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Familial transthyretin amyloid polyneuropathy
Curator: Larry H. Bernstein, MD, FCAP
First-Ever Evidence that Patisiran Reduces Pathogenic, Misfolded TTR Monomers and Oligomers in FAP Patients
We reported data from our ongoing Phase 2 open-label extension (OLE) study of patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic polyneuropathy (FAP). Alnylam scientists and collaborators from The Scripps Research Institute and Misfolding Diagnostics, Inc. were able to measure the effects of patisiran on pathogenic, misfolded TTR monomers and oligomers in FAP patients. Results showed a rapid and sustained reduction in serum non-native conformations of TTR (NNTTR) of approximately 90%. Since NNTTR is pathogenic in ATTR amyloidosis and the level of NNTTR reduction correlated with total TTR knockdown, these results provide direct mechanistic evidence supporting the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. Furthermore, complete 12-month data from all 27 patients that enrolled in the patisiran Phase 2 OLE study showed sustained mean maximum reductions in total serum TTR of 91% for over 18 months and a mean 3.1-point decrease in mNIS+7 at 12 months, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics. Importantly, patisiran administration continues to be generally well tolerated out to 21 months of treatment.
View the non-native TTR poster (480 KB PDF)
View the complete 12-month patisiran Phase 2 OLE data presentation (620 KB PDF)
We are encouraged by these new data that provide continued support for our hypothesis that patisiran has the potential to halt neuropathy progression in patients with FAP. If these results are replicated in a randomized, double-blind, placebo-controlled study, we believe that patisiran could emerge as an important treatment option for patients suffering from this debilitating, progressive and life-threatening disease.
Hereditary ATTR Amyloidosis with Polyneuropathy (hATTR-PN)
ATTR amyloidosis is a progressive, life-threatening disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in multiple organs, but primarily in the peripheral nerves and heart. ATTR amyloidosis can lead to significant morbidity, disability, and mortality. The TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein – one of the vehicles used to transport vitamin A around the body. Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils that typically contain both mutant and wild-type TTR that deposit in tissues such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.
ATTR represents a major unmet medical need with significant morbidity and mortality. There are over 100 reported TTR mutations; the particular TTR mutation and the site of amyloid deposition determine the clinical manifestations of the disease whether it is predominantly symptoms of neuropathy or cardiomyopathy.
Specifically, hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease leading to death within 5 to 15 years. It is due to a mutation in the transthyretin (TTR) gene, which causes misfolded TTR proteins to accumulate as amyloid fibrils predominantly in peripheral nerves and other organs. hATTR-PN can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death.
It is estimated that hATTR-PN, also known as FAP, affects approximately 10,000 people worldwide. Patients have a life expectancy of 5 to 15 years from symptom onset, and the only treatment options for early stage disease are liver transplantation and TTR stabilizers such as tafamidis (approved in Europe) and diflunisal. Unfortunately liver transplantation has limitations, including limited organ availability as well as substantial morbidity and mortality. Furthermore, transplantation eliminates the production of mutant TTR but does not affect wild-type TTR, which can further deposit after transplantation, leading to cardiomyopathy and worsening of neuropathy. There is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.
Our ATTR program is the lead effort in our Genetic Medicine Strategic Therapeutic Area (STAr) product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of rare diseases with high unmet medical need. We are developing patisiran (ALN-TTR02), an intravenously administered RNAi therapeutic, to treat the hATTR-PN form of the disease.
Patisiran for the Treatment hATTR-PN
APOLLO Phase 3 Trial
In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran and revusiran, for the treatment of ATTR amyloidosis in Japan and the broader Asian-Pacific region. In early 2014, this relationship was extended as a significantly broader alliance to advance RNAi therapeutics as genetic medicines. Under this new agreement, Alnylam will lead development and commercialization of patisiran in North America and Europe while Genzyme will develop and commercialize the product in the rest of world.
Hereditary ATTR Amyloidosis with Cardiomyopathy (hATTR-CM)
ATTR amyloidosis is a progressive, life-threatening disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in multiple organs, but primarily in the peripheral nerves and heart. ATTR amyloidosis can lead to significant morbidity, disability, and mortality. The TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein – one of the vehicles used to transport vitamin A around the body. Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils that typically contain both mutant and wild-type TTR that deposit in tissues such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.
Click to Enlarge http://www.alnylam.com/web/assets/tetramer.jpg
ATTR represents a major unmet medical need with significant morbidity and mortality. There are over 100 reported TTR mutations; the particular TTR mutation and the site of amyloid deposition determine the clinical manifestations of the disease, whether it is predominantly symptoms of neuropathy or cardiomyopathy.
Specifically, hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM), also known as familial amyloidotic cardiomyopathy (FAC), is an inherited, progressive disease leading to death within 2 to 5 years. It is due to a mutation in the transthyretin (TTR) gene, which causes misfolded TTR proteins to accumulate as amyloid fibrils primarily in the heart. Hereditary ATTR amyloidosis with cardiomyopathy can result in heart failure and death.
While the exact numbers are not known, it is estimated hATTR-CM, also known as FAC affects at least 40,000 people worldwide. hATTR-CM is fatal within 2 to 5 years of diagnosis and treatment is currently limited to supportive care. Wild-type ATTR amyloidosis (wtATTR amyloidosis), also known as senile systemic amyloidosis, is a nonhereditary, progressive disease leading to death within 2 to 5 years. It is caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in the heart. Wild-type ATTR amyloidosis can cause cardiomyopathy and result in heart failure and death. There are no approved therapies for the treatment of hATTR-CM or SSA; hence there is a significant unmet need for novel therapeutics to treat these patients.
Our ATTR program is the lead effort in our Genetic Medicine Strategic Therapeutic Area (STAr) product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of rare diseases with high unmet medical need. We are developing revusiran (ALN-TTRsc), a subcutaneously administered RNAi therapeutic for the treatment of hATTR-CM.
Revusiran for the Treatment of hATTR-CM
ENDEAVOUR Phase 3 Trial
In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran and revusiran, for the treatment of ATTR amyloidosis in Japan and the broader Asian-Pacific region. In early 2014, this relationship was extended as a broader alliance to advance RNAi therapeutics as genetic medicines. Under this new agreement, Alnylam and Genzyme have agreed to co-develop and co-commercialize revusiran in North America and Europe, with Genzyme developing and commercializing the product in the rest of world. This broadened relationship on revusiran is aimed at expanding and accelerating the product's global value.
Pre-Clinical Data and Advancement of ALN-TTRsc02 for Transthyretin-Mediated Amyloidosis
We presented pre-clinical data with ALN-TTRsc02, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis). In pre-clinical studies, including those in non-human primates (NHPs), ALN-TTRsc02 achieved potent and highly durable knockdown of serum TTR of up to 99% with multi-month durability achieved after just a single dose, supportive of a potentially once quarterly dose regimen. Results from studies comparing TTR knockdown activity of ALN-TTRsc02 to that of revusiran showed that ALN-TTRsc02 has a markedly superior TTR knockdown profile. Further, in initial rat toxicology studies, ALN-TTRsc02 was found to be generally well tolerated with no significant adverse events at doses as high as 100 mg/kg.
Emerging Therapies for Transthyretin Cardiac Amyloidosis Could Herald a New Era for the Treatment of HFPEF
Oct 14, 2015 | Adam Castano, MD; David Narotsky, MD; Mathew S. Maurer, MD, FACC
Heart failure with a preserved ejection fraction (HFPEF) is a clinical syndrome that has no pharmacologic therapies approved for this use to date. In light of failed medicines, cardiologists have refocused treatment strategies based on the theory that HFPEF is a heterogeneous clinical syndrome with different etiologies. Classification of HFPEF according to etiologic subtype may, therefore, identify cohorts with treatable pathophysiologic mechanisms and may ultimately pave the way forward for developing meaningful HFPEF therapies.1
A wealth of data now indicates that amyloid infiltration is an important mechanism underlying HFPEF. Inherited mutations in transthyretin cardiac amyloidosis (ATTRm) or the aging process in wild-type disease (ATTRwt) cause destabilization of the transthyretin (TTR) protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure (Figure 1). In an autopsy study of HFPEF patients, almost 20% without antemortem suspicion of amyloid had left ventricular (LV) TTR amyloid deposition.2 Even more resounding evidence for the contribution of TTR amyloid to HFPEF was a study in which 120 hospitalized HFPEF patients with LV wall thickness ≥12 mm underwent technetium-99m 3,3-diphosphono-1,2-propranodicarboxylic acid (99mTc-DPD) cardiac imaging,3,4 a bone isotope known to have high sensitivity and specificity for diagnosing TTR cardiac amyloidosis.5,6 Moderate-to-severe myocardial uptake indicative of TTR cardiac amyloid deposition was detected in 13.3% of HFPEF patients who did not have TTR gene mutations. Therefore, TTR cardiac amyloid deposition, especially in older adults, is not rare, can be easily identified, and may contribute to the underlying pathophysiology of HFPEF.
Figure 1
As no U.S. Food and Drug Administration-approved drugs are currently available for the treatment of HFPEF or TTR cardiac amyloidosis, the development of medications that attenuate or prevent TTR-mediated organ toxicity has emerged as an important therapeutic goal. Over the past decade, a host of therapies and therapeutic drug classes have emerged in clinical trials (Table 1), and these may herald a new direction for treating HFPEF secondary to TTR amyloid.
Table 1
TTR Silencers (siRNA and Antisense Oligonucleotides)
Ribonucleic acid interference (RNAi) has surfaced as an endogenous cellular mechanism for controlling gene expression. Small interfering RNAs (siRNAs) delivered into cells can disrupt the production of target proteins.7,8 A formulation of lipid nanoparticle and triantennary N-acetylgalactosamine (GalNAc) conjugate that delivers siRNAs to hepatocytes is currently in clinical trials.9 Prior research demonstrated these GalNAc-siRNA conjugates result in robust and durable knockdown of a variety of hepatocyte targets across multiple species and appear to be well suited for suppression of TTR gene expression and subsequent TTR protein production.
The TTR siRNA conjugated to GalNAc, ALN-TTRSc, is now under active investigation as a subcutaneous injection in phase 3 clinical trials in patients with TTR cardiac amyloidosis.10 Prior phase 2 results demonstrated that ALN-TTRSc was generally well tolerated in patients with significant TTR disease burden and that it reduced both wild-type and mutant TTR gene expression by a mean of 87%. Harnessing RNAi technology appears to hold great promise for treating patients with TTR cardiac amyloidosis. The ability of ALN-TTRSc to lower both wild-type and mutant proteins may provide a major advantage over liver transplantation, which affects the production of only mutant protein and is further limited by donor shortage, cost, and need for immunosuppression.
Antisense Oligonucleotides
