Well........I'm off today (holiday), so needless to say I'm researching again. Get this! (I stumble onto the strangest things!)
We all know of my previous and continuing research regarding the drug desipramine. So, this morning, I thought I'd check to see what new items of interest might be coming down the pike regarding desipramine. (Please stay with me here........this is another of my "here's how I put it together" scenarios.) I'll highlight, as usual. Blue for my comments, red for what was "interesting".
First..........here is what I found regarding desipramine that I had not known before.
Free Radic Res. 2004 Jun;38(6):613-21. Related Articles, Links
Involvement of ceramide in the mechanism of Cr(VI)-induced apoptosis of CHO cells.
Muranaka S, Kanno T, Fujita H, Kobuchi H, Akiyama J, Yasuda T, Utsumi K.
Institute of Medical Science, Kurashiki Medical Center, Kurashiki 710-8522, Japan.
Mitochondria reduce Cr(VI) to Cr(V) with concomitant generation of reactive oxygen species, thereby exhibiting cytotoxic effects leading to apoptosis in various types of cells. To clarify the mechanism by which Cr(VI) induces apoptosis, we examined the effect of Cr(VI) on Chinese hamster ovary (CHO) cells. Cr(VI) increased cellular levels of ceramide by activating acid sphingomyelinase (ASMase) and inhibiting the phosphorylation of pleckstrin homology domain-containing protein kinase B (Akt). Cr(VI) also induced cyclosporin A- and trifluoperazine-sensitive depolarization of mitochondria and activated caspase-3, 8 and 9, thereby causing fragmentation of cellular DNA. The presence of desipramine, an inhibitor of ASMase, and membrane permeable pCPT-cAMP suppressed the Cr(VI)-induced activation of caspases and DNA fragmentation.
These results suggested that accumulation of ceramide play an important role in the Cr(VI)-induced apoptosis of CHO cells through activation of mitochondrial membrane permeability transition.
PMID: 15346652 [PubMed - in process]
I thought, Ok....cool! We all know how activation of caspases and DNA fragmentation may (i.e. probably) is very integral in MS (hence why minocycline may help MS via inhibition of activation of caspase 3). My first thought, was GREAT! Another beneficial substantiation for desipramine's use in MS! THEN my next thought was, "Ok, what the heck is CRVI?" A general search told me this:
...."Chromium-VI is the basis of the movie, 'Erin Brockovich.'
Chromium-VI is a bad one, one of these metals the EPA (Environmental Protection Agency) doesn't like floating around in groundwater," Strongin said.
Chromium-VI attacks the respiratory tract in humans, leading to coughing, wheezing, shortness of breath, pneumonia and asthma.
It also injures the gastrointestinal tract, causing vomiting, abdominal pains and hemorrhaging. In addition, chromium-VI may damage the liver, kidneys, immune system, brain and spine, and possibly the blood,
as well as potentially triggering complications during pregnancy and childbirth. Chromium-VI is used often in the chrome-plating and stainless steel industries. ...."
Then I find:
"....Chromium hexavalent (CrVI) compounds, often called hexavalent chromium, exist in several forms. Chromates are often used as pigments for photography, and in pyrotechnics, dyes, paints, inks, and plastics. They can also be used for stainless steel production, textile dyes, wood preservation, leather tanning, and as anti-corrosion coatings."
Ok....here's what I say to myself.......WHAT???? It's hexavalent chromium??? You've got to be kidding me!! This is something I know quite a bit about due DIRECTLY to the type of work I am in, and part of what I am familiar with!
"....October 24, 2002
According to a new study conducted by consumer interest group Public Citizen, many blue-collar employers are continuing to expose their workers to hexavalent chromium, a known carcinogen and industrial by-product of several manufacturing processes, including the production of steel, chrome plating and certain pigments. As part of its study, published in next month's issue of the American Journal of Industrial Medicine, Public Citizen monitored a number of companies, determining that over 20 percent violated the Occupational Safety and Health Administration's (OSHA) eight-hour permissible exposure limit (PEL) for hexavalent chromium.
