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I am slinking this to the Think Tank - perhaps some of our modeling experts there can chime in.
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Messages from Bonn 2011: Water, Energy and Food Security Nexus
How will the planet cope with two more billion people in an increasingly urbanized and wealthy world? Can there be solutions to dealing with the significant additional pressure on energy, water and food demands, whilst avoiding further ecosystem degradation? …
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Big boost for wildlife conservation: 23 new SOS projects
Top wildlife experts from around the world have allocated $US 3.3 million to 23 species conservation projects. Gorillas, cockatoos, and frogs are some of the many threatened species that are receiving a helping hand from SOS (Save Our Species), a global conservation fund initiated by IUCN, the World Bank and the Global Environment Facility (GEF). … | French | Spanish
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Discover IUCN (International Union for Conservation of Nature), the world's largest global environmental network. We are working in more than 160 countries, gathering the latest knowledge on biodiversity, running hundreds of conservation projects around the world and being nature's voice on the international stage. Watch this video and find out who we are and how we work for a just world that values and conserves nature. …
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Découvrez les activités de l'Union internationale pour la conservation de la nature, le plus vaste réseau mondial de protection de l'environnement. Nous travaillons dans plus de 160 pays, dans trois grands domaines : la réalisation de projets sur le terrain, le développement de connaissances scientifiques sur l'état de la biodiversité, et l'influence au niveau international. …
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The Royal Botanic Gardens Kew, an IUCN Member, have launched the UKOTs Online Herbarium. It is a species and specimens database containing plant diversity information for all UK Overseas Territories (UKOTs) and geographically related islands. …
07 Feb 2012 | News story
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The Government of the Republic of Iraq has officially announced its decision to join IUCN by endorsing the IUCN Statutes. The Ministry of Environment has been designated by the Government of the Republic of Iraq as its liaison with the IUCN Secretariat. … | French | Spanish
06 Feb 2012 | News story
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Every year World Wetlands Day is celebrated on 2 February, marking the day of the adoption of the Ramsar Convention on Wetlands, 41 years ago in the Iranian city of Ramsar. This year the theme of World Wetlands Day is 'Wetland Tourism, A Great Experience'. …
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Naturally Europe
In the past, Europe was more rural that today. People had a daily connection to nature for their livelihoods and well-being. Today, many living in cities throughout the region have lost this connection. Perhaps more than anywhere else in the world, European landscapes have been changed by human activity during the past centuries. The relentless march of economic development and urban settlement has put the continent's natural resources under immense pressure and much of the region's biodiversity has been lost. …
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The day I met Godzilla...
Fred Burton heads a mission in the British Overseas Territory of the Cayman Islands to rescue the iconic Grand Cayman Blue Iguana from extinction. His story is a rare thing in conservation: success on a shoestring. …
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fan sign for fan sign, on myspace or any other socieal networking website you can make a fan sign for a friend, and theyll make one back in return
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by LISAfromSOSANFRAN April 06, 2008


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Mila Kunis, whose sex scene with Natalie Portman in 'Black Swan' has drummed up huge publicity for the movie, strips down again in her next next film, 'Friends With Benefits' - this time alongside Justin Timberlake. She talks about how they kept a semblance of modesty in a new interview with The Advocate:
We had two weeks' worth of sex scenes to shoot. Justin would just wear a sock that covered his frontal parts, so yeah, I could pretty much see everything. And I had tiny nipple pasties and a little pasty on my hoo-ha. We couldn't have been more uncomfortable in the beginning, but by the fourteenth day, we'd just drop our robes, like, "Hey, how's it goin'?"
Since the interview was done, Mila announced her split from Macaulay Culkin. When asked whether her longtime boyfriend ever gets jealous when she shoots nude scenes, she didn't really answer:
Well, when you sign up for a movie called Friends With Benefits, you kind of know what you're getting yourself into. But it's work. It's all very strategic, because there are 150 crew members trying to light you and make sure no one can see your pasties. And Justin couldn't have been more of a gentleman, because it can be very awkward.
Read the rest of the interview, in which Mila talks about simulating oral sex with Zoe Saldana, being bullied as a kid and playing the younger version of Angelina Jolie's character in 'Gia,' at The Advocate.


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Listen each week as TENNIS magazine's top editors discuss and analyze the
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Fed Cup Final
2010-11-04 14:09:11+00:00
The United States and Italy meet for the second straight year in the Fed Cup final. Can the Americans win this time around?
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2010-11-02 00:07:19+00:00
Who was the WTA player of the year, and what's in store for the women's tour in 2011? We discuss.
Dementieva's Done
2010-10-31 12:40:50+00:00
The editors discuss Elena Dementieva's sudden retirement, Jim Courier's new post and Thomas Muster's comeback.
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2010-10-27 15:51:12+00:00
The season-ending championships are supposed to be a showcase event for the tours. But are they?
Andy and Ana
2010-10-18 19:00:36+00:00
Andy Murray won yet another Masters title, while Ana Ivanovic won her first title in two years. We discuss both champions.


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The clip said "ripping apart" I didn't see any action like that
That's one hell of a cock for sucking the cum out of!
No cum, so dissapointing


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|Publication number
|Publication type
|Application number
|Publication date
|Oct 26, 1999
|Filing date
|Jan 16, 1998
|Priority date
|Jan 16, 1997
|Fee status
|Also published as
|Publication number
|James W. Simpkins, Kelly E. Gridley, Pattie S. Green
|Original Assignee
|University Of Florida Research Foundation, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (1), Non-Patent Citations (14), Referenced by (36), Classifications (26), Legal Events (8)
|External Links: USPTO, USPTO Assignment, Espacenet
This application claims benefit of the earlier filing date of U.S. provisional patent applications, Ser. No. 60/058,104 dated Sep. 5, 1997, Ser. No. 60/053,516 dated Jul. 23, 1997 and Ser. No. 601035,537 dated Jan. 16, 1997, these provisional applications are incorporated herein by reference.
There is a need for treatments that protect cells from cell death resulting from episodes of disease, trauma, isolation and removal of tissues or cells from the body, or exposure to toxins. This need extends to treatments for nerve cell loss associated with chronic or acute neurodegenerative disorders or trauma; treatments to minimize tissue damage resulting from ischemia where ischemia may occur as a result of stroke, heart disease, a transplantation event, or other event resulting in a cut-off in nutritional supply to tissues; and treatment to modulate cell death associated with conditions such as osteoporosis or anemia. The absence of an effective cytoprotective therapy can result in either loss of life or a general decline in the quality of life including permanent disability with high health care costs to patients, their families and the health care providers. One approach to minimize pathologic changes has been to attempt to neutralize the oxidative stress that is associated with an accumulation of free radicals in the extracellular space. Mooradian, J. Steroid Biochem. Molec. Biol. 45 (1993) 509-511 has reported that certain estrogens have significant anti-oxidant properties in in vitro biochemical assays but this effect is not seen with all estrogens. Because of the variation in anti-oxidant properties noted by Mooradian in his biochemical assays, he concluded that steroid molecules must have certain anti-oxidant determinants which were as yet unknown. Similar observations concerning steroids with phenolic A rings were reported in WO 95/13076 using biochemical assays to show anti-oxidant activity. The assays used by Mooradian and by WO 95/13076 were biochemical assays and as such did not directly examine the effects on cells of these molecules. U.S. Pat. No. 5,554,601 (1996) however described cell based assays to determine a method of conferring neuroprotection on a population of cells using estrogen compounds based on demonstrated cell protective effects.
Oxidative damage has been associated with a variety of neurodegenerative diseases including Alzheimer's disease (AD); and the aging process. (Benzi et al. Free Radic. Biol. Med. 19, (1995); 77-101, and U.S. Pat. No. 5,554,601 incorporated herein by reference) . Cell death also occurs following an ischemic event in the body resulting from nutrient deprivation which may be associated with oxygen deprivation resulting from an occlusion in a cerebrovascular or cardiovascular location or may be associated with trauma or disease.
There is a need for improved methods of protecting both men and women from the consequences of abnormal cell death in body tissues.
In an embodiment of the invention, a method is provided for conferring cytoprotection on a population of cells that includes providing a polycyclic phenol compound, and an anti-oxidant compound; and administering the polycyclic phenol compound and the anti-oxidant compound to the population of cells at an effective dose so as to confer cytoprotection such that the combined cytoprotective effect of the polycyclic phenolic compound and the anti-oxidant compound is greater than the additive effect of each compound administered separately under otherwise similar conditions.
A further embodiment of the invention is a method of conferring cytoprotection on a population of cells in a subject, including the steps of providing a combination therapeutic dose containing an anti-oxidant and a polycyclic phenolic compound in a pharmaceutical formulation; administering the formulation in an effective dose to the population of cells such that the cytoprotective effect of the combination in the subject is greater than the additive effect of each compound provided separately; and protecting cells in the subject that would otherwise deteriorate and die in the absence of the pharmaceutical formulation.
