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Frank Zhigang Wang - Semantic Scholar
Frank Zhigang Wang, Na Helian, +4 authors Mamun Ur Rashid
Frank Zhigang Wang, Na Helian, +6 authors Austin Parker
Hybrid Hard Disk Drive was originally concepted by Samsung, which incorporates a Flash memory in a magnetic disk. The combined ultra-high-density benefits of magnetic storage and the low-power and… (More)
Evolutionary Storage: Speeding up a Magnetic Disk by Clustering Frequent Data
Frank Zhigang Wang, Yuhui Deng, +4 authors Austin Parker
To counteract the performance degradation in magnetic disks, it is proposed to develop an evolutionary storage system that is evolving over time. The frequent data is clustered and moved to a flash… (More)
A Memristor-CAM (Content Addressable Memory) Cell: New Design and Evaluation
Xiao Yang, Wanlong Chen, Frank Zhigang Wang
Content addressable memory (CAM) is one kind of the associative memory; it can be used in several high-speed searching applications. In this paper, we propose a new CAM cell that employs memristors… (More)
Huankai Chen, Frank Zhigang Wang, Na Helian
Resource allocation optimization is a typical cloud project scheduling problem: a problem that limits a cloud system’s ability to execute and deliver a project as originally planned. The entropy, as… (More)
Network Topology Generation and Discovery Tools
Muhammad Azizur Rahman, Frank Zhigang Wang
Achieving a deep understanding of the Internet topology has proved very challenging since it involves solving difficult task, e.g. mapping the actual topology, characterising it and developing… (More)
Investigations of the staircase memristor model and applications of memristor-based local connections
The memristor is postulated by Chua (IEEE Trans Circuit Theory, 18(5):507–519, 1971) as the fourth fundamental passive circuit element and experimentally validated by HP labs in 2008. It is an… (More)
Benchmarking a non-relational database in a wireless environment
Bin Ye, Jimmy Mian-Guan Lim, Frank Zhigang Wang
Non-relational databases are specially designed mainly for cloud environments, which there are normally millions users accessing the data center. This project aims to developed a middleware to… (More)
Keynote speaker 3: How will computers evolve over the next 10 years?
Computer science has impact on many parts of our lives. Computer scientists craft the technologies that enable the digital devices we use every day and computing will be at the heart of future… (More)
Welding defect classification of ultrasonic detection based on PCA and KNN
Ailing Qi, Jingfang Wang, Frank Zhigang Wang, Unekwu Idachaba, Gbola Akanmu

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One foot in the grave. / The Christmas specials (DVD 비디오, 2009) [WorldCat.org]
제목: One foot in the grave. / The Christmas specials
저자: David Renwick; Susan Belbin; Esta Charkham; Christine Gernon; Richard Wilson; Annette Crosbie; BBC Worldwide Ltd
출판사: [London] : BBC Worldwide, ©2009.
David Renwick; Susan Belbin; Esta Charkham; Christine Gernon; Richard Wilson; 모든 저자
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type: global

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Our Earth Our Cure: A Handbook of Natural Medicine for Today: Raymond Dextreit, Michel Abehsera: 9780806510132: Amazon.com: Books
17 used & new from $73.19 See All Buying Options
Raymond Dextreit (Author), Michel Abehsera (Editor, Translator)
The Macrobiotic Approach to life-long health. A handbook of natural medicine for today.
Paperback$10.23 Prime Living Clay Nature's Own Miracle Cure
Paperback$9.86 Prime Our Earth Our Cure (A Swan House Book)
Publisher: Citadel Pr (October 1993)
ISBN-10: 0806510137
ISBN-13: 978-0806510132
Amazon Best Sellers Rank: #873,728 in Books (See Top 100 in Books)
See all 10 customer reviews The book has very useful information.SwiegieThen, I started to read it, and the clay remedies are very detailed and form an extensive part of the book.DonGloI have tried to buy this book for years for my friends and it has been always out of print.!"agarridodemoss"
24 of 24 people found the following review helpfulUnbelievable !! Just try the healing clay on yourself!!!
"agarridodemoss"
I have owned this book for well over 15 years and have used their recomendations on myself, my family, friends over and over hundred of times and I have never been dissappointed with the results.I just can't believe that clay is not more widelly used for its magnificent healing properties. I can only imagine that its unpopularity is based on the fact that "it is just too cheap and it is so readily available every where" and also because it may become a bit messy to handle until you get the hung of it.I am still as amazed at the cure properties of the clay as the very first time I used it. I'll only mention my last experience with it:today I am 80% recovered from a terribly painfull and stiff neck, I had applied warm clay on it twice yesterday after a couple of days in agony.I have tried to buy this book for years for my friends and it has been always out of print.!
14 of 14 people found the following review helpfulOur Earth, Our Cure by Ramond Dextreit
I specialise in researching minerals for health and am writing a book on the subject, so bought this book as part of my research. Although it contains only a fairly short chapter about clays, it is very comprehensive information. I am also highly impressed with the book's analysis of various herbal remedies. Truly a work of a great naturopath!NaturalRussia
11 of 11 people found the following review helpfulExcellent natural cures with detailed execution instructions
I didn't realize that the book wasn't solely about clay healing, as it covers herbal treatments, also, and at first I was disappointed. Then, I started to read it, and the clay remedies are very detailed and form an extensive part of the book. I am happy with it.
10 of 10 people found the following review helpfulUnbelievable !! Just try the healing clay on yourself!!!
2 of 2 people found the following review helpfulMy favorite clay and herbal natural remedy book
This book has so much information in it. Not just what natural remedies work, but how to make each formula, and how much to take for what (and examples of situations where the remedies worked well).I am very interested in healing with clay, as I've successfully used it (clay gel wraps) on my mom's swollen diabetic legs. She gets immediate relief from pain, and after about 3 hours, she says her legs feels like new. (She has poor circulation due to arteriosclerosis). With clay in particular, some other good books are Jason Eaton's 'Upon a Clay Tablet',(the author also responds to emails to clarify how clay can be used therapeutically), Cano Graham's The Clay Disciples, and "Clay Cures", by Anjou Musafir & Pascal Chazot.
Comprehensive and interesting. This is a good reference work for alternative health care knowledge. A nice addition to your library--
Published 16 months ago by Dark Walker
This book is 30+ years old, I have been searching for one which in good condition, and for the right price for some time.
Published 22 months ago by Eric F. Cunningham
Great book, but very smelly!
First, I want to say that the book is awesome. We have gained a lot of great information about clay and its thousands of uses.
Published on February 28, 2013 by Blair Massey
earth cures drugs dont
All I can say is read this book and follow it to the letter and you will not need a doctor, we have followed the guide line in this book and we dont need the drugs to keep us...
Published on February 8, 2013 by red
WONDERFUL USEFUL INFO
The amazing effect clay has on your skin as in facials is wonderful. I use clay for wounds, facials, and you can even drink little amounts for great results.
Published on January 11, 2013 by Swiegie
Our Earth Our Cure (A Swan House Book) by Raymond Dextreit Paperback
The Clay Cure : Natural Healing from the Earth by Ran Knishinsky Paperback

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text:
visa immigration logo | Graphic Design | Logo Design
visa immigration logo
I have a small start up company offering visa services and education consultancy services in the UK to most Chinese clients. The company name is - 51 VISA. I am looking for simple designs for website and letter heads. I don't have much idea on this myself.
Because it has the number 51 in it, it may be an idea to have this as a focus point. On Chinese websites, 51 translates to 'I want'.
If Chinese characters can be incorporated into the design or attached separately, please see attached jpg of Chinese characters.
Please send in some of your sample works.
See more: immigration logo design, uk logo designs, looking for logo designs, logo UK, logo services uk, logo it works, logo for consultancy services, logo designs services, logo design for it consultancy, logo design company uk, logo design company in uk, logo design characters, letter as logo, letter a logo designs, letter a graphic designs, immigration services, graphic design logo uk, design your logo uk, designs for a letter logo, design logo works, company name and a logo uk, clients looking for logo designs, logo designs websites, chinese characters, visa
Project ID: #1252123
punitagarwal4
i can do in one day
ronaldocardoso
Ronaldo Cardoso Graphic and Web Designer. Special Design from Brazil.
umeshdemon
( [login to view URL] ) Plz copy paste this link to youtube. u can see my work.
We are expert in logo designing, banner, flyer, poster, theme, catalogue, brochure, business card, letter head, etc. If given the chance, we will prove ourselves. We can prepare mock-ups to start with. Your feedback is More
Hi,ready to start! Please check PM for more details.
Hello, I have reviewed your description and interested. Thanks [login to view URL]

value: This website is an Australian freelance marketplace website, which allows potential employers to post jobs that freelancers can then bid to complete. Founded in 2009, its headquarters is located in Sydney, Australia, though it also has offices in Vancouver, London, Buenos Aires, Manila, and Jakarta.


