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The below quote from the first issue of the Noticias del Puerto de Monterey sets the intention of the Monterey and Art Association in production of a quarterly newsletter focused on Monterey history. Publication began in 1957 and continued until the last volume was published in 2008. Over the course of the years, publication as a quarterly became irregular, sometimes only one or two issues in some years, and after a one-year gap in 2007 a final very large 50th anniversary commemorative issue was published. Noticias articles generally address people, places, and events in and around Monterey. The articles were researched and written by local historians and/or topic-knowledgeable members of the Association. The MHOD Library holdings include a complete set of the Noticias. Our online collection has been scanned and is available as searchable pdf's, there are a few issues missing from the online collection. Also, at MHOD and online is an Index for years 1968 through 2000 and a Table of Contents for years 1957 through 2000.
"Since its founding in 1931, the Association has had as its primary objective the preservation of those reminders of historic Monterey: the old adobe homes and significant buildings of the early days of Spanish, Mexican and American California. The Association has also obtained through purchase and loan numerous articles for exhibition in public museums such as the old Customs House, the Stevenson House, and Colton Hall. It has taken an active part in impressing on the people of Monterey the inestimable value of the City's place in history, the uniqueness of their heritage, and the importance of retaining for succeeding generations of Californians, adopted or native-born, those irreplaceable relics of a bygone age which embody the state's romantic story.
However, there is a feeling that the Association has another obligation: the encouragement of general interest in local history through the publication of articles covering Monterey's colorful four hundred years as the "cradle of California history." Furthermore, the decisions of the Board of Directors, the calendar of coming events, and news of important acquisitions need wider circulation among the members. For these reasons the Board has sponsored this quarterly.
The editors propose to make the Noticias del Puerto de Monterey not only an item of interest for local members, but a genuine contribution to the history of California by including in each issue an article drawn from hitherto unpublished primary historical sources."
Early Issues Table of Contents and Indexes
table_of_contents_1957_-_1966.pdf
noticias_index.pdf
vol_1_num_1_march_1957.pdf
vol_1_num_2_june_1957.pdf
vol_1_num_3_september_1957.pdf
vol_1_num_4_december_1957.pdf
vol_10_num_1_march_1966.pdf
vol_10_num_3_september_1966.pdf
vol_10_num_2_june_1966.pdf
vol_10_num_4_december_1966.pdf
vol_17num_1_march_1973.pdf
vol_17_num__4_december_1973.pdf
vol_17_num_2___3_june_and_september_1973.pdf
vol_23_num_2_june-september_1979.pdf
vol_23_num_4_april_1980.pdf
vol_25_special_edition_august_1984.pdf
vol_45_num_1_summer_1993.pdf
vol_49_num_1_oct_1998.pdf
vol_49_num_2_mar_1999.pdf
vol_50_num_2_november_2000.pdf
vol_51_num_1_february_2002.pdf
vol_51_num_3_fall_2002.pdf
vol_51_num_4_winter_2002.pdf
vol_52_num_1_spring_2003.pdf
vol_55_num_2-3_spring-summer_2006.pdf
vol_57_num_1_fall-winter_2008.pdf


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Bad Kreuznach (do 1924 Kreuznach) – uzdrowiskowe miasto powiatowe w zachodnich Niemczech, w kraju związkowym Nadrenia-Palatynat, siedziba powiatu Bad Kreuznach, gmin związkowych Bad Kreuznach oraz Bad Münster am Stein-Ebernburg.

Według danych z 2009 roku miasto zamieszkiwało 47 337 mieszkańców. Leży nad rzeką Nahe. W pobliżu miasta znajduje się region winiarski.

Historia
Miasto ma długą historię, sięgającą czasów antycznych – odkryto tutaj ruiny dużej rzymskiej willi-pałacu z III wieku. Przez następne stulecia dzieliło losy niespokojnego pogranicza niemiecko-francuskiego. W XVII wieku prężny ośrodek miejski został poważnie zniszczony przez wojska szwedzkie, francuskie i hiszpańskie w czasie wojny trzydziestoletniej – liczba mieszkańców spadła wówczas z 8 do 3,5 tys. W 1689 po raz kolejny miasto padło ofiarą działań wojennych w czasie wojny o Palatyn.

Na przełomie XVIII i XIX wieku przez kilkanaście lat tereny te przeszły w granice rewolucyjnej Francji, następnie Kongres wiedeński przyznał je Prusom, które włączyły je do prowincji reńskiej (Rheinprovinz). W granicach Prus miasto znajdowało się do zakończenia II wojny światowej, kiedy to znalazło się we francuskiej strefie okupacyjnej, po zdobyciu miasta przez Amerykanów, którzy stacjonowali w dawnych koszarach Wehrmachtu od początku lat 50. aż do 2001 roku. Obecnie koszary w większości przypadków stoją puste, część przebudowano na mieszkania lub biura. Specyficzną pamiątką jest synagoga miejska, znajdująca się w dawnej kaplicy wojskowej US Army.

1 lipca 2014 do miasta przyłączono miasto Bad Münster am Stein-Ebernburg, które stało się jego dzielnicą. Bad Kreuznach stało się zarazem siedzibą gminy związkowej Bad Münster am Stein-Ebernburg.

Wybrane zabytki
 Römerhalle – muzeum prezentujące pozostałości po Rzymianach, m.in. dwie duże mozaiki z motywami handlowymi oraz walk gladiatorów,
 ruiny zamku Kauzenburg,
 pozostałości murów miejskich,
 most Alte Nahebrücke z XV wieku,
 kościół św. Pawła (Pauluskirche), w którym w 1843 roku ślub wziął Karol Marks,
 gotycki St. Nikolauskirche z XIII wieku,
 wieża, pozostałość po luterańskim Wilhelmskirche z końca XVII wieku,
 neogotycki kościół św. Krzyża (Heilig-Kreuz-Kirche) z lat 1895–1897, uszkodzony w 1945 roku,
 dom Johanna Georga Fausta z 1507 roku,
 dawny obszar dworski Bangert (Rittergut Bangert) z parkiem pałacowym i muzeami,
 Stare i Nowe miasto z kamieniczkami z okresów od średniowiecza do początku XX wieku,
 zabudowa uzdrowiskowa z przełomu XIX i XX wieku,
 zespoły koszar wojskowych z lat 30. XX wieku.