In further embodiments of the invention, the combined effect may be a 100-10,000 fold enhancement, more particularly a 100-5,000 fold enhancement, more particularly a 1,000-5,000 fold enhancement of cytoprotection resulting from the combined effect of the polycyclic compound and the anti-oxidant compared with each compound separately. In further embodiments of the invention, the polycyclic phenol compound is an estrogen compound more particularly an estrogen compound having insubstantial sex activity exemplified by the (x isomer of estradiol. In certainembodiments of the invention, the anti-oxidant is selected from the group consisting of a thiol, a phenol, a spin trapping agent, an aromatic amine, a carotenoid, a flavonoid, a selenium, an aminosteroids and an ubiquinones. In a further embodiment of the invention, cytoprotection includes neuroprotection.
FIG. 1 shows the effect of glutathione (GSH) and 17β-estradiol on neuronal cells (SK-N-SH cells) treated with neurotoxic β-amyloid protein (βAP) where βAP is a peptide of 10 amino acids (amino acids 25-35), hereafter referred to as "βAP 25-35". The effects of 17β-estradiol (2 nM) and GSH (3.25 μM) on the toxicity induced by βAP 25-35 (20 μM) on SK-N-SH cells (106 cells/ml) in different cell culture media lacking GSH in the cell culture recipe is shown. Cells were plated at 106 cells/ml and were exposed to vehicle, βAP 25-35, 17β-estradiol, GSH, or a combination as indicated. Controls represent the mean value for the vehicle, GSH, 17β-estradiol and GSH+17β-estradiol groups; were pooled together after it was determined they were not statistically significant from each other. Depicted are the mean values�SEM for 4-5 wells/group. *p<0.05 versus controls determined by ANOVA followed by Scheffe's post hoc test.
FIG. 2 shows the effect of GSH and 17β-estradiol on live SK-N-SH cell number treated with neurotoxic βAP 25-35 in the presence or absence of a non-protective dose of 17β-estradiol (2 nM). Cells were plated at 106 cell/ml. The effect of varying concentrations of GSH in the presence of 17β-estradiol (filled triangles) were compared with cells treated with GSH in the absence of 17β-estradiol (open triangles). Depicted are the mean values�SEM for 6 wells per group. The effect of 17β-estradiol on the response to GSH was highly significant (F=41.48; p<0.001). A comparison of the EC50 values for the different dose response curves using the Mann-Whitney Rank Sum Test showed a p=0.036 where the EC50 for βAP25-35+17β-estradiol (2 nM) was 0.041�0.025 and for βAP 25-35 (20 μM) was 82.5�60.4.
FIG. 3 shows the effect of GSH and 17β-estradiol on live SK-N-SH cell number subjected to a challenge with βAP 25-35 (20 μM) at varying concentrations of 17β-estradiol in the presence of 3.25 μM GSH (filled triangles) compared with effects in cells treated with 17β-estradiol in the absence of GSH (open triangles). Depicted are the mean values�SEM for 4 wells per group. The effect of GSH on the response to 17β-estradiol was highly significant (F=44.33; p<0.001). A comparison of the EC50 values for the different dose response curves using the Mann-Whitney Rank Sum Test showed a p<0.057 where the EC50 for βAP 25-35+GSH(3.25 μM) was 0.33�0.031 and for βAP 25-35 (20 μM) was 126�87.8.
FIG. 4 shows the effects of dose of 17β-estradiol on the average number of rat primary cortical neurons per photographic field when subjected to a βAP 25-35 challenge in the presence and absence of a non-protective dose of GSH. Cells were plated and exposed to treatments as previously indicated at the doses noted. Depicted are the mean values�SEM for 4-7 wells per group. The effect of GSH on the response to 17β-estradiol was highly significant (F=8.53; p<0.005). A comparison of the EC50 values for the different dose response curves using the Mann-Whitney Rank Sum Test showed a p<0.057.
FIG. 5 shows the effects of estratrienes in the presence and absence of GSH on the neurotoxicity induced by βAP(25-35) in HT22 cells. The symbols represent:
______________________________________with GSH (3.25 μM) without GSH______________________________________--∘-- 17β-estradiol ---- 17β-estradiolestradiol-- αestradiol --▴-- α--□-- E-3-ol --▪-- E-3-ol______________________________________
FIG. 6 shows the effects of 17β-estradiol in the presence and absence of GSH on the neurotoxicity induced by βAP 1-40 in HT22 cells. □ indicates the presence of GSH and ▪ indicates the absence of GSH. The line represents the value of the control group (no βAP 1-40). The data are presented as the mean�SEM for 4 wells per group. *=p<0.05 versus the βAP 1-40 alone group **=p<0.05 versus both the βAP 1-40 alone group and the control (no βAP 1-40) group.
A preferred embodiment of the invention is directed to the novel finding that the cytoprotective effect of polycyclic phenol compounds is substantially enhanced when administered with at least one additional anti-oxidant compound.
The term "cytoprotection" is defined here and in the claims as the protection of cells against cell death or cell damage that would otherwise occur in the absence of a protective agent, where the cell death or cell damage might be caused by any mechanical damage, nutritional deprivation including oxygen deprivation, trauma, disease processes, damage due to exposure to chemicals or temperature extremes, aging or other cause.
The term "estrogen compound" as used here and in the claims is defined as any of the structures described in the 11th Edition of "Steroids" from Steraloids Inc., Wilton N.H., here incorporated by reference. Included in this definition are isomers and enantiomers including non-steroidal estrogens formed by modification or substitution of the compounds in the Steraloid reference. Other estrogen compounds included in this definition are estrogen derivatives, estrogen metabolites and estrogen precursors as well as those molecules capable of binding cell associated estrogen receptor as well as other molecules where the result of binding specifically triggers a characterized estrogen effect. Also included are mixtures of more than one estrogen, where examples of such mixtures are provided in Table II below. Examples of α estrogen structures having utility either alone or in combination with other agents are provided in FIG. 9.
The terms "17-E2, β-estradiol, 17β-estradiol, β-17-E2, 17β-E2, E2, 17βE2, βE2" as used here and in the claims are intended to be synonymous. Similarly, the terms "α17-E2, α-17-E2 , α-estradiol 17 α-estradiol, 17αE2, αE2" as used here and in the claims are intended to be synonymous and correspond to the a isomer of 17β-estradiol.
The abbreviation "E-3-ol" as used here and in the claims represents estratriene-3-ol
The terms"polycyclic phenolic compound, polycyclic compounds or polycyclic phenols" as used here and in the claims are meant to be synonymous and are defined according to patent application Ser. No. 08/685,574 herein incorporated by reference and includes any compound having a phenolic A ring as defined below and may contain up to 3 additional ring structures exemplified by the following:
(a) Cyclopentanophen (A) anthrene ring compounds having two, three or four rings and a hydroxyl group on carbons 1, 2, 3 and/or 4 of the A ring. Additionally, R groups selected from sodium, potassium and/or ammonium salts may be attached to the alpha or beta positions to replace hydrogen on any available carbon in the structure. Such compounds may be further substituted on the A ring so as to preserve a single-OH group and further form a pyridine, pyriazine, pyrimidine, s-triazine, v-triazne, or as-triazine.
(b) The phenol A ring with possible additional substitutions listed above may further be linked to a six carbon ring having one or more of the following structures-benzene, cyclohexane, 1, 2-pyran; 1, 4-Pyran, 1, 2-pyrone, 1, 4-pyrone; 1, 2-Dioxin; 1, 3-Dioxin (dihydro form) pyridine; pyridazine; pyrimidine; pyrazine; piperazine; s-triazine; as triazine, v-triazine, 1, 2, 4-Oxazine; 1, 3, 2-Oxazine; 1, 3, 6-Oxazine (Pentoxazole); 1, 2, 6 Oxazine; p-Isoxazine; 1, 2, 5-Oxathiazine; 1, 2, 6-Oxathiazine; 1, 4, 2-Oxadiazine, 1, 3, 5, 2-Oxadiazine; morpholine (tetrahydro-p-isoxazine). Any six ringed structure listed above may be linked to any of the following 5 ring structures: Furan; Thiphene (Thiofuran); pyrrole (Azole); isopyrrole (isoazole); 3-isopyrrole (isoazole); Pyrazole (1, 2-Daizole); 2-isoimidazole (1, 3-isodiazole); 1, 2, 3-triazle; 1, 2, 4 triazole; 1, 2-diothiole; 1, 2, 3-oxathiole, isoxazole (furo(a) monozole); oxazole (furo(b) monazole); thiazole; isothiazole; 1, 2, 3-oxadiazole; 1, 2, 3, 4-oxatiazole; 1, 2, 3, 5-oxatriazole; 1, 2, 3-dioxazole; 1, 2, 4-dioxazole; 1, 3, 2-diaxazole; 1, 3, 4-dioxazole; 1, 2, 5-oxathiazole; 1, 3-oxathiole, cyclopentane.
(c) Any compound listed above where the cyclopentanophen (a) anthrene ring compound is selected from the group consisting of 1, 3, 5 (10), 6, 8-estrapentaen; 1, 3, 5 (10), 6, 8, 11-estrapentaen; 1, 3, 5 (10), 6,-estratetraen 1, 3, 5 (10), 7-estratetraen ; 1, 3, 5 (10) 8-estratetraen; 1, 3, 5 (10) 16-estratetraen; 1, 3, 5 (10) 15-estratetraen; 1, 3, 5 (10)-estratrien; 1, 3, 5 (10) 15-estratrien.