Antisense oligonucleotides (ASOs) are under clinical investigation for their ability to inhibit hepatic expression of amyloidogenic TTR protein. Currently, the ASO compound, ISIS-TTRRx, is under investigation in a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with familial amyloid polyneuropathy (FAP).11 The primary objective is to evaluate its efficacy as measured by change in neuropathy from baseline relative to placebo. Secondary measures will evaluate quality of life (QOL), modified body mass index (mBMI) by albumin, and pharmacodynamic effects on retinol binding protein. Exploratory objectives in a subset of patients with LV wall thickness ≥13 mm without a history of persistent hypertension will examine echocardiographic parameters, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and polyneuropathy disability score relative to placebo. These data will facilitate analysis of the effect of antisense oligonucleotide-mediated TTR suppression on the TTR cardiac phenotype with a phase 3 trial anticipated to begin enrollment in 2016.
TTR Stabilizers (Diflunisal, Tafamidis)
Several TTR-stabilizing agents are in various stages of clinical trials. Diflunisal, a traditionally used and generically available nonsteroidal anti-inflammatory drug (NSAID), binds and stabilizes familial TTR variants against acid-mediated fibril formation in vitro and is now in human clinical trials.12,13 The use of diflunisal in patients with TTR cardiac amyloidosis is controversial given complication of chronic inhibition of cyclooxygenase (COX) enzymes, including gastrointestinal bleeding, renal dysfunction, fluid retention, and hypertension that may precipitate or exacerbate heart failure in vulnerable individuals.14-17 In TTR cardiac amyloidosis, an open-label cohort study suggested that low-dose diflunisal with careful monitoring along with a prophylactic proton pump inhibitor could be safely administered to compensated patients.18 An association was observed, however, between chronic diflunisal use and adverse changes in renal function suggesting that advanced kidney disease may be prohibitive in diflunisal therapy.In FAP patients with peripheral or autonomic neuropathy randomized to diflunisal or placebo, diflunisal slowed progression of neurologic impairment and preserved QOL over two years of follow-up.19 Echocardiography demonstrated cardiac involvement in approximately 50% of patients.20 Longer-term safety and efficacy data over an average 38 ± 31 months in 40 Japanese patients with hereditary ATTR amyloidosis who were not candidates for liver transplantation showed that diflunisal was mostly well tolerated.12 The authors cautioned the need for attentive monitoring of renal function and blood cell counts. Larger multicenter collaborations are needed to determine diflunisal's true efficacy in HFPEF patients with TTR cardiac amyloidosis.
Tafamidis is under active investigation as a novel compound that binds to the thyroxine-binding sites of the TTR tetramer, inhibiting its dissociation into monomers and blocking the rate-limiting step in the TTR amyloidogenesis cascade.21 The TTR compound was shown in an 18-month double-blind, placebo-controlled trial to slow progression of neurologic symptoms in patients with early-stage ATTRm due to the V30M mutation.22 When focusing on cardiomyopathy in a phase 2, open-label trial, tafamidis also appeared to effectively stabilize TTR tetramers in non-V30M variants, wild-type and V122I, as well as biochemical and echocardiographic parameters.23,24 Preliminary data suggests that clinically stabilized patients had shorter disease duration, lower cardiac biomarkers, less myocardial thickening, and higher EF than those who were not stabilized, suggesting early institution of therapy may be beneficial. A phase 3 trial has completed enrollment and will evaluate the efficacy, safety, and tolerability of tafamidis 20 or 80 mg orally vs. placebo.25 This will contribute to long-term safety and efficacy data needed to determine the therapeutic effects of tafamidis among ATTRm variants.
Amyloid Degraders (Doxycycline/TUDCA and Anti-SAP Antibodies)
While silencer and stabilizer drugs are aimed at lowering amyloidogenic precursor protein production, they cannot remove already deposited fibrils in an infiltrated heart. Removal of already deposited fibrils by amyloid degraders would be an important therapeutic strategy, particularly in older adults with heavily infiltrated hearts reflected by thick walls, HFPEF, systolic heart failure, and restrictive cardiomyopathy. Combined doxycycline and tauroursodeoxycholic acid (TUDCA) disrupt TTR amyloid fibrils and appeared to have an acceptable safety profile in a small phase 2 open-label study among 20 TTR patients. No serious adverse reactions or clinical progression of cardiac or neuropathic involvement was observed over one year.26 An active phase 2, single-center, open-label, 12-month study will assess primary outcome measures including mBMI, neurologic impairment score, and NT-proBNP.27 Another phase 2 study is examining the tolerability and efficacy of doxycycline/TUDCA over an 18-month period in patients with TTR amyloid cardiomyopathy.28 Additionally, a study in patients with TTR amyloidosis is ongoing to determine the effect of doxycycline alone on neurologic function, cardiac biomarkers, echocardiographic parameters, modified body mass index, and autonomic neuropathy.29
Anti-SAP Antibodies
In order to safely clear established amyloid deposits, the role of the normal, nonfibrillar plasma glycoprotein present in all human amyloid deposits, serum amyloid P component (SAP), needs to be more clearly understood.30 In mice with amyloid AA type deposits, administration of antihuman SAP antibody triggered a potent giant cell reaction that removed massive visceral amyloid deposits without adverse effects.31 In humans with TTR cardiac amyloidosis, anti-SAP antibody treatments could be feasible because the bis-D proline compound, CPHPC, is capable of clearing circulating human SAP, which allow anti-SAP antibodies to reach residual deposited SAP. In a small, open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis, none of whom had clinical evidence of cardiac amyloidosis, were treated with CPHPC followed by human monoclonal IgG1 anti-SAP antibody.32 No serious adverse events were reported and amyloid deposits were cleared from the liver, kidney, and lymph node. Anti-SAP antibodies hold promise as a potential amyloid therapy because of their potential to target all forms of amyloid deposits across multiple tissue types.
Mutant or wild-type TTR cardiac amyloidoses are increasingly recognized as a cause of HFPEF. Clinicians need to be aware of this important HFPEF etiology because the diverse array of emerging disease-modifying agents for TTR cardiac amyloidosis in human clinical trials has the potential to herald a new era for the treatment of HFPEF.
- Maurer MS, Mancini D. HFpEF: is splitting into distinct phenotypes by comorbidities the pathway forward? J Am Coll Cardiol 2014;64:550-2.
- Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113-22.
- González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015.
- Castano A, Bokhari S, Maurer MS. Unveiling wild-type transthyretin cardiac amyloidosis as a significant and potentially modifiable cause of heart failure with preserved ejection fraction. Eur Heart J 2015 Jul 28. [Epub ahead of print]
- Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120:1203-12.
- Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6:195-201.
- Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998;391:806-11.
- Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001;411:494-8.
- Kanasty R, Dorkin JR, Vegas A, Anderson D. Delivery materials for siRNA therapeutics. Nature Mater 2013;12:967-77.
- U.S. National Institutes of Health. Phase 2 Study to Evaluate ALN-TTRSC in Patients With Transthyretin (TTR) Cardiac Amyloidosis (ClinicalTrials.gov website). 2014. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01981837. Accessed 8/19/2015.
- U.S. National Institutes of Health. Efficacy and Safety of ISIS-TTRRx in Familial Amyloid Polyneuropathy (Clinical Trials.gov Website. 2013. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01737398. Accessed 8/19/2015.
- Sekijima Y, Dendle MA, Kelly JW. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 2006;13:236-49.
- Tojo K, Sekijima Y, Kelly JW, Ikeda S. Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neurosci Res 2006;56:441-9.
- Epstein M. Non-steroidal anti-inflammatory drugs and the continuum of renal dysfunction. J Hypertens Suppl 2002;20:S17-23.
- Wallace JL. Pathogenesis of NSAID-induced gastroduodenal mucosal injury. Best Pract Res Clin Gastroenterol 2001;15:691-703.
- Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.
- Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160:777-84.
- Castano A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail 2012;18:315-9.
- Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013;310:2658-67.
- Quarta CCF, Solomon RH Suhr SD, et al. The prevalence of cardiac amyloidosis in familial amyloidotic polyneuropathy with predominant neuropathy: The Diflunisal Trial. International Symposium on Amyloidosis 2014:88-9.
- Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A 2002;99 Suppl 4:16427-32.
- Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79:785-92.
- Merlini G, Plante-Bordeneuve V, Judge DP, et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res 2013;6:1011-20.
- Maurer MS, Grogan DR, Judge DP, et al. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ Heart Fail 2015;8:519-26.
- U.S. National Institutes of Health. Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy (ATTR-ACT) (ClinicalTrials.gov website). 2014. Available at: http://www.clinicaltrials.gov/show/NCT01994889. Accessed 8/19/2015.
- Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 2012;19 Suppl 1:34-6.
- U.S. National Institutes of Health. Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis (ClinicalTrials.gov website). 2011. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01171859. Accessed 8/19/2015.
- U.S. National Institutes of Health. Tolerability and Efficacy of a Combination of Doxycycline and TUDCA in Patients With Transthyretin Amyloid Cardiomyopathy (ClinicalTrials.gov website). 2013. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01855360. Accessed 8/19/2015.
- U.S. National Institutes of Health. Safety and Effect of Doxycycline in Patients With Amyloidosis (ClinicalTrials.gov website).2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01677286. Accessed 8/19/2015.
- Pepys MB, Dash AC. Isolation of amyloid P component (protein AP) from normal serum as a calcium-dependent binding protein. Lancet 1977;1:1029-31.
- Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 2010;468:93-7.
- Richards DB, Cookson LM, Berges AC, et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med 2015;373:1106-14.
The Acid-Mediated Denaturation Pathway of Transthyretin Yields a Conformational Intermediate That Can Self-Assemble into Amyloid†
Zhihong Lai , Wilfredo Colón ,‡ and Jeffery W. Kelly *
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255
Biochemistry, 1996, 35 (20), pp 6470–6482 http://dx.doi.org:/10.1021/bi952501g
Publication Date (Web): May 21, 1996 Copyright © 1996 American Chemical Society
