;mononeuropathy;mononeuropathy multiplex;diabetic amyotrophy;and autonomic neuropathy.
Amyloidosis is a group of diseases in which abnormal proteins,known as amyloid fibrils,build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue,peripheral edema,weight loss,shortness of breath,palpitations,and feeling faint with standing. In AL amyloidosis,specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis,non-cardiac symptoms include:bilateral carpal tunnel syndrome,lumbar spinal stenosis,biceps tendon rupture,small fiber neuropathy,and autonomic dysfunction.
Peripheral neuropathy,often shortened to neuropathy,refers to damage or disease affecting the nerves. Damage to nerves may impair sensation,movement,gland function,and/or organ function depending on which nerve fibers are affected. Neuropathies affecting motor,sensory,or autonomic nerve fibers result in different symptoms. More than one type of fiber may be affected simultaneously. Peripheral neuropathy may be acute or chronic,and may be reversible or permanent.
Polyneuropathy is damage or disease affecting peripheral nerves in roughly the same areas on both sides of the body,featuring weakness,numbness,and burning pain. It usually begins in the hands and feet and may progress to the arms and legs and sometimes to other parts of the body where it may affect the autonomic nervous system. It may be acute or chronic. A number of different disorders may cause polyneuropathy,including diabetes and some types of Guillain–Barrésyndrome.
Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness,"pins and needles" sensations,numbness and itching.
Familial amyloid polyneuropathy,also called transthyretin-related hereditary amyloidosis,transthyretin amyloidosis abbreviated also as ATTR,or Corino de Andrade's disease,is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis,and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade,in 1952. FAP is distinct from senile systemic amyloidosis (SSA),which is not inherited,and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied. FAP can be ameliorated by liver transplantation.
Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid,a misfolded and insoluble protein,can become a deposit in the heart's atria,valves,or ventricles. These deposits can cause thickening of different sections of the heart,leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed,with a corrected analysis only during autopsy. Advancements of technologies have increased earlier accuracy of diagnosis. Cardiac amyloidosis has multiple sub-types including light chain,familial,and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.
Eva Lucille Feldman is an American physician-scientist who is a leading authority on neurodegenerative disease. She serves as the Russell N. DeJong Professor of Neurology at the University of Michigan,as well as Director of the NeuroNetwork for Emerging Therapies and ALS Center of Excellence at Michigan Medicine. She was also named the James W. Albers Distinguished University Professor of Neurology.
Epalrestat is a carboxylic acid derivative and a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy,which is one of the most common long-term complications in patients with diabetes mellitus. It reduces the accumulation of intracellular sorbitol which is believed to be the cause of diabetic neuropathy,retinopathy and nephropathy It is well tolerated,with the most commonly reported adverse effects being gastrointestinal issues such as nausea and vomiting,as well as increases in certain liver enzymes. Chemically,epalrestat is unusual in that it is a drug that contains a rhodanine group. Aldose reductase is the key enzyme in the polyol pathway whose enhanced activity is the basis of diabetic neuropathy. Aldose reductase inhibitors (ARI) target this enzyme. Out of the many ARIs developed,ranirestat and fidarestat are in the trial stage. Others have been discarded due to unacceptable adverse effects or weak efficacy. Epalrestat is the only ARI commercially available. It is easily absorbed into the neural tissue and inhibits the enzyme with minimum side effects.
The familial amyloid neuropathies are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.
Tafamidis,sold under the brand names Vyndaqel and Vyndamax,is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms,familial amyloid cardiomyopathy and familial amyloid polyneuropathy,as well as wild-type transthyretin amyloidosis,which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis,transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart.
A diabetic foot disease is any condition that results directly from peripheral artery disease (PAD) or sensory neuropathy affecting the feet of people living with diabetes. Diabetic foot conditions can be acute or chronic complications of diabetes. Presence of several characteristic diabetic foot pathologies such as infection,diabetic foot ulcer and neuropathic osteoarthropathy is called diabetic foot syndrome. The resulting bone deformity is known as Charcot foot.
Familial amyloid cardiomyopathy (FAC),or transthyretin amyloid cardiomyopathy (ATTR-CM) results from the aggregation and deposition of mutant and wild-type transthyretin (TTR) protein in the heart. TTR is usually circulated as a homo-tetramer—a protein made up of four identical subunits—however,in FAC populations,TTR dissociates from this typical form and misassembles into amyloid fibrils which are insoluble and resistant to degradation. Due to this resistance to degradation,when amyloid fibrils accumulate in the heart's walls,specifically the left ventricle,rigidity prevents the heart from properly relaxing and refilling with blood:this is called diastolic dysfunction which can ultimately lead to heart failure.