text:
Get Capone : the secret plot that captured America's most wanted gangster (Livre, 2010) [WorldCat.org]
http://www.worldcat.org/oclc/424555565
Titre: Get Capone : the secret plot that captured America's most wanted gangster
Auteur: Jonathan Eig
Éditeur: New York : Simon & Schuster, 2010.
ISBN/ISSN: 9781416580591 141658059X 9781416580744 1416580743
OCLC:424555565
9781416580591 141658059X 9781416580744 1416580743
424555565
ix, 468 pages, [16] pages of plates : illustrations, map ; 25 cm
pt. 1. Capone rising --
The getting of it --
Good-bye, Diamond Jim --
A little house on South Prairie --
"I'm sure it was Capone" --
Funny notions --
A man of destiny --
"He will knock you flat just for fun" --
The peacemaker --
Q is for Quincy --
Sorry about that, Hymie --
A smile and a gun --
The grinder --
The better element --
pt. 2. King Capone --
"There's worse fellows in the world than me" --
Uneasy lies the head --
Deepest in dirt --
Pineapples and coconuts --
The graduation of Frankie Yale --
Hooverization --
"I do not stay up late" --
The enforcer --
The formidable Alphonse --
Litter Caeser --
St. Valentine's day --
pt. 3. Capone falling --
"An unsolved crime" --
"The most sore necessity of our times" --
The brightest days --
"Have you got Capone yet?" --
Locked up --
Elegant mess --
The Napoleon of Chicago --
The big fellow chills --
"Lady, nobody's on the legit" --
Public enemy number one --
"There is no friendship among hoodlums" --
Contempt --
Death and taxes --
United States against Al Capone --
The so-called untouchables --
"Who wouldn't be worried" --
Based on newly released government documents and wiretaps, "Get Capone!" tells how the nation's most-wanted criminal was really caught.
Synopsis de l’éditeur "Riveting. . . . Eig's book is full of fascinating details about the Windy City, as well as the rest of America in the 1920s." --Elizabeth Bennett, "Dallas Morning News"
Ajoutez des tags pour "Get Capone : the secret plot that captured America's most wanted gangster".
abbymarch
mise à jour 2012-10-30
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Get Capone : the secret plot that captured America's most wanted gangster/Jonathan Eig; New York : Simon & Schuster, 2010.


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SRMueller1 379Contributions 93 Reviews 279 Ratings 7 Photos Continue Browsing »
Travel Style History Buff 60+ Traveler Art and Architecture Lover Show all cities (771) Show all cities (771)Been (760)Want (16)Fave (11)
203,825 total miles traveled 29% of the world traveled Send Message 760Cities 22Countries About Me Since Feb 2010Lives in Littleton, Colorado 50-64 year old male Recently retired avid traveler - and cruiser.
I've been blessed to have visited every State in the USA, and look forward to several long driving trips per year for the next few years.
We are also Elite members of the Princess Captain's Circle. As of this writing, I have a number of green dots around Northern Europe - looking forward to cruising there in the next few months.
I used to travel about 75 nights per year for work, and 15-25 nights per yea for fun. Obviously, I like to travel - but when I was working I rarely had time to see much of the areas that I visit. I'm looking forward to changing this in retirement, and hoping to spend more time in different parts of our beautiful country - and some world travels as well. I'm seeing some big holes in my travel map that need to be filled. Badges 93 reviews (Top Contributor)29 hotel reviewsReviewed 3 Travelers' Choice winners32 restaurant reviews32 attraction reviewsReviews in 37 cities57 Helpful votes5 Explorer reviews
×Collect your Explorer badge for being one of the first to review a hotel, restaurant, or attraction in a given language. There's no limit to the number of Explorer reviews you can write. Boudreaux's Cajun KitchenOutback SteakhouseDoubleTree by Hilton Hotel North SalemLittle Basil Asian GrillInari'sMembers collect the Travelers' Choice Reviewer badge when a property they favorably reviewed, or the destination in which it's located, goes on to win a Travelers' Choice Award. The Travelers' Choice Awards honor the best hotels, attractions, restaurants and destinations worldwide, based on millions of traveler reviews.Las VegasLos AngelesAthens
SRMueller1's Contributions Sort by: Most contributions Most contributions Alphabetical Date posted Grid View List View Contributions by type Reviews (93) Ratings (279) Photos (7) Littleton, CO, USA42Contributions Denver, CO, USA35Contributions Las Vegas, NV, USA14Contributions Athens, Greece12Contributions Washington DC, DC, USA10Contributions Palisade, CO, USA8Contributions Key West, FL, USA7Contributions Honolulu, HI, USA6Contributions Los Angeles, CA, USA6Contributions San Francisco, CA, USA5Contributions SeaTac, WA, USA5Contributions Houston, TX, USA4Contributions Explore the world! TripAdvisor has reviews and information on over 400,000 locations, including: Travel Destinations
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text:
Patent US8008353 - Alzheimer's disease; small molecule amine salts - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsMethods for modulating macrophage proliferation in an individual afflicted with or at risk for a macrophage-associated disease are provided. The methods employ a polyamine analog, or salt or protected derivative thereof. Macrophage proliferation has been implicated in a number of serious disorders, including...http://www.google.com/patents/US8008353?utm_source=gb-gplus-sharePatent US8008353 - Alzheimer's disease; small molecule amine saltsAdvanced Patent SearchPublication numberUS8008353 B2Publication typeGrantApplication numberUS 11/022,153Publication dateAug 30, 2011Filing dateDec 22, 2004Priority dateOct 27, 1997Also published asCA2308274A1, CA2308274C, DE69840048D1, EP1027040A2, EP1027040B1, US7087648, US20050159493, US20120022166, WO1999021542A2, WO1999021542A3Publication number022153, 11022153, US 8008353 B2, US 8008353B2, US-B2-8008353, US8008353 B2, US8008353B2InventorsMichael S. McGrathOriginal AssigneeThe Regents Of The University Of CaliforniaExport CitationBiBTeX, EndNote, RefManPatent Citations (33), Non-Patent Citations (34), Referenced by (2), Classifications (24), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetAlzheimer's disease; small molecule amine saltsUS 8008353 B2Abstract Methods for modulating macrophage proliferation in an individual afflicted with or at risk for a macrophage-associated disease are provided. The methods employ a polyamine analog, or salt or protected derivative thereof. Macrophage proliferation has been implicated in a number of serious disorders, including AIDS (HIV)-associated dementia, AIDS-associated non-Hodgkin's lymphoma, and Alzheimer's disease. The invention also provides methods for aiding diagnosis and monitoring therapy of a macrophage-associated non-HIV associated dementia, especially Alzheimer's disease. The invention also provides methods of delaying development of macrophage-associated non-HIV associated dementias, including Alzheimer's disease, which entail administration of an agent which modulates macrophage proliferation.
1. A method of treating a subject afflicted with, or at risk for, HIV-associated dementia or delaying development or onset of HIV-associated dementia in said subject comprising administering to said subject effective amount of a composition comprising mitoguazone or a salt of mitoguazone, wherein the patient does not have AIDS-related non-Hodgkin's lymphoma.
2. The method of claim 1, wherein the composition comprises mitoguazone dihydrochloride.
3. A method of modulating macrophage proliferation in an individual afflicted with, or at risk for, HIV-associated dementia comprising administering to the individual an effective amount of a composition comprising mitoguazone or a salt of mitoguazone, wherein the patient does not have AIDS-related non-Hodgkin's lymphoma.
4. The method of claim 3, wherein the composition comprises mitoguazone dihydrochloride.
5. A method of modulating macrophage proliferation in an individual afflicted with, or at risk for, a macrophage-associated disease comprising administering to the individual an effective amount of a composition comprising mitoguazone or a salt of mitoguazone, wherein the disease is HIV-associated dementia or non-HIV-associated dementia, wherein the patient does not have AIDS-related non-Hodgkin's lymphoma.
6. The method of claim 5, wherein the composition comprises mitoguazone dihydrochloride.
7. A method of treating a subject afflicted with, or at risk for, a macrophage-associated disease or delaying onset or development of a macrophage-associated disease in said subject comprising administering to said subject an effective amount of a composition comprising mitoguazone or a salt of mitoguazone to reduce macrophage proliferation in said subject, wherein the disease is HIV-associated dementia or non-HIV-associated dementia, wherein the patient does not have AIDS-related non-Hodgkin's lymphoma.
8. The method of claim 7, wherein the composition comprises mitoguazone dihydrochloride.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 09/179,383, filed Oct. 26, 1998, which application claims the benefit of U.S. Provisional Application Ser. Nos. 60/063,317 and 60/063,318, both filed Oct. 27, 1997, each of which applications are incorporated by reference.