The term "anti-oxidant" as defined here and in the claims refers to any molecule that prevents oxidation of a particular substrate by a second molecule. Although not limiting, examples of anti-oxidants included in the invention are the following:
Thiols including glutathione, taurine, cystein, homocysteine, and α-lipoic acid; phenols: including probucol, salicylates, Trolox C, 3 ,4-dihydroxytoluene, 3 , 4-dihydroxycinnamic acid, nordihydroxyquaiarectic acid, 2", 4'-dihydroxyacetophenone, 2', 5'-dihydroxyacetophenone, 3'4'-dihydroxyacetophenone, propylgallate; spin trapping agents including dimethyl-1-pyrroline-N-oxide, N-tert-butyl-α-phenylnitrone; aromatic amines including promethazine, chlorpromazine, ethoxquin, allopurinol, uric acid; carotenoids including β-carotene, α-carotene, γ-carotene, lypcopene, Caratol; flavonoids including (+)-catechin, dihydroquercetin, hesperetin, texasin, biochanin A, kaempferol, quercetin, and 6,7-dhydroxy-4'-methoxy-isoflavanol; selenium aminosteroids including trilazad mesylate, methyl prednisolone, suleptnate, lazaroids; and ubiquinones such as coenzyme Q2, coenzyme Q10. This list shall not be limiting.
Polycyclic Compounds Having a Terminal Phenolic A Ring in Combination with Anti-oxidants for Enhancing Cytoprotective Potency in a Synergistic Manner.
We have shown for the first time that an anti-oxidant in the extracellular milieu provides enhanced cytoprotection when administered to a subject together with a polycyclic compound having a phenolic A ring, such as estrogen, at physiologically and pharmacologically relevant doses. The enhanced effect of the combination of polycyclic phenolic compounds and anti-oxidants, more particularly compounds having insubstantial sex activity in combination with anti-oxidant thiols, more particularly estrogen compounds having insubstantial sex activity and glutathione, occurs to promote cell protection beyond that observed with any single compound. The combination of anti-oxidant and polycyclic phenolic compounds including estrogens has utility in protecting cells from damage resulting from any of a number of events that are known to be detrimental to the cell including chemical damage such as caused by free radicals, excitatory aminoacids and amyloid plaque. For example, the above combination is more effective for neuroprotection than either anti-oxidant or polycyclic phenolic compound alone and therefore presents a novel therapeutic approach to treating neuron loss in human subjects that occurs in neurodegenerative diseases such as Alzheimer's disease. In addition the combination therapy disclosed here has utility in treating other disease conditions which result from enhanced cell death including ischemia, trauma and aging.
The above observations are a surprising and unexpected extension on earlier observations made by us in which we identified the application of polycyclic phenolic compounds having a phenolic A ring for cell protection. Previously, we showed that polycyclic phenol compounds could protect against: neurodegeneration (U.S. Ser. No. 08/685,574 herein incorporated by reference); cell death associated with ischemia (U.S. Ser. No. 08/749,703 incorporated herein by reference); osteoporosis (Ser. No. 08/318,042, herein incorporated by reference); and cell death in tissues during tissue removal from the body and transplantation. (U.S. Ser. No. 08/782,883 incorporated herein by reference).
As shown in FIG. 1, the cytoprotective effect of 17β-estradiol and glutathione on human neuronal cells (SK-N-SH) was significantly greater than the cytoprotective effect of 17β-estradiol and glutathione individually. This effect was consistently observed when the cells were incubated in different media. FIG. 2 further illustrates this effect where maximum cell protection was observed earlier and at lower concentrations of glutathione when 17β-estradiol was included in the media. A similar observation was made in FIGS. 3 and 4 when glutathione was added in a constant amount to increasing concentrations of 17β-estradiol in human neuron cells and also rat primary cortical neurons. A marked synergistic effect was also noted when an estrogen having insubstantial sex activity was used (α-estradiol). (FIG. 5). FIG. 5 further shows increases in neuroprotective effect of 100-600 fold for three different estrogen compounds. We have found that estratrienes exhibit approximately 1000-5000 fold enhancement in their cytoprotective effect when administered with the anti-oxidant, glutathione. In embodiments of the invention, the enhancement observed with different combinations of agents falls within the range of 100 fold to 10,000 fold. The synergistic effect of anti-oxidant and estrogen compound was further observed in cells that lacked an estrogen receptor. FIG. 6 shows the synergistic effect of glutathione with 17β-estradiol in HT-22 cells.
The methods of assaying the cytoprotective effect described in these examples may readily be applied to identifying the extent of the synergistic effect between additional polycyclic phenolic compounds and anti-oxidants, beyond those disclosed herein. Furthermore, cells other than neuronal cells may be used according to the assays described here to demonstrate the cytoprotective effect of polycyclic phenolic compounds with anti-oxidants. These assays and applications are within the scope of the invention as embodied here.
Although the above examples describe synergy using glutathione as an anti-oxidant, other anti-oxidants may be used to obtain the observed synergistic effect. Table 1 provides a summary of the effects of 17β-estradiol together with a variety of anti-oxidants, and their combination on neuronal cells.
The applicants are under no duty or obligation to explain the mechanism by which the invention works. However, the following mechanism is suggested to explain the observed synergistic effect. It is known in the prior art that estrogen compounds are lipophilic molecules. Given the lipophilic character of estrogen, estrogen may insert into the membrane. Based upon the observation that an intact phenolic group is desirable for cytoprotection, the hydroxyl hydrogen may be donated to prevent the cascade of membrane lipid peroxidation. Additionally, the enhanced potency of estrogens may result from its ability to donate from several positions on the A ring (Jellnick and Bradlow, 1990). A relatively stable oxidized form of estradiol may result from this hydrogen ion donation. It is proposed here that for example, a glutathione peroxidase can regenerate the reduced form of estrogen. This enzyme relies on GSH as its substrate for donation of the hydrogen group back to estrogen, and thereby result in a synergy between the activity of the two molecules.
The specificity of estrogens interaction for this glutathione system is supported by two lines of evidence. First, there are no apparent interactions noted between estrogen and the other thiols tested, lipoic acid or taurine, or any other anti-oxidants, including ascorbic acid or atocopherol. It should be noted that while α-tocopherol is a powerful anti-oxidant in its own right, estrogen has been argued to be even more powerful. Second, the ability of oxidized glutathione to work in this system, argues that estrogen may be interacting with the glutathione peroxidase/reductase process.
The presence of estrogen in cell membranes is a reflection of the amounts of estrogen introduced into the blood stream. If estrogen is available, it may insert into the cell membranes of any available cell without specificity thereby providing a cell protective effect. However, as the amounts of estrogen become limiting, estrogens may predominantly located in the membranes of cells bearing estrogen receptors.
On the basis of the above mechanism, applicants assert that cell protection resulting from the synergistic effect of polycyclic phenolic compounds and anti-oxidants may occur for any of the cells of the body and is not restricted to the examples provided here. Applicants have previously demonstrated the cell protective effect of polycyclic phenolic compounds alone on neurons, glial cells, (U.S. Pat. No. 5,554,601) endothelial cells (U.S. Ser. No., 08/749,703) skeletal muscle, and erythrocytes (U.S. Ser. No. 08/782,883). In addition, osteoblasts, smooth muscle cells including cardiac muscle cells, fibroblasts, and stem cells should all be protected by the synergistic effect of polycyclic phenolic compounds and anti-oxidants.
The Synergistic Effect is Receptor Independent.
We have shown that the observed synergistic effect does not depend on the nuclear estrogen receptor (ER). This observation may lead to new methods of designing drugs for treating abnormal cellular loss in human subjects.
The ER-independent synergistic effect was confirmed by experiments using the murine neuronal cell line (HT-22), which lacks a functional estrogen receptor (FIGS. 5 and 6). When these cells were exposed to the neurotoxic βAP 25-35 about 50-60 % of the cells were killed. Concurrent treatment with either of three estratrienes, β-estradiol, α-estradiol or estratriene-3-ol, resulted in dose-dependent neuroprotection. (FIG. 5). The presence of specific 3 H estradiol binding to both nuclear extracts and whole cell preparations was determined by assays described by Miranda et al. J. Neurobiol 31, (1996), 77-87; and Nakao et al. Atherosclerosis 38 (1981) 75-80). Binding of estradiol to HT22 cells was compared with binding to MCF-7 cells carrying the ER receptor. HT-22 cells did not demonstrate specific binding in either assay with only 6�3.93 fmol specific binding per million cells compared to 56�6.5 for the ER positive MCF-7 cell line in the whole cell preparation and 0.05 fmol per million cells compared to 35.21 for the MCF-7 cells in the crude nuclear pellet. The protection conferred by physiological doses of estrogens on these cells confirms that a major portion of the protective effects of estrogens is independent of the ER.