Współpraca
Miejscowości partnerskie:
 Bourg-en-Bresse, Francja
 Neuruppin, Brandenburgia

Linki zewnętrzne
 oficjalna strona miasta

Przypisy

Miasta w Nadrenii-Palatynacie
Powiat Bad Kreuznach
Uzdrowiska w Niemczech

redpajama_set_name: RedPajamaWikipedia


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On Dave Margoshes' "Latimer's Statement to the Police"
Ron Charach
Writing poems based on journalistic reportage is perilous at the best of times. The poems risk becoming too freighted with the politics or moral implications of the event itself. Yet no poet, or poetic novelist, with blood in their veins can steer clear of the stranger-than-fiction events that fill the newspapers and airwaves. Regina poet and novelist Dave Margoshes takes on both the unspeakable and the ineffable in this poem about Robert Latimer's decision to kill of his severely disabled daughter Tracy. The poem was written several years after the actual murder took place, but while news of the trial and its controversial verdict were very much in the public eye…
Writing poems based on journalistic reportage is perilous at the best of times. The poems risk becoming too freighted with the politics or moral implications of the event itself. Yet no poet, or poetic novelist, with blood in their veins can steer clear of the stranger-than-fiction events that fill the newspapers and airwaves. Regina poet and novelist Dave Margoshes takes on both the unspeakable and the ineffable in this poem about Robert Latimer's decision to kill of his severely disabled daughter Tracy. The poem was written several years after the actual murder took place, but while news of the trial and its controversial verdict were very much in the public eye.
It begins with a blunt, prosaic couple of lines, more a legal statement than a true confession from the soul, but gradually evolves into the latter. Robert Latimer's nature as a practical farmer is underlined in phrases of startlingly simple cadence, "I put her in the half-ton", as simple a cadence as he uses to describe the black hose being on the bench "right there . . . where I left it." By contrast, "we sat there for a while" offers a lingering pause, as father and daughter listen to a country & western song, ("Your Cheatin' Heart" comes to this reader's mind.)
The farmer in Latimer has decided to put down one of his own herd not meant to make it. His fateful decision is viewed against a much wider backdrop, that of an indifferent universe of stars, invisible by day to the eye, but winking down at Earth all the same. Only someone who has lived on the prairie can fully understand how the human element becomes minimized in contrast to the enormity of an infinite, featureless plain, beneath an immensity of unbroken sky.
Margoshes designs his lines to allow for rich openness and ambiguity. The words implicitly and explicitly exchanged between father and daughter are rendered in _cri de coeur_ italics rather than quotation marks. In the second stanza, the break "I got out, told her [_be right back, ain't_]" makes the second line virtually nullify itself, before continuing: "[_I always?_] and went into the machine." What machine is it that Latimer enters? Not merely the literal "machine / shed" of the break, but the machinery of fate, of doom", of his own decision to objectify his beloved, suffering, insufferable daughter?
Star-crossed lovers, this father and daughter start out in the poem sharing a Country & Western song above the rumble of the car heater, a homey tableau shattered by a black snake filled with poison that chokes both its victim and her father/murderer. Snakes are, of course, symbols of temptation, and this father is about to give in to the same temptation transcended, or warded off, by all parents of all severely disabled children who face a lifetime of severe pain.
The last four lines are a powerful image of human vulnerability in an incomprehensible universe: "I stood in the barnyard / in the snow, my boots open, no gloves, / my hands cold, looking / up at those damned stars."? It is an image you don't have to be Robert Latimer to comprehend.
Dave MargoshesPoetrypoetsRon Charach

