Abstract
Background
Transthyretin amyloidosis (ATTR) is due to TTR tissue accumulation. Both patients without mutations in the TTR gene (wild–type ATTR, ATTRwt) and those with such mutations (variant ...ATTR, ATTRv) may develop cardiac amyloidosis (CA). ATTR–CA has a deep impact on the quality of life. The ITALY study aimed 1) to create the first patient–reported outcome measures (PROMs) for ATTRv– and ATTRwt–CA, 2) to assess the feasibility of their administration, 3) to investigate the relationship between score values, clinical and laboratory findings, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Short Form Health Survey 36 (SF–36) scores.
Methods
Five Italian referral centers were involved (Pisa, Pavia, Ferrara, Florence, Messina). Item selection involved expert clinicians and 2 groups of 10 patients. The questionnaires were administered to consecutive patients evaluated at baseline and 6 months.
Results
Two 30–items questionnaires were created. Each item has 5 answers graded from 4 (best option) to 0 (worst option). The score ranged from 100 (best condition) to 0 (worst condition). As of November 2022, 82 patients (65 ATTRwt–CA, 17 ATTRv–CA) have completed the follow–up. At baseline, 30% of patients needed help to fill the questionnaire, and 20% at 6 months; 65% completed the questionnaire at baseline and 63% at 6 months. At baseline, median score values were 64 (interquartile range IR 54–74) in ATTRwt–CA and 59 (IR 51–71) in ATTRv–CA. ITALY score were correlated with global KCCQ and SF–36 scores at baseline and 6 months (r values from 0.7 to 0.8 in ATTRwt–CA and from 0.5 to 0.7 in ATTRv–CA). In patients with ATTRwt–CA, all KCCQ and SF–36 domains were univariate predictors of ITALY score values at baseline. All the KCCQ and SF–36 domains were independently predictive of ITALY score values in models including age, NYHA class, 6MWT, NT–proBNP; these results were confirmed at 6 months. In ATTRv–CA, All the KCCQ and SF–36 domains were independently predictive of ITALY score values in models including LV ejection fraction, at baseline and at 6 months.
Conclusions
The ITALY questionnaires are the first specific PROMs for ATTRwt– and ATTRv–CA. They have been created by experts in CA and patients and validated in a multicenter Italian cohort with 2 assessments over 6 months. Questionnaire completion is usually feasible. ITALY scores display close relationships with non–ATTR–specific measures of quality of life (KCCQ and SF–36).
We present a measurement of the ratio R=Γ(K
0
e3γ
;E
*
γ
> 30 MeV, θ
*
γ
>20
°
)/Γ(K
0
e3
) and a first measurement of the direct emission contribution in semileptonic K
L
decays. The measurement was ...performed at the DA NE φ factory by selecting φ→K
L
K
S
decays with the KLOE detector. We use 328 pb
-1
of data, corresponding to about 3.5 million K
0
e3
events and about 9000 K
0
e3γ
radiative events. Our result is R=(924±23
stat
±16
syst
)×10
-5
for the branching ratio and 〈X〉=-2.3±1.3
stat
±1.4
syst
for the effective strength parameter describing direct emission.
Abstract
Introduction
Transthyretin–mediated (ATTR) amyloidosis is a progressive and fatal disease. Patients with hereditary or wild–type ATTR amyloidosis frequently develop cardiomyopathy (CM). ...Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, is approved for the treatment of hATTR amyloidosis with polyneuropathy.
Methods
In APOLLO–B, patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM, and had prior hospitalization for heart failure (HF) due to ATTR amyloidosis or clinical evidence of HF. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Exploratory parameters at M12 included changes in cardiac biomarkers, echocardiography and Tc scintigraphy.
Results
APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age, 76.0 yrs; male, 89%; wtATTR, 80%; on tafamidis at baseline, 25%. Patisiran showed a significant benefit compared with placebo in 6–MWT (median 95% CI change from baseline: patisiran, –8.15 –16.42, 1.50; placebo, –21.35 –34.05, –7.52; HL estimate of median difference: 14.69 0.69, 28.69; p=0.0162). Patisiran demonstrated favorable trends in change from baseline of NT–proBNP (mean fold change ratio 95% CI: 0.80 0.73, 0.89; p=1.825×10–5) and troponin I (mean fold change ratio 95% CI: 0.87 0.80, 0.95; p=0.0011) at M12 vs placebo. Patisiran also demonstrated a trend towards benefit in change from baseline of most evaluated echocardiographic parameters at M12 vs placebo. Patisiran–treated patients evaluable for scintigraphy (n=37) experienced a reduction (37.8%) or no change (62.2%) in Perugini grade at M12 compared with baseline. Among placebo patients (n=28) at M12, none experienced a reduction from baseline in Perugini grade, and 1 (3.6%) increased in grade. Patisiran demonstrated an acceptable safety profile; AEs were mostly mild or moderate in severity, and there were no cardiac safety concerns.