Transthyretin (TTR) amyloid fibril formation is observed during partial acid denaturation and while refolding acid-denatured TTR, implying that amyloid fibril formation results from the self-assembly of a conformational intermediate. The acid denaturation pathway of TTR has been studied in detail herein employing a variety of biophysical methods to characterize the intermediate(s) capable of amyloid fibril formation. At physiological concentrations, tetrameric TTR remains associated from pH 7 to pH 5 and is incapable of amyloid fibril formation. Tetrameric TTR dissociates to a monomer in a process that is dependent on both pH and protein concentration below pH 5. The extent of amyloid fibril formation correlates with the concentration of the TTR monomer having an altered, but defined, tertiary structure over the pH range of 5.0−3.9. The inherent Trp fluorescence-monitored denaturation curve of TTR exhibits a plateau over the pH range where amyloid fibril formation is observed (albeit at a higher concentration), implying that a steady-state concentration of the amyloidogenic intermediate with an altered tertiary structure is being detected. Interestingly, 1-anilino-8-naphthalenesulfonate fluorescence is at a minimum at the pH associated with maximal amyloid fibril formation (pH 4.4), implying that the amyloidogenic intermediate does not have a high extent of hydrophobic surface area exposed, consistent with a defined tertiary structure. Transthyretin has two Trp residues in its primary structure, Trp-41 and Trp-79, which are conveniently located far apart in the tertiary structure of TTR. Replacement of each Trp with Phe affords two single Trp containing variants which were used to probe local pH-dependent tertiary structural changes proximal to these chromophores. The pH-dependent fluorescence behavior of the Trp-79-Phe mutant strongly suggests that Trp-41 is located near the site of the tertiary structural rearrangement that occurs in the formation of the monomeric amyloidogenic intermediate, likely involving the C-strand−loop−D-strand region. Upon further acidification of TTR (below pH 4.4), the structurally defined monomeric amyloidogenic intermediate begins to adopt alternative conformations that are not amyloidogenic, ultimately forming an A-state conformation below pH 3 which is also not amyloidogenic. In summary, analytical equilibrium ultracentrifugation, SDS−PAGE, far- and near-UV CD, fluorescence, and light scattering studies suggest that the amyloidogenic intermediate is a monomeric predominantly β-sheet structure having a well-defined tertiary structure.
Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics
Per Hammarström*, R. Luke Wiseman*, Evan T. Powers, Jeffery W. Kelly† + Author Affiliations
Science 31 Jan 2003; 299(5607):713-716 http://dx.doi.org:/10.1126/science.1079589
Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 → methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.
Rational design of potent human transthyretin amyloid disease inhibitors
Thomas Klabunde1,2, H. Michael Petrassi3, Vibha B. Oza3, Prakash Raman3, Jeffery W. Kelly3 & James C. Sacchettini1
Nature Structural & Molecular Biology 2000; 7: 312 – 321. http://dx.doi.org:/10.1038/74082
The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein–drug complexes have been determined to allow detailed analyses of the protein–drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4,6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.
First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy
Adams, Davida; Suhr, Ole B.b; Hund, Ernstc; Obici, Laurad; Tournev, Ivailoe,f; Campistol, Josep M.g; Slama, Michel S.h; Hazenberg, Bouke P.i; Coelho, Teresaj; from the European Network for TTR-FAP (ATTReuNET)
Current Opin Neurol: Feb 2016; 29 – Issue – p S14–S26 http://dx.doi.org:/10.1097/WCO.0000000000000289
Purpose of review: Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe.
Recent findings: The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes.
Summary: This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP.
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly debilitating and irreversible neurological disorder presenting symptoms of progressive sensorimotor and autonomic neuropathy [1▪,2▪,3]. TTR-FAP is caused by misfolding of the transthyretin (TTR) protein leading to protein aggregation and the formation of amyloid fibrils and, ultimately, to amyloidosis (commonly in the peripheral and autonomic nervous system and the heart) [4,5]. TTR-FAP usually proves fatal within 7–12 years from the onset of symptoms, most often due to cardiac dysfunction, infection, or cachexia [6,7▪▪].
The prevalence and disease presentation of TTR-FAP vary widely within Europe. In endemic regions (northern Portugal, Sweden, Cyprus, and Majorca), patients tend to present with a distinct genotype in large concentrations, predominantly a Val30Met substitution in the TTR gene [8–10]. In other areas of Europe, the genetic footprint of TTR-FAP is more varied, with less typical phenotypic expression [6,11]. For these sporadic or scattered cases, a lack of awareness among physicians of variable clinical features and limited access to diagnostic tools (i.e., pathological studies and genetic screening) can contribute to high rates of misdiagnosis and poorer patient outcomes [1▪,11]. In general, early and late-onset variants of TTR-FAP, found within endemic and nonendemic regions, present several additional diagnostic challenges [11,12,13▪,14].
Delay in the time to diagnosis is a major obstacle to the optimal management of TTR-FAP. With the exception of those with a clearly diagnosed familial history of FAP, patients still invariably wait several years between the emergence of first clinical signs and accurate diagnosis [6,11,14]. The timely initiation of appropriate treatment is particularly pertinent, given the rapidity and irreversibility with which TTR-FAP can progress if left unchecked, as well as the limited effectiveness of available treatments during the later stages of the disease [14]. This review aims to consolidate the existing literature and present an update of the best practices in the management of TTR-FAP in Europe. A summary of the methods used to achieve a TTR-FAP diagnosis is presented, as well as a review of available treatments and recommendations for treatment according to disease status.
Patients with TTR-FAP can present with a range of symptoms [11], and care should be taken to acquire a thorough clinical history of the patient as well as a family history of genetic disease. Delay in diagnosis is most pronounced in areas where TTR-FAP is not endemic or when there is no positive family history [1▪]. TTR-FAP and TTR-familial amyloid cardiomyopathy (TTR-FAC) are the two prototypic clinical disease manifestations of a broader disease spectrum caused by an underlying hereditary ATTR amyloidosis [19]. In TTR-FAP, the disease manifestation of neuropathy is most prominent and definitive for diagnosis, whereas cardiomyopathy often suggests TTR-FAC. However, this distinction is often superficial because cardiomyopathy, autonomic neuropathy, vitreous opacities, kidney disease, and meningeal involvement all may be present with varying severity for each patient with TTR-FAP.
Among early onset TTR-FAP with usually positive family history, symptoms of polyneuropathy present early in the disease process and usually predominate throughout the progression of the disease, making neurological testing an important diagnostic aid [14]. Careful clinical examination (e.g., electromyography with nerve conduction studies and sympathetic skin response, quantitative sensation test, quantitative autonomic test) can be used to detect, characterize, and scale the severity of neuropathic abnormalities involving small and large nerve fibres [10]. Although a patient cannot be diagnosed definitively with TTR-FAP on the basis of clinical presentation alone, symptoms suggesting the early signs of peripheral neuropathy, autonomic dysfunction, and cardiac conduction disorders or infiltrative cardiomyopathy are all indicators that further TTR-FAP diagnostic investigation is warranted. Late-onset TTR-FAP often presents as sporadic cases with distinct clinical features (e.g., milder autonomic dysfunction) and can be more difficult to diagnose than early-onset TTR-FAP (Table 2) [1▪,11,12,13▪,14,20].
Genetic testing is carried out to allow detection of specific amyloidogenic TTR mutations (Table 1), using varied techniques depending on the expertise and facilities available in each country (Table S2, http://links.lww.com/CONR/A39). A targeted approach to detect a specific mutation can be used for cases belonging to families with previous diagnosis. In index cases of either endemic and nonendemic regions that do not have a family history of disease, are difficult to confirm, and have atypical symptoms, TTR gene sequencing is required for the detection of both predicted and new amyloidogenic mutations [26,27].
Following diagnosis, the neuropathy stage and systemic extension of the disease should be determined in order to guide the next course of treatment (Table 4) [3,30,31]. The three stages of TTR-FAP severity are graded according to a patient's walking disability and degree of assistance required [30]. Systemic assessment, especially of the heart, eyes, and kidney, is also essential to ensure all aspects of potential impact of the disease can be detected [10].
Table 4
Image Tools
The goals of cardiac investigations are to detect serious conduction disorders with the risk of sudden death and infiltrative cardiomyopathy. Electrocardiograms (ECG), Holter-ECG, and intracardiac electrophysiology study are helpful to detect conduction disorders. Echocardiograms, cardiac magnetic resonance imaging, scintigraphy with bone tracers, and biomarkers (e.g., brain natriuretic peptide, troponin) can all help to diagnose infiltrative cardiomyopathy[10]. An early detection of cardiac abnormalities has obvious benefits to the patient, given that the prophylactic implantation of pacemakers was found to prevent 25% of major cardiac events in TTR-FAP patients followed up over an average of 4 years [32▪▪]. Assessment of cardiac denervation with 123-iodine meta-iodobenzylguanidine is a powerful prognostic marker in patients diagnosed with FAP [33].
Tafamidis is a first-in-class therapy that slows the progression of TTR amyloidogenesis by stabilizing the mutant TTR tetramer, thereby preventing its dissociation into monomers and amyloidogenic and toxic intermediates [55,56]. Tafamidis is currently indicated in Europe for the treatment of TTR amyloidosis in adult patients with stage I symptomatic polyneuropathy to delay peripheral neurological impairment [57].
In an 18-month, double-blind, placebo-controlled study of patients with early-onset Val30Met TTR-FAP, tafamidis was associated with a 52% lower reduction in neurological deterioration (P = 0.027), a preservation of nerve function, and TTR stabilization versus placebo [58▪▪]. However, only numerical differences were found for the coprimary endpoints of neuropathy impairment [neuropathy impairment score in the lower limb (NIS-LL) responder rates of 45.3% tafamidis vs 29.5% placebo; P = 0.068] and quality of life scores [58▪▪]. A 12-month, open-label extension study showed that the reduced rates of neurological deterioration associated with tafamidis were sustained over 30 months, with earlier initiation of tafamidis linking to better patient outcomes (P = 0.0435) [59▪]. The disease-slowing effects of tafamidis may be dependent on the early initiation of treatment. In an open-label study with Val30Met TTR-FAP patients with late-onset and advanced disease (NIS-LL score >10, mean age 56.4 years), NIS-LL and disability scores showed disease progression despite 12 months of treatment with tafamidis, marked by a worsening of neuropathy stage in 20% and the onset of orthostatic hypotension in 22% of patients at follow-up [60▪].
Tafamidis is not only effective in patients exhibiting the Val30Met mutation; it also has proven efficacy, in terms of TTR stabilization, in non-Val30Met patients over 12 months [61]. Although tafamidis has demonstrated safe use in patients with TTR-FAP, care should be exercised when prescribing to those with existing digestive problems (e.g., diarrhoea, faecal incontinence) [60▪].
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Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID) that, similar to tafamidis, slows the rate of amyloidogenesis by preventing the dissociation, misfolding, and misassembly of the mutated TTR tetramer [62,63]. Off-label use has been reported for patients with stage I and II disease, although diflunisal is not currently licensed for the treatment of TTR-FAP.
Evidence for the clinical effectiveness of diflunisal in TTR-FAP derives from a placebo-controlled, double-blind, 24-month study in 130 patients with clinically detectable peripheral or autonomic neuropathy[64▪]. The deterioration in NIS scores was significantly more pronounced in patients receiving placebo compared with those taking diflunisal (P = 0.001), and physical quality of life measures showed significant improvement among diflunisal-treated patients (P = 0.001). Notable during this study was the high rate of attrition in the placebo group, with 50% more placebo-treated patients dropping out of this 2-year study as a result of disease progression, advanced stage of the disease, and varied mutations.
One retrospective analysis of off-label use of diflunisal in patients with TTR-FAP reported treatment discontinuation in 57% of patients because of adverse events that were largely gastrointestinal [65]. Conclusions on the safety of diflunisal in TTR-FAP will depend on further investigations on the impact of known cardiovascular and renal side-effects associated with the NSAID drug class [66,67].