redpajama_set_name: RedPajamaCommonCrawl


text:
JACC Journals
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Source -- All Journals --JACC: Basic to Translational ScienceJACC: Cardiovascular ImagingJACC: Cardiovascular InterventionsJACC: Case ReportsJACC: Heart FailureJACC: Clinical ElectrophysiologyJournal for the American College of Cardiology
Source -- All Journals --JACC: Basic to Translational ScienceJACC: Cardiovascular ImagingJACC: Cardiovascular InterventionsJACC: Case ReportsJACC: Heart FailureJACC: Clinical ElectrophysiologyJournal of the American College of Cardiology
Volume 71, Issue 25, June 2018 DOI: 10.1016/j.jacc.2018.03.536
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Myocardial Edema and Prognosis in Amyloidosis
Tushar Kotecha, Ana Martinez-Naharro, Thomas A. Treibel, Rohin Francis, Sabrina Nordin, Amna Abdel-Gadir, Daniel S. Knight, Giulia Zumbo, Stefania Rosmini, Viviana Maestrini, Heerajnarain Bulluck, Roby D. Rakhit, Ashutosh D. Wechalekar, Janet Gilbertson, Mary N. Sheppard, Peter Kellman, Julian D. Gillmore, James C. Moon, Philip N. Hawkins and Marianna Fontana
Author + information
vol. 71 no. 25 2919-2931
https://doi.org/10.1016/j.jacc.2018.03.536
Received October 30, 2017
Revision received March 26, 2018
Accepted March 26, 2018
Published online June 18, 2018.
2018 American College of Cardiology Foundation
Tushar Kotecha, MBChBa,b,c,∗,
Ana Martinez-Naharro, MDa,b,∗,
Thomas A. Treibel, MBBSb,d,
Rohin Francis, MBBSa,b,
Sabrina Nordin, MBBSb,d,
Amna Abdel-Gadir, MBBSb,d,
Daniel S. Knight, MDa,c,
Giulia Zumbo, MDa,
Stefania Rosmini, MDd,
Viviana Maestrini, PhDd,e,
Heerajnarain Bulluck, MBBSb,
Roby D. Rakhit, MDb,c,
Ashutosh D. Wechalekar, MDa,c,
Janet Gilbertson, MSca,
Mary N. Sheppard, MDf,
Peter Kellman, PhDg,
Julian D. Gillmore, MD, PhDa,c,
James C. Moon, MDd,
Philip N. Hawkins, PhDa,c and
Marianna Fontana, PhDa,b,c,∗ (m.fontana{at}ucl.ac.uk), @UCL@RoyalFreeNHS
aNational Amyloidosis Centre, University College London, Royal Free Hospital, London, United Kingdom
bInstitute of Cardiovascular Science, University College London, London, United Kingdom
cRoyal Free Hospital, London, United Kingdom
dBarts Heart Centre, London, United Kingdom
eDepartment of Cardiovascular, Respiratory, Nephrology, Anesthesiology & Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
fMolecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom
gNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
↵∗Address for correspondence:
Dr. Marianna Fontana, National Amyloidosis Centre, University College London, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, United Kingdom.
Central Illustration
Background Prognosis in light-chain (AL) and transthyretin (ATTR) amyloidosis is influenced by cardiac involvement. ATTR amyloidosis has better prognosis than AL amyloidosis despite more amyloid infiltration, suggesting additional mechanisms of damage in AL amyloidosis.
Objectives The aim of the study was to assess the presence and prognostic significance of myocardial edema in patients with amyloidosis.
Methods The study recruited 286 patients: 100 with systemic AL amyloidosis, 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 on 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid), 11 asymptomatic individuals with amyloidogenic TTR gene mutations, and 30 healthy volunteers. All subjects underwent cardiovascular magnetic resonance with T1 and T2 mapping and 16 underwent endomyocardial biopsy.
Results Myocardial T2 was increased in amyloidosis with the degree of elevation being highest in untreated AL patients (untreated AL amyloidosis 56.6 ± 5.1 ms; treated AL amyloidosis 53.6 ± 3.9 ms; ATTR amyloidosis 54.2 ± 4.1 ms; each p < 0.01 compared with control subjects: 48.9 ± 2.0 ms). Left ventricular (LV) mass and extracellular volume fraction were higher in ATTR amyloidosis compared with AL amyloidosis while LV ejection fraction was lower (p < 0.001). Histological evidence of edema was present in 87.5% of biopsy samples ranging from 5% to 40% myocardial involvement. Using Cox regression models, myocardial T2 predicted death in AL amyloidosis (hazard ratio: 1.48; 95% confidence interval: 1.20 to 1.82) and remained significant after adjusting for extracellular volume fraction and N-terminal pro–B-type natriuretic peptide (hazard ratio: 1.32; 95% confidence interval: 1.05 to 1.67).
Conclusions Myocardial edema is present in cardiac amyloidosis by histology and cardiovascular magnetic resonance T2 mapping. T2 is higher in untreated AL amyloidosis compared with treated AL and ATTR amyloidosis, and is a predictor of prognosis in AL amyloidosis. This suggests mechanisms additional to amyloid infiltration contributing to mortality in amyloidosis.
T2 mapping
Systemic amyloidosis is a fatal disease characterized by progressive deposition of abnormal, insoluble protein fibrils in the extracellular space, which disrupts normal tissue architecture and function (1). The associated progressive increase in ventricular mass and stiffness (2) are thought to explain much of the pathophysiology. Nearly all cardiac amyloidosis is monoclonal immunoglobulin light-chain (AL) (or primary systemic) type or transthyretin (ATTR) (formerly senile) type, with cardiac involvement being the major determinant of survival in both. While there are currently no proven disease modifying therapies available for ATTR amyloidosis, the prognosis of AL amyloidosis is improved with chemotherapy that suppresses aberrant light chain production from the underlying plasma cell clone in bone marrow (3). However, despite novel chemotherapy agents, 1-year mortality in established cardiac AL amyloidosis remains high, reflecting late diagnosis and need for better tolerated, less toxic, and more rapidly acting therapies (4).
Cardiovascular magnetic resonance (CMR) can be used to noninvasively measure cardiac amyloid burden. CMR can visualize, with late gadolinium enhancement (LGE), and quantitate, with T1 mapping, the continuum of cardiac amyloid deposition (5). Transmurality of LGE, elevation in native T1 and extracellular volume fraction (ECV) all correlate with amyloid burden and provide incremental information on outcome (5). Amyloid infiltration in cardiac ATTR amyloidosis is usually more severe than in AL in terms of ventricular wall thickness, left ventricular (LV) mass, transmurality of LGE, and ECV (6). However, severity of clinical heart failure and survival are generally worse in AL amyloidosis (median survival from presentation 6 months in AL and 6 years in ATTR) (2,7). This discordance remains poorly understood but has been ascribed to additional toxic effects of AL amyloid or faster rate of amyloid deposition in AL amyloidosis compared with ATTR amyloidosis, leading to increased myocardial damage (7,8).
T2 is a CMR biomarker that increases in myocardial edema, for example, in acute myocardial infarction (9) and myocarditis (10), but also in heart failure, where it appears to track chronic inflammation (11) and cardiac Fabry disease, where T2 may be elevated in LGE areas and tracks blood troponin release (12). While T2 ratio has been assessed in cardiac amyloidosis (13,14), T2 mapping has not previously been studied. Furthermore, no histological studies have demonstrated the presence of myocardial edema in cardiac amyloidosis.
The aim of this study was to assess the presence of myocardial edema using histology and T2 mapping in patients with amyloidosis and determine the prognostic significance in AL and ATTR amyloidosis subtypes.