Conclusions
Exploratory analyses after 12 months provide further evidence for the potential benefit of patisiran treatment on cardiac biomarkers and manifestations of cardiac amyloid involvement in patients with ATTR amyloidosis. The long–term impact of patisiran will be assessed in the ongoing APOLLO–B open–label extension.
The overall survival for patients with metastatic melanoma is very poor, with a median survival of 8.5 months. In this Phase II trial, we assessed the efficacy, safety, and tolerability of a ...sequential biochemotherapy schedule, using dacarbazine as antiblastic agent and immunomodulant doses of interleukin-2 and interferon-alfa. Thirty-one eligible patients with metastatic melanoma received dacarbazine IV as antiblastic therapy and interluekin-2, plus interferon-alfa SC as sequential immunotherapy, for 6 months. Responding and nonprogressing patients were subsequently maintained on immunotherapy treatment for further 6 months. Twenty-nine patients had an adequate trial, and were assessable for both response and toxicities, with a median follow-up of 49 months. The overall response rate was 52 percent (3 CR and 12 PR), SD was 8 (27 percent) and PD were achieved in 6 patients (21 percent). The median survival duration of responders was 28 months, significantly longer (p < 0.001) than the 16 months of nonresponders. Therapy was well tolerated and produced a significant improvement in progressive-free survival. Further studies, thus, are recommended for larger groups of patients not only to confirm these results, but also to apply this biochemotherapy regimen as adjuvant postsurgical treatment in early stages of malignant melanoma.
Objective. Advanced glycation endproducts (AGEs), including Nvarepsilon-(carboxymethyl)lysine-protein adducts (CML) are involved in micro/macrovascular changes and are co-localized with adhesion ...molecules in inflamed tissues. Serum levels of CML were investigated in systemic sclerosis (SSc) characterized by microvascular modifications and correlated with indices of micro/macrovascular damage. Methods. In 66 SSc patients (limited SSc, n = 55; diffuse SSc, n = 11) and 20 controls, CML serum levels were measured by enzyme-linked immunosorbent assay. Nailfold capillaroscopy, intima-media thickness (IMT) and the ankle-brachial index (ABI) were also recorded, to characterize micro/macrovascular involvement. Results. CML levels were significantly higher in SSc (79.2 ± 39 mg/ml vs 49.6 ± 26.1 mg/ml, mean ± s.d.; P<0.01), without significant differences between SSc subsets. CML levels were significantly higher in all capillaroscopic patterns: the 'early' pattern showed higher levels than 'active' and 'late' patterns. IMT was significantly higher in SSc (P<0.01) than in controls, whilst ABI was no different from controls. Conclusions. These data indicate that although both CML formation and macrovascular involvement are increased in SSc, there is no correlation between these two parameters. However, the characteristic early nailfold capillaroscopy changes of SSc are associated with proportionally greater CML formation, suggesting that AGEs are involved in SSc microangiopathy.
A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5–20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to ...start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international arbitrary units) and by an equatorial index Dst falling to −112 and −81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.
We have measured the cross section σ(e+e−→π+π−γ) at an energy W=mϕ=1.02 GeV with the KLOE detector at the electron–positron collider DAΦNE. From the dependence of the cross section on the invariant ...mass of the two-pion system, we extract σ(e+e−→π+π−) for the mass range 0.35<s<0.95 GeV2. From this result, we calculate the pion form factor and the hadronic contribution to the muon anomaly, aμ.
Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be ...impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation.
Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogen properties. Increased circulating ET-1 levels were found in patients with atherosclerosis as well as in patients with ...non–insulin-dependent diabetes mellitus (NIDDM) suggesting a role in the pathogenesis of these disorders. The aim of the present study was to ascertain the influence of the NIDDM on plasma ET-1 levels in patients with advanced atherosclerotic lesions. The circulating ET-1 levels were measured in 16 NIDDM patients (68.4 ± 8.4 years) with macroangiopathy and in ten patients (65.3 ± 11 years) with atherosclerosis without NIDDM. Twenty-two healthy subjects (43.1 ± 18.3 years) served as controls. Circulating ET-1 levels were higher in NIDDM patients (6.8 ± 2.8 pg/mL) than both controls (3.1 ± 1 pg/mL;
p < 0.001) and patients with vascular disease but without NIDDM (4.7 ± 1.6 pg/mL;
p < 0.04). No significant relationship was found between age and ET-1 concentrations, and no differences were noted between men and women in the control group. This study demonstrated that circulating ET-1 levels are increased in patients with atherosclerosis and that those with NIDDM showed the highest ET-1 levels. These observations strongly support a role for ET-1 in the pathogenesis of atherosclerosis and also suggest that this peptide may be involved in the development of atherosclerotic lesions in the NIDDM. We speculated that chronic exposure to hyperinsulinemia and hypertriglyceridemia in the diabetic patients could account for the increased ET-1 levels found in these patients.
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