TECHNICAL FIELD This invention relates to macrophage proliferation. More specifically, it relates to the use of polyamine analogs or salts or protected derivatives thereof to modulate macrophage proliferation, particularly in individuals afflicted with or at risk for a macrophage-associated disease. The invention also relates to methods of aiding diagnosis monitoring therapy, and delaying development of macrophage proliferation disorders (in the context of non-HIV associated dementias, such as Alzheimer's disease) that entail detection and/or modulation of macrophage proliferation.
BACKGROUND ART Cell proliferative diseases represent a major health problem and threat worldwide. Such diseases are characterized by the single or multiple abnormal proliferation of cells, groups of cells or tissue(s). See U.S. Pat. No. 5,665,588. Cell proliferative diseases include, but are not limited to, AIDS dementia, various cancers, atherosclerosis, vitreoretinopathy, psoriasis, neurodegenerative disorders and nephropathy. See U.S. Pat. Nos. 5,639,600, 4,847,257 and 5,672,746. Dementias, or progressive mental failures, particularly present a serious worldwide health problem, both in terms of the extent of debilitation and health care costs. Dementias include non-HIV-associated dementias (such as Alzheimer's disease or AD) and HIV-associated dementia.
Macrophages are terminally differentiated cells generally incapable of further cell division. Surprisingly, macrophage proliferation has been implicated in certain serious proliferative diseases such as lymphoma, cardiovascular disease, and nephrosclerosis. U.S. Pat. No. 5,639,600. Gabrielian et al. reported the role of macrophage infiltration in traumatic proliferative vitreoretinopathy. (1994) Curr. Eye. Res. 13:1-9. McGrath et al. disclosed the involvement of clonally expanded macrophages in the induction of cancerous tumor growth and AIDS dementia. U.S. Pat. Nos. 5,639,600 and 5,580,715; see also Pulliam et al. (1997) Lancet 349:692-695; McGrath et al. (1995) J. Acquired Imm. Def. Syn. Hum. Retro. 8: 379-385; Shiramizu et al. (1994) Cancer Res. 54:2069-2072.
Several different classes of chemical compounds have been reported that can inhibit abnormal cellular proliferation. These classes include, for example, anionic oligomers, amino 1,2,3-triazoles, valproic acid derivatives and polyamines. Cardin et al. reported that certain anionic oligomers possess antiproliferative activity. U.S. Pat. No. 5,460,807. Water soluble polyureas and polyamides with a molecular weight of less than 10,000 inhibit smooth muscle cell proliferation in culture and in vivo. Cardin et al. state that the anionic oligomers can be used in the treatment of atherosclerosis. Hupe et al. disclosed that certain triazoles are antiproliferatives. U.S. Pat. No. 4,847,257. Amino 1, 2, 3 triazoles inhibit labeled thymidine incorporation into intact pig skin and also inhibit keratinocyte proliferation. Hupe et al. state that the triazoles can be used in the treatment of psoriasis, a chronic skin disease which is characterized by hyperproliferation of the epidermis Nau et al. discovered that certain acids inhibit cell mitosis. U.S. Pat. No. 5,672,746. Derivatives of valproic acid decrease neuro-2a cell proliferation in vitro. Nau et al. state that the valproic acid derivatives can be used for the prevention and treatment of neurodegenerative disorders such as Alzheimer's disease. The treatment would be aimed at preventing the adverse effects of the disease by directly inhibiting pathologic neural cell growth.
The level of polyamines is intimately related to cell proliferation. Cellular levels of polyamines are carefully regulated by opposing synthetic and catabolic pathways. Compounds that are able to lower polyamine levels are proposed for use in the treatment of rapidly proliferating host cells such as cancer and psoriasis. A key polyamine catabolizing enzyme spermidine-spermine N1-acetyltransferase (SSAT) is among the few genes known to be inducible by the natural polyamines. Certain polyamine analogs exaggerate this response. 1,11-diethylnorspermine (DENSPM) increases SSAT mRNA levels in human melanoma cells up to 20-fold, with an increase in immunodetectable SSAT protein by 300-fold. By comparison, natural polyamine spermine is far less effective, increasing SSAT mRNA by �3-fold and immunodetectable protein by �7-fold. Fogel-Petrovic et al. (1996) Biochemistry 35:14435. Polyamine analogs also induce Z-DNA structure in vitro. This property correlates inversely with the effects on cis-diaminedichloroplatinum (II) (CDDP) cytotoxicity in human brain tumor cells. Basu et al. (1996) Anticancer Res. 16:39.
U.S. Pat. No. 5,498,522 outlines the use of SSAT as a prognostic indicator or tumor response marker. Either SSAT enzyme activity, SSAT enzyme protein, or mRNA transcripts can be measured directly, or other determinants related to SSAT induction can be measured, such as SSAT co-factor acetylCoA, and the SSAT products N1-acetylspermine and N1-acetylspermidine. Measurement of these determinants is proposed as a prognostic indicia and tumor response marker to evaluate the clinical effectiveness of anticancer agents comprising polyamine analogs. Determination is performed by collecting tumor cells by biopsy before or after treatment, and measuring the selected determinant. Hibasami et al. [(1989) Cancer Res. 49:2065] prepared an inhibitor of the natural polyamine synthetic pathway. The compound, methylglyoxal-bis(cyclopentylamidinohydrazone) (MGBCP) inhibited S-adenosylmethionine decarboxylase, spermine synthase, and spermine synthetase, competing with S-adenosylmethionine, spermidine, and putrescine, respectively. MGBCP depleted spermidine and spermine in leukemic ascites cells, and prolonged survival time of mice bearing P388 leukemia.
U.S. Pat. No. 5,541,230 (Basu et al.) indicates that spermine derivatives decrease growth in a number of human tumor cell lines, and propose their use in cancer chemotherapy. Bergeron et al. (Cancer Chemother. Pharmacol.) showed that the polyamine analogs 1,14-bis(ethylamino)-5,10-diazatetradecaone (BE-4-4-4), and 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) directly affects growth, survival, and cell cycle progression in human brain tumor cell lines. The synthesis of BE-4-4-4-4 is disclosed in U.S. Pat. No. 5,541,230. U.S. Pat. No. 5,516,807 (Hupe et al.) claims a method for treating vascular proliferative disorders following balloon angioplasty. Bis-ethyl norspermine was found to inhibit the growth of rat aortic smooth muscle cells in culture for 8 to 15 days. It is proposed that restenosis following balloon angioplasty, graft, shunt, or athereotomy can be treated or prevented by administration of an effective amount of a polyamine, although no such experiments were performed. For other publications relating to the synthesis and use of certain polyamines, the reader is referred to EP 277,635, EP 162,413, EP 399,519, JP 85/6348, and U.S. Pat. No. 5,679,682; and to Bellevue et al. (1996) Bioorg. Med. Chem. Lett. 6:2765, and Porter et al. (1992) Falk Symposium 62:201; Marton and Pegg (1995) Ann Rev. Pharmacol. Toxicol. 35:55-91.
DISCLOSURE OF THE INVENTION The present invention provides methods for modulating macrophage proliferation using a composition comprising a polyamine analog or salt or protected derivative thereof (or using a polyamine analog or salt or protected derivative thereof), preferably in an individual afflicted with or at risk for a disease with which macrophage proliferation is associated, wherein the composition (or compound) is administered in an amount sufficient to modulate macrophage proliferation. In one embodiment, the disease is a non-HIV-associated dementia, particularly Alzheimer's disease. In another embodiment, the individual is HIV-infected and the disease is HIV-associated, such as HIV-associated dementia. Preferably, all the nitrogens of the polyamine analog are secondary, tertiary, or quaternary amino groups. The composition can further comprise a pharmaceutically acceptable excipient. In some embodiments, the composition comprises mitoguazone dihydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A and 1B are graphs denoting percent inhibition or killing in vitro of macrophage proliferation by varying concentrations of polyamine analogs DEHOP (SunPharm) and BE-4444, compared to antineoplastic agent cyclosphosphamide. Blood was obtained from patients with AIDS dementia.
MODES FOR CARRYING OUT THE INVENTION We have discovered that polyamine analogs are particularly effective in modulating macrophage proliferation. We have also discovered elevated, abnormal levels of macrophage proliferation in peripheral blood of patients with Alzheimer's disease (AD). We have also observed that macrophage proliferation is associated with a number of other serious disorders, including AIDS dementia, AIDS-associated non-Hodgkin's lymphoma, cardiovascular disease and nephrosclerosis. U.S. Pat. No. 5,639,600; see also commonly owned U.S. provisional application U.S. Ser. No. 60/063,318. Without wishing to be bound by a particular theory, we note that this macrophage proliferation phenomenon is associated with, and may contribute to the disease sequelae of, non-HIV associated dementias such as AD.