In March, the Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE), along with Public Citizen, filed a lawsuit asking a United States Court of Appeals to order OSHA to lower the PEL for the by-product. The case will be argued November 5. ...."
"....Hexavalent chromium is an industrial by-product of several manufacturing processes, including those to make steel, chrome plating and certain pigments. The element is considered highly toxic and has been labeled a potent lung carcinogen by several health organizations. According to the Occupational Safety and Health Administration (OSHA), one million workers are exposed to hexavalent chromium each year. Medical officials say hundreds of laborers will die of lung cancer due to contact with the toxic substance.
Recently, the Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE), along with the watchdog group Public Citizen, filed a lawsuit asking a United States Court of Appeals to order OSHA to lower the permissible exposure limit (PEL) for hexavalent chromium. Public Citizen and PACE claim to have detected dangerously high levels of hexavalent chromium at several workplaces across the country. The substance made news recently when it was featured in a popular movie, "Erin Brockovich," the fact-based story of one woman's fight to win compensation for residents exposed to hexavalent chromium."
"April 11, 2003
4/2/03 ORDER (Chief Judge Becker, Authoring Judge, McKee and *Hill, Circuit Judges)
This 2nd day of April, 2003, upon consideration of the Report and Recommendation by the Honorable Walter K. Stapleton who was appointed as mediator, and the comments of the parties thereon, and for the reasons set forth in this court's opinion of December 24, 2002, It is ordered that:
1. The Occupational Safety and Health Administration ("OSHA") and the Secretary of Labor ("the Secretary") shall pursue on an expedited basis the rule-making process initiated on December 4, 2002, directed to the permissible exposure limit for hexavalent chromium.
2. OSHA and the Secretary shall publish a proposed rule on or before October 4, 2004.
3. OSHA and the Secretary shall publish a final rule on or before January 18, 2006.
4. The compliance dates set forth above will be altered by the court only in the event of materially altered circumstances that cannot currently be anticipated.
5. Within one week of each of the following dates: August 4, 2003, December 4, 2003, April 4, 2004 July 4, 2004, October 4, 2004, January 4, 2005 May 4, 2005, August 4, 2005, November 4, 2005 and February 4, 2006, OSHA shall provide to the court, to counsel for the petitioner, and to counsel for the intervenors, a written report describing its progress in the rulemaking.
The Court shall retain jurisdiction over this matter and the implementation of this order.
*The Honorable James C. Hill, United States Circuit Judge for the Eleventh Circuit, sitting by designation, filed. (tyw)"
Ok, I say.....I'm not mistaken about my familiarity with it. As a matter of fact, due to a recent industrial accident just a few months ago, the Director of Safety and Health where I work brought up his overwhelming concern about all of the "hexavalent chromium" that was released in the air!! And not long ago, we were working with Brokovich's law firm on another unrelated water contamination case here in Dickson County. I talked to them myself and they visited! So, then I say to myself.........how in the world does or MIGHT this correlate with MS? So....off I go on THAT search! Here's what I found:
Am J Forensic Med Pathol. 1989 Sep;10(3):213-5. Related Articles, Links
Clustering of multiple sclerosis in Galion, Ohio, 1982-1985.
School of Public Health, Boston University School of Medicine, Massachusetts.
Epidemiologic evidence indicates that the outbreak of 30-40 cases of multiple sclerosis and other demyelinating syndromes in Galion, Ohio, USA, during 1982-1985 was related to an excess concentration of heavy-metal wastes, especially of cadmium and chromium in sewage and river water. Both multiple sclerosis and myasthenia gravis were diagnosed by board-certified neurologists.
PMID: 2782299 [PubMed - indexed for MEDLINE]
Sci Total Environ. 1989 Aug;84:45-59. Related Articles, Links
Geotoxicology of multiple sclerosis: the Henribourg, Saskatchewan, Cluster Focus. I. The water.
Irvine DG, Schiefer HB, Hader WJ.
