Psoriatic Arthritis List NEWSLETTER

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News & Views Newletter
edited by Jack Nicholas, cornishpro@aol.co

PSORIATIC ARTHRITIS NEWS AND VIEWS
VOL. 2 ISSUE 16 July 20, 2002
PSORIATIC ARTHRITIS MEDICAL NEWS

ANATOMY OF THE BIOTECH INDUSTRY

The challenges facing this young industry don't end with drug discovery and FDA approval Immunex Corp. (IMNX ) was riding high when Enbrel, its breakthrough drug for rheumatoid arthritis, won Food & Drug Administration approval in 1998. A dramatic advance in controlling the inflammation that is a hallmark of arthritis, Enbrel was heralded as one of the first major successes of the biotech industry. Sales reached $650 million in 2000, $150 million more than estimated by the company, and the stock rose as high as $80 that year.

But Immunex didn't have enough production capacity to meet demand, and the shortfall cost it as much as $200 million in sales last year, analysts estimate. The end result: the stock dropped as low as $11 and biotech giant Amgen Inc. (AMGN ) struck a deal in December to scoop up the smaller firm for a mere $25 a share. A new Enbrel plant under construction in Rhode Island, meanwhile, isn't likely to be ready until early 2003, Amgen says.

Welcome to the dark side of biotech. Hardly a month goes by without some promising new biologic drug experiencing a manufacturing snafu.

Granted, the biotech industry is hitting the big time after two decades of intense industry building. An Arthur D. Little study estimates that, while the pharmaceutical industry as a whole will grow 7% to 8% over the next five years, biotech will likely grow by as much as 15% a year. There are some 30 biopharmaceuticals already on the market and an additional 700 or so in various stages of development. And though no biotech firms show up on the BW50 list yet, some, such as Amgen, could well make an appearance in the next year or two--if they can successfully maneuver promising drugs over the approval and manufacturing hurdles.

That's no easy task, given that these protein-based drugs are extremely difficult to manufacture. Hence, the biotech industry's catch-22: The more successful the product, the worse the production bottleneck. "While there have been big advances in discovery technologies, there has not been a corresponding increase in development capacity," says Peter B. Davis, chief financial officer of Berkeley (Calif.) biotech firm Xoma Ltd. "Now, the worry is less whether [the industry] can find a molecule than what to do with the molecule it finds."

It is a worry that increasingly preoccupies companies and investors. A recent US Bancorp Piper Jaffray report found that all the biotech plants currently operational are running at or near capacity. Meanwhile, there are 99 biotech drugs in late stages of clinical development, and as many as 40 of these could reach the market by 2005--setting the stage for a major manufacturing crunch. Given that building a new biologics plant is technically challenging, and costs anywhere from $300 to $500 million, there is no guarantee that new facilities will arrive in time to meet demand.

It doesn't help that this is not the biotech industry's bailiwick--there's a big difference between discovering a new drug and making one. "Manufacturing is usually the lowest priority for a biotech startup," says Roland J. Andersson, a partner with Boston consulting firm Strategic Decisions Group. "That is just not the business they are in."

Even traditional drug companies, which have been in the manufacturing business for decades, don't always get it right. Schering-Plough Corp. (SGP ) was hit with a $500 million fine last year, and approval of Clarinex, its important new allergy drug, was delayed by the FDA due to inadequate quality control at four plants. Industry leader Pfizer Inc. (PFE ), No. 3 on the BW50 ranking, was cited by the FDA in March for quality-control problems at an Indiana plant. Manufacturing problems have so delayed a range of vaccines made by Merck (MRK ) (No. 40), Wyeth (WYE ), and Aventis (AVE ) that children across the country are being turned away by doctors who have run out of routine shots.

And those are the kinds of drugs that are supposed to be easy to make. Biotech drugs are far more complex, built from fragile molecules meant to mimic natural disease-fighting proteins found in the body. Because these protein-based drugs are too big to be absorbed through the gut, they must be injected directly into the bloodstream, not swallowed as pills.

That's unfortunate, because pills, which are chemical entities, are pretty straightforward. If you can make one, you can make millions just like it without much worry. Biologics are made from living cells or bacteria, and are inherently harder to control. First, cells that express the appropriate proteins are grown in fermentation tanks, a process that takes two to three weeks. Another two to four weeks is required to extract and purify the protein. At that point the protein is placed in vials, and rigorous quality tests are conducted for up to two months.

This whole process might have to be significantly altered when a company moves from research to mass production, and even minor changes can affect the drug's action in the body. That's one reason the FDA sent back a psoriasis drug under joint development by Xoma (XOMA ) and Genentech (DNA ) for more clinical trials: The agency wants to ensure that manufacturing changes made to allow mass production didn't change the way the drug performs.

The whole process can be just as challenging for Big Pharma as for small startups. Johnson & Johnson (JNJ ), No. 1 in the BW50, makes and markets a version of Amgen's Epogen anemia drug for the European market, called Eprex. In November, J&J warned European doctors that dozens of patients taking Eprex had come down with a potentially fatal blood disorder. "Our guess is that this is probably related to a manufacturing problem," says Anthony Gringeri, a vice-president at Amgen, which manufactures all versions of the drug sold in the U.S. In America, the complication has shown up only once, in Amgen's Epogen. A J&J spokesperson says no causative link has been established between the drug and recent blood disorder cases, but the company is looking at everything from manufacturing to how the drug is stored and handled.