As discussed below, preferred agents for modulation of macrophages are polyamine analogs especially 1,11-bis(ethyl)norspermine; 1,8-bis(ethyl)spermidine (BES); 1,12-bis(ethyl)spermine (BESm; DESPM (N1,N12-diethylspermine); 1,11-bis(ethylamino)-4,8-diazaundecane (BE-3-3-3); 1,14-bis(ethylamino)-5,10-diazatetradecane (BE-4-4-4) (Diethylhomospermine, N1,N14-diethylhomospermine; DEHOP or DEHSPM); diethyl-norspermine (DENOP); 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4); N-ethyl-N′-(2-(3′-ethylamino-propylamino methyl)-cis-cyclopropylmethyl)-propane 1,3-diamine tetrahydrochloride (SL-11037); N-ethyl-N′-(2-(3′-ethylamino-propylamino methyl)-trans-cyclobutylmethyl)-propane 1,3-diamine tetrahydrochloride (SL-11038); N-ethyl-N′-(2-(3′-ethylamino-propylamino methyl)-trans-cyclopropylmethyl)-propane 1,3-diamine tetrahydrochloride (SL-11044; and N,N′-bis(3-ethylaminopropyl)-cis-but-2-ene-1,4-diamine tetrahydrochloride (SL-11047).
A �macrophage-associated� disease, disorder or indication is a disease, disorder or indication that is associated with an elevated, or abnormal, level of macrophage proliferation as compared to control sample(s). Such disorders include, but are not limited to, AIDS-associated dementia, Alzheimer's disease (AD), AIDS lymphoma, follicular lymphoma, mycoses fungoides, T cell and B cell lymphomas with significant macrophage compartments, atherosclerosis, kidney disease such as focal segmental glomerulosclerosis and membrane proliferative glomerulo nephropathy, psoriaform dermatitities, AIDS-associated diarrhea, prelymphomatis autoimmune disease such as AILD (angioimmunoblastic lymphadenophathy with dysproteinemia) and herpes virus associated diseases such as Castleman's disease and Kaposi's sarcoma. The terms �disorder� and �disease� are used interchangeably herein. �Macrophage-associated dementia� is a dementia that is associated with an elevated, or abnormal, level of macrophage proliferation as compared to control sample(s). Such dementias include, but are not limited to, AD. A macrophage-associated disorder, disease or dementia can be HIV-mediated or non-HIV-mediated, or HIV-associated or non-HIV associated. A �non-HIV-mediated� disease or dementia is a disease or dementia which is not caused by HIV, either directly or indirectly. A �non-HIV-associated� disease or dementia is a disease or dementia not normally associated with or secondary to HIV infection. An �HIV-mediated� disease, dementia or indication is directly or indirectly caused by (and/or linked to) HIV infection. An �HIV-associated� disease, dementia or indication is defined more broadly as generally associated with or secondary to an HIV infection; �HIV-mediated� diseases, for example, are included in those considered to be �HIV-associated.�
An individual �afflicted with� a macrophage associated disorder or non-HIV associated dementia means that the individual individual has been diagnosed as having, or is suspected as having, a macrophage associated disoreder or a non-HIV associated dementia.
By �polyamine analog� is meant an organic cation structurally similar but non-identical to naturally-occurring polyamines such as spermine and/or spermidine and their precursor, diamine putrescine. Polyamine analogs can be branched or un-branched, or incorporate cyclic moieties. Examples of polyamine analogs include, without limitation, N1, N14-diethylhomo-spermine (DEHSPM) and N1,N12-diethylspermine (DESPM). See, for example, WO 98/17624 and U.S. Pat. No. 5,541,230. U.S. Pat. Nos. 5,037,846 and 5,242,947 disclose polyamines comprising primary amino groups. Especially preferred are polyamine analogs wherein all nitrogen atoms of said polyamine analogs are independently secondary, tertiary, or quartenary amino groups.
An �alkyl� is a cyclic, branched, or straight chain chemical group containing carbon and hydrogen, such as methyl, butyl, t-butyl, pentyl, cyclopropyl, and octyl. Alkyl groups can be either unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyl. Alkyl groups can be saturated or unsaturated (e.g., containing �C═C� or �C≡C� subunits), at one or several positions. Unless otherwise specified, alkyl groups will comprise 1 to 8 carbon atoms, preferably 1 to 6, and more preferably 1 to 4 carbon atoms. �Cycloalkyl� refers to cyclic alkyl groups only, such as cyclopropyl, cyclobutyl, cyclopentyl, etc. �n-alkyl� refers to a linear (i.e., straight-chain) alkyl group only, while �branched alkyl� refers to branched alkyl groups to the exclusion of cyclic and linear alkyl groups. �Alkenyl� refers to a cyclic, branched, or straight chain chemical group containing carbon and hydrogen where at least one bond is monounsaturated, such as ethenyl, cyclopentenyl, or 1,3-butadienyl. Alkenyl groups can be substituted as indicated for alkyl groups. Alkenyl groups can be designated as cyclic, linear (n-alkenyl) or branched in an analogous fashion to the preceding designations for alkyl. An �aryl� is an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl), or multiple condensed rings (e.g., naphthyl), which can optionally be unsubstituted or substituted with amino, hydroxyl, alkyl, alkoxy, chloro, halo, mercapto and other substituents.
As used herein, �biological sample� encompasses a variety of sample types obtained from an individual and can be used in a diagnostic or monitoring assay. The definition encompasses blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen or tissue cultures or cells derived therefrom, and the progeny thereof. The definition also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components, such as proteins or polynucleotides. The term �biological sample� encompasses a clinical sample, and also includes cells in culture, cell supernatants, cell lysates, serum, plasma, biological fluid, and tissue samples. Generally, the sample will be, or be derived from, peripheral blood. Preferably, the blood will have been enriched for a macrophage fraction, by using, for example, glass or plastic adherence.
As used herein, �aiding diagnosis� means that these methods assist in making a clinical determination regarding the classification, or nature, of the dementia, and may or may not be conclusive with respect to the definitive diagnosis. The method of aiding diagnosis of a macrophage-associated disease can comprise the step of detecting the level of proliferating macrophages in a biological sample from the individual, wherein the disease is dementia, such as a non-HIV-associated dementia, such as Alzheimer's disease. Dementias may or may not be associated with clonal macrophage proliferation, and making this classification may assist in developing and recommending treatment strategies as well as evaluating prognosis.
�Development� of a dementia herein means initial manifestations and/or ensuing progression of the disorder. Development of disease can be detectable and assessed using standard clinical techniques, such as neurofunction/cognitive tests and brain scanning technologies such as MRI. However, development also refers to disease progression that may be undetectable. For purposes of this invention, progression refers to the biological course of the disease state. �Development� includes occurrence, recurrence, and onset. As used herein �onset� or �occurrence� of a neurological disorder includes initial onset and/or recurrence. As used herein, �delaying� development of disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disorder and/or the medical profile of the individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop detectable disease. A method that �delays� development of disease is a method that reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects, although this knowledge can be based upon anecdotal evidence. �Delaying development� can mean that the extent and/or undesirable clinical manifestations are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering the agent. Thus the term also includes, but is not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, and remission (whether partial or total) whether detectable or undetectable.
�Modulating� macrophage proliferation means that the rate of proliferation is altered when compared to not administering an agent that interferes with natural polyamine interaction with DNA (including, but not limited to, interfering with a polyamine biosynthetic pathway, interfering with the intracellular concentration of spermidine, competitors, inhibitors of DNA interaction by a natural polyamine, interfering with polyamine metabolism, etc.), such as a polyamine analog. Preferably, �modulating� macrophage proliferation means a change in the rate of macrophage proliferation of at least 25%, preferably at least 50%, more preferably at least 75%, and even more preferably at least 90%. Generally, for purposes of this invention, �modulating� macrophage proliferation means that the rate of proliferation is decreased when compared to the rate of proliferation in that individual when no agent is administered. However, during the course of therapy, for example, it may be desirable to increase the rate of proliferation from a previously measured level. The degree of modulation may be assessed by measurement of macrophage proliferation, which will be discussed below, and generally entails detecting a proliferation marker(s) in a macrophage population or uptake of certain substances such as BrdU or 3H-thymidine (which would provide a quantitative measure of proliferation). Further, it is possible that, if the macrophages are proliferating due to a genetic alteration (such as transposition, deletion, or insertion), this alteration could be detected using standard techniques in the art, such as RFLP (restriction fragment length polymorphism).