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Preserving the Patagonian ecosystem by protecting endangered species. This is the starting point of the "Awasi" philosophy.
When a team of biologists arrived asking for help from this property on a study of endangered species, the answer was an immediate yes. To better understand these species, they deployed a network of 'photo traps'. A respect of Nature is in the DNA of the property: initially being built on stilts to protect the land and plantlife. It is also a major client for the local organic farmer. Regular visits to neighbouring schools help share this 'green' ethic so that Patagonia remains an exceptional place.

subset: commoncrawl


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Florida Snake Identification Key
Ringneck Snake
Scientific name: Diadophis punctatus (LINNAEUS 1766)
The following will separate the two Ringneck Snakes found in Florida. If you are unable to distinguish between them based on the characteristics in the key below, you probably can do so using the geographic location alone.
Select the box below that is the closest match to your snake:
Slightly or no neck ring; Lower Florida Keys.
Your snake could be a Key Ringneck Snake, Diadophis punctatus acricus.
Distinct neck ring, but usually broken in the middle; peninsular Florida north through southern Alabama and the coastal plain to southeastern Virginia.
Your snake could be a Southern Ringneck Snake, Diadophis punctatus punctatus.
I'd like to start over from the beginning
I'd like to try identifying my snake another way.
More resources:


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There have been very few individuals who have had such a great impact on small fruit virology as Robert R. Martin. Martin was born on a dairy farm, near Athens, WI, and received a B.S. degree in forestry and a Ph.D. degree in plant pathology from the University of Wisconsin-Madison. After receiving his doctorate, Martin moved to Corvallis, OR, as a post-doctoral fellow at the USDA-ARS Horticultural Crops Research Laboratory (HCRL) from 1980 to 1982 where he studied virus diseases of strawberry under the guidance of Richard Converse, a renowned small fruit virologist. In 1982, Martin accepted a position as a plant pathologist with Agriculture and Agri-Food Canada in Vancouver, British Columbia, before moving back to the HCRL in Corvallis, OR, in 1995.
Currently, Martin is a research plant pathologist and the research leader of the Horticultural Crops Research Unit. In addition, Martin holds appointments as professor in the Department of Botany and Plant Pathology and in the Molecular and Cellular Biology Program at Oregon State University. Martin has been the leading figure worldwide in the identification, characterization, and management of viruses affecting small fruit crops (blackberry, raspberry, strawberry, cranberry, and blueberry). His research groups in Canada and the United States have identified and characterized more than 40 virus species in small fruit, ornamental, and vegetable crops. An example of his accomplishments is the fact that he has been involved in the molecular characterization of more than half of the 24 viruses known to infect strawberry. He was the first to obtain the sequence of a small fruit virus (Strawberry mild yellow edge virus) and is the leader in the development of virus-resistant small fruit crops using genetic engineering. He has developed raspberry lines resistant to Raspberry bushy dwarf virus, an accomplishment that has the potential to eliminate one the greatest problems growers face in the Pacific Northwest.
During the last 10 years, Martin has published more than 25 articles in Phytopathology, Plant Disease, and Plant Health Progress dealing with the characterization, detection, and epidemiology of strawberry, raspberry, blackberry, blueberry, cranberry, and grape viruses. He works closely with growers, identifying and addressing problems as they arise in the field and developing methods for both diagnostics and disease management. This work has had tremendous impact and resulted in economic benefits for small fruit growers in the United States and throughout the world where these crops are planted. An example of the impact of his work is the identification of a group of viruses as the causal organisms of a strawberry decline on the west coast of North America over the past six years. The IPM scheme developed in California has virtually eliminated the disease and has saved California growers an estimated $25 million/year. Martin is always eager to help colleagues around the world, and scientists from Canada, the United Kingdom, Argentina, Hungary, Germany, Tunisia, and Israel have visited his laboratory to learn new techniques developed in the Martin Lab for the detection and study of small fruit viruses. He has been invited to several countries in the Middle East and South America where he developed and presented workshops on identification and detection of small fruit viruses. Martin also has an outstanding record of professional service, especially through his many contributions to professional societies including APS. He has served APS both as a member and chair of the Biotechnology Impact Assessment and the Detection and Diagnosis Committees, and as a member of the Virology Committee. He has served as senior editor for APS PRESS and as an associate editor for Phytopathology and Plant Disease, and he has organized several APS symposia.
Given Martin's extraordinary accomplishments, we feel he is a most deserving candidate for the Lee M. Hutchins Award.