Patients with amyloidosis were recruited and underwent comprehensive assessment at the National Amyloidosis Centre, Royal Free Hospital, London, United Kingdom, from 2011 to 2015. Patients were systematically followed up from date of CMR until March 22, 2017, the date of censoring. Accuracy of occurrence and date of death among deceased patients, and ongoing survival among those who were censored, was ensured on the basis of UK death certification data from the UK Office of National Statistics. A total of 286 patients were categorized into 3 groups.
AL amyloid patients
One hundred patients with biopsy proven systemic AL amyloidosis (61 men, mean age 63.6 ± 10.9 years) were recruited. Cardiac categorization was based on CMR findings (5). Categories were: 1) cardiac amyloidosis with transmural LGE (features on CMR consistent with cardiac amyloidosis and transmural LGE); 2) cardiac amyloidosis with subendocardial LGE (features on CMR consistent with cardiac amyloidosis and subendocardial LGE); and 3) no evidence of cardiac involvement (normal wall thickness on CMR with normal serum biomarkers and no LGE). Patients within groups 1 and 2 were considered to have definite cardiac involvement. Patients were also classified as treated or untreated. Untreated patients were defined as those that underwent CMR scanning before initiation of chemotherapy to treat AL amyloidosis or associated myeloma. Treated patients were those who had completed or were currently undergoing chemotherapy at the time of CMR scanning.
ATTR amyloidosis patients
A total of 163 consecutive patients (139 men, mean age 74.6 ± 8.1 years) with cardiac ATTR amyloidosis and 12 with possible cardiac ATTR amyloidosis (8 men, mean age 73.3 ± 14.4 years) were recruited. Cardiac ATTR amyloidosis was defined as the combination of heart failure symptoms with echocardiography consistent with or suggestive of cardiac amyloidosis, grade 2 or 3 cardiac uptake on the 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy in the absence of a monoclonal gammopathy or, in the presence of monoclonal gammopathy, a cardiac biopsy positive for TTR (15). Possible cardiac ATTR amyloidosis was defined by grade 1 cardiac uptake on 99mTc-DPD. All subjects underwent sequencing of exons 2, 3, and 4 of the TTR gene.
TTR gene mutation carriers
Eleven TTR gene mutations carriers were recruited (4 men, 36%; age 45.6 ± 7.5 years). These were defined as individuals with TTR gene mutation but no evidence of clinical disease, no cardiac uptake on 99mTc-DPD scintigraphy, and normal echocardiography, N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T.
Thirty healthy volunteers (21 men, mean age 54.4 ± 12.3 years) were recruited through advertising in the hospital, university and general practices. All had no history of cardiovascular disease, hypertension or diabetes mellitus. All had normal 12-lead electrocardiography and normal CMR scan.
All amyloidosis patients underwent transthoracic echocardiography, 12-lead electrocardiography, and 6-min walk test where health and patient choice permitted (e.g., not performed in the presence of severe arthritis, postural hypotension, or neuropathy), and provided blood samples for NT-proBNP. The ATTR group also underwent 99mTc-DPD scintigraphy. Nineteen patients underwent clinically indicated endomyocardial biopsy (e.g., if biopsies from other sites had failed to confirm the presence and type of amyloidosis).
The University College London/University College London Hospital Joint Committees on the Ethics of Human Research approved the study, and all participants provided written informed consent.
Patients with standard contraindications to CMR or glomerular filtration rate <30 ml/min/1.73 m2 were excluded.
CMR protocol
All participants underwent CMR on a 1.5-T scanner (Avanto, Siemens Healthcare, Erlangen, Germany). A standard volume and LGE study was performed. The gadolinium-based contrast agent used was 0.1 mmol/kg gadoterate meglumine (Dotarem, Guerbet SA, Paris, France). The LGE sequence used was either standard fast low-angle single-shot inversion recovery (FLASH-IR) or true fast imaging with steady-state free precession (true-FISP) sequence with phase-sensitive inversion recovery (PSIR) or magnitude reconstruction. For native T1 mapping, basal and midventricular short axis, and 4-chamber long-axis were acquired using the shortened modified Look-Locker inversion recovery (ShMOLLI) sequence after regional shimming, as previously described (16). Post-contrast T1 mapping was performed using the same sequence and slice positions. For T2 mapping, a 4-chamber long-axis matching the T1 map was acquired using an investigational prototype (WIP 448B, Siemens Healthcare, Erlangen, Germany). This sequence (17) uses 3 single-shot T2-prepared steady state free precession (SSFP) readouts each separated with 3 heartbeats for T1 recovery. The echo times (TE) for the individual T2 preparations were 0, 25, and 45 ms. A monoexponential fit to a 2-parameter model, S=PDexp(-TE/T2), was used at each pixel to estimate proton density (PD) and T2.
CMR image analysis
All analysis was performed offline. LGE was graded as none, subendocardial, or transmural as previously described (5). T1 and T2 measurements were performed by drawing a region of interest in the basal to mid septum of the 4-chamber map. For ECV measurement, a single region of interest was drawn in each of the 4 required areas: myocardial T1 estimates (basal to midseptum in 4-chamber map) and blood T1 estimates (LV cavity blood pool in 4-chamber map, avoiding the papillary muscles) before and after contrast administration. Hematocrit was taken immediately before each CMR study. ECV was calculated as: myocardial ECV = (1 – hematocrit) × (ΔR1myocardium/ΔR1blood), where R1=1/T1 (18).
Endomyocardial biopsies
Biopsies were obtained from 19 patients. All procedures were performed percutaneously under fluoroscopic guidance and samples obtained from the right ventricle. Samples were stained with hematoxylin and eosin (HE) and interpreted by an experienced histopathologist (M.N.S.) blinded to the CMR results. Observations were graded for presence and extent of edema. To confirm presence of amyloid, histological analysis was performed by Congo red staining on 6-μm formalin-fixed and paraffin-embedded sections, and viewed under bright-field, cross-polarized, and fluorescent light. Three HE samples were unsuitable for analysis due to insufficient material so edema assessment was performed for 16 samples. Samples were also labeled with monospecific antibodies (CD68 for macrophages and CD45 for leukocytes) to assess for myocardial inflammation, which was defined as ≥14 infiltrating immune cells/mm2 (10,19,20). Six historical myocardial biopsy samples stained with HE from patients with confirmed acute myocarditis were also analyzed for the presence of edema and inflammation.