It should be noted that whereas β-estradiol is a sex hormone and known to act through the estrogen receptor, α-estradiol or estratriene-3-ol are generally believed to be biologically inactive according to the art. These compounds are all examples of polycyclic phenolic compounds. The invention encompasses the use of any of the class of polycyclic phenolic compounds independent of their ability to bind the estrogen receptor.
We tested estradiol conjugated to bovine serum albumin (BSA) to determine if estradiol could protect HT-22 cells from β-AP (25-35) if the estrogen was restricted to the extracellular environment. Immobilization of the steroid by BSA conjugation (17β-estradiol-6-(carboxymethyl) oxime: BSA containing 20 μM 17β-estradiol) abolished the ability of the steroid to protect HT22 cells from βAP (25-35) toxicity in the presence of GSH (Example 2a, Table 2). This is consistent with similar observations with SK-N-SH cells. Collectively, these data suggest that desirability of free interaction of the estratrienes with the cell membrane or the intracellular space so as to exert their neuroprotective effects.
The dose of GSH used in these studies had no effect on β-AP (25-35) induced toxicity by itself inasmuch as β-AP (25-35) caused a 54�4% and a 55�3% decrease in cell viability in the absence and presence of 3.25 pM GSH, respectively. However, a GSH dose of 325 μM showed significant protection from β-AP toxicity in SK-N-SH neuroblastoma cells (FIG. 2). Further, exposure of HT-22 cells to 3.25 μM GSH alone, 200 nM 17β-estradiol alone, or both in combination did not cause an increase in cell number in the absence of an insult (FIG. 6) indicating that the increase in cell number is due to protection and not to a mitogenic effect of the compounds.
Applications of the Observed Synergistic Effect Between Polycyclic Phenolic Compounds and Anti-oxidants.
A pharmaceutical preparation including a polycyclic phenolic compound and an anti-oxidant may be used for treating subjects suffering from trauma, chronic degenerative diseases or acute disease such as induced by an ischemic attack. Examples include Alzheimer's disease, Parkinson's disease, stroke, ischemia, heart attack or angioplasty, or brain or spinal cord trauma, hypoglycemia, anoxia, burns or surgeries that result in the loss of nutrient flow to the tissues.
Embodiments of the invention may further be applied to the procedure of tissue transplantation, prior, during or after removal or reperfusion of cells, tissues or organs or during storage of the cells, tissues or organs and is applicable to any of the cells in the body. The following examples are presented are not intended to be limiting but nonetheless effectively illustrate the novel biological effect of the invention.
Glutathione was selected as an anti-oxidant and 17β-estradiol was selected as the polycyclic compound. The assay utilized the human neuroblastoma cells SK-N-SH. The cells were treated with toxins, known to cause cell death, found in amyloid plaque-β-AP(1-40) and β-AP (25-35). The numbers following "AP" correspond to the size and type of protein fragment identified by amino acid residue number.
Materials: Lyophilized βAP 25-35 (1 mg) (Bachem, Torrance, Calif.) was initially dissolved in 200 μl ddH20 and with the addition of 800 μl of PBS, rapid aggregation was observed. 17β-estradiol (17β-estradiol, Steraloids, Wilton, N.H.), was initially dissolved at 10 mg/ml in absolute ethanol (Fisher Scientific Inc., Orlando, Fla.) and diluted in cell culture media to obtain the necessary concentrations. α-tocopherol acetate was initially dissolved in 200 μl absolute ethanol and diluted in cell culture media to the appropriate concentrations. Lipoic acid (thiotic acid), taurine (2-aminoethanoic acid), and ascorbic acid were initially dissolved in cell culture media and used at the concentrations indicated. Unless otherwise noted, materials were obtained from Sigma Chemical Corp SK-N-SH Neuroblastoma Cell Culture: SK-N-SH neuroblastoma cells were obtained from American Type Tissue Collection (Rockville, Md.). Cell cultures were grown to confluency in RPMI-1640 media (Fisher Scientific, Inc.) supplemented with 10% charcoal/dextran-treated fetal bovine serum (FBS), (Hyclone�), Logan, Utah), 100 U/ml penicillin G and 100 mg/ml streptomycin (Sigma Chemical Corp.) in monolayers in Corning 150 cm2 flasks (Fisher Scientific, Inc.) at 37� C. under 5% CO2, 95% air. Media was changed three times weekly. Cells were observed with a phase contrast microscope (Nikon Diaphot-300).
(a) SK-N-SH cells used in the following experiments were in passes 4 to 12. The growth media was initially decanted and the cells were rinsed with 0.02% EDTA for 30 min at 37� C. Cells were then counted on a Neubauer hemacytometer (Fisher Scientific) and resuspended in appropriate media. Studies were initiated by plating 1�106 cells per well in 24 well plates, allowing attachment in regular media and then decanting that media and replacing with the appropriate treatment after 4 h. Cells were cultured in DMEM or RPMI-1640 without GSH (reduced), supplemented with 10% FBS and antibiotics, with absolute ethanol as a vehicle control, or supplemented with the addition of βAP 25-35 (20 μM), 17β-estradiol (0.002 -200 nM ), GSH (0.0325-325 μM), α-tocopherol acetate (50 μM), ascorbic acid (100 μM), lipoic acid (10 μM), taurine (5 mM), or a combination as indicated. The 20 μM concentration of βAP was selected as we have shown that it is near the LD50 for this peptide (Green et al., 1996). Selection of anti-oxidant concentrations were made on the basis of preliminary dose-response evaluations used to identify the concentration at which neuroprotection was not obtained.
SK-N-SH cell viability was determined utilizing the trypan blue exclusion method (Black and Berenbaum, 1964; Tennant, 1964). After 72 h of incubation, treatment media was decanted and cells were lifted by incubating with 0.2 ml 0.02% EDTA for 30 min at 37� C. Cells were suspended by repeated pipetting. One-hundred μl aliquots from each cell suspension were incubated with 100 μl aliquots of 0.4 % trypan blue stain for 5 min at room temperature. All suspensions were counted on a Neubauer hemacytometer within 10 min of addition of trypan blue stain. Two independent counts of live and dead cells were made for each aliquot.
TABLE 1__________________________________________________________________________Effects of 17 β-estradiol (17β-estradiol), a variety ofanti-oxidants, andtheir combination on the βAP 25-35 induced toxicity in SK-N-SH livecell number. The numbers indicate live cell numbersAscorbicAcid Tocopherol Taurine Lipoic Acid GSH GSSG(100 μM) (50 μM) (5 mM) (10 μM) (3.25 μM) (1.5 μM)__________________________________________________________________________Control 365 � 9 641 � 25 628 � 13 628 � 13 657 � 30.0 657 � 30βAP 118 � 9* 366 � 24* 408 � 10* 408 � 10* 331 � 17* 331 � 17*βAP + βE2 144 � 9 407 � 21 394 � 3 393 � 3 357 � 19 357 � 19βAP + TRT 124 � 6* 448 � 12* 402 � 9* 406 � 7* 369 � 7* 350 � 29*βAP + βE2 188 � 11* 456 � 14* 439 � 11* 416 � 10* 534 � 16* 513 � 7*+ TRT__________________________________________________________________________
*-p<0.05 versus vehicle treated controls
x=p<0.05 versus βAP treated controls
TRT=treatment with anti-oxidant indicated
Statistics: The significant treatment effects on cell viability were determined using ANOVA followed by Scheffe's post hoc test, with significance determined at p<0.05. For dose-response evaluations, EC50 values were calculated by randomly assigning cell counts at the indicated doses to generate 3-5 lines per treatment and determining the average value for those lines. Mann-Whitney Rank Sum non-parametric analysis were used on EC50 values because the variances for the standard deviation were not equivalent. Comparisons between dose response relationships were calculated using two-way ANOVA to determine the significance of GSH or 17β-estradiol presence or absence.
(b) Human SK-N-SH were back cultured into 96 well plates in an RPMI media lacking glutathione. Four hours later, one group of plates of cells were treated simultaneously with the neurotoxic β-amyloid protein βAP 25-35: (20 μM) and a series of concentrations of glutathione ranging from 0-325 μM. A second group of plates of cells were treated simultaneously with Aβ 25-35: (20 μM), a series of concentrations of glutathione ranging from 0-325 μM and a single dose concentration of 17β-estradiol (2 nM). After 72 hours incubation, live cells were determined with Trypan Blue exclusion. As shown in FIG. 2, in the absence of 17β-estradiol, glutathione had an ED50 of 32.5 μM and showed little neuroprotective effect at 3.25 μM. In contrast, in the presence of 17β-estradiol, the ED50 was shown to be 0.325 μM providing 1000 fold greater neuroprotectivity then with glutathione alone.
(c) Using the assay described above, SK-N-SH cells were treated with Aβ 25-35(20 μM) a single concentration of glutathione (3.25 μM.) and a variable concentrations of 17β-estradiol in the range of 0-200 nM. After 72 hours incubation, the cells were stained with Trypan Blue. Neuroprotection was observed at concentrations of 200 nM 17β-estradiol in the absence of glutathione with an ED50 of 100 nM. In the presence of glutathione and 17β-estradiol, the ED50 was 0.02 nM. Thus the neuroprotective potency of 17β-estradiol reaches 5000 fold in the presence of glutathione compared to in the absence of glutathione. (FIG. 3).