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RALEIGH, N.C. - A team of 10 doctors and their assistants crowd around an operating table. An anesthesiologist warns Dr. Greg Lewbart that his patient's heart rate has dropped to 35 beats per minute. But that's a good rate, the doctor says, for a seven-pound endangered sea turtle.
Veterinarians successfully completed experimental skull surgery on a green sea turtle Thursday at N.C. State University in Raleigh. They say the turtle, which is too young to easily tell its gender, needed the operation to close a three-inch gash to the head that had exposed the protective membrane sheathing its tiny brain.
The turtle called Holden III washed up a month ago on Holden Beach in the southern area of the state, apparently the victim of a boat propeller. Its front left flipper was fractured and the turtle was possibly blinded in one injured eye.
Beachgoers brought the turtle to the Karen Beasley Sea Turtle Hospital and Rehabilitation Center on Topsail Island where volunteers nursed it back to health. Volunteers then sought out medical options to help Holden III get back on its flippers.
"It's amazing; these little greens have such determination to live," said volunteer Peggy LeClair with the turtle hospital. "They have just strong personalities."
Green sea turtles, which can live more than 80 years and grow up to 5 feet and 700 pounds, regularly ply Atlantic waters along the Southeast coast. For a long time, the endangered turtles were hunted to make handbags and turtle soup. Later, the animal was popularized by the characters Squirt and Crush in the Disney movie "Finding Nemo."
Dr. Lewbart led the surgical team seeking to help the turtle's skull heal correctly. Skull surgery on turtles is not unprecedented, Lewbart said, adding that the university had conducted six similar surgeries during the past decade. It was Lewbart's second skull surgery on a turtle, but the first time an external brace had been used on a sea turtle.
The surgery lasted 90 minutes and included an ophthalmologist, anesthesiologist, radiologist and several lab assistants. They surrounded the table that held the 16-inch green turtle, whose brain is about as big around as a penny.
The vets decided early on that the turtle didn't have to be put under general anesthesia. Turtles have to make the conscious effort to breathe, and putting them under is typically the most dangerous part of the operation. Instead, Holden III got morphine.
Dr. Lewbart oversaw the installation of an external brace on Holden III's skull made out of stainless steel surgical wire, clothing hooks and glue. The plan, he said, was to stabilize the skull fragments and allow it to heal into a normal, functional shape.
"There was no way we could knit everything back today, there weren't enough pieces left for us to do that," Lewbart said. "We're going to let the turtle fill in those gaps with mineralized tissue."
Dr. Lewbart said Holden III was a very calm patient and was "resting comfortably" after surgery.
The doctors hope the knowledge gained will help with other turtles in the future. Meanwhile they are hopeful there are no complications.
Holden III is back at the turtle hospital where the animal will undergo rehabilitation. Lewbart plans to check back in with his patient in two weeks and volunteers hope to have the turtle back into the wild by next spring or fall 2013.
The turtle hospital volunteer LeClair said she was struck by the resilience of turtles like Holden III.
"Some of these turtles, with what they have gone through, it's amazing to see them heal and go back into the ocean."


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To get free sites on the Web, you can try USAsearch.gov for state as well as federal websites, reports, studies, hearings, etc. Possible searches would include: "reality tv" sexist (3 hits), "reality tv" sexism (2 hits); and "reality shows" profit* (50 hits). USAsearch seems to be a bit more predictable with the * (truncation) than Google is. Compare Google's only 44 hits for: "reality shows" profit* site:gov but 70 for "reality shows" profitability site:gov
You can also use site:edu to try to get more "official" or at least better documented information. Google gets at least 345 unique hits for "reality shows" profitability trends site:edu and 14 for "reality shows" "average revenue" site:edu. These site:edu, site:ac.uk, sites may also have a lot more research on sociological issues such as sexism, racism, or stereotypes in general. For example, "reality shows" sexist site:edu gets 137 unique hits in Google. We do have to beware that "site:edu" does not guarantee scholarship. Many students and staff are quite free to have their own blogs or personal websites hosted on a university server, and "peer review" is definitely not the rule for such sites.


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Saturday, December 4, 2010
December 4, 2010 'Waiting For The Glow'
More pressing is something that's going on with me right now... I have images pouring into the well, even getting me up at 2a.m. this morning and not letting me get back to sleep! The images are vague, full of mood, and are resulting from the many field sketches that I am surrounded by in the studio. I'm seeing these images based on the studies but they are 'not' the studies. This is a lot of fun. I'm seeing new ways to interpret the work from my past into something new, maybe even completely different than what I attempted to do in the original sketches. I'm not sure why this is happening, but it's driving my engine right now so I'm going to run with it.
'Waiting For The Glow' - oil on panel - 20x24 © Marc R. Hanson 2010
This is the first one, painted yesterday but tidied up about 3a.m. this morning. It's loosely based on a couple of studies I did in Sarasota, FL last May and June. What I wanted to play with was the gorgeous color that I witnessed while there. I've chosen to just include a few figures for compositional reasons, but the beaches were full of people sitting and looking out towards the water. I couldn't figure out why so many people showed up just before sunset... the beach was almost empty until then. I've been in the midwest for a long time now and had no idea about the "Glow" at the exact moment of sunset. That's what the people on the beach were doing... not going skinny dipping at night as I sort of suspected they might be getting ready to do!
A slightly blurry detail of the figures...
21 comments:
- Unknown said...
Beautiful rendition of wonderful light conditions.
- December 4, 2010 at 11:50 AM
- Ben Bauer said...
marc this is amazing! I could see somthing like this with snow and grey! Great stuff.
- December 4, 2010 at 11:58 AM
- Mary Byrom said...
Marc, Its a big event to watch this glow. My family in Sarasota took us to the beach at sunset just for this reason - and yes, everybody was arriving for the show...same thing happens in Key West and on Cadillac Mountain, in Maine for sunrise and sunset. I'm out there painting all by myself then suddenly all these cars pull up, everyone is there for the big show... very nice direction you are going in with your paintings! I'm looking forward to seeing more.
- December 4, 2010 at 12:06 PM
- rob ijbema said...
fred cumming comes to mind marc
atmosphere and mood,nothing but atmosphere and mood...
have a little look here
- December 4, 2010 at 2:19 PM
- firstname.lastname@example.com said...
Great work mark
- December 4, 2010 at 2:32 PM
- Marc R. Hanson said...
Thanks for your comments everyone. I appreciate it.
Mick and Ben I'm working on an idea now that's coming from a small gouache car study from last year. Big broad shapes...
Mary I'm glad that I'm not the only one who wasn't there for the 'glow.
Rob... Yes! I saw that and another one and picked up the DVD. In my painting life so far about 2% of the work has taken me to the place I'd like to be. They happen about one or two a year. The last one that did this was a painting last year called "Labor Day", it's on the blog here. It had the mood and sensibility that I like to paint, that speaks to me emotionally.
Robert Cuming is a painter who I think has a great balance between his skills and his awareness that first and foremost, he's a painter, not a likeness replicator.
I'm not that freed up... yet... but I am looking towards his work and that of others like him as a great inspiration to me to let loose of the grip of needing to be too literal... and just make decisions based on making the image work.
That's a wonderful freeing feeling and one that I plan to pursue with dogged determination.
I'd recommend those DVD's to everyone. There is a lot to be learned about the Art Spirit in watching and listening to him. I don't think he barely mentions his materials, so it's not a "how to" video. It's a 'why' video.
Atmosphere and mood... a good motto to have. :)
Thanks Rob.
- December 4, 2010 at 3:16 PM
- Unknown said...
pure atmosphere - just beautiful work marc
- December 4, 2010 at 3:41 PM
- Claire Beadon Carnell said...
This talks to the heart, Marc. Exquisite work.
- December 4, 2010 at 3:49 PM
- Unknown said...
Beautiful! Like a Turner.
- December 4, 2010 at 6:47 PM
- Susan Liles said...
Gorgeous lighting! I've experienced FL sunsets too and they are fantastic. You've done an excellent job!
- December 5, 2010 at 2:15 AM
- graziano tessarolo said...
beautiful paintings!!!
- December 5, 2010 at 4:50 AM
- billspaintingmn said...
This is wonderful Marc. You're going in a direction that is amazing.
- December 5, 2010 at 9:12 AM
wityrisThere is beauty in simplicity, and these are simply beautiful.
- December 5, 2010 at 9:16 AM
ugh, I've done this before, ignore that word, it's the verification
- December 5, 2010 at 9:17 AM
- Marc R. Hanson said...
Thank you all. I'm very happy to hear the reactions to this one! You're reinforcing my feelings about what I feel best about putting into a painting. It's very valuable to me... checks are in the mail... ;-)
- December 5, 2010 at 9:48 AM
- michael clark fine art said...
great mood in this one you captured the humidity and light of the coast perfectly. What kind of board are you using these days? Seems smother than the old modeling paste gesso ones.
- December 5, 2010 at 10:19 AM
- Elaine Hurst said...
This is wonderful! I love the sense of luminosity!! It makes me think of George Inness and the amazing glow he had in so many paintings. Keep it up you are on a great track!
- December 5, 2010 at 1:55 PM
- mel magee said...
wow. just when i thought you couldnt get better. these are lovely. i see you will be teaching at scottsdale..
- December 5, 2010 at 6:53 PM
- Steve PP said...
Stunning, I'm walking on that beach! Warms me up on a cold night!
- December 6, 2010 at 4:46 PM
- Hampton House Art and Framing said...
Beautiful piece (not too shabby on the frame selection either).
- December 6, 2010 at 5:00 PM
- Jala Pfaff said...
So so beautiful. Aaaah.
Glad to know I'm not the only one whose brain keeps them awake sometimes with ideas.
- December 13, 2010 at 6:15 PM