Statistical analysis was performed using SPSS Statistics version 24 (IBM Corporation, Armonk, New York). All continuous variables were normally distributed (Shapiro-Wilk), other than NT-proBNP and C-reactive protein, which were therefore log-transformed for bivariate testing; continuous variables are presented as mean ± SD with nontransformed NT-proBNP and C-reactive protein as median and interquartile range. Comparisons between groups were performed by 1-way analysis of variance, after checking for homogeneity of variance, with post hoc Bonferroni corrected pairwise comparisons. Linear association between T2 and other markers was assessed using Pearson's correlation coefficient for continuous variables and Spearman's correlation coefficient for ordinal variables. Cox proportional hazards regression analysis with univariable and multivariable modeling was used to assess predictors of mortality. Considering the low number of events, to avoid overfitting, separate multivariable models were performed, each with T2 and 2 other clinically relevant predictors. The log-rank test and Kaplan-Meier survival analysis were used to compare groups with elevated and normal T2.
We enrolled 286 patients. Baseline characteristics are shown in Table 1. The TTR mutations were: V122I (n = 32), T60A (n = 22), V30M (n = 10), S77Y (n = 2), and E54G, E89K, D38Y, G47V, E89L, I84S, I107F, and L12P in 1 case each. Of the AL patients, 54% were new referrals and had not commenced chemotherapy at the time of CMR scanning (untreated AL amyloidosis). The remainder were undergoing or had completed chemotherapy (treated AL amyloidosis). Of these treated patients, 24 (52%) had a full response or very good partial clonal response, 16 (35%) had a partial response, and 6 (2%) had no response to treatment. The majority of patients were New York Heart Association functional class I or II (84% AL amyloidosis group, 81% ATTR amyloidosis group). Overall, 46% of patients were in sinus rhythm, 40% in atrial fibrillation, and 3% in atrial flutter. All patients had a heart rate of <110 beats/min at the time of CMR scan. Median time from CMR to cardiac biopsy was 72 days.
Baseline Characteristics of Participants With AL Amyloidosis With and Without Cardiac Involvement, Cardiac ATTR Amyloidosis, Possible Cardiac ATTR Amyloidosis, and TTR Gene Mutation Carriers
Sixty-five (65%) AL amyloidosis and 163 (88%) ATTR amyloidosis patients had definite cardiac amyloidosis. Compared to patients with cardiac AL amyloidosis, patients with cardiac ATTR amyloidosis had higher LV mass index (137 ± 33 g/1.73 m2 vs. 101 ± 35 g/1.73 m2; p < 0.001), lower EF (54 ± 13% vs. 64 ± 13%; p < 0.001), and higher ECV (0.63 ± 0.10 vs. 0.51 ± 0.10; p < 0.001) (Figure 1). There were no significant differences in native T1 or serum NT-proBNP.
Characteristic Cardiovascular Magnetic Resonance Scans
Example of cardiovascular magnetic resonance images of patients with cardiac light-chain (AL) amyloidosis (top row), cardiac transthyretin (ATTR) amyloidosis (middle row), and a healthy volunteer (bottom row). Images (left to right): steady-state free precession cine at end-diastole (ED), late gadolinium enhancement (LGE) imaging (phase-sensitive inversion recovery), native T1 map (modified Look-Locker inversion recovery), T2 map, and extracellular volume (ECV) map.
T2 was increased in amyloidosis (AL and ATTR) compared with healthy volunteers and highest in treatment naive AL amyloidosis patients (untreated AL amyloidosis 56.6 ± 5.1 ms; treated AL amyloidosis 53.6 ± 3.9 ms; ATTR amyloidosis 54.2 ± 4.1 ms; control subjects 48.9 ± 2.0 ms; p < 0.01 for all pairwise comparisons except treated AL amyloidosis vs. ATTR amyloidosis) (Figure 2A). These differences remained present after exclusion of patients with no cardiac amyloid and TTR mutation carriers (untreated AL amyloidosis 58.5 ± 5.5 ms; treated AL amyloidosis 55.1 ± 5.5 ms; ATTR amyloidosis 54.5 ± 4.1 ms; control subjects 48.9 ± 2.0 ms; p < 0.05 for all pairwise comparisons except AL amyloidosis treated vs. ATTR amyloidosis). ECV was highest in ATTR amyloidosis (untreated AL amyloidosis 0.48 ± 0.13; treated AL amyloidosis 0.42 ± 0.10; ATTR amyloidosis 0.60 ± 0.13, 0.28 ± 0.03; control subjects; p < 0.01 for all pairwise comparisons except untreated AL amyloidosis vs. treated AL amyloidosis) (Figure 2B). In the overall population, and separately in AL and ATTR, there was weak association between T2 and markers of disease severity including native T1, ECV, extent of LGE, LV mass index, and NT-proBNP, and no correlation with New York Heart Association functional class, heart rate, or C-reactive protein (Table 2).
Mean T2 and ECV in Cardiac Amyloidosis and Healthy Volunteers
(A) Mean T2 showing increased T2 in untreated cardiac AL amyloidosis compared with treated cardiac AL and cardiac ATTR amyloidosis. (B) Mean ECV showing increased ECV in cardiac ATTR amyloidosis compared with treated and untreated AL amyloidosis. Abbreviations as in Figure 1.
Correlation Between T2 and Cardiac Function, Biomarkers, and 6-Min Walk Test
At follow-up (mean 22.8 ± 14.7 months), 75 (26%) of 286 patients had died, 28 (28%) in the AL amyloidosis group and 47 (25%) in the ATTR amyloidosis group. In AL amyloidosis, survival curves indicate that at 18 months there was approximately 88% chance of survival if T2 was <55 ms compared with 67% if T2 was more than 55 ms (p = 0.01) (Figure 3), while in ATTR amyloidosis there was no relationship between T2 and prognosis (p = 0.126). Using Cox regression models, T2 predicted mortality in AL amyloidosis (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.20 to 1.82; p < 0.001) and remained significant after adjusting for ECV and NT-proBNP (HR: 1.32; 95% CI: 1.05 to 1.67; p < 0.05) (Table 3). ECV and NT-proBNP also remained independently predictive of mortality. After removal of patients with no cardiac involvement, the model remained predictive (HR: 1.37; 95% CI: 1.10 to 1.70; p < 0.05; HR after adjusting for ECV and NT-proBNP: 1.35; 95% CI: 1.04 to 1.74; p < 0.05). Alternative models were explored and T2 remained predictive of outcome after adjusting for New York Heart Association functional class and E/e′ (left ventricular early diastolic filling wave/lateral mitral annulus velocity) (HR: 1.34; 95% CI: 1.09 to 1.64; p < 0.01), LV ejection fraction and LV mass (HR: 1.44; 95% CI: 1.16 to 1.80; p = 0.001), and LV ejection fraction and E/e′ (HR: 1.41; 95% CI: 1.13 to 1.76; p < 0.01). For ATTR, T2 was not predictive of mortality (HR: 0.84; 95% CI: 0.68 to 1.04; p = 0.104).
T2 and Survival in AL Amyloidosis
Kaplan-Meier survival curves for patients with light-chain (AL) amyloidosis with high T2 and normal T2 values.
Cox Proportional Hazards Regression Analysis of Predictors of Mortality in AL Amyloidosis
Histological analysis
Of the 16 biopsy samples analyzed, 14 (87.5%) had evidence of myocardial edema on HE, defined as expansion of the interstitial space between myocytes (21,22) in the absence of fibrosis or amyloid. Increased space between myocytes was also observed with Congo red staining under bright field and fluorescent light in patients who had evidence of edema on samples stained with HE. The extent of edema was assessed by visual analysis and ranged from 5% to 40%. All samples had evidence of amyloid infiltration on Congo red staining and demonstrated apple-green birefringence under cross-polarized light. There was no correlation between visually assessed percent edema on biopsy and myocardial T2 (r = –0.265; p = 0.321). Figures 4 and 5⇓⇓ show 2 examples of patients with and without myocardial edema and their respective T2 maps on CMR.
Myocardial Biopsy and T2 Map of Patient With AL Amyloidosis
Hematoxylin and eosin (HE) staining shows increased space around myocytes (black arrows) consistent with edema. Congo red staining viewed under bright field (CR) and fluorescent light (FL) shows amyloid deposits (yellow arrows) and increased space between cells (white arrows). T2 map shows diffuse increased in T2 (57 ms in septum).
Myocardial Biopsy and T2 Map of Patient With ATTR Amyloidosis
