1,339 research outputs found
Pharmacological treatment for familial amyloid polyneuropathy
Background:
Diseaseâmodifying pharmacological agents for transthyretin (TTR)ârelated familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on diseaseâmodifying pharmacological treatment for TTRârelated and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors.
Objectives:
To assess and compare the efficacy, acceptability, and tolerability of diseaseâmodifying pharmacological agents for familial amyloid polyneuropathies (FAPs).
Search methods:
On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites.
Selection criteria:
We included randomised clinical trials (RCTs) or quasiâRCTs investigating any diseaseâmodifying pharmacological agent in adults with FAPs.
Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial.
Data collection and analysis:
We followed standard Cochrane methodology.
Main results:
The review included four RCTs involving 655 people with TTRâFAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a metaâanalysis.
One RCT compared tafamidis with placebo in earlyâstage TTRâFAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) â3.21 points, 95% confidential interval (CI) â5.63 to â0.79; P = 0.009; lowâcertainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of LifeâDiabetic Neuropathy (Norfolk QOLâDN) total score; MD â4.50 points, 95% CI â11.27 to 2.27; P = 0.19; very lowâcertainty evidence). No clear betweenâgroup difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very lowâcertainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very lowâcertainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very lowâcertainty evidence).
One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD â4.90 points, 95% CI â7.89 to â1.91; P = 0.002; lowâcertainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD â18.10 points, 95% CI â26.03 to â10.17; P < 0.001; lowâcertainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36âItem ShortâForm Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very lowâcertainty evidence) and the mental component (MD 4.40 points, 95% CI â0.19 to 8.99; P = 0.063; very lowâcertainty evidence). There was no clear betweenâgroup difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very lowâcertainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very lowâcertainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very lowâcertainty evidence) during the trial.
One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Raschâbuilt Overall Disability Scale; leastâsquares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderateâcertainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests â Alnylam version; leastâsquares MD â33.99 points, 95% CI â39.86 to â28.13; P < 0.001; moderateâcertainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOLâDN total score; leastâsquares MD â21.10 points, 95% CI â27.20 to â15.00; P < 0.001; lowâcertainty evidence). There was little or no betweenâgroup difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; lowâcertainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; lowâcertainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; lowâcertainty evidence) during the trial.
One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests â Ionis version; MD â19.73 points, 95% CI â26.50 to â12.96; P < 0.001; moderateâcertainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOLâDN total score; MD â10.85 points, 95% CI â17.25 to â4.45; P < 0.001; lowâcertainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; lowâcertainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; lowâcertainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; lowâcertainty evidence).
There were no studies addressing apolipoprotein AIâFAP, gelsolinâFAP, and betaâ2âmicroglobulinâFAP.
Authors' conclusions
Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTRâFAP. No studies directly compare diseaseâmodifying pharmacological treatments for TTRâFAP. Results from placeboâcontrolled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTRâFAP, but further investigations are needed. Since direct comparative studies for TTRâFAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, longâterm nonârandomised openâlabel studies monitoring their efficacy and safety are needed
Pharmacological treatment for familial amyloid neuropathy
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess and compare the efficacy, acceptability, and tolerability of pharmacologic diseaseâmodifying agents for familial amyloid neuropathy (FAP)
Intramedullary non-specific inflammatory lesion of thoracic spine: A case report
<p>Abstract</p> <p>Background</p> <p>There are several non-neoplastic lesions which mimick intramedullary spinal cord neoplasm in their radiographic and clinical presentation. These can be classified as either infectious (TB, fungal, bacterial, parasytic, syphilis, CMV, HSV) and non-infectious (sarcoid, MS, myelitis, ADEM, SLE) inflammatory lesions, idiopathic necrotizing myelopathy, unusual vascular lesions and radiation myelopathy. Although biopsy may be indicated in many cases, an erroneous diagnosis of intramedullary neoplasm can often be eliminated pre-operatively.</p> <p>Case description</p> <p>the authors report a very rare case of intramedullary non-specific inflammatory lesion of unknown origin, without signs of infection or demyelinization, in a woman who showed no other evidence of systemic disease.</p> <p>Conclusions</p> <p>Intramedullary lesions that mimick a tumor can be various and difficult to interpret. Preoperative MRI does not allow a certain diagnosis because these lesions have a very similar signal intensity pattern. Specific tests for infective pathologies are useful for diagnosis, but histological examination is essential for establishing a certain diagnosis. In our case the final histological examination and the specific tests that we performed have not cleared our doubts regarding the nature of the lesion that remains controversial.</p
Measurement of the t(t)over-bar production cross section in the dilepton channel in pp collisions at âs=8 TeV
The top-antitop quark (t (t) over bar) production cross section is measured in proton-proton collisions at root s = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb(-1). The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239 +/- 2 (stat.) +/- 11 (syst.) +/- 6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness
cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder ÎČ-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system
Left ventricular twist mechanics during incremental cycling and knee extension exercise in healthy men
Purpose: The objective of the present study was to investigate left ventricular (LV) twist mechanics in response to incremental cycling and isometric knee extension exercises. Methods: Twenty-six healthy male participants (age = 30.42 ± 6.17 years) were used to study peak twist mechanics at rest and during incremental semi-supine cycling at 30 and 60% work rate maximum (W) and during short duration (15 s contractions) isometric knee extension at 40 and 75% maximum voluntary contraction (MVC), using two-dimensional speckle tracking echocardiography. Results: Data presented as mean ± standard deviation or median (interquartile range). LV twist increased from rest to 30% W (13.21° ± 4.63° to 20.04° ± 4.76°, p  0.05), whilst twisting velocity increased (rest 89.15° ± 21.77° s to 75% MVC 124.32° ± 34.89° s, p  0.05) then increased from 40 to 75% MVC [â98.44 (43.54)° s to â138.42 (73.29)° s, p < 0.01]. Apical rotations and rotational velocities were greater than basal during all conditions and intensities (all p < 0.01). Conclusion: Cycling increased LV twist to 30% W which then remained unchanged thereafter, whereas twisting velocities showed further increases to greater intensities. A novel finding is that LV twist was unaffected by incremental knee extension, yet systolic and diastolic twisting velocities augmented with isometric exercise
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