Alnylam Pharmaceuticals,Inc. is an American biopharmaceutical company focused on the discovery,development and commercialization of RNA interference (RNAi) therapeutics for genetically defined diseases. The company was founded in 2002 and is headquartered in Cambridge,Massachusetts. In 2016,Forbes included the company on its "100 Most Innovative Growth Companies" list.
Wild-type transthyretin amyloid (WTTA),also known as senile systemic amyloidosis (SSA),is a disease that typically affects the heart and tendons of elderly people. It is caused by the accumulation of a wild-type protein called transthyretin. This is in contrast to a related condition called transthyretin-related hereditary amyloidosis where a genetically mutated transthyretin protein tends to deposit much earlier than in WTTA due to abnormal conformation and bioprocessing. It belongs to a group of diseases called amyloidosis,chronic progressive conditions linked to abnormal deposition of normal or abnormal proteins,because these proteins are misshapen and cannot be properly degraded and eliminated by the cell metabolism.
Arnold Lee Dellon is an American plastic surgeon known for pioneering and developing the modern field of peripheral nerve injury. He is a professor of Plastic Surgery and Neurosurgery at Johns Hopkins University and the founder of Dellon Institutes for Peripheral Nerve Surgery.
Quantitative sensory testing (QST) is a panel of diagnostic tests used to assess somatosensory function,in the context of research and as a supplemental tool in the diagnosis of somatosensory disorders,including pain insensitivity,painless and painful neuropathy. The panel of tests examine a broad range of different sensations,including hot,cold,touch,vibration. It has both positive and negative tests. QST reflects a formalisation of existing neurological tests into a standardised battery designed to detect subtle changes in sensory function. Large datasets representing normal responses to sensory tests have been established to quantitate deviation from the mean and allow comparison with normal patients. It is thought that a detailed evaluation of somatosensory function may be useful in identifying subtypes of pain and as a potential tool to identify asymptomatic neuropathy,which may represent up to 50% of total people with neuropathy. In clinical use,it is often combined with other tests such as clinical electrophysiology. In research settings it is increasingly applied in combination with advanced imaging such as fMRI,epidermis "nerve" biopsies and microneurography to classify subtypes of painful disorders.
Electrochemical skin conductance (ESC) is an objective,non-invasive and quantitative electrophysiological measure of skin conductance through the application of a pulsating direct current on the skin. It is based on reverse iontophoresis and steady chronoamperometry. ESC is intended to provide insight into and assess sudomotor function and small fiber peripheral neuropathy. The measure was principally developed by Impeto Medical to diagnose cystic fibrosis from historical research at the Mayo Clinic and then tested on others diseases with peripheral neuropathic alterations in general. It was later integrated into health connected scales by Withings.
Vutrisiran,sold under the brand name Amvuttra,is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which,if untreated,is fatal within 5 to 10 years.
Acoramidis,sold under the brand name Attruby,is a medication used for the treatment of cardiomyopathy. It is a near-complete (>90%) transthyretin stabilizer,developed to mimic the protective properties of the naturally-occurring T119M mutation,to treat transthyretin amyloid cardiomyopathy. It is taken by mouth.
References
- ↑ "POLYDEFKIS, DIMITRI G." The Baltimore Sun. January 7, 2007. Retrieved August 30, 2020.
- 1 2 3 "MICHAEL J. POLYDEFKIS CV" (PDF). hopkinsmedicine.org. Retrieved August 30, 2020.
- 1 2 3 "CMD2017 Bios" (PDF). frederickhealth.org. 2017. p. 1. Retrieved August 30, 2020.
- ↑ "Weak muscles can put diabetics at risk on stairs". reuters.com. October 28, 2014. Retrieved August 31, 2020.
- ↑ Peikoff, Kira (January 1, 2018). "A Drug Straight Out of Science Fiction Has Arrived". leapsmag.com. Retrieved August 31, 2020.
- ↑ "First Effective Treatment for Transthyretin Amyloidosis". hopkinsmedicine.org. January 8, 2019. Retrieved August 31, 2020.
- ↑ "Donlin M. Long Awards". hopkinsmedicine.org. Retrieved August 31, 2020.
- ↑ @HopkinsPain (April 18, 2019). "Congratulations to Dr. Michael Polydefkis, winner of the 2019 Donlin M. Long award honoring those who have served the Johns Hopkins community in advancing the standards of pain care and embodied the institution's dedication to alleviate suffering and pain associated with illness" (Tweet) – via Twitter.
- ↑ "Cohort Biographies" (PDF). hopkinsmedicine.org. 2010. p. 7. Retrieved August 30, 2020.
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