HE staining shows no evidence of edema. CR and FL show amyloid deposits (yellow arrows). T2 map shows normal T2. Abbreviations as in Figures 1 and 4.
All samples had presence of macrophages (CD68+) and leukocytes (CD45+), but none of the samples reached diagnostic criteria for inflammatory infiltration (≥14 infiltrating immune cells/mm2) (19,20). It was observed that clustering of leukocytes and macrophages occurred around areas of amyloid infiltration (Figure 6). All of the myocarditis samples showed evidence of edema on HE, which appears similar to that seen in the amyloid samples. The myocarditis samples also showed extensive infiltration of immune cells, reaching diagnostic criteria for inflammation in all cases (Figure 7)
Example of Histology Images of a Patient With Cardiac Amyloidosis
Presence of leukocytes (CD45) and macrophages (CD68) adjacent to area of amyloid infiltration (white arrows). Amyloid infiltration (yellow arrows) demonstrated on Congo red staining under bright field (CR) and polarized light (PL) demonstrating apple green birefringence.
Comparison of Cardiac Amyloidosis and Acute Myocarditis on Histology
Myocardial biopsies of patients with (A) cardiac amyloidosis and (B, C) acute myocarditis. Hematoxylin and eosin staining shows increased space around myocytes in both amyloidosis and myocarditis (white arrows) consistent with edema. Myocarditis shows much greater infiltration of immune cells compared with amyloidosis (yellow arrows). C also shows an area of abscess (red arrows).
The presence and degree of cardiac involvement in amyloidosis is the major determinant of survival (23,24). In this study, we demonstrate evidence of myocardial edema in amyloidosis on histology and using CMR myocardial T2. Patients with untreated AL amyloidosis show the greatest increase in myocardial T2. Myocardial T2 is predictive of prognosis in AL amyloidosis even when adjusted for ECV and NT-proBNP, but not in ATTR.
CMR is now considered the imaging tool of choice for diagnosis of cardiac involvement in systemic amyloidosis. Recently, interest has emerged in measuring amyloid burden using CMR to improve the risk stratification models and provide insight into pathogenesis (25–27), but a discrepancy has emerged with the degree of amyloid infiltration typically being more severe in ATTR amyloidosis but survival being worse in AL amyloidosis (5,28). This paradox suggests that additional mechanisms beyond amyloid infiltration may contribute to the greater mortality in AL amyloidosis, such as light chain toxicity, previously demonstrated in vitro (8), or faster rate of amyloid deposition. In the present study, we confirm this discrepancy and, with the use of histology and T2 mapping, have demonstrated evidence of myocardial edema, a possible additional mechanism of myocardial damage in AL amyloidosis. The use of T1 mapping, LGE, ECV quantification, and T2 mapping allowed us to visualize and quantify both myocardial infiltration and edema, adding this latter dimension to tissue characterization that has traditionally focused solely on amyloid infiltration.
In the present study, we demonstrate T2 elevation in both types of amyloidosis. The degree of T2 elevation was highest in AL amyloidosis patients before initiation of chemotherapy, with treated AL patients having lower T2 levels, comparable to those found in ATTR amyloidosis. ECV and NT-proBNP are known to be independent predictors of outcome in both AL and ATTR amyloidosis (3,29). We demonstrate that additionally, T2 is also a predictor of mortality in AL amyloidosis after adjusting for ECV and NT-proBNP, supporting an independent role for myocardial edema in outcomes.
Our histological analysis is the first to show high prevalence of myocardial edema in patients with cardiac amyloidosis. Edema is difficult to assess histologically, being defined as the presence of increased space between cells (21,22) due to accumulation of serous fluid. Animal studies with heart water content measured at autopsy have shown that myocardial T2 is elevated in edematous tissue (30). Acute myocarditis is a condition known to be associated with myocardial edema and inflammation. When compared with myocarditis biopsy samples, our amyloid biopsy samples show similar cellular separation (consistent with edema) but a much lower level of immune cell infiltration. Edema can be secondary to an inflammatory process, systemic or localized, but can also be present without inflammation. In line with previous in vitro studies, we suggest that in cardiac amyloidosis edema is associated with light-chain or fibril toxicity or differing rates of amyloid deposition and not secondary to an inflammatory process (8,31). The absence of active inflammation is in keeping with previous work showing that there is rarely significant inflammation on histology or evidence of systemic inflammatory reaction to amyloid deposits (32). This is also consistent with the low C-reactive protein levels and minimal histological evidence of inflammation in our cohort. There was no correlation between percent edema on biopsy and CMR-measured T2, and there are a number of reasons for this. There is currently no validated method to objectively quantify edema on biopsy samples and therefore assessment in this study was by visual analysis. It is known that amyloid deposition is very patchy in affected organs (33). We believe that edema distribution too will be nonuniform and it is therefore not possible to accurately correlate extent of edema within a biopsy sample taken from a small area of myocardium with T2 value measured over a much larger area, and a different location. Future studies with postmortem whole heart assessment of water content would be required to confirm this hypothesis.
Both the elevated myocardial T2 and histology of biopsy samples suggest the presence of myocardial edema. We suggest that in cardiac amyloidosis edema is present but less prominent than infiltration, and this is consistent with the range of T2 values observed, which are lower than typically seen in myocarditis and acute myocardial infarction where edema is a much more prominent feature (9,10). These results suggest that cardiac involvement in AL amyloidosis is a spectrum characterized by variable degrees of amyloid infiltration and superimposed myocardial edema, with ECV and T2 defining separate processes that both contribute to risk (Central Illustration, Figure 1).
Myocardial Edema in Amyloidosis
In this study, cardiovascular magnetic resonance with T2 mapping and histological analysis were used to characterize myocardial edema in amyloidosis. Edema is prevalent on endomyocardial biopsy of patients with amyloidosis. Myocardial T2 is elevated in amyloidosis compared with healthy control subjects, with the degree of elevation being the highest in untreated light-chain (AL) amyloidosis patients. T2 is predictive of prognosis in AL amyloidosis, remaining significant when adjusted for extracellular volume and N-terminal pro–B-type natriuretic peptide.