For purposes of this invention, an individual suitable for administration of a polyamine analog (or, in certain contexts, such as non-HIV associated dementia other than AD, an agent which modulates macrophage proliferation) is one who has been diagnosed as having a macrophage-associated disorder, such as AIDS dementia, AIDS non-Hodgkin's lymphoma, Alzheimer's disease, or who is adjudged to be at high risk for developing such a disorder. In some embodiments, an individual suitable for administration of an agent which modulates macrophage proliferation is one who has been diagnosed as having a macrophage-associated, non HIV associated dementia other than AD, or who is adjudged to be at risk for developing such a dementia. As is evident to one skilled in the art, these methods can apply to those individuals not displaying any symptoms. An �at risk� or �high risk� individual is an individual who has a discrete and significant risk of developing disease (a macrophage-associated disorder). An �at risk� or �high risk� individual may or may not have detectable disease, and may or may not have displayed detectable disease prior to receiving the method(s) described herein. �High risk� (or �at risk�) denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of disease. An individual having one or more of these risk factors has a higher probability of developing disease than an individual without these risk factor(s). These risk factors include, but are not limited to, genetic (i.e., hereditary) considerations (including family history and genetic markers), and presence or absence of appropriate chemical markers and exposure to environments, conditions, or factors which would increase the possibility of acquiring a particular disease. Retroviral infections, especially retroviral insertions into particular genetic loci (such as fur or PDGF), may also be considered a risk factor. A high risk individual has one, preferably two, more preferably three, risk factors. However, it is understood that having only one risk factor can often indicate high risk.
Because all risk factors for developing macrophage-associated disease are not known, and the interplay among these factors (in terms of overall risk) are not fully understood, it is clear to one skilled in the art that individuals suitable for administration of an agent for purposes of this invention can have clinical features in common, and that individuals not falling clearly in the categories described above can nonetheless be considered suitable candidates for administration of an agent. For example, an individual having a genetic marker for development of a neurodegenerative disorder (such as the apoE gene) could be considered at risk for developing Alzheimer's disease, even though no previous disease has been observed. In this context, administration of an agent to such an individual could result in delay of occurrence of disease, even to the extent that the individual does not develop AD within his or her lifetime (or develops it later than would have been expected). Another example is an individual who is being treated using other modes of therapy, and who is showing clinical responsiveness to the therapy (i.e., stabilization or remission). Such an individual may be adjudged as at �high risk� even though the initial course of therapy is not yet completed, due to projection of clinical progress by the clinician, and can be a suitable candidate for receiving an agent before completion of the initial therapy. The clinician, as one skilled in the art, has discretion to determine whether treatment using an agent may be indicated.
In those individuals considered at high or significant risk of developing dementia, detection of proliferating macrophages in a biological sample may also assist in alerting the individual and/or the clinician of possible precursor disease. Thus, the invention also includes methods of monitoring an individual at risk or high risk of developing dementia, comprising detection of proliferating macrophages in a biological sample from that individual. Preferably, the individual is �afflicted with� (e.g., diagnosed as having, suffering from and/or displaying one or more clinical symptoms of) a particular disease, disorder or indication, or at �risk� for (e.g., having a genetic predisposition for, or family history of, or being environmentally exposed to factors which increase the probability of acquiring) a particular disease, disorder, or indication.
Detection of proliferating macrophage(s) can be achieved using any of several techniques. In some embodiments of the invention, proliferation is measured in relation to circulating macrophages, and is performed on a leukocyte preparation from peripheral blood. In other embodiments of the invention, proliferation is measured in relation to tissue-fixed macrophages, typically performed on tissue sections. Proliferating macrophages may be detected, for example, by assaying cell proliferative markers, such as PCNA, Ki67 or uptake of bromodeoxyuridine (BrdU) or 3H-thymidine. These markers are distinct from those that identify only �activated� macrophages (as opposed to proliferating macrophages), such as CD69 and CD25. The cellular subset representing macrophages may in turn be identified by detection of certain cell specific markers, such as CD14, CD68, CD16, or nonspecific esterase. Detection of these cell-type and/or proliferative markers use methods standard in the art, such as staining techniques and FACS sorting and analysis. These methods are further described in Example 1. Further, it is possible that these proliferating macrophages could be distinguished based on other characteristics, such as cell density (as measured in PERCOLL� gradients, for example). These determinations may be established empirically using standard techniques in the art.
where R2, R3, R4 and R5 are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkyl-C3-C6 cycloalkyl-C1-C6 alkyl C3-C10 aryl, and C1-C6 alkyl-C3-C10-aryl-C1-C6 alkyl;
More preferably, the polyamine analogs will include compounds of the structures 2 and 3, where R3, R5, R7 and R9 are independently (CH2), groups, where x is an integer from 2 to 6, and where R4, R6 and R8 are hydrogen atoms, and where R1 and R10 are alkyl groups, and further where R2 and R11 are hydrogen atoms.
where R4 is C2-C6 n-alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, or C3-C6 aryl;
Preferably, all the nitrogens of the polyamine analog are independently secondary, tertiary, or quaternary amino groups.
1,11-bis(ethyl)norspermine (1,11-bis(ethylamino)-4,8-diazaundecane; BE-3-3-3) 1,8-bis(ethyl)spermidine (BES) 1,12-bis(ethyl)spermine (BESm; DESPM (N1,N12-diethylspermine; SunPharm); 1,14-bis(ethylamino)-5,10-diazatetradecane (BE-4-4-4) (Diethylhomospermine, N1,N14-diethylhomospermine; DEHOP or DEHSPM; SunPharm) diethyl-norspermine (DENOP; SunPharm) 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) N-ethyl-N′-(2-(3′-ethylamino-propylamino methyl)-cis-cyclopropylmethyl)-propane 1,3-diamine tetrahydrochloride (SL-11037), provided by S'LIL, Madison, Wis. N-ethyl-N′-(2-(3′-ethylamino-propylamino methyl)-trans-cyclobutylmethyl)-propane 1,3-diamine tetrahydrochloride (SL-11038), S'LIL N-ethyl-N′-(2-(3′-ethylamino-propylamino methyl)-trans-cyclopropylmethyl)-propane 1,3-diamine tetrahydrochloride (SL-11044), S'LIL. N,N′-bis(3-ethylaminopropyl)-cis-but-2-ene-1,4-diamine tetrahydrochloride (SL-11047), S'LIL
Besides the polyamine analogs listed above, stereoisomers, salts or protected derivatives thereof, may be used. The invention also comprises methods of using an effective amount of any of the polyamine analogs listed above, or stereoisomers, salts or protected derivatives thereof (or a composition comprising an effective amount of any of the polyamine analogs listed above, or stereoisomers, salts or protected derivatives thereof) in modulating macrophage proliferation (or in treating or delaying development of macrophage-associated diseases, including HIV-associated dementia and AD). The invention also comprises any polyamine analog listed above, or stereoisomers, salts or protected derivatives thereof, for use in preparing compositions (i.e., medicaments) useful for treating macrophage-associated diseases, including HIV-associated dementia, and Alzheimer's disease.
A polyamine analog (or stereoisomer, salt or protected derivative) may be administered alone, or in conjunction with other substances and/or therapies, depending on the context of administration (i.e., desired end result, condition of the individual, and indications). �In conjunction with� means that an agent is administered prior to, concurrently, or after other substance or therapy. Examples of substances that might be administered in conjunction with an agent include, but are not limited to, brain neurochemical modulators (in the context of macrophage-associated dementias), and classic anti-neoplastic agents and/or anti-lymphocytic agents such as steroids and cyclosporine derivatives. For example, a polyamine analog (or a stereoisomer, salt or protected derivative thereof) can be administered in conjunction with mitoguazone dihydrochloride.
The mechanistic effectiveness of various polyamine analogs and enzyme inhibitors can be determined at least in part by their ability to deplete intracellular polyamine pools. Kramer et al. [(1995) Biochem. Pharmacol. 50:1433[describe the use of 4-fluoro-L-ornithine to monitor metabolic flux through the polyamine biosynthetic pathway. It was determined that the metabolic flux indicated by the rate of appearance of fluorinated polyamines, reflected the proliferation status of the cells. U.S. Pat. No. 5,498,522 outlines the use of SSAT as a prognostic indicator or tumor response marker. Either SSAT enzyme activity, SSAT enzyme protein, or mRNA transcripts can be measured directly, or other determinants related to SSAT induction can be measured, such as SSAT co-factor acetylCoA, and the SSAT products N1-acetylspermine and N1-acetylspermidine. To further determine the effect of a polyamine analog's administration, an individual may be monitored for disease (or precursor disease) progression as well as biochemical and/or genetic markers of disease (or precursor disease). With respect to disease progression, multiple rating scales (i.e., indices of clinical function) have been established and are known in the art for various macrophage proliferative disorders such as AD and lymphomas. For macrophage-associated neurological disorders, cognitive functions can be tested and, in some cases, imaging modalities such as MRI may be used.