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Back to the Future T-Shirts, Gifts & Merch
Can you believe that we've now left October 21st, 2015 behind us, the date Marty McFly, Doc Brown and Jennifer Parker arrive in the future at the start of cult '80s movie Back to the Future 2?! Though we don't yet own hover boards or flying cars (sigh!), you can future-proof your wardrobe with our super-awesome Back to the Future T-Shirts, which pay tribute to the retro-tastic movie trilogy!
Whether it's a blast from the past (hello, 1955!) with our 'The Enchantment Under The Sea Dance' printed tee or and punchy, graphic-style Cafe 80s tee, paying tribute to the famous hang out spot; showing your love for the coolest car (and time machine!) to ever grace our screens, the Delorean; or simply flaunting some old-school movie love with our exclusive Back to the Future and Back to the Future 2 film poster T-Shirts, our tees and Back to the Future gifts feature tons of clever nods to some of the films' most memorable moments. It's time to relive those adventures, TruffleShuffle-style!
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If you run into problems where you run some command and the command is not found and you have to install it and run the program again then why not use the command not found plugin for Packagekit. Here is the description:
A simple helper that offers to install new packages on the command line using PackageKit.URL
You can install this with the command:
sudo yum install PackageKit-command-not-found.i686
amit@localhost> sl
Command not found. Install package \'sl\' to provide command \'sl\'? [N/y] y
* Running..
* Resolving dependencies..
* Waiting for authentication..
* Resolving dependencies..
* Downloading packages..
* Checking signatures..
* Testing changes..
* Installing packages..
* Scanning applications..
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Poverty was on the minds of Cardinal Timothy M. Dolan of New York and Bishop Nicholas DiMarzio of Brooklyn, N.Y., yesterday, the feast of St. Vincent de Paul, the 17th-century saint who devoted his life to serving the poor.
In The Gospel in the Digital Age blog on the Archdiocese of New York's website, the two church leaders commended the work of the Society of St. Vincent de Paul, but also lamented the high rates of poverty and unemployment in the Bronx and Brooklyn as pointed out by New York Times blogger Michael Powell.
But it's not just in New York where poverty runs rampant, the prelates wrote. "The basic human needs of good jobs, food, and housing continue to challenge tens of millions throughout this country," they wrote.
While acknowledging that "we are fortunate as a society … to provide for those struggling" through the use of billions of dollars donated to charities annually, they also commended government programs that "provide enormous support to poor Americans."
Cardinal Dolan and Bishop DiMarzio also raised two concerns about the support offered to people living in poverty, as related here:
It is not enough. Even with the generosity of the American people, and the works of groups like the St. Vincent de Paul Society and so many others, much more needs to be done, and not just by private charity. The government must continue to play its part as well.
There are very dark clouds. Too much rhetoric in the country portrays poor people in a very negative way. At the same time, this persistent sluggish economic (sic) and slow pace of recovery does two things that hurt the poor: it does not provide sufficient jobs for poor people to earn decent living to support themselves and it provides less resources for government to do its part for Americans in need.
These situations are "devastating to struggling families," they wrote.
In conclusion the prelates called for solidarity with the poor.
"There is too much finger pointing and not enough joining hands," they said.


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AmJam Designs was created just last month when it appeared as a website, but not too much time passed before the business was established in Morenci's downtown.
Brandon and Amy Milliman opened the business at 125 W. Main St. earlier this month with the major focus on company logo apparel. The couple has an industrial embroidery machine capable of replicating logos, school mascots or most any other design.
School-related items are the biggest draw currently, Amy said.
"We can handle varsity jackets, put a bulldog on a duffle bag or T-shirt," she said.
Brandon is in the store every day while Amy works in another job, but when someone wants AmJam to design a logo, that's when Amy takes her part in the business.
Brandon has about 10 years experience in the embroidery business, working first with a colleague and later on his own.
AmJam also does heat-pressed vinyl lettering on clothing and for signs.
The Millimans live in Fremont, Ind., but they have purchased a house in Morenci and intend to work on it over the winter and move here in the spring.
AmJam is open weekdays from 10 a.m. to 6 p.m. and Saturdays from 10 a.m. to 4 p.m. The phone number is 458-1300.


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A prayer for a miracle: the sudden, complete and lasting obliteration of COVID-19
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"This blog is like a fusion of the Baroque 'salon' with its well-tuned harpsichord around which polite society gathered for entertainment and edification and, on the other hand, a Wild West "saloon" with its out-of-tune piano and swinging doors, where everyone has a gun and something to say. Nevertheless, we try to point our discussions back to what it is to be Catholic in this increasingly difficult age, to love God, and how to get to heaven." – Fr. Z
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- JakeMC: I have a sneaking suspicion that posed this photo to poke fun at the whole "soc ial distancing " thing.
- veritas vincit: In contemplat ing return to the Mass (NO) on Pentecost, I have devoted a great deal of thought as to how to receive on the tongue. In addition to holding my breath, I plan to make...
- PostCatholic: I was the challenger , but I am not your benefactor in this instance. Congratula tions on the risotto. And I'm glad you have a generous friend out there. I do love our multi-c...
- JustaSinner: Oh no, NOT technology ! Those new fangled BBQ lighters must go the way safety tipped matches went… ;they̵ 7;re full of the Devil̵ 7;s dirt– ;sulfur! Aaaaahh...
- RCS: When do we get the official Fr Z cookbook ;)
- Joy1985: bobbortoli n That is probably due to skyrocketi ng insurance premiums
- bobbortolin: Sorry about that, "I think they' ;re awful "
- bobbortolin: My parish as push-butto n, electric votive candles. Personally , I think there awful.
- Joy1985: "Fer retti says: 25 May 2020 at 3:12 PM Votive candles for spiritual intercessi on and grilling steaks and hot dogs. There's a difference . Napalm? 221; Well what is worse light...
- Fr PJM: A look at the Ordinary of the Mass shows that there is no "exi t antiphon 8221; to which would correspond a replacing hymn or song. So when the priest or deacon says "go in...
- Moro: Honestly, while I am no theologian or canonist, I have to think just having the parents doing the baptism themselves at home would have been an incredible improvemen t. Depending upon the...
- WmHesch: Interestin gly violet vestments were worn if there was a Requiem at the side altar during 40 Hours
- tho: Experienci ng what we once had, and seeing what we have now, is very depressing . Our hierarchy reminds me of the Democrats, telling us that socialism is a viable form of government , in spite...
- Anita Moore, O.P.(lay): Yeah, the stupid is already there when it comes to baptisms. We have been inured to stupidity for a good many years. For example, years ago, at the wreckovate d cathed...
- Reflector: Missae coram sanctissim o were indeed common in Austria on "ado ration days" ;, even in the 1970ies in the novus ordo, where a high Mass was sung in the vernacular versus...
- Ferretti: Votive candles for spiritual intercessi on and grilling steaks and hot dogs. There̵ 7;s a difference . Napalm?
- dallenl: Father MartinR 17;s problem is quite comparable to a number of others in this type of situation. They are commenting on matters outside their competence . An example that comes to mind...
- ChrisP: It does seem that God allowed this virus lockdown to show us how bad things have got WORLDWIDE. Idiots and pantomime everywhere , covered by less than scrupulous and caring leaders. And...
- Joy1985: " when people started lighting candles in church with barbeque lighters 8221; Pardon me but what is wrong with that?
- Andrew Saucci: This sort of stuff should have been nipped in the bud when people started lighting candles in church with barbeque lighters, but since we didn' ;t condemn it forcefully enough...
- capchoirgirl: Ooooh! I am very much intrigued by the Contraptio n! Also seems like a good thing for smaller kitchens 8230;.I 217;m going to have to check this out.
- MargaretC: Thank you, Father, for answering this question. My own diocese has resumed public masses under very controlled conditions , but our Archbishop has continued the dispensati on from the...
- Elizabeth D: At my parish they have been doing night prayer for parishione rs, via Zoom. I do not have a cellphone/ camera, do not like videoconfe rencing or even conference calling and I do not do...
- Imrahil: Dear Alice, I think theologian s disagree on how much of the Mass one has to attend to fulfill the obligation . They don' t, strictly speaking. The obligation , as such, is from...
- Joy1985: "The re is no good reason to FOOL AROUND WITH SACRAMENTS !" Exactly Father. Never ever should play around with the Sacraments .
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- Fulton Sheen
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Fr John Zuhlsdorf
Tridentine Mass Society of Madison
733 Struck St.
Madison, WI 53744-4603
For email HERE
"The modern habit of doing ceremonial things unceremoniously is no proof of humility; rather it proves the offender's inability to forget himself in the rite, and his readiness to spoil for every one else the proper pleasure of ritual."
- C.S. Lewis
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I was at this conference last year. I'll probably go this year! That's how enjoyable it was. I've marked my calendar.
As for Latin…
"But if, in any layman who is indeed imbued with literature, ignorance of the Latin language, which we can truly call the 'catholic' language, indicates a certain sluggishness in his love toward the Church, how much more fitting it is that each and every cleric should be adequately practiced and skilled in that language!" - Pius XI
"Let us realize that this remark of Cicero (Brutus 37, 140) can be in a certain way referred to [young lay people]: 'It is not so much a matter of distinction to know Latin as it is disgraceful not to know it.'" - St. John Paul II
Recent Posts
- ASK FATHER: Mass at a side altar during Exposition of the Blessed Sacrament? And a short rant.
- 25 May – HOLY MASS (TLM) St. Gregory VII – LIVE VIDEO: 1200h CDT (GMT/UTC -5)
- How stupid are things getting in this time of Coronavirus, you ask?
- Fr. Z's Kitchen: The Contraption
- Your Sunday after Ascension 2020 Sermon Notes and the Exorcism against Satan and Apostate Angels
- PRIESTS: Are you available to take a "Gregorian Mass" intention?
- ACTION ITEM: A tip for receiving Communion on the tongue in time of COVID-1984: HOLD YOUR BREATH!
- Fearmongering @JamesMartinSJ goes to the zoo on national TV about churches reopening and about @RealDonaldTrump
- UPDATE: BAPTISMAL FONT PROJECT – INSTALLATION! Video message to YOU READERS!
- ASK FATHER: What is physically required for the laity to participate at Mass?
- 23 May – HOLY MASS (TLM) St. Giovanni Battista de Rossi – LIVE VIDEO: 1200h CDT (GMT/UTC -5)
- ASK FATHER: Can you fulfill your Sunday Mass obligation during "lockdown" by watching online?
- 22 May – HOLY MASS (TLM) St. Rita of Cascia – LIVE VIDEO: 1200h CDT (GMT/UTC -5)
- Terrific rant!
- Your Ascension Thursday 2020 Sermon Notes
- Church that refused to close during lock down gets burned down
- Fr. Z with thanks to benefactors and a reminder
- COVID-1984, Your iPhone, and You
- 21 May – HOLY MASS (TLM) for Ascension Thursday – LIVE VIDEO: 1200h CDT (GMT/UTC -5)
- Forty, a poem, and ancient garlic cheese spread
- CELEBRATE! 26th Anniversary of "Ordinatio sacerdotalis"!
- Confuse a liberal
- 20 May – St. "Golden Girl", Aurea of Ostia and a fascinating Latin inscription
- 20 May – HOLY MASS (TLM) for Rogation Wednesday – LIVE VIDEO: 1200h CDT (GMT/UTC -5)
- ASK FATHER: "Why aren't Masses restarted without Holy Communion?"
- Fr. Z's Kitchen: Supper For The Promotion of Clericalism™ – Beef!
- 19 May – HOLY MASS (TLM) St. Peter Celestine – LIVE VIDEO: 1200h CDT (GMT/UTC -5)
- A new marching cadence in the time of Coronavirus. (Fun.)
- 100th Birthday of St. John Paul II. Wherein Fr. Z muses and reminisces.
Let us pray…
Grant unto thy Church, we beseech Thee, O merciful God, that She, being gathered together by the Holy Ghost, may be in no wise troubled by attack from her foes. O God, who by sin art offended and by penance pacified, mercifully regard the prayers of Thy people making supplication unto Thee,and turn away the scourges of Thine anger which we deserve for our sins. Almighty and Everlasting God, in whose Hand are the power and the government of every realm: look down upon and help the Christian people that the heathen nations who trust in the fierceness of their own might may be crushed by the power of thine Arm. Through our Lord Jesus Christ, Thy Son, who liveth and reigneth with Thee in the unity of the Holy Ghost, God, world without end. R. Amen.
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Daily Archives: 7 May 2017
Important research with implications for feminist geography
Allow me to preface this with the reminder that I hate squirrels. That said, I promise you I am not making this up. I was alerted to this from the – no… really… Journal of Feminist Geography. No… really. Here is an … Continue reading
Posted in Lighter fare, You must be joking! Tagged feminism, feminist geography, Tracer Bullet 51 Comments
Rome – Day 4: Caprese, Carbonara and Consecration
It has been a quiet Sunday in the Eternal City, with perfect weather. This is exactly what you expect of Rome right now. ikeunchtime… which glass is mine? This entire Caprese is mine. Each strand of this is mine, also. … Continue reading
Posted in On the road, SESSIUNCULA, What Fr. Z is up to 2 Comments
Rome – Day 3: Beheadings and Swearings
It was a full day yesterday. After Mass yesterday we broke the fast and then headed off the the Palazzo Braschi for the Artemesia exhibit. Artemesia Gentileschi was the daughter of Orazio Gentileschi and a fine painter in her own right, … Continue reading
Posted in On the road, What Fr. Z is up to Tagged armor, Artemesia, Judith, Rome, Swiss Guard 7 Comments