Neuroprotection provided by 17β-estradiol alone was 628-fold less than in the presence of GSH. Following βAP (1-40) treatment of cells, a 200 nM 17β-estradiol dose provided 99.9% and 35.6% protection in the presence and absence of GSH, respectively (FIG. 1). α-17-E2 and E-3-ol estrogens both behaved similarly to with an ED50 of 6 nM and 14 nM, respectively, in the presence of GSH and ED50 of 1014 nM and 3683 nM, respectively, in the absence of GSH.
(a) Effects of 17β-estradiol and 17β-estradiol-6-(carboxy-methyl)oxime: BSA conjugate on βAP 25-35 Induced Toxicity on HT-22 cells.
Experiments were initiated by plating cells in NuncX 24 well plate and cells were allowed to attach for 4 h before treatment. Cells were exposed to 20 μM βAP 25-35 in the presence of the indicated dose of 17β-estradiol or 17β-estradiol-BSA in RPMI media containing 3.25 μM GSH. After 48 h cells were suspended and viability determined using the trypan blue due exclusion method (Tennant J. R. (1964) Transplantation 2 (1964) 685-694. Steroids and βAP were prepared as previously described (Green et al. Neuroscience Lett. 218, (1996) 165-168). Data were analyzed by a one way Analysis of Variance and a Scheffe's post-hoc analysis was used for planned comparisons between groups. Data are presented as mean�sem for 4 wells per group. *=p<0.05 versus the βAP (20 μM) group.
TABLE 2______________________________________Effects of 17β-estradiol and 17β-estradiol-6 (carboxy-methyl)oxime:BSA Conjugate on βAP (25-35) Induced Toxicityon HT-22 Cells Live Cell NumberTreatment (�103 cells) � SEM______________________________________Control (No βAP) 427 � 11*βAP (20 μM) 189 � 11βAP + 0.2 μM β17-E2 324 � 14*βAP + 20 μM β17-E2:BSA 216 � 17______________________________________
(b) Effects of Estratrienes in the Presence and Absence of Gluthathione on the Neurotoxicity Induced by βAP 25-35 in HT-22 cells.
Experiments were initiated by plating cells in NuncX 24 well plate cells were allowed to attach for 4 h before treatment. Cells were exposed to 20 μM βAP in the presence of the indicated dose of 17β-estradiol or α17-E2 or E-3-ol (0-20,000 nM) either in RPMI media containing 3.25 μM GSH or RPMI media without GSH. After 48 h cells were suspended and viability determined using the trypan blue dye exclusion method (Tennant 1964). Steroids and βAP were prepared as previously described (Green et al. 1996). ED50 values were analyzed by a two way Analysis of Variance. Differences among effects were determined by a Scheffe's post hoc analysis with a p<0.05 considered significant. The glutathione effect is significant with a p<0.001. Data are normalized to the βAP free control group as 100% protection and the βAP alone group as 0% protection. The mean�sem for 3-5 wells per group are presented in FIG. 3
(c) Effects of 17β-estradiol in the presence and absence of glutathione on the neurotoxicity induce by βAP (1-40) in HT-22 cells.
Experiments were carried out as described in Example 2(b) with the exception of βAP (1-40) was allowed to incubate for 4 days before dilution to 20 μM in the culture media. The aging of βAP is necessary to aggregate the peptide, so as to render the toxic effect on the cells (Pike et al. J.Neurosci, 13 (1993) 1676-1687). Data were presented as mean�sem for 3-4 wells per group. Data was analyzed by one way Analysis of Variance and p<0.05 was considered significant.(FIG. 5)
The results as shown in FIG. 5 and 6 demonstrate the neuroprotective effect of both GSH with β-estradiol on HT22 cells following treatment with one of two types of the neurotoxin β-AP. A synergistic interaction between neuroprotective estrogens and the protection conferred by the intracellular anti-oxidant GSH was observed. 17β-estradiol, the potent naturally occurring estrogen, protected HT-22 cells from cell death induced by the neurotoxic amyloid fragment, β-AP (25-35) fragment with an ED30 of 5 nM and significant neuroprotection with 2 nM of the steroid and 3.25 μM GSH (FIG. 5).
To ensure that the synergistic effect observed in Examples 1 and 2 was not due to cell origin or tumorigenicity, we performed similar experiments in rat primary cortical neurons. Primary Rat Cortical Culture: Primary neuronal cultures were prepared according to the method used by Chandler et al. Alcoholism: Clinical and Experimental Research, 17 (1993) 54-60.
Treatments were made directly to primary cultures on culture day 10, maintaining a constant volume added regardless of treatment as follows: Controls: absolute ethanol and PBS, samples: βAP 25-35 (10 μM), 17β-estradiol (0.02 nM-2 μM), GSH (3.25 μM), or combinations as indicated. Once treatments were added, primary cultures were incubated for an additional 24 h and viability determined using the LIVE/DEAD� viability/cytotoxicity kit (Molecular Probes, Eugene, Oreg.) according to manufacturer's instructions. Live cells are distinguished by the presence of intracellular esterase activity which cleaves the calcein AM dye, producing a bright green fluorescence when excited. Ethidium homodimer enters cells with damaged membranes, and upon binding to nucleic acids, produces a red fluorescence. Both dyes are excited at 485 nm, and cultures plates were viewed with a fluorescent microscope (Nikon Diaphot-300). Three random fields were photographed, and the average number of live cells per field was determined by counting the number of bright green cells. Again, the ability of estradiol was evaluated in the presence and absence of GSH (3.25 μm) (FIG. x). The addition of βAP 25-35 (10 μM) to primary cortical neurons resulted in a 39% to 40% reduction in the average number of viable cells per field in the absence and presence of GSH, respectively (FIG. 4). When increasing doses of 17β-estradiol were evaluated with βAP 25-35, the 200 μM dose of 17β-estradiol was the lowest dose found to be protective, which is in full agreement with our SK-N-SH cell line studies (FIGS. 1-3). With the addition of GSH (3.25 μM) to 17β-estradiol, all doses of 17β-estradiol of 2 μM or higher were neuroprotective (FIG. 4). Evaluation of EC50 values demonstrate similar changes in potency, from 68.1�79 μM in the absence of GSH, to 4.3�5.9 μM in the presence of GSH. Likewise, evaluation of the effect of GSH on the neuroprotective effect of 17β-estradiol in rat primary cultures using two-way ANOVA demonstrated a significant effect (F:8.53; p<0.005).
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|International Classification
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|European Classification
|Apr 23, 1998
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text:
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This time popular TV actress Aupee Karim has become engaged with acting rather than previous years. She will be seen to act in three plays in Eid-ul-Fitr. Of those plays, she acted in lead role in Sagor Jahan's directed play titled Eid Shohor Madhobilatar Na.
Former vocalist of popular band Black, Jon performed against popular TV actress Tisha in a play titled Payback on the occasion of ensuing Eid-ul-Fitr.Directed by Mabrur Rashid Bannah the play will be aired on RTV at 9:20pm on Eid day. Its script was also written by director Bannah.
Habib Wahid is all set to bring out his new music video "Mon Ghumaire" after this Eid. The talented singer who likes to work with traditional Bengali folk music and contemporary techno beats, "Mon Ghumaire" is yet another example of his love for fusion. Habib is currently working on finalising a teaser for the music video, the full version of which is set to be released just after Eid-ul-Fitr.
For the first time ever Bidya Sinha Mim and Soham Chakrabarti are collaborating in a movie in association with Bangladesh and East Bengal film industry. The co-produced film titled 'Rocket' is being produced by Kolkata producer Raja Chand and Dhallywood producer Kamal Muhammad Kibria Lipu.
She maintains that her first priority has always been teaching and architecture. But she is a dancer too. And she has danced between many roles: from being a teacher to an architect and from a dancer to an actor. Just like the wide array of roles she has played as an actor, in her real life too, she is versatile -- juggling between different interests and professions.
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By Catholic Online
8/1/2013 (2 years ago)
Catholic Online (www.catholic.org)
"Is Christ the centre of my life? Do I really put Christ at the centre of my life?" Because there is always the temptation to want to put ourselves in the centre. And when a Jesuit puts himself and not Christ in the centre, he goes astray. In the first Reading, Moses forcefully calls upon the people to love the Lord, to walk in His ways, "because He is your life" (cf. Deut. 30, 16-20). Christ is our life! The centrality of Christ corresponds also to the centrality of the Church: they are two flames that cannot be separated: I cannot follow Christ except in and with the Church.
Pope Francis at Rome's Gesu Church on the Memorial of St Ignatius of loyola, the founder of the Jesuits. Pope Francis is a member of the Society of Jesus. He concelebrated the Holy Mass with members of the community from around the world
By Catholic Online
Catholic Online (www.catholic.org)
8/1/2013 (2 years ago)
Published in Europe
Keywords: Jesuits, Feast of Ignatius Loyola, Society of Jesus, spirituality, holiness, Year of Faith
VATICAN CITY (Catholic Online) - Here is the official Vatican Radio transcript of the homily preached by Pope Francis at Rome's Gesu Church to commemorate the Memorial of St Ignatius of loyola, the founder of the Jesuits. Pope Francis is a member of the Society of Jesus. He concelebrated the Holy Mass with members of the community from around the world.