EXAMPLES Example 1 Testing Various Polyamine Analogs for Effect on Macrophage Proliferation in the Context of Macrophage-Associated Disorders Separation of Peripheral Blood Monocytes
Five�105 PBMC's isolated through a 1.087 g/cc Percoll/saline gradient were exposed to varied concentrations of agent after baseline CD14/PCNA staining was performed. The cells were cultured at 5�105 cells in RPM1-1640/10% fetal calf serum in a polypropylene tube (Falcon) at 37� C. for five days. After five days CD14/PCNA staining was performed on control and agent-treated cultures. FACSCAN analysis of PCNA-positive cells in control cultures was compared with agent-treated cultures and the percentage of control PCNA/CD14 cells was calculated. The results of such an experiment in which the effect of polyamine analog DEHOP (SunPharm; Florida) on proliferating macrophages (as detected by PCNA) from the blood of four patients with AIDS dementia are shown in FIG. 1A (with underlying data provided in Table 3). This polyamine analog significantly reduced the percentage of proliferating macrophages. A comparison of the inhibitory effect of DEHOP and cyclosphosphamide, another anti-proliferative agent, was performed in vitro using the blood of one of these patients (�CB�). The results are shown in Table 1. This experiment showed that DEHOP was superior in inhibition. This polyamine analog effect is relative and specific as indicated by a lack of in vitro toxicity in this assay system by cyclosphosphamide, a classic anti-neoplastic agent.
A comparison of polyamine analogs SL-11037, SL-11038 (S'LIL Pharmaceuticals) and DENOP (SunPharm) on macrophage proliferation from the blood of one patient with AIDS dementia is shown in Table 2. All 3 agents showed inhibitory effects. FIG. 1B similarly shows that polyamine analog BE-4444 demonstrates potent killing of PCNA+/CD14+ cells. The data shown in FIG. 5 similarly demonstrate that polyamine analogs SL-11047, SL-11048 and SL-11044 (S'LIL Pharmaceuticals) are potent inhibitors of PCNA+ macrophage detection from peripheral blood of HIV+ sarcoid patient. 60% of input CD14 cells were PCNA+; the assay was performed 96 hr after drug exposure and culture. The data shown in FIG. 6 demonstrate that polyamine analogs DEHOP and SL-11047 all decrease PCNA+/CD14 cell survival. The data presented are averages of several (N) experiments performed. Thus, the data shown herein demonstrate that BE-4444, SL-11037, SL-11038, SL-11044, SL-11047, SL-11048, DEHOP and DENOP all demonstrated potent inhibition and/or killing of blood PCNA+/CD14+ cells.
Effect of DEHOP and Cyclophosphamide (Cytoxan �, Bristol-
Myers Squibb) on CD14+, PCNA+ peripheral blood macrophage
Patient CB at time 0:
% of CD14+ that were CD69+: 0
% of CD14+ that were PCNA+: 28%
median SSC for all CD14+: 420
Example 2 Suppression of In Vitro Cell Killing by Supernatants from Peripheral Blood from an AIDS Dementia Patient We have previously observed a cell killing effect of mononuclear cell supernatants from peripheral blood of patients with AIDS dementia. Pulliam et al. (1997) Lancet 349: 692-695. We tested a similarly prepared supernatant which was treated with the polyamine analog DEHOP.
Human fetal brain tissue from between 16 and 18 weeks' gestation was obtained from elective abortions for preparation of brain cell aggregates. These aggregates contain all the cells of the central nervous system including neurons, astrocytes, oligodendrocytes with accompanying myelin, and microglial cells. After 10 days in culture, and before experimentation, aggregates were tested for viability by trypan-blue exclusion. Aggregates were divided into flasks at 50 mg wet-weight in 2 mL exchange medium (DMEM with 15% fetal calf serum). Aggregates were treated with mononuclear cell supernatants (20%) for 3 days. The flasks contents were centrifuged; the supernatant was used for lactate dehydrogenase assay and the aggregate pellet for DNA fragmentation (programmed cell death) assay.
Brain cell aggregates were treated with 20% supernatant from cultured CD14 cells from a demented AIDS patient. Treatment was for 72 h. After treatment, the aggregates were washed and fixed in Karnovsky's solution. The cells were post-fixed in 1% osmium tetroxide dehydrated for staining with uranyl acetate and lead citrate. Thin sections were examined in a JEOL 1OOSX electron microscope.
Example 3 Detection of Proliferating Macrophages in Patients with Alzheimer's Disease Participants and Methods
5 mL blood was obtained from patients and controls. 100 μL whole heparinised blood was stained with fluorescein-conjugated anti-CD14 (DAKO Corp.) and with phycoerythrin-conjugated anti-PCNA (Becton Dickinson). Red-blood cells were lysed by the addition of FACSLYSE solution (Becton Dickinson). The cell suspensions were centrifuged and the cell pellets resuspended in phosphate-buffered saline containing sodium azide and paraformaldehyde and stored at 4� C. To stain intracellularly for PCNA, cell pellets were resuspended in �Permeabilising Solution� (Becton Dickinson). Buffer was added to each tube, followed by centrifugation. Cell pellets were resuspended in buffer and stained with phycoerythrin-conjugated PCNA. The cells were washed, fixed, and stored as above.
Cells were analysed with a FACSCAN flow cytometer (Becton Dickinson). At least 2000 cells per sample were analysed. Negative staining was defined as the area of dot plots that contained over 99% of isotype-stained (DAKO) �control cells�. The results are shown in FIG. 4. The patients with AD displayed a significantly higher percentage of proliferating macrophages or non-disease controls as well as diseased controls, including AIDS dementia. Individual values (percentage PCNA/CD14 cells) were: (a) non-disease controls, 10; 16; 19; 20; 27; 46; (b) disease controls: ALS, 17; 25; Parkinson's, 27; 45; MS, 7; 20; HIV dementia, 6; 28; 37; 52; 54; 61; 96; (c) AD patients, 44; 47; 91; 97; 98; 100.
Example 4 Effect of Polyamine Analogs on PCNA Expression of Peripheral Macrophages from Patients with AD Separation of Peripheral Blood Monocytes
Five�105 PBMC's isolated through a 1.087 g/cc Percoll/saline gradient were exposed to varied concentrations of agent after baseline CD14/PCNA staining was performed as described in Example 3. The cells were cultured at 5�10 cells in RPM1-1640/10% fetal calf serum in a polypropylene tube (Falcon) at 37� C. for five days. After five days CD14/PCNA staining was performed on control and agent-treated cultures. FACSCAN analysis of PCNA-positive cells in control cultures was compared with agent-treated cultures and percentage of control PCNA/CD14 cells was calculated. Two polyamine analogs, DENOP (SunPharm; Florida) and SL-11037 were tested. As shown in FIG. 3, both agents significantly reduced the percentage of proliferating macrophages.
Example 5 Using Polyamine Analog to Treat an Individual with a Macrophage-Associated Dementia A 72-year-old male presents with increasing loss of memory and confusion. A blood sample is obtained, and the percentage of PCNA-expressing CD14 cells is significantly elevated over the control. The patient is given DESPM (a polyamine analog) at 125 mg/m2/day for six days, repeated every three weeks. Blood samples are obtained routinely to monitor the level of PCNA-expressing CD14 cells.
Example 6 Effects of Polyamine Analog Diethylhomospermine (DEHOP) on Chemotherapy Resistant AIDS Related Lymphoma Patients Four patients who had failed standard chemotherapy for treatment of their AIDS related lymphoma (therapy included at least CHOP chemotherapy up to six cycles) were evaluated for response to DEHOP administration in vivo. Patients had blood drawn pre administration of drug for evaluation of macrophage activation. This blood was also evaluated for response to DEHOP in vitro. The trial was set up to evaluate clinical response to drug given for 5 days subcutaneously (sq) at a dose of 25 mg/m2 (2 patients) and 50 mg/m2 (2 patients). Blood was obtained at 1 week after completion of the first and second cycles of therapy. The blood specimens were evaluated for macrophage proliferation (proliferating cell nuclear antigen, PCNA expression), and activation (percentage CD69 expression). Response to therapy was evaluated by direct observation of tumor (3 patients) and persistence or resolution of symptoms (1 patient with GI lymphoma).