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You can follow the discussion on Balance Your Spending With a Single-Income Budget without having to leave a comment. Cool, huh? Just enter your email address in the form here below and you're all set.
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MyHeritage.com ResearchPosted in MyHeritage
MyHeritage.com has developed a free - an interesting search feature built specifically for genealogy is which is capable of searching hundreds of databases in one query. Similar to the Ellis Island search query, it gives you variations of what your surname *could* be spelled as which allows you to search using a particular variation. My surname yielded 30 possibilities which I printed off and inserted into my research binder as a reference guide.
From their site:
"MyHeritage.com Research is a search engine built specifically for genealogy, capable of searching hundreds of major genealogy databases in a single query. It's the most comprehensive genealogy research tool existent today and the first of its kind. In simple terms, this search engine runs each query simultaneously in hundreds of genealogy databases, aggregates the results and displays them in one consolidated report. This gives you more genealogy search power than has ever been available before, in a simple, friendly and convenient interface."
For more on this or to use the feature, visit their pages at: MyHeritage Genealogy.


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Apollo Blinds brings a particular skill in designing and installing creative and practical window coverings, blinds and shutters. With a choice of thousands of fabrics, finishes and styles we have exactly the products you need to add essential elements of privacy, shade and style to your home.
Our fabric collections are constantly changing to reflect the latest fashions in home furnishings and with seasonal offers that are hard to beat, we are proud to bring our range of blinds and shutters into homes across the UK all made, measured and installed for you.
You can view our Privacy Policy here.


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Hypopituitarism, also known as an underactive pituitary gland, is a condition that affects the anterior lobe of the pituitary gland, in which the pituitary gland does not produce normal amounts of some or all of its hormones. Symptoms of hypopituitarism vary depending on which hormone is no longer being produced by the pituitary gland.
Treatments for hypopituitarism also vary. If the condition is caused as the result of a pituitary tumor, surgery may be needed for treatment. In some cases, hormone therapy is what's needed to effectively treat hypopituitarism.
However, in the November 2011 issue of Nature, a new report shows promise for the future of hypopituitarism treatment. Japanese scientists successfully treated hypopituitary mice by transplanting pituitary gland tissue they grew from embryonic mice stem cells. After the hypopitiutary mice received the transplanted cells, they began to produce hormones they were previously missing.
Researchers used the mouse stem cells arranged in a three dimensional culture and grew pituitary tissue over the course of three weeks from that culture. The resulting tissue contained all five cell types found in a normal pituitary gland.
Using such technology as a possible treatment for humans suffering from hypopituitarism is not an immediately viable option. Scientists caution that is it unlikely that pituitary tissue grown in labs will behave like functioning pituitary glands. The hope is that someday, treatment for patients with pituitary disorders will be feasible via growing pituitary tissues from the patient's own tissue.
"If and when the technology becomes developed for humans, it will require the skills of an experienced team of a pituitary endocrinologist and neurosurgeon working together with other specialists in a dedicated pituitary center to fully realize the potential opportunity for patients with pituitary hormonal deficiency," says Dr. Nelson M. Oyesiku, Co-Director Emory Pituitary Center.
For more information on hypopituitarism, or the endocrinology & neurosurgery treatment teams at Emory, visit the Emory Pituitary website.
Tags: hypopituitarism, news, pituitary gland, research, stem cells, study