Previous work on myocardial T2 signal in cardiac amyloidosis has reported conflicting results. Two studies (n = 35 and n = 36, respectively) reported that myocardial T2 ratio (between myocardium and skeletal muscle) was reduced in patients with cardiac amyloidosis (13,14), while 1 study (n = 12) using T2 mapping reported no difference between patients with cardiac amyloidosis and control subjects (34). Several reasons could be responsible for these findings. First, amyloid deposition can be present in the skeletal muscle and skeletal muscle T2 may be activity dependent (35), introducing a possible confounder when the T2 ratio between myocardium and skeletal muscle is used. Secondly, these studies all had small patient numbers with no separate analysis of AL amyloidosis and ATTR amyloidosis patients. Third, the traditional dark blood turbo spin echo techniques as used in the first 2 of these studies may be prone to myocardial signal variation and signal loss (36).
T2 mapping measurements may also be prone to technical confounders. T2 measurement using multiple single-shot T2-prepared SSFP images (17) uses 3 recovery beats. The estimate of T2 is slightly confounded by tissue T1 for 2 reasons. First, there is T1-dependent regrowth of magnetization following T2-preparation because a linear phase encode order is employed, causing a slight T1-dependent bias (37). When we simulated this effect using our protocol, T2 falls <1 ms for a 100-ms elevation in T1. Second, there is incomplete magnetization using 3 recovery beats reducing measured T2 slightly as T1 increases. It has previously been demonstrated that age and heart rate have little effect on measured T2 in healthy volunteers (17). Within our cohort, there was no correlation of heart rate, age, or hematocrit with T2.
While T1 is elevated in cardiac amyloidosis, the correlation between native T1 and myocardial T2 is weak. Native T1 is a measure of myocardial relaxation influenced by the extracellular and intracellular compartments, both free water and water bound to large molecules such as collagen or amyloid (38), whereas T2 is more specific for free water. We propose that the measured T1 signal in cardiac amyloidosis is a composite of amyloid burden and myocardial edema whereas T2 is more specific for edema, with the overall population comprising a spectrum with varying degrees of amyloid infiltration and myocardial edema.
Our findings have potential implications for clinical management. Currently, patient stratification by CMR is mainly based on parameters linked to amyloid infiltration such as LGE pattern and ECV. A multiparametric mapping approach has potential to change this. T2 mapping is a noncontrast technique, which could also be applied to patients with renal failure, although further studies will need to validate the role of T2 mapping in this setting.
Further work is needed to confirm the hypothesis linking myocardial edema to light-chain or AL amyloidosis fibril toxicity or the typically rapid rate of amyloid deposition in AL amyloidosis. Our model suggests that if light-chain production is "switched off" using chemotherapy, T2 may be expected to fall, tracking reduction in free light chains and brain natriuretic peptide. This is supported by the fact that untreated AL patients demonstrated higher T2 levels than did those established on treatment. Prospective follow-up studies assessing changes within patients during chemotherapy will be able to more fully assess this hypothesis and explore the role of T2 mapping to monitor treatment response.
Study limitations
A limitation of this study is that we did not have information on the causes of death, as the National Amyloidosis Centre assesses patients from throughout the United Kingdom. As a result, when patients die locally, only notification of death rather than cause of death is received. This is a single-center study, with no paired scans performed before and after chemotherapy. Furthermore, the T2 values may not have the same reference range in other CMR scanners. Finally, troponin was measured only in a minority of patients and therefore not included in the final analysis.
Myocardial edema is present in cardiac amyloidosis as confirmed on histology and measured by CMR with T2 mapping. T2 mapping provides unique information in AL amyloidosis, with elevation associated with increased risk of death and remaining an independent predictor of prognosis after adjustment for known prognostic factors. These findings support the concept of AL amyloidosis not being a disease of pure infiltration, but one in which additional mechanisms contribute to mortality; the study highlights the potential role of CMR with multiparametric mapping for evaluating this patient population.
COMPETENCY IN MEDICAL KNOWLEDGE: Myocardial edema, a common histological finding in patients with cardiac amyloidosis, can be measured by CMR T2 mapping and may be a useful tool in risk stratification.
TRANSLATIONAL OUTLOOK: Longitudinal studies are needed to clarify the role of T2 mapping in monitoring the response to treatment in patients with cardiac AL amyloidosis.
The authors are grateful for the contributions of patients, and the administrative and clinical staff at the National Amyloidosis Centre and the Heart Hospital.
↵∗ Drs. Kotecha and Martinez-Naharro contributed equally to this work and are joint first authors.
This study was supported by the National Amyloidosis Centre, University College London. Dr. Gillmore has served on the advisory board for GlaxoSmithKline/Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
Abbreviations and Acronyms
99mTc-DPD
99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid
light chain
transthyretin
confidence interval
cardiovascular magnetic resonance
extracellular volume fraction
hematoxylin and eosin
hazard ratio
LGE
late-gadolinium enhancement
left ventricular
NT-proBNP
N-terminal pro–B-type natriuretic peptide
SSFP
steady-state free precession
Received October 30, 2017.
Revision received March 26, 2018.
Accepted March 26, 2018.
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Tushar Kotecha, Ana Martinez-Naharro, Thomas A. Treibel, Rohin Francis, Sabrina Nordin, Amna Abdel-Gadir, Daniel S. Knight, Giulia Zumbo, Stefania Rosmini, Viviana Maestrini, Heerajnarain Bulluck, Roby D. Rakhit, Ashutosh D. Wechalekar, Janet Gilbertson, Mary N. Sheppard, Peter Kellman, Julian D. Gillmore, James C. Moon, Philip N. Hawkins, Marianna Fontana
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Planet Hollywood Converting Its Times Square All Star Cafe to Regular Restaurant
ORLANDO-Fighting to return to profitability, the locally-based, celebrity-themed chain also plans to close its 57th Street Planet Hollywood unit in New York by year end. The 45th Street Official All Star Cafe closed last week.
By Alex Finkelstein | Updated on October 02, 2000
ORLANDO-Emerging from Chapter 11 protection from creditors last year, the reorganized 60-restaurant Planet Hollywood company is sticking to its core operations converting, closing or selling unprofitable locations.
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The chain has two All Star Cafes remaining in Miami Beach, FL and Myrtle Beach, SC. Company officials are undetermined what the fate will be of those two properties but industry sources suggest they may be either closed, sold to a franchised operator or converted to a Planet Hollywood restaurant.
Worldwide, Planet Hollywood has 29 company-owned outlets and generates liclensing revenue from another 28 franchised Planet Hollywoods and four All Star Cafes. One All Star Cafe is operated in Lake Buena Vista, FL by Walt Disney World.
California Approves San Francisco's Plan to Build 82K Homes
Eight-year plan calls for rezoning for half of total be done by 2026.
Developers to Build $850M Walkable Village at Phoenix's Metrocenter Mall
The redevelopment project is to begin immediately.