To test whether patient macrophages would respond to administration of DEHOP in vitro, CD14 cells in a peripheral blood mononuclear cell preparation (PBMC) were exposed to different concentrations of DEHOP and the proportion of CD14 positive cells surviving at the end of 5 days of culture was assessed in drug treated cells as compared to controls. Specimens obtained pre chemotherapy were compared to specimens obtained 2 weeks post therapy. Table 4 summarizes CD14+ cell responses to DEHOP in vitro in the 4 AIDS lymphoma patients evaluated; FIG. 7 shows the CD14+ cell response to DEHOP in vivo. For patient FL, the first specimen was obtained one day after the first cycle of DEHOP; the second specimen was obtained one week later. The effective dose 50 (where 50% of cells were killed), and effective dose 80 (where 80% of cells were killed) were calculated for each set of patient specimens exposed to DEHOP in vitro. In post in vivo DEHOP administration blood specimens, patient FTJ was persistently resistant to drug whereas patient LT and FL, both of whom responded clinically to DEHOP, showed marked drug sensitivity in vitro.
CD14 Cell Polyamine Analog Sensitivity: In vitro dose response in NHL patient PBMC; total CD14+ cell survival, ED50 and ED80 Patient
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Pharmacol. 50:1433-1443.16Lim et al., "MGBG Therapy of Relasped Extralymphatic HIV-Associated Non-Hodgkins Lymphoma (HIV NHL)," (Mar. 14, 1995) Proc. Annu. Meet. Am. Soc. Clin. Oncol. 14:A1274.17Marton et al., "Polyamines As Targets for Therapeutic Intervention" (1995) Ann Rev. Pharmacol. Toxicol. 35:55-91.18Mascolini. "Oncologists Scout New Direction for KS and Lymphoma Therapies," (1995) J. Int. Assoc. Physicians Aids Care 1(5):10-14.19McGrath et al., "Indentification of A Clonal Form Of HIV In Early Kaposi's Sarcoma: Evidence For A Novel Model Of Oncogenesis, 'Sequential Neoplasia'"(1995) J. Acquired Inn. Def. Syn. Hum. Retro. 8:379-385.20McGrath et al., "Indentification of A Clonal Form Of HIV In Early Kaposi's Sarcoma: Evidence For A Novel Model Of Oncogenesis, �Sequential Neoplasia�"(1995) J. Acquired Inn. Def. Syn. Hum. Retro. 8:379-385.21Messina et al., "Polyamine Involvement In Functional Activation of Human Macrophages," (1992) J. Leukoc. 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"Pharmacokinetic profile of mitoguazone (MGBG) in patient with AIDS related non-Hodgkin's lymphoma," Investigational New Drugs, 1996, vol. 14, pp. 227-234.30Rizzo et al., "Pharmacokinetic Profile of Mitoguazone (MGBG) In Patients With AIDS Related Non-Hodgkins Llymphoma," (1996), Inventigational New Drug, vol. 14, pp. 227-234.31Shiramizu et al., "Identification of a Common Clonal Human Immunodeficiency Virus Integration Site in Human Immunodeficiency Virus-Associated Lymphomas", (1994) Cancer Res. 54:2069-2072.32 *Von Hoff "MGBG: Teaching an old drug new tricks," Annals of Oncology, 1994, vol. 5, pp. 487-493.33Von Hoff, "MGBG: Teaching an Old Drug New Tricks," (1994), Annals of Oncology, vol. 5. pages 487-493.34Wojewodzka et al., "Structure-Activity Relationship of Polyamine Derivatives of 1, 3-Dichloracetone-Thiosemicarbazone: Induction of Metastases and Increase In Sialylation of Murine Lymphoma L5178Y-R Cells," Chem. Biol. Interactions, 74 (1990) 221-223.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS20110091418 *Dec 21, 2010Apr 21, 2011Pathlogica, LLCMethods for treating viral infections using polyamine analogsUS20120022166 *Jul 25, 2011Jan 26, 2012Mcgrath Michael SMethods for Modulating Macrophage Proliferation Using Polyamine Analogs* Cited by examinerClassifications U.S. Classification514/635, 514/634International ClassificationA61P43/00, G01N33/569, A61K31/131, G01N33/50, A61K31/132, A61K31/155, A61K31/13, G01N33/68, A61P25/28Cooperative ClassificationA61K31/155, G01N2800/2821, G01N33/6896, A61K31/13, A61K31/131, G01N33/56972, G01N33/5055European ClassificationG01N33/50D2F2F, G01N33/68V2, A61K31/131, G01N33/569H2, A61K31/155, A61K31/13Legal EventsDateCodeEventDescriptionMar 6, 2012CCCertificate of correctionJun 20, 2005ASAssignmentOwner name: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, CALIFFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MCGRATH, MICHAEL S.;REEL/FRAME:016162/0495Effective date: 19981218RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google

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Amazon.co.uk: Roy P. Godfrey's review of Jim Dunlop The Original Crybaby Pedal
One of the greats, 9 Nov 2008
By Roy P. Godfrey
A must for any performing lead guitar player. You cannot go wrong with the cry baby, it sounds awesome with a gig setup. This and a tubescreamer with a tube amp slightly overheated and you will be in guitar heaven.
Roy P. Godfrey
Initial post: 27 Nov 2012 18:06:18 GMT
I have tubescreamer too. do you put that in front of the CryBaby, or after?
Top Reviewer Ranking: 4,135,796


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Great fun - Review of Taff Valley Quad Bike & Activity Centre, Pontypridd, Wales - TripAdvisor
Great fun - Taff Valley Quad Bike & Activity Centre
Nature & Parks, Fun & Games, Outdoor Activities, Game & Entertainment Centers, Off-Road & ATV Trails More
We went here for a Stag-Do (14 of us) for the shooting. We booked breakfast with them, it was... read more
Came to Wales for a stag weekend and booked in for a morning of clay pigeon shooting and quad... read more
Discover32506425616
Great quads, friendly staff and good tuition. You are given a quad according to your size as I am 4ft 10 and this is great.More
Ask Ann S about Taff Valley Quad Bike & Activity Centre
DarlingWales, Manager at Taff Valley Quad Bike & Activity Centre, responded to this reviewResponded July 17, 2013
Thank you for the review. Glad you enjoyed the quad biking. We pride ourselves on catering for all ages, sizes and abilities, the bikes we have and the ground we have are ideal for it so I'm pleased we could accommodate you. We look forward to your next visit!
All reviews clay pigeon shooting great fun stag do assault course my son local pub working farm open fields practice track fantastic experience safety briefing these guys small track off road excellent tuition well worth the money on site
We went here for a Stag-Do (14 of us) for the shooting. We booked breakfast with them, it was tasty, then we got into a Land Rover Defender to take us to and from the shooting area. The instruction was great, it was really good fun. They have loads of different activities to do, that is perfect for a Stag Do. Recommended.
Ask sierraromeobravo about Taff Valley Quad Bike & Activity Centre
Came to Wales for a stag weekend and booked in for a morning of clay pigeon shooting and quad biking. Staff were all really friendly, the equipment was tip-top, and despite being a group of hungover lads, no one died! Five stars.
Also hadn't expected the gorgeous view. Great place. Recommend!
Ask Discover32506425616 about Taff Valley Quad Bike & Activity Centre
Thank Discover32506425616
Took my grandson for his birthday. It was absolutely fantastic. All equipment supplied. Staff were wonderful very helpful. We all had a wonderful time.
Ask wsusan123 about Taff Valley Quad Bike & Activity Centre
Adventure55611500590
New levels of cold
Went for a stag do, started with the quads had a ball course wasn’t the most exciting but they make it fun! Then onto the gorge walk with Aaron an Lee who were fantastic! Got involved with the group so didn’t feel like instructors which was great. Best cold I’ve ever felt an would repeat in a heart beat!
Ask Adventure55611500590 about Taff Valley Quad Bike & Activity Centre
Thank Adventure55611500590
We visited for a quad biking experience on Saturday. My youngest, 7 went into the junior field and my daughter 12 and myself went on a trek for the hour. Up and down through fields. We all had an amazing time. Staff were great and helpful. Little cafe for drinks and stuff although we didn’t use it.
Ask Kscoobs about Taff Valley Quad Bike & Activity Centre
We had a wonderful day with clay pigeon shooting, quad biking and archery. The instructors were excellent with good safety briefings and instructions. The quality of all the equipment was well maintained and to a good standard. The facilities could do with improving though, the toilets were a bit disgusting and some more instructions could be given as to timings and where to wait but other than that a fantastic experience. It’s not cheap so would have appreciated nicer facilities and somewhere to sit whilst waiting.
Ask Nic-ldn about Taff Valley Quad Bike & Activity Centre
Just been to the quad biking centre run by Hopkin Davies. I bought gift vouchers for my three grandsons, ages 10,15 and 17. The instruction was thorough and patient and boots and helmets supplied. Take your own boots if you can as the engine gets hot and ankles need protecting. 10 year old was nervous but with the patient tuition from the instructor, he soon gained confidence and was off. He started on a track but later went out onto the fields which he loved. The other two went out on to the fields and they all came back with huge smiles on their faces. If you want to give a welcome present for Christmas call the centre and they will print them on Christmas card for you. You can then choose when you want to go.
