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Background: Amyloidosis is a group of diseases with the common pathophysiology of protein misfolding and aberrant deposition in tissue. There are both acquired and hereditary forms of this disease, and this review focuses on the latter hereditary transthyretin-mediated (hATTR). hATTR affects about 50,000 individuals globally and mostly appears as one of three syndromes - cardiac, polyneuropathy, and oculoleptomeningeal. Polyneuropathy is the most common form, and there is usually some overlap in individual patients. Results: Recently, novel therapeutic options emerged in the form of groundbreaking drugs, Patisiran and Inotersen, small interfering RNA molecules that target TTR and reduce the production of this protein. By targeting TTR mRNA transcripts, Inotersen decreases protein translation and production, reducing the deposition of misfolded proteins. It was shown to be both effective and safe for use and specifically formulated to concentrate in the liver - where protein production takes place. Conclusion: hATTR is a rare, progressive, and debilitating disease. Its most common presentation is that of polyneuropathy, and it carries a very poor prognosis and a natural history conveying a median survival of < 12 years. Novel therapeutic options are groundbreaking by providing disease-modifying specific, targeted therapies against TTR production and deposition. The use of RNA interference (RNAi) opens the door to the treatment of hereditary diseases by targeting them at the genetic level.
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Charcot spine arthropathy (CSA), a result of reduced afferent innervation, is an occurrence of Charcot joint, a progressive, degenerative disorder in vertebral joints, related mostly to spinal cord injury. The repeated microtrauma is a result of a lack of muscle protection and destroys cartilage, ligaments, and disc spaces, leading to vertebrae destruction, joint instability, subluxation, and dislocation. Joint destruction compresses nerve roots, resulting in pain, paresthesia, sensory loss, dysautonomia, and spasticity. CSA presents with back pain, spinal deformity and instability, and audible spine noises during movement. Autonomic dysfunction includes bowel and bladder dysfunction. It is slowly progressive and usually diagnosed at a late stage, usually, on average, 20 years after the first initial insult. Diagnosis is rarely clinical related to the nature of nonspecific symptoms and requires imaging with computed tomography (CT) and magnetic resonance imaging (MRI). Conservative management focuses on the prevention of fractures and the progression of deformities. This includes bed rest, orthoses, and braces. These could be useful in elderly or frail patients who are not candidates for surgical treatment, or in minimally symptomatic patients, such as patients with spontaneous fusion leading to a stable spine. Symptomatic treatment is offered for autonomic dysfunction, such as anticholinergics for bladder control. Most patients require surgical treatment. Spinal fusion is achieved with open, minimally-open (MOA) or minimally-invasive (MIS) approaches. The gold standard is open circumferential fusion; data is lacking to determine the superiority of open or MIS approaches. Patients usually improve after surgery; however, the rarity of the condition makes it difficult to estimate outcomes. This is a review of the latest and seminal literature about the treatment and chronic management of Charcot spine. The review includes the background of the syndrome, clinical presentation, and diagnosis, and compares the different treatment options that are currently available.
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BACKGROUND/OBJECTIVES: Sepsis is a severe systemic response to infection with a high mortality rate. A higher incidence has been reported for older people, in persons with a compromised immune system including cancer patients, and in ethnic minorities. We analyzed sepsis mortality and its predictors by ethnicity in the Multiethnic Cohort (MEC). SUBJECTS/METHODS: Among 191,561 white, African American, Native Hawaiian, Japanese American, and Latino cohort members, 49,347 deaths due to all causes and 345 deaths due to sepsis were recorded during follow-up from 1993-96 until 2010. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated and adjusted for relevant confounders. In addition, national death rates were analyzed to compare mortality by state. RESULTS: Age-adjusted rates of sepsis death were 5-times higher for Hawaii than Los Angeles (14.4 vs. 2.7 per 100,000). By ethnicity, Native Hawaiians had the highest rate in Hawaii (29.0 per 100,000) and African Americans in Los Angeles (5.2 per 100,000). In fully adjusted models, place of residence was the most important predictor of sepsis mortality (HR = 7.18; 95%CI: 4.37-11.81 Hawaii vs. Los Angeles). African Americans showed the highest risk (HR = 2.08; 95% CI: 1.16-3.75) followed by Native Hawaiians (HR = 1.88; 95% CI: 1.34-2.65) as compared to whites. Among cohort members with cancer (N = 49,794), the 2-fold higher sepsis mortality remained significant in Native Hawaiians only. The geographic and ethnic differences in the MEC agreed with results for national death data. CONCLUSIONS: The finding that African Americans and Native Hawaiians experience a higher mortality risk due to sepsis than other ethnic groups suggest ethnicity-related biological factors in the predisposition of cancer patients and other immune-compromising conditions to develop sepsis, but regional differences in health care access and death coding may also be important.