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Ready to Sparkle Fashions
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Born in Scotland to Italian parents, Paolozzi attended evening classes at the Edinburgh College of Art and studied at St. Martin's School of Art, later transferring to London's Slade School of Art, where he graduated in 1947. He moved to Paris for three years where he became involved in Dadaism and Surrealism. In 1950, Paolozzi returned to London, quickly becoming a leading member of the Independent Group.
A significant member of the Group, Paolozzi greatly influenced the development of Pop Art. He emerged fully onto the Pop Art scene in 1962 with his abstract, robot-like figures such as Four Towers and Solo, but of all his work his screenprints are said to have had the largest impact on Pop Art. He taught all over the world as guest professor and lecturer, and was knighted in 1988. Eduardo Paolozzi died in 2005.


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Shemar Moore TV Roles
An iconic, enduring soap opera, this is the steamer set in Genoa City, where the Newman and Abbott dynasties stir it up in the bedroom and the boardroom. Best known for long-term love triangles, issue-oriented plots, a multi-ethnic cast and slick production values, `Y&R' has been showered with Emmys, launched countless careers and spawned the equally la (more…)An iconic, enduring soap opera, this is the steamer set in Genoa City, where the Newman and Abbott dynasties stir it up in the bedroom and the boardroom. Best known for long-term love triangles, issue-oriented plots, a multi-ethnic cast and slick production values, `Y&R' has been showered with Emmys, launched countless careers and spawned the equally lavish `The Bold and the Beautiful.' Former cast members include Tom Selleck and David Hasselhoff.
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The temperature in Missoula, Montana in April is highly unpredictable, so use the forecast as a guide, but be ready for anything!
Even in the heart of summer, temperatures in Missoula rarely reach 70 degrees. Temperatures average in the 60s from June to August, but they are much cooler the rest of the year. Five months of the year, Missoula averages temperatures in the 20s and 30s. As a result, camping in the area requires plenty of warm clothing and extra blankets. Missoula is not very wet, as it only averages 13.5 inches of rain annually.
The National Bison Range in Moiese is a landmark wildlife refuge. Established in 1908, it's one of the United States' oldest wildlife refuges. Visitors can see hundreds of buffalo that live on the range, along with elk, deer, black bears and bighorn sheep. Traveler's Rest State Park, a centuries-old Native American campsite used by Lewis and Clark, offers outdoor activities like fishing, boating and swimming, and is located about 45 miles from Missoula. Flathead Lake is another popular outdoor destination near Missoula. Visitors to Flathead Lake can go swimming at its many beaches or fish.
Dickinson, Jeff. "RV Camping in Missoula, Montana." Travel Tips - USA Today, https://traveltips.usatoday.com/rv-camping-missoula-montana-19910.html. Accessed 24 April 2019.
University (Main) Hall, University of Montana, in Missoula, Montana, United states.
Climbed to "The M" with a tripod to play with my new Canon Digital Rebel XT by taking some sunset pics of Missoula and the surrounding scenery.