My grandsons voted them a great present.
It is difficult to get to and the lanes are very narrow but there are passing places and still worthwhile visiting.
Ask CardiffBeaver about Taff Valley Quad Bike & Activity Centre
Thank CardiffBeaver
Wow! We were a group of 17 on a hen party and did gorge walking. Matt, James and Lee were amazing - they kept us safe and ensured we had fun. They also adapted the route for our group and our timings. Really friendly and fun staff. They took lots of photos. The gorge walking was so fun, everyone loved it. Thank you!!
Ask Sophie P about Taff Valley Quad Bike & Activity Centre
Excellent clay pigeon shooting session
My 23yr old daughter and I had an excellent clay pigeon shooting session today. Our instructor, John, was great, very easy going and knowledgable, and he made it a fun session.
Ask ColinAndJayne about Taff Valley Quad Bike & Activity Centre
Absolutely amazing group of people with excellent hospitality and a brilliant sense of humour to boot. Five of us visited them after a weekend of quad biking around the Port Talbot and Merthyr Tydfil area. Clay Pigeon shooting was first with Bryn and he had excellent knowledge of the sport and pointed us all in the right direction to be able to hit at least some of the clays (which was more than most of us bargained for). He was in fact so competent and confidence inspiring that I now heavily considering talking up clay pigeon shooting as a second hobby to mountain biking. Quad biking was a blast, and the loop that they set up was short and sweet, with enough to ensure that we all had the hang of the controls without taking up too much of our ride time. The circuit we completed was challenging but had plenty enough opportunities to wring the necks of the bikes we rode and get a good thrill from it all. Archery was also excellent, with good tuition and a fair amount of competitiveness encouraged by our coach, and a brilliant sense of humour shown. Will definitely be back for more. Ash
Ask Ash J about Taff Valley Quad Bike & Activity Centre


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Are You the Business Owner of Akimbo Card?
Akimbo Card has had their Business Review viewed 87 time(s) over the last 30 days. Click to view where these inquiries originated.
Complaint: My Akimbo Prepaid Visa Debit Card has been restricted since October 2013. I have a balance of $745.14. I have sent in requested documents numerous times, even a Notarized Affidavit of Identity. When I call, I get the run around. I'm told to call back, or call another number, or send an email. I am thoroughly exhausted trying to get information on my OWN MONEY & ACCOUNT. I have requested for my Akimbo Account to be closed & send me the remaining balance, but Akimbo has not acknowledged any of my phone calls, faxes, or emails. Please help.Thank YouDesired Settlement: Either take the restriction off of my Akimbo Prepaid Visa Debit Card Account, so I can pay bills & spend my money or close my Akimbo Prepaid Visa Debit Card Account & send me my $745.14 ASAP
This individual provided identifying documents which were determined to be altered or otherwise counterfeit by our issuing bank, The ******* Bank, Member FDIC. The ******* Bank identified numerous discrepancies and abnormalities in both the state ID card and the Social Security card provided by the customer. The same falsified state ID card was shown to a Notary Public in order to obtain the 'affidavit of identity' that was provided to Akimbo and The ******* Bank, and so this affidavit was also not honored.
Both The ******* Bank and Akimbo Financial believe that this individual has provided counterfeit documents and potentially committed a felony offense by affirming these documents were legitimate to both a US financial institution and a notary public.
If the individual believes our determination to be in error, she may follow arbitration proceedings as defined in our cardholder agreement. (***********************************************************)
The copies sent are not Counterfeit, they are a copy of a copy and maybe the quality isn't so good. But in July, when I applied for the account and sent in the same copy of the documents, there wasn't any problems & I was approved for the Account. Obviously Akimbo no longer wants to have me as a customer, and it's been over two months since they blocked the Account, so why haven't they closed it yet? Also, on 11/27/2013, they deposited $245.14, into my account that wasn't my money. I have a total of $500 of my money, not theirs, in the account. Shouldn't the account be closed and the balance settled?
Thank you for the prompt response, I appreciate your help with this matter.
This individual did not provide these documents in July. Documents were not required to 'open' an Akimbo Card account. This individual used the name, DOB, and SSN for "******* *******," to open the account with Akimbo Card online.
It was not until this account had a temporary block placed on itm that these documents were requested and subsequently provided by the individual. Upon review of these documents, multiple irregularities and inconsistencies were found by the Fraud Department of ******* Bank, and these documents were then deemed counterfeit or otherwise altered.
Is Akimbo expected to respond to every allegation this individual makes?
I am rejecting this response because: I still don't have an answer to what happens to my $500?

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Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. - PubMed - NCBI
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See comment in PubMed Commons belowJ Matern Fetal Neonatal Med. 2005 Jan;17(1):3-18.Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia.Chaiworapongsa T1, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, Bujold E, Gonçalves L, Gomez R, Edwin S, Mazor M.Author information1Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.AbstractOBJECTIVE: Accumulating evidence suggests that the balance between vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and their receptors is important for effective vasculogenesis, angiogenesis, and placental development. Recently, the soluble form of VEGFR-1 (sVEGFR-1), an antagonist to VEGF and PIGF, has been implicated in the pathophysiology of pre-eclampsia. Plasma sVEGFR-1 concentration is elevated in pre-eclampsia at the time of clinical diagnosis and correlates with the severity of the disease. The purpose of this study was to determine whether the concentrations of sVEGFR-1 in plasma of pre-eclamptic patients change prior to the clinical manifestations of the disease.METHODS: A longitudinal case-control study was conducted in normal pregnant women (n = 44) and patients with pre-eclampsia (n = 44). Blood sampling was performed at six intervals: (1) 7-16 weeks; (2) 16-24 weeks; (3) 24-28 weeks; (4)28-32 weeks; (5) 32-36 weeks; and (6) more than 37 weeks of gestation. To examine the relationship between plasmasVEGFR-1 concentration and interval to clinical diagnosis of pre-eclampsia, plasma samples of pre-eclamptic patients at different gestational ages were stratified according to the interval from blood sampling to clinical development of the disease into five groups: (1) at clinical manifestation; (2) 2-5 weeks; (3) 6-10 weeks; (4) 11-16 weeks; and (5) 17-25 weeks before clinical manifestations. Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. Parametric statistics and repeated measure procedures were used for the analysis.RESULTS: The mean plasma sVEGFR-1 concentration in pre-eclamptic patients before the clinical manifestation of the disease was significantly higher than in normal pregnant women at 24-28, 28-32, and 32-37 weeks of gestation (p = 0.02,p < 0.001, and p < 0.001, respectively). In contrast, no significant differences in the mean plasma sVEGFR-1 concentration between patients with pre-eclampsia and normal pregnant women were observed both at 7-16 weeks and 16-24 weeks of gestation (p= 0.1 and p= 0.9). Similarly, the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclamptic patients than in normal pregnant women at clinical manifestation, at 2-5 weeks (mean 3.8 weeks), and at 6-10 weeks (mean 8.2 weeks) prior to the development of clinical pre-eclampsia (p < 0.001, p < 0.001, and p = 0.002,respectively). Among patients with early-onset pre-eclampsia (defined as gestational age of 34 weeks or less), the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclampsia (before clinical diagnosis) than in normal pregnant women at 24-28 (mean 26.4) weeks of gestation (p = 0.008). In contrast, among patients with the late-onset disease(defined as gestational age of more than 34 weeks), plasma sVEGFR-1 concentration in pre-clinical pre-eclampsia was significantly higher than in normal pregnant women at 28-32 (mean 30.2) weeks of gestation (p < 0.001).CONCLUSIONS: Plasma sVEGFR-1 concentration is elevated in pre-eclampsia prior to the clinical diagnosis of the disease. This elevation began 6-10 weeks prior to the clinical manifestations, and the increase was more pronounced at 2-5 weeks before the diagnosis, as well as at clinical presentation. Furthermore, in early-onset pre-eclampsia, plasma concentration ofsVEGFR-1 is elevated earlier than the late-onset disease.PMID: 15804781 DOI: 10.1080/14767050400028816 [Indexed for MEDLINE] ShareMeSH terms, SubstanceMeSH termsAdultCase-Control StudiesFemaleGestational AgeHumansLongitudinal StudiesOsmolar ConcentrationPre-Eclampsia/blood*Pre-Eclampsia/diagnosis*PregnancyRetrospective StudiesSolubilityVascular Endothelial Growth Factor Receptor-1/blood*Vascular Endothelial Growth Factor Receptor-1/chemistrySubstanceVascular Endothelial Growth Factor Receptor-1LinkOut - more resourcesFull Text SourcesTaylor & FrancisOther Literature SourcesCOS Scholar UniverseCited by Patents in - The LensMedicalEclampsia - Genetic AlliancePubMed Commons home

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