HOMILY of POPE FRANCIS
In this Eucharist in which we celebrate our Father Ignatius of Loyola, in light of the Readings we have heard, I would like to propose three simple thoughts guided by three expressions: to put Christ and the Church in the centre; to allow ourselves to be conquered by Him in order to serve; to feel the shame of our limitations and our sins, in order to be humble before Him and before the brothers.
1. The emblem of us Jesuits is a monogram, the acronym of "Jesus, the Saviour of Mankind" (IHS). Every one of you can tell me: we know that very well! But this crest continually reminds us of a reality that we must never forget: the centrality of Christ for each one of us and for the whole Company, the Company that Saint Ignatius wanted to name "of Jesus" to indicate the point of reference. Moreover, even at the beginning of the Spiritual Exercises he places our Lord Jesus Christ, our Creator and Saviour (Spiritual Exercises, 6) in front of us.
And this leads all of us Jesuits, and the whole Company, to be "decentred," to have "Christ more and more" before us, the "Deus semper maior", the "intimior intimo meo", that leads us continually outside ourselves, that brings us to a certain kenosis, a "going beyond our own loves, desires, and interests" (Sp. Ex., 189). Isn't it obvious, the question for us? For all of us?
"Is Christ the centre of my life? Do I really put Christ at the centre of my life?" Because there is always the temptation to want to put ourselves in the centre. And when a Jesuit puts himself and not Christ in the centre, he goes astray. In the first Reading, Moses forcefully calls upon the people to love the Lord, to walk in His ways, "because He is your life" (cf. Deut. 30, 16-20). Christ is our life!
The centrality of Christ corresponds also to the centrality of the Church: they are two flames that cannot be separated: I cannot follow Christ except in and with the Church. And even in this case we Jesuits and the whole Company, are not at the centre, we are, so to speak, "displaced", we are at the service of Christ and of the Church, the Bride of Christ our Lord, who is our Holy Mother Hierarchical Church (cf. Sp. Ex. 353).
To be men routed and grounded in the Church: that is what Jesus desires of us. There cannot be parallel or isolated paths for us. Yes, paths of searching, creative paths, yes, this is important: to go to the peripheries, so many peripheries. This takes creativity, but always in community, in the Church, with this membership that give us the courage to go forward. To serve Christ is to love this concrete Church, and to serve her with generosity and with the spirit of obedience.
2. What is the way to live this double centrality? Let us look at the experience of Saint Paul, which was also the experience of Saint Ignatius. The Apostle, in the Second Reading that we heard, writes: I press on towards the perfection of Christ, "because I have indeed been conquered by Jesus Christ" (Phil. 3:12). For Paul it came along the road to Damascus, for Ignatius in his house at Loyola, but the fundamental point is the same: to allow oneself to be conquered by Christ.
I seek Jesus, I serve Jesus, because He sought me first, because I was conquered by Him: and this is the heart of our experience. But He is first, always. In Spanish there is a word that is very graphic, that explains this well: He "primerea" first ahead of us, "El nos primerea". He is always first. When we arrive, He has already arrived and is expecting us. And here I want to recall the meditation on the Kingdom in the Second Week.
Christ our Lord, the eternal King, calls each one of us, saying to us: "He who wants to come with Me must work with Me, because following Me in suffering, he will follow after Me likewise in glory" (Sp. Ex. 95): Being conquered by Christ in order to offer to this King our whole person and all our hard work (cf. Sp. Ex. 96); to say to the Lord that he would do anything for His greater service and praise, to imitate Him in bearing even injury, contempt, poverty (Sp. Ex. 98).
But I think of our brother in Syria in this moment. To allow ourselves to be conquered by Christ means to be always directed towards what is in front of me, toward the goal of Christ (cf. Phil. 3:14), and to ask oneself with truth and sincerity: "What have I done for Christ? What am doing for Christ? What must I do for Christ?" (cf. Sp. Ex. 53).
3. And I come to the final point. In the Gospel, Jesus says to us: "Whoever would save his life will lose it, but whoever loses his life for my sake will save it . If anyone is ashamed of me . " (Lk 9:23). And so on. The shame of the Jesuit. The invitation that Jesus makes is for us to never be ashamed of Him, but to always follow Him with total dedication, trusting Him and entrusting ourselves to Him.
But looking at Jesus, as Saint Ignatius teaches us in the First Week, above all looking at Christ crucified, we have that very human and noble feeling that is the shame of not reaching the highest point; we look at the wisdom of Christ and at our ignorance; at His omnipotence and our weakness; at His justice and our iniquity; at His goodness and our wickedness (cf. Sp. Ex. 59).
Ask for the grace of shame; the shame that comes from the constant dialogue of mercy with Him; the shame that makes us blush before Jesus Christ; the shame that puts us in tune with the heart of Christ who is made sin for me; the shame that harmonises our heart in tears and accompanies us in the daily following of "my Lord". And this always brings us, as individuals and as a Company, to humility, to living this great virtue.
Humility that makes us understand, each day, that it is not for us to build the Kingdom of God, but it is always the grace of God working within us; humility that pushes us to put our whole being not at the service of ourselves and our own ideas, but at the service of Christ and of the Church, like clay pots, fragile, inadequate, insufficient, but having within them an immense treasure that we carry and that we communicate (2 Cor. 4:7).
It is always pleasant for me to think of the sunset of the Jesuit, when a Jesuit finishes his life, when the sun goes down. And two icons of the sunset of the Jesuit always come to me: one classical, that of Saint Francis Xavier, looking at China. Art has painted this sunset so many times, this 'end' of Xavier. Even in literature, in that beautiful peace by Pemŕn. At the end, having nothing, but in the sight of the Lord; it does me good to thing about this.
The other sunset, the other icon that comes to me as an example, is that of Padre Arrupe in the last interview in the refugee camp, when he told us - something he himself said - "I say this as if it were my swan song: pray." Prayer, the union with Jesus. And, after having said this, he caught the plane, and arrived at Rome with the stroke that was the beginning of so long and so exemplary a sunset. Two sunsets, two icons that all of us would do well to look at, and to go back to these two. And to ask for the grace that our sunset will be like theirs.
Dear brothers, let us turn again to Our Lady, to her who bore Christ in her womb and accompanied the first steps of the Church. May she help us to always put Christ and His Church at the centre of our lives and of our ministry. May she, who was the first and most perfect disciple of her Son help us to allow ourselves to be conquered by Christ in order to follow Him and to serve Him in every situation.
May she that answered the announcement of the Angel with the most profound humility: "Behold the handmaid of the Lord, be it done unto me according to thy word" (Lk 1:38), make us feel the shame for our inadequacy before the treasure that has been entrusted to us, in order to live the virtue of humility before God. May our journey be accompanied by the paternal intercession of Saint Ignatius and of all the Jesuit saints, who continue to teach us to do all things "ad majorem Dei gloriam" ["to the greater glory of God"].
By Kenya Sinclair (CALIFORNIA NETWORK)
Vatican auditors closed nearly 5,000 suspected Vatican bank accounts on suspicion of tax evasion. LOS ANGELES, CA (Catholic Online) - The scandal includes a three-year investigation of 544 suspected transactions mainly involving tax evasion.To meet international ... continue reading
By David Drudge (CALIFORNIA NETWORK)
Hackers have just released thousands of documents in a new document dump to the media, this time, they contain the secrets of the Masons. The data dump is known as "Masonleaks" and journalists say it will take several months to complete their review of the documents. ... continue reading
By David Drudge (CALIFORNIA NETWORK)
A Belgian minister has a telling warning for his country as hearings begin into the Brussels attack that killed 32 people at an airport in March. The reason for the warning is quite compelling. LOS ANGELES, CA (California Network) - A Belgian minister is warning ... continue reading
By Marshall Connolly (CALIFORNIA NETWORK)
A woman in Northern Ireland has been convicted of aborting her child, and sentenced to a three-month, suspended jail sentence. The woman left her baby in a trash bag for eight days until police were contacted. The case has sparked renewed debate over abortion in ... continue reading
By Kenya Sinclair (CALIFORNIA NETWORK)
Thirty years after the greatest nuclear disaster the world has ever seen, Ukrainians solemnly commemorate the 1986 Chernobyl nuclear power plant accident. LOS ANGELES, CA (Catholic Online) - The meltdown at the Russian plant began when an uncontrolled reaction ... continue reading
By Kenya Sinclair (CALIFORNIA NETWORK)
A Cambridge researcher and world-class medieval music performer combined their talents to perform an ancient song for the first time in over 1,000 years. LOS ANGELES, CA (Catholic Online) - The music, titled "Songs of Consolation," was performed for the first time on ... continue reading
By Kenya Sinclair (CALIFORNIA NETWORK)
Students from the French university Sciences Po Paris held a Hijab Day to raise awareness of the discrimination and verbal abuse Muslim women face every day - and it went exactly how you might expect. LOS ANGELES, CA (Catholic Online) - With the influx of Muslim ... continue reading
By Kenya Sinclair (CALIFORNIA NETWORK)
German and Italian intelligence agencies discovered ISIS' plan to pose as refugees to detonate bombs and suicide vests buried beneath lounge chairs across Spanish, French and Italian beaches this summer. LOS ANGELES, CA (Catholic Online) - According to the Mirror, ... continue reading
By David Drudge (CALIFORNIA NETWORK)
The conditions that Norwegian mass murderer Anders Behring Breivik have been subjected to are inhumane, according to a Norwegian court. Breivik was convicted of killing 77, and injured 319. Many of his victims were children. LOS ANGELES, CA (California Network) - Life ... continue reading
By CNA/EWTN News
On April 29, the Trevi Fountain, one of the most popular and emblematic tourist spots in Rome, will be dyed red in recognition of all Christians who even today give their life for the faith. Rome, Italy (CNA/EWTN News) - The event is being organized by Aid to the ... continue reading


text:
3DS Games
This page contains Resident Evil: Revelations Video Walkthroughs for 3DS called "Walkthrough Part 8 - Ep. 4 A Nightmare Revisited." and has been posted or updated on May 26, 2013 by AyaAnnyGaming.
