Objectives This study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR). Background CMR is ...increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis. Methods We performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis. Results Patients' median age was 68 ± 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g 202 to 267 g) compared with AL type (167 g 137 to 191 g) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity. Conclusions Transmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Background About 4% of African Americans possess the isoleucine 122 (V122I) variant of transthyretin, associated with cardiac amyloidosis beyond ages of 55 to 60 years. Transthyretin amyloidosis ...associated with variant V122I (ATTR V122I) is likely to be an important cause of heart failure in Afro-Caribbean populations, but the high prevalence of left ventricular hypertrophy (LVH) and lack of awareness of this genetic disorder pose diagnostic hurdles. We report the electrocardiographic (ECG) features of ATTR V122I in the largest clinical series to date. Methods Patients with ATTR V122I were identified in collaboration with the UK National Amyloidosis Centre. The ECG at presentation was assessed for cardiac rhythm, axis, and voltage complex size. Results We include 64 patients with ATTR V122I, with a median age of 74 years (range, 57-88 years). Normal or increased ECG voltage was present in 44.3% of patients, and overall 25% met the criteria for LVH. A significant negative correlation between voltage complex size and duration of illness was seen ( P < .05). First-degree heart block was evident in 56% of patients in sinus rhythm. During follow-up (n = 17; median, 28 months), 50% of patients with initial first-degree heart block required pacing. Conclusion Electrocardiographic voltages meet the criteria for LVH in one quarter of patients with ATTR V122I cardiac amyloidosis. The widely held belief that cardiac amyloidosis is associated with low-voltage complexes is likely to contribute to underdiagnosis of ATTR V122I. First-degree heart block is common at diagnosis and identifies patients at high risk for subsequent pacing requirement.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. ...We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. Methods In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 μg/kg plus ribavirin 800–1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400–1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00423670. Findings Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 54%, 95% CI 44–64, p=0·013 for PRB28; 58/103 56%, 44–66, p=0·005 for PR4/PRB24; 69/103 67%, 57–76, p<0·0001 for PRB48; and 77/103 75%, 65–83, p<0·0001 for PR4/PRB44; vs 39/104 38%, 28–48 for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 27%), and a rate of relapse (six of 27 22%) similar to control (12/51 24%). Boceprevir-based groups had higher rates of anaemia (227/416 55% vs 35/104 34%) and dysgeusia (111/416 27% vs nine of 104 9%) than did the control group. Interpretation In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. Funding Merck.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Background In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and ...cardiovascular events among adults with chronic kidney disease (CKD). Study Design Prospective cohort. Setting & Participants 3,006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictors 4 lifestyle factors (regular physical activity, body mass index BMI of 20-<25 kg/m2 , nonsmoking, and “healthy diet”), individually and in combination. Outcomes CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. Measurements Multivariable-adjusted Cox proportional hazards. Results During a median follow-up of 4 years, we observed 726 CKD progression events, 355 atherosclerotic events, and 437 deaths. BMI ≥ 25 kg/m2 and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 95% CI, 0.58-0.97 and 0.61 95% CI, 0.45-0.82 for BMIs of 25 to <30 and ≥30 kg/m2 , respectively, versus 20 to <25 kg/m2 ; HR for nonsmoking of 0.68 95% CI, 0.55-0.84 compared to the current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 95% CI, 0.46-0.96 for BMI of 25-<30 vs 20-<25 kg/m2 and 0.55 95% CI, 0.40-0.75 vs current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 95% CI, 0.52-0.79 vs inactive), BMI ≥ 30 kg/m2 (HR, 0.64 95% CI, 0.43-0.96 vs 20-<25 kg/m2 ), and nonsmoking (HR, 0.45 95% CI, 0.34-0.60 vs current smoker). BMI < 20 kg/m2 was associated with increased all-cause mortality risk (HR, 2.11 95% CI, 1.13-3.93 vs 20-<25 kg/m2 ). Adherence to all 4 lifestyle factors was associated with a 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11-0.89). Limitations Lifestyle factors were measured only once. Conclusions Regular physical activity, nonsmoking, and BMI ≥ 25 kg/m2 were associated with lower risk of adverse outcomes in this cohort of individuals with CKD.
Background Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to ...what extent 1α,25-dihydroxyvitamin D3 (1α,25OH2 D3 ) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3 ), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. Objective We sought to assess whether the vitamin D3 metabolites 25OHD3 and 1α,25(OH)2 D3 can repress IgE-dependent mast cell activation through mast cell–25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell–VDR activity. Methods We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro , as well as the vitamin D3 –induced curtailment of PCA responses in WBB6F1 - KitW/W-v or C57BL/6J- KitW-sh/W-sh mice engrafted with mast cells that did or did not express VDR or CYP27B1. Results Here we show that mouse and human mast cells can convert 25OHD3 to 1α,25(OH)2 D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell–derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro . Furthermore, epicutaneously applied vitamin D3 metabolites significantly reduced the magnitude of skin swelling associated with IgE-mediated PCA reactions in vivo ; a response that required functional mast cell–VDRs and mast cell–CYP27B1. Conclusion Taken together, our findings provide a mechanistic explanation for the anti-inflammatory effects of vitamin D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Abstract Triolo RJ, Bailey SN, Miller ME, Rohde LM, Anderson JS, Davis JA Jr, Abbas JJ, DiPonio LA, Forrest GP, Gater DR Jr, Yang LJ. Longitudinal performance of a surgically implanted ...neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury. Objective To investigate the longitudinal performance of a surgically implanted neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury. Design Case series. Setting Research or outpatient physical therapy departments of 4 academic hospitals. Participants Subjects (N=15) with thoracic or low cervical level spinal cord injuries who had received the 8-channel neuroprosthesis for exercise and standing. Intervention After completing rehabilitation with the device, the subjects were discharged to unrestricted home use of the system. A series of assessments were performed before discharge and at a follow-up appointment approximately 1 year later. Main Outcome Measures Neuroprosthesis usage, maximum standing time, body weight support, knee strength, knee fatigue index, electrode stability, and component survivability. Results Levels of maximum standing time, body weight support, knee strength, and knee fatigue index were not statistically different from discharge to follow-up ( P >.05). Additionally, neuroprosthesis usage was consistent with subjects choosing to use the system on approximately half of the days during each monitoring period. Although the number of hours using the neuroprosthesis remained constant, subjects shifted their usage to more functional standing versus more maintenance exercise, suggesting that the subjects incorporated the neuroprosthesis into their lives. Safety and reliability of the system were demonstrated by electrode stability and a high component survivability rate (>90%). Conclusions This group of 15 subjects is the largest cohort of implanted lower-extremity neuroprosthetic exercise and standing system users. The safety and efficiency data from this group, and acceptance of the neuroprosthesis as demonstrated by continued usage, indicate that future efforts toward commercialization of a similar device may be warranted.
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