Toxicology Research Centre, University of Saskatchewan, Saskatoon, Canada.
Some childhood-related, geographically-linked factor predisposes towards (or protects against) multiple sclerosis (MS). It is quite plausible that this factor could be one or more chemicals in the environment, and that chemical study of the environment or "focus" of an MS cluster might maximize the chances of detecting such an etiological link. The water chemistry of such a focus (Henribourg, Saskatchewan) was compared with North American norms, and with the chemistry of water from a nearby control area with a near-zero incidence of MS and of childhood homes of MS cases. Overall, the results suggest that an environment predisposing to MS may have a number of water chemistry characteristics such as: relative deficiency of selenium and sulfate, but relative abundance of barium, calcium, chloride, chromium, magnesium, manganese, molybdenum, nitrate plus nitrite, strontium and zinc.
Possible explanations for the apparent link between the excess rate of MS and the water geochemistry findings at Henribourg are discussed.
PMID: 2772624 [PubMed - indexed for MEDLINE]
Well, ........isn't that interesting, I say. Didn't they find and don't you always read about an "unexplainable" higher level of MS in the more "industrialized" geographical locations? hmmmmmmmmmmm............ I wonder why they dropped this particular investigation? So, ok.........I went on to see if I could find any recent scientific studies regarding this. Here's what I found:
Toxicol Appl Pharmacol. 2004 Jun 1;197(2):96-106. Related Articles, Links
Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells.
Hayashi Y, Kondo T, Zhao QL, Ogawa R, Cui ZG, Feril LB Jr, Teranishi H, Kasuya M.
Department of Radiological Sciences, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.
It has been reported that the hexavalent chromium compound (Cr(VI)) can induce both p53-dependent and p53-independent apoptosis.
While a considerable amount of information is available on the p53-dependent pathway, only little is known about the p53-independent pathway. To elucidate the p53-independent mechanism, the roles of the Ca(2+)-calpain- and mitochondria-caspase-dependent pathways in apoptosis induced by Cr(VI) were investigated.
When human lymphoma U937 cells, p53 mutated cells, were treated with 20 microM Cr(VI) for 24 h, nuclear morphological changes and DNA fragmentation were observed. Production of hydroxyl radicals revealed by electron paramagnetic resonance (EPR)-spin trapping, and increase of intracellular calcium ion concentration monitored by digital imaging were also observed in Cr(VI)-treated cells.
An intracellular Ca(2+) chelator, BAPTA-AM, and calpain inhibitors suppressed the Cr(VI)-induced DNA fragmentation. The number of cells showing low mitochondrial membrane potential (MMP), high level of superoxide anion radicals (O(2)(-)), and high activity of caspase-3, which are indicators of mitochondria-caspase-dependent pathway, increased significantly in Cr(VI)-treated cells.
An antioxidant, N-acetyl-l-cysteine (NAC), decreased DNA fragmentation and inhibited the changes in MMP, O(2)(-) formation, and activation of caspase-3 induced by Cr(VI). No increase of the expressions of Fas and phosphorylated JNK was observed after Cr(VI) treatment. Cell cycle analysis revealed that the fraction of G2/M phase tended to increase after 24 h of treatment, suggesting that Cr(VI)-induced apoptosis is related to the G2 block. These results indicate that Ca(2+)-calpain- and mitochondria-caspase-dependent pathways play significant roles in the Cr(VI)-induced apoptosis via the G2 block, which are independent of JNK and Fas activation. The inhibition of apoptosis and all its signal transductions by NAC suggests that intracellular reactive oxygen species (ROS) are important for both pathways in Cr(VI)-induced apoptosis of U937 cell.
PMID: 15163545 [PubMed - indexed for MEDLINE]
Very interesting is all I can say. As you know from all my previous posts, I've gabbed a lot about Ca2 (how integral it is in causing permanent disability in MS) and caspases (caspase 3, in particular) and how they are important players in MS.
So,......why was all the study regarding CRVI pollution and its possible connection to clusters or some forms of MS suddenly stopped?