Boxshot & Details
- Developer: Capcom
- Publisher: Capcom
- Genre: Action Adventure
- Release: Feb 7, 2012
- ESRB: Mature
Video Walkthroughs
Walkthrough Part 8 - Ep. 4 A Nightmare Revisited.
Watch this step-by-step Video Walkthrough, which may help and guide you through each and every level part of this game.
Report Problem
Please submit a problem for any incomplete, non-working or fake cheat listed above.
More Video Walkthroughs
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Stuck in this game? Set a specific, clearly defined question and let other gamers answer your question or view answers to previously asked questions. If you think you are an expert then please try to help others with their questions.
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text:
email: email@example.com
Doc Searls is Senior Editor of Linux Journal
Re: Hacking Penguin Pile-Up: World Domination in Miniature
Having just spent the last (in addition to many other) rainly weekends playing this game I have got to let you know that should you purchase this game you will become addicted to it. My son, brother and I have even once managed to get all 24 tuxes balanced. I'd post the victory picture if I had a scanner. I was glad to see it's still for sale- just bought two copies for the cousin's this coming Christmas.
Re: Hacking Penguin Pile-Up: World Domination in Miniature
1) The Subversion of Microsoft Youth
2) A moment before the mission.
3) The Innocence Campaign
4) "You can see by this example, the potential growth Linux could have if each of us made it a point to teach two people how to use it..."
5) "We shall be victorious."
6) "Okay guys, we're going to pretend I'm an NT administrator and I want you all to attack me..."
7) "It is not that you are weak and I am strong, it is that I use Linux and you people are relying on something else entirely!"
8) "You all have done very well at using Linux, now it is time to get to know your enemy..."
9) "Everyone, pretend you're a windows XP box!"
10) "While you're down there, I want you to realize that this is no place for a penguin to be. Broken windows fall to the floor, but penguins can not be broken."
11) "When you look into the eyes of your fellow penguins, you see no PDC's or BDC's, but all may serve and be served."
12) "I thought I smelled an NTFS volume."
13) "Bring your windows into this community will you?"
14) "And this is why we practice redundancy."
Re: Hacking Penguin Pile-Up: World Domination in Miniature
1. Once upon a time there was a game involving penguins.
2. For a while the penguins were happy on their iceberg.
3. But after falling over once too often
4. They ganged up together
5. And got a bit mean.
6. One penguin, however didn't agree with this new policy
7. and all his friends
8. dragged him to the Penguin Council
9. But he had really bad breath
10. after all, he had been eating fish :p
11. Once the council revived, though
12. They dragged him off to his doom,
13. but he was too heavy, and they dropped him,
14. and so he breathed his last (halitosis) breath
Re: Hacking Penguin Pile-Up: World Domination in Miniature
2) "Ok... this is getting old fast guys."
3) "No, really, I'm tellin ya, they wore sparkling bathing suits & got paid for swimming like this!"
4) "Hey... you guys hear something rollng this way?"
6) "Um.. Windows, why? What do you guys use?"
7) "What? Like you guys never clicked on an attachment before."
8) "Ok... new rule, the the names of fish are not allowed passwords."
9/10) "D**m... It's good to be sysadmin."
11) "Suse!" "Debian!" "Suse!" "Debian!" "Suse!" "Debian!" "Suse!" "Debian!" ....
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|Apr 29, 2016
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|Apr 28, 2016
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- May 2016 Issue of Linux Journal
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- The Death of RoboVM
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Geek Guides
In modern computer systems, privacy and security are mandatory. However, connections from the outside over public networks automatically imply risks. One easily available solution to avoid eavesdroppers' attempts is SSH. But, its wide adoption during the past 21 years has made it a target for attackers, so hardening your system properly is a must.
Additionally, in highly regulated markets, you must comply with specific operational requirements, proving that you conform to standards and even that you have included new mandatory authentication methods, such as two-factor authentication. In this ebook, I discuss SSH and how to configure and manage it to guarantee that your network is safe, your data is secure and that you comply with relevant regulations.Get the Guide


text:
College signings
April 21, 2016 Name: Finnley Christine High school: Tyrone Area Hometown: Tyrone Sport: Basketball Position: Shooting guard College choice: Penn State Altoona Other colleges considered: Penn State Behrend Why I... more »»
Benzel, Swogger get all-state status
April 10, 2016 By Philip Cmor pcmor@altoonamirror. more »»
B-A's Davis on 2nd team
April 10, 2016 Nathan Davis put together quite an impressive resume in his final season of basketball at Bellwood-Antis High School. He signed a letter-of-intent with Division II Seton Hill. more »»
College signing
April 9, 2016 Name: Jacob Holsopple High school: Hollidaysburg Area Hometown: Duncansville Sport: Basketball Position: Forward College choice: Juniata Other colleges considered: Penn State Why I picked... more »»
College signing
April 9, 2016 Name: Kaley Strittmatter High school: Penn Cambria Hometown: Ashville Sport: Basketball Position: Guard College choice: Penn State Altoona Other colleges considered: Pitt-Greensburg, Mount Aloysius... more »»
Smith, Knauss spark Dragons
April 5, 2016 MARTINSBURG — The Central boys volleyball team improved to 2-1 with a 25-13, 25-15, 25-16 win over West Shamokin Monday night in high school action. more »»
Bracken helps Blue all-stars to Ameriserv win
April 4, 2016 By Paul Buriak For the Mirror JOHNSTOWN — Fifty-three players from throughout Districts 5 and 6 concluded their scholastic basketball careers Sunday at the ninth annual Ameriserv Senior Hoops... more »»
Altoona basketball coach Hasson resigns
April 2, 2016 Altoona Area High School is currently conducting a search for a new head football coach after the resignation of John Franco in February. more »»
Krise's 28 sets record in boys' win
April 2, 2016 CRESSON — Austin Krise made his reputation at West Branch High School by getting the ball to teammates in a position to score. Such a player is a prized commodity in all-star competition. more »»
Irwin stars in close call
April 2, 2016 CRESSON — Before Friday's 11th annual girls Altoona Mirror Basketball Classic game, it was assumed that Central PA's Kyla Irwin would probably take home the most valuable player awar. more »»
UConn-bound Irwin turns in stellar showing
April 2, 2016 CRESSON — Thirty players that have been part of the Altoona Mirror Basketball Classic have gone on to play for Division I colleges. more »»
Eberhart, Brown come from small schools, but add to the Blair boys' overall size
April 1, 2016 For six years, Luke Eberhart has been trying to outplay Peyton Brown. "I know every time we were going up against each other, it was going to be a battle," Eberhart said. more »»
Altoona well represented on D6-AAAA all-stars
April 1, 2016 LEWISTOWN — Altoona placed two boys and two girls on the District 6 Class AAAA all-star basketball teams for the 2015-16 season. more »»
Blair girls must find a way
March 30, 2016 By Philip Cmor email@example.com As an Altoona Area Lady Lion, Brittany Stouffer has gone up against some of the best girls basketball talent the state has to offer. more »»
Cronin Beam, McGeary set as captains
March 30, 2016 From Mirror reports A former area high school and collegiate standout and a distinguished official will serve as honorary captains for the 11th annual Altoona Mirror Basketball Classic on Friday... more »»
Past Mirror girls basketball all-stars
March 28, 2016 2015-16 FIRST TEAM: #Karson Swogger, Bellwood-Antis; Kasey Engle, Tyrone; Lili Benzel, Bishop Guilfoyle; Taylor Boring, Central Cambria; Alyssa Martinazzi, Bishop Carroll SECOND TEAM: Jourdan... more »»
Past Mirror boys basketball all-stars
March 28, 2016 2015-16 FIRST TEAM: #Nathan Davis, Bellwood-Antis; David Swatsworth, Bishop Carroll; Ryan Adams, Hollidaysburg; Anthony Politza, Tyrone; Josh Trybus, Bishop Guilfoyle SECOND TEAM: Max Sheetz,... more »»
Davis sacrifices scoring for victories
March 27, 2016 There never was any question that Nathan Davis had some outstanding scoring tools — great size and a handle at 6-foot-3 and a very sweet shooting stroke. more »»
Swogger shows off her all-around game
March 27, 2016 The heir to a proud family tradition in basketball — her grandfather, the late John Swogger, was a Hall of Fame scholastic coach — Karson Swogger always has something to prove when she takes the... more »»
Coaches selected for Mirror Classic
March 24, 2016 The coaches are set for the 11th annual Altoona Mirror Basketball Classic. more »»


text:
Volunteer opportunities
Communities In Schools – Volunteers are needed to help site coordinators at Shaw Middle School and/or Sheridan Elementary School. Volunteers will be asked to commit to a minimum of four hours per week to help with paperwork, student programs, watching students during/between classes, lunch times, recess times and tutoring. Positions require a Washington State Patrol background check. For an application, call (509) 414-1436 or email email@example.com.