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Frangipanier Acrylic Print
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Frangipanier by Muriel Dolemieux - 8" x 8"
Acrylic Print
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Frangipanier acrylic print by Muriel Dolemieux. Bring your artwork to life with the stylish lines and added depth of an acrylic print. Your image gets printed directly onto the back of a 1/4" thick sheet of clear acrylic. The high gloss of the acrylic sheet complements the rich colors of any image to produce stunning results. Two different mounting options are available, see below.
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2 - 3 business days
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About Acrylic Prints
Mounting Option #1
Mounting Option #2
Bring your artwork to life with the stylish lines and added depth of an acrylic print. Your image gets printed directly onto the back of a 1/4" thick sheet of clear acrylic.
The image is the art - it doesn't get any cleaner than that!
All acrylic prints ship within 3 - 4 business days and arrive "ready to hang" with four aluminum mounting posts (Option #1) or hanging wire (Option #2).
The high gloss of the acrylic sheet complements the rich colors of any image to produce stunning results.
There are two different ways to mount your acrylic print.
Option #1 (Mounting Posts) - Attach your print to your wall with four aluminum mounting posts. The cylindrical cap of each mounting post can be removed, allowing you to thread a small screw along the center axis of the of post and into the wall. When you're finished, simply reattached each cap, and you're done. The mounting posts act as stand-offs and keep your print separated from the wall by 1". All of the required mounting hardware (i.e. posts, screws, and wall anchors) is included with your print. Click here for mounting details.
Option #2 (Hanging Wire) - With this option, your acrylic print is attached to a 1/4" thick black board which has a wooden frame and hanging wire attached to the back. There are no metal mounting posts at the corners. Simply put a nail in your wall, hang your print from the hanging wire, and you're done. Due to the thickness of the black board and mounting frame, your print is separated from the wall by 1.50" Click here for mounting details.
Acrylic Print Reviews (1182)
Average Rating (4.88 Stars):
Kevin Verner
May 25th, 2020
This is an amazing photo and the quality of the print is fantastic! Thank You!
Suzanne Miller
May 21st, 2020
I purchased this for my son for his birthday - This is a great tribute piece of Kobe and my son is going to love it. Very good quality, colors are bright, excellent product. Would purchase again.
Suzanne Miller
May 21st, 2020
I purchased this as a birthday gift for my son. It is very high quality and very moving and while it will bring up a lot of emotion, it will also bring up a lot of good feelings every time he looks at it. I know my son is going to love this!
Connie Cartwright
May 21st, 2020
Very nice
Lovie KAUFERT
May 20th, 2020
Update: It shipped you guys, 34 days after it was purchased. I hope it was worth the wait because I am happy that it's moving.Update: 5/20/2020 I still have not received my 48X48 acrylic Joker print and this is the second time this week I have tried to contact fine art via email with no return of information. I am so overwhelmed with this company right now and I have been more than accommodating with time and patience. Update: 5/16/2020. Today marks one month from the purchase date and it has not shipped and it is still processing. 🥺Update: 5/13/2020, A not certain woman named Judy called the manufacturer and told me that the manufacturer received a bad batch of acrylic and they were waiting for more and that she will try to get me a ship date. It would have been nice for someone at the manufacturer to let me know but hey an answer is better than no answer. If this item does not ship by the 17th I am going to have to get my money back and try to find this item elsewhere. Such a sadness. Update: Its the 5/7/20 and customer service did not reply to my 5/4 inquiry about when item will ship. On 5/16/20 it will be a month that they have not shipped my item but has had my money since the first day. Will keep you all posted on what's going on. Update: It is 5/4/20 and the order is still processing I had to contact customer service again and no answers again. I sent concerns about my item not being shipped, and the response from fine art: "wait or refund due to the pandemic, but no information about how long". First impression for a $500 purchase is disappointed. The birthday I ordered it for was 4/26 and there was an estimated ship date of 4/22. I believe that you should hold on to your money until after the pandemic, the representative said they.may not be staffed and my order may not have been started. So far not so good, but once I actually receive the product I will post date I get it and the picture quality.
Margaret Cole
May 20th, 2020
Great picture of my dog. Just love it!!!
About Muriel Dolemieux
I am a French Artist living in Redlands, California. I Paint Acrylic on canvas, my painting is figurative. Nature inspires me and is my means of expression to translate emotions and feelings. Nature is beautiful, I don't try to embellish or transform it, I just see it. Art sanctifies it. I studiously walk, search, try, attempt to tame colors, materials…
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Our return policy is very simple:
If you're not happy with a purchase that you made on FineArtAmerica.com, for any reason, you can return it to us within 30 days of the order date. As soon as it arrives, we'll issue a full refund for the entire purchase price. Please note - Fine Art America does not reimburse the outgoing or return shipping charges unless the return is due to a defect in quality.
Fine Art America sells thousands of pieces of artwork each month - all with a 100% money-back guarantee. We take great pride in the fact that hundreds of thousands of artists have chosen Fine Art America to fulfill their orders, and we look forward to helping you select your next piece!
All acrylic prints ship from our production facility within 2 - 3 business days of your order.


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ARTA Welcomes Leduc Regional Housing Foundation!
As a retiree of Leduc Regional Housing Foundation, you have access to preferred pricing for your group. For more information, please review the corresponding documents and information provided below.
Plan Summary
- 4 page overview of the Retiree Benefits Plan including premium rates
- ARTA Membership Application
- There is no ARTA membership application for private service sector applicants as ARTA membership fees will be included in these applicants Health & Wellness Benefit Plan premiums
- Public/Private Sector Benefits Plan Application Form
- Application to join the ARTA Retiree Benefits Program


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Admin24 necesitaba un nuevo diseño de página web y lanzó un concurso de diseño en 99designs.
Un ganador ha sido elegido entre 40 diseños de 4 diseñadores freelance.
We manage two web services.
First one is over 18 months and does really well.
Its marketing tenant is to offer the best price to publish a "public notice" in a newspaper, using a price comparator.
This is pretty much a D-I-Y web service, that does not suit everybody.
Wanting to enlarge our market share, we've decided to extend the concept to a web service with real human assistance, by phone, email, fax...
Thus we've created a new site for this.
The first design (made though 99designs.com had to be changed for legal issue). We got our team to revamp the site using the first one as a model. But the result has been negative... Loads of clics, no order.
We think, the site is too dark, too basic, the name being a little bit scarry to users, etc....(legal and judicial notices)
This is how it looks like right now: http://www.annoncelegalejudiciaire.com/
Business, existing or starting up, lawyers, accountants, solicitors...
We need you to revamp this site using the same basic layout (html structure) if possible, in order to make it appealing, sexy and securing to use.
See in attachment, models we're worked on, but you're free to see it otherwise.
Use the text from the PDF document and not from the picture doc.
See above
See above


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Shane Carruth made his name in the independent film world in 2004 with his debut, "Primer," a sci-fi, time-travel thriller that he wrote, directed, produced, edited, scored and starred in for a paltry sum of $7,000.
Critics loved it. Very few others actually saw it. But within a particular nook of the industry, "Primer" was duly heralded for its vision and precision, and it won the grand jury prize at the Sundance Film Festival, which is all the more impressive given that Carruth, a former engineer, taught himself how to be a filmmaker.
Nine years later, he's back with his much-anticipated follow-up, "Upstream Color," which is just as daring and original at the opposite end of the aesthetic spectrum. If "Primer" was cerebral and methodical in allowing its mystery to unfurl, "Upstream Color" creates a totally different kind of suspense as a hypnotic sensory experience.
This is a capital-A art-house movie, definitely not for everyone. Carruth throws you in the deep end at the start and challenges you until the end. His mesmerizing use of imagery - of textures and sounds, of crisp lighting and radiant natural beauty - has a haunting, lyrical quality reminiscent of Terrence Malick. Earth churns, grass crunches, leaves snap. A hand softly caresses a bedsheet; hard, loud rain falls on a parking lot. But he also injects some moments that are so horrific and squirm-inducing, they're downright Cronenbergian.
Although its title suggests a sense of direction, "Upstream Color" defiantly eschews a traditionally linear narrative format; it moves ahead in time but in an elliptical, hypnotic way. And Carruth's rhythmic style of editing draws you in and keeps you hooked even when it may not be entirely clear what you're watching. He's technically meticulous but the results are dreamlike.
Which brings us to the matter of describing what "Upstream Color" is about. Partly because I won't even begin to pretend that I understand it all, and partly because I don't want to give too much away, I will be as vague as possible while still hoping you'll give it a try, if you're up for something different. If it's helpful - and it's not, really, it's intentionally obscure - here's the official description from the film's press materials in its entirety: "A man and woman are drawn together, entangled in the life cycle of an ageless organism. Identity becomes an illusion as they struggle to assemble the loose fragments of wrecked lives."
OK, let's start there, shall we?
Kris (Amy Seimetz, showing bravery and great range) and Jeff (Carruth himself, quick-witted and impulsive) find themselves strangely intrigued by each other while riding the same commuter train every morning. (It doesn't say so, but "Upstream Color" takes place in Dallas, and renders its downtown streets and suburban neighborhoods in a quietly anonymous way that's chilling.) They don't realize it for a while, but they both have been subjected to scientific experimentation that has damaged their lives, finances and careers, the details of which come back in fleeting wisps of memory.
And so as each struggles to re-establish a feeling of identity and security individually, they dare try to forge something meaningful and lasting with each other. The traditionally romantic, getting-to-know-you elements of the film are the most conventional, but even within them it's clear that both of these people are still a little fragile and off-kilter.
"Upstream Color" also features, not necessarily in this order: grub worms, financial fraud, blue orchids, long night swims and Henry David Thoreau's "Walden." These are crucial pieces within a puzzle that may be impossible to solve, and Carruth's synth-heavy score - which, on screen, often comes from a mysterious musician/pig farmer (Andrew Sensenig) who never speaks - magnifies the sensation of danger and dread.
Carruth's film ends on an unexpectedly optimistic note, given all that's come before it. What it means exactly will be open for interpretation just like everything else. But the artistry on display is indisputable, and thrilling.
"Upstream Color," an erbp release, is not rated but contains some violence and some bloody and disturbing images. Running time: 96 minutes. Three and a half stars out of four.


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Ford CEO Alan Mulally was up early for a Today Show interview in New York with NBC's Matt Lauer. Lauer fearlessly probed Mulally, peppering him with a slew questions. Smiling like a Cheshire cat, Mulally non-answered every one of them.
The only real answer Alan "Boeing! Boeing!" Mulally gave was when Matt Lauer asked the question of whether Ford's the underdog with federal help. He claims they support the decision. But then when Matt asked Mulally whether he believed GM could turn into a Vietnam-type situation for President Obama. Alan answered only by saying "We are focused on Ford and we're making the best cars and trucks consumers...will value..." Then something like "Have you seen the new Ford Taurus outside?" Decline to answer and then...pivot back to message. This guy's pretty good with the whole "message" thing, ain't he?
Here's the video of Alan "Message" Mulally parrying, pivoting and answering absolutely nothing on the Today Show today.