Arc of Spokane – The Arc of Spokane Advocacy and Family Support is in need of a library aide to review the library and its organization, checking for inaccuracies. Other duties would include re-shelving books and updating the content list. Volunteers are needed on a monthly basis. For more information call volunteer coordinator Brian Holloway at (509) 328-6326 or visit www.arc-spokane.org.
Camp Fire USA Inland Northwest Council – Opportunities are available to be a club co-leader in the Spokane and Coeur d'Alene area. Contact Marcia Asmussen, program coordinator, at (509) 747-6191.
Corbin Senior Activity Center – Lunch helpers are needed to set and clear tables, make coffee and serve food on Wednesdays. Volunteers are also needed to pick up food once a month. A food handler's permit is preferred. For more information, call Christa Richardson at (509) 327-1584 or visit www.corbinseniorcenter.org.
This list is a sample of opportunities included on the Spokane County United Way Volunteer Solutions website. For a complete list visit www.unitedwayspokane.org.
The most difficult talk of all
sponsored Kids learn about money from their parents.


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Welcome To St. Paul's
Saint Paul's is an active place where God's people are knit together for service. People of all ages come to find a connection with God and with Christ. People come and are nurtured through relationships they find with other caring people. As we deepen our own faith and serve others in need we recognize the healing and transforming power of God at work in us and in the world.
I invite you to a place where God draws people together through worship, caring, learning and service. As you explore Saint Paul's through our website, perhaps you will find ways you would like to connect with God and others. We welcome your questions in person if you don't find what you're looking for on the site. Most of all, come and see! We welcome you most warmly.
The Rev. Thomas Skillings
Pentecost – Sunday, May 15th
Join us for this very
special day!
8am: Celebratory Holy Eucharist
followed by a brunch hosted
by the youth group.
9am: Family Journey
which will celebrate the
birthday of the church!
10am: Festive Holy Eucharist
including music from our boy and girl Choristers, and communion
bread made by our spring sacraments class participants. This service will also be followed by a brunch hosted by the youth group.
The color of the day is RED,
so wear red if you can!
Join us for the final
Evensong of the season
Regular Service Schedule
Sunday 8 am
Holy Eucharist without music
Sunday 10 am
Holy Eucharist choir and organ
Children's Worship
Sunday 2 pm - Tongan Services
Tongan Prayer
1st Sunday Tongan Eucharist
2nd Sunday Tongan Evensong
4th Sunday Tongan Communion
Wed. 11am Healing Service
Sunday's Sermon
and Service Recording
More sermon and service
recordings are here
Does your child like to sing?
Join us in the St. Paul's Choir School!
Contact Dr. Susan Jane Matthews,
Director of Music
Auditions for fall enrollment offered through June 9.
St Pauls Burlingame


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I am having trouble with boost copy_file(version 1.40.0) method, I would like to overwrite the destination file completely, but it ends up merging source file and destination file if destination text file has more lines.
copy_file(source, destination, overwrite_if_exists)
I would envision it working totally differently, after this operation I would expect source and destination to be exactly the same.
Is this the way this method supposed to work?
Yes I can rename the destination file, copy the source to destination path and if all goes well, I can delete the destination file, but it shocks me that there is no atomic way of doing this in boost.


text:
Travel Inn Space Valley, Sao Jose dos Campos
Main amenities
- 85 apartments
- Outdoor pool
- Breakfast available
- Fitness center
- Tour/ticket assistance
What's around
- Lojas Renner Centervale Shopping Mall (0.3 mi / 0.5 km)
- Santos Dumont Park (0.6 mi / 1 km)
- Technological Institute of Aeronautics (0.7 mi / 1.2 km)
- SESC (0.8 mi / 1.2 km)
- Parque Vicentina Aranha (1 mi / 1.7 km)
Travel Inn Space Valley, Sao Jose dos Campos
Hotel Info: 866-539-8117from $45
- Standard Single Room
- Standard Double Room
Also popular with travelers from the USA
At a glance
Key facts
Hotel size
- This hotel has 85 rooms
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Parents must have child's birth certificate and photo ID *
Nearby Three Star Sao Jose dos Campos hotels
In the hotel
- Breakfast (surcharge)
- Outdoor pool
- Fitness facilities
- Steam room
- Tours/ticket assistance
In the room
- Balcony
- Hair dryer
- Cable TV channels
- Desk
- Refrigerator
- Kitchen
- In-room safe
Top Sao Jose dos Campos hotels
Nearby hotels
Travel Inn Space Valley, Sao Jose dos Campos's small print
Parents or a legal guardian traveling with children under 18 years must present the child's birth certificate and an identity card with photo (passport, for example) at the check-in. For international travels from Brazil, if just one of the parents is traveling with the child, she/he must present – in addition to the child's certificate of birth and identity card with photo – a letter authorizing the trip signed by the other parent with a notarial certification of signature. In case the parents or the legal guardian, as applicable, cannot or are unwilling to give this authorization, a judicial authorization is required. People who intend to travel to Brazil with children must consult with the Brazilian consulate before traveling for more information.
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
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I am not really out to antagonise – this is just a personal point of view. I'd love to know the opinions of both industry and any consumers reading/watching.
Tag: Cup-of-Excellence
CoE Colombian Auction
Nice to see the lowest price there was over $5. Stumptown picked up the winner at just under $20 and I have to say that when cupping the samples I thought it was a truly great coffee. I rarely get as excited about the number 1 as I do about other coffees on the table, but in this case it is a belter.
Full results here.


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October 27th, 2015 by WCBC Radio
Clayton Pastorius Jr. from Ridgeley passed away Thursday at the Frostburg Village. A former prominent businessman in the area, Pastorius was the owner of Clayton Electric for decades in South Cumberland. Friends will be received at the Adams Family Funeral Home, 404 Decatur Street Wednesday from 2 to 4 p.m., and 6 to 8 p.m.
August 29th, 2011 by WCBC Radio
A local retired prominent businessman has passed away. David Michael Brotemarkle, with residences in Bel Air locally and Myrtle Beach South Carolina, died Friday at the Western Maryland Health System. Born in Cumberland in 1947, Brotemarkle and his wife JoAnn were past owners of a number of businesses in Cumberland, LaVale and Hagerstown- most notably Brotemarkle's family business of a catalog showroom, Goldsmit-Black in LaVale. Prior to his business career, Brotemarkle served in Vietnam and was decorated with a Bronze Star for his service. In addition to his wife, he is survived by two children and four grandchildren and a brother. Friends will be received at the Upchurch Funeral Home on Greene Street in Cumberland Tuesday from 7-9 p.m. The funeral service will be conducted in the funeral home Wednesday at 1 p.m. Interment will be in Sunset Memorial Park where military honors will be accorded by Post #13 Veterans Honor Guard. Memorial contributions can be made to the Allegany College of Maryland Foundation where a scholarship will be established in his honor. David Brotemarkle was 64
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Born 9-30-32 -- Died 8-12-2005
Margaret Lorraine Davis, 72, of Ash Flat died Aug. 12, 2005, at her home.
Davis was born Sept. 30, 1932, in Memphis, Tenn. the daughter of James Asa Ham and Margaret Louise (Hill) Ham. She had worked as an LPN in the Memphis area before moving to Arkansas.
She is survived by three sons -- Vernon Wayne Crawford of Oakland, Tenn., Kenneth R. Davis of Brooksville, Fla., and Thomas L. Davis II of Ash Flat; two daughters -- Loretta A. Wilkerson of Ash Flat, and Kathy L. Holliday of Benton, Ark.; one sister, Dorothy J. Hamm of Ash Flat; eight grandchildren; and 17 great-grandchildren.
She was preceded in death by her parents.
The funeral service was held Aug. 16 at Williford Church of Christ with Rev. Harold Russell officiating. Burial followed in the Williford Cemetery.
Pallbearers were Vernon Wayne Crawford, Kenneth R. Davis, Thomas L. Davis, Kenny Holliday, Dan Ramel and James Calvin Erwin.
Honory pallbearer was John Davis.
Arrangements were under the direction of Tri-County's Cherokee Chapel of Highland.