To avoid manufacturing headaches, many biotech firms turn to contract manufacturers such as the Lonza Biologics unit of Swiss-based Alusuisse Lonza Group, or Germany's Boehringer Ingelheim. But these companies can demand stiff contract terms or refuse to deal with biotech companies they deem too small. And they do not guarantee smooth sailing. Approval of Eli Lilly & Co.'s (LLY ) breakthrough sepsis drug, Xigris, was delayed for several weeks last year because of FDA concerns with the contract manufacturer.

Manufacturing debacles could ease over time. The Piper Jaffray survey estimates that 938,000 liters of biotech production volume will come on line in the next four to five years--a 200% increase in capacity. Most of this increase, however, is being added by just a few companies: Amgen, Boehringer Ingelheim, Biogen (BGEN ), Genentech, and Idec Pharmaceuticals (IDPH ). And any of them could run into delays. Small biotech, meanwhile, must hash out their own solutions, if and when they have a successful product. One can only wonder which of these might be the next Enbrel.

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THE AMAZING IMPORTANCE OF FOLIC ACID TO YOUR HEALTH
From the British Medical Journal of June 22, 2002

It is becoming clear that folic acid affects mood and thinking, especially in older individuals.

Folic acid is important for functioning of the nervous system for everyone. In the fetus the relation between maternal folate status and the risk of neural tube defects is well established. Clinical trials have shown that preventive treatment prior to conception with 400 µg or higher of folic acid significantly reduces the risks of such defects.

In neonates, infants, children, and adolescents, inborn errors of folate transport and metabolism are associated with a variety of overlapping syndromes that are influenced by age of clinical presentation. These include: Developmental delay, Cognitive deterioration, Motor and gait abnormalities, Behavioral or psychiatric symptoms, Seizures, Signs of demyelination or failure of myelination, and Vascular changes seen on magnetic resonance imaging or postmortem examination. Less commonly, subacute combined degeneration and peripheral neuropathy may also occur.
In adult patients presenting with anemias due to folate deficiency, approximately two thirds have neuropsychiatric disorders which overlap considerably with those associated with anemia due to vitamin B-12 deficiency.

The degree of anemia is poorly correlated with the presence of neuropsychiatric disorders, but if these anemias were left untreated nearly all patients would eventually develop neuropsychiatric complications.

Over the past 35 years numerous studies have shown a high incidence of folate deficiency correlated with mental symptoms, especially depression and cognitive decline in epileptic, neurological, psychiatric, geriatric, and psychogeriatric populations. Furthermore, recent studies in elderly people suggest a link between folic acid, homocysteine, ageing, depression, and dementia, including Alzheimer's disease and vascular disease.

Patients with Epilepsy - Many studies of folate in serum, red cells, or cerebrospinal fluid have shown a consistent association between drug induced deficiency and mental changes, especially depression, apathy, psychomotor retardation and dementia.

Treatment of 26 folate deficient epileptic patients with 5 mg of folic acid daily for one to three years resulted in: Improved drive, Initiative, Alertness, Concentration, Mood, and Sociability in most.

This contradicted the prevailing view that folic acid was harmful only to the nervous system, although that concept was reinforced by the additional observation that seizure control deteriorated in several of the patients.

Although short term clinical trials of folic acid for one to three months produced conflicting results with respect to mental changes and seizure control, there is abundant experimental evidence now of the excitatory properties of folate derivatives, especially when the efficient blood-brain barrier mechanism for the vitamin is circumvented. In addition, folic acid influences DIlantin metabolism, leading to a fall in blood concentrations of this drug.

Neurological Patients - Several of the earliest reports of neurological disease associated with severe folate deficiency emphasize the importance of dementia and depression reversible with vitamin therapy. On the basis of clinical, neuropsychological, computed tomography, and radionuclidecisternographic findings, researchers concluded that chronic folate deficiency could induce cerebral atrophy.

Psychiatric Patients - On the basis of serum or red cell assays, folate deficiency has been reported in up to one third of psychiatric outpatients or inpatients, more so in the former.

Depressed patients with folate deficiency had higher depression scores, higher affective morbidity indices, and a poorer response to standard treatment with antidepressants.

The few controlled clinical trials of vitamin therapy in addition to standard psychotropic medication have all reported positive effects on patients' mental state. In a double blind placebo controlled trial in depressive patients treated with lithium, the addition of 200 µg of folic acid for one year significantly improved affective morbidity. Similarly, the addition of 500 µg of the vitamin to Prozac for 10 weeks significantly improved antidepressant response, especially in women.

Geriatric and Psychogeriatric Patients: The highest incidence of folate deficiency as measured by serum and red cell folate concentrations is in elderly populations, especially psychogeriatric patients. A close association with dementia and depression, apathy, withdrawal, and lack of motivation has been noted.

One reason for the apparently high incidence of folate deficiency in elderly people is that folate concentrations in serum and cerebrospinal fluid fall and plasma homocysteine rises with age, perhaps contributing to the ageing process.

In a prospective community based study of 370 healthy elderly Swedish subjects, folate or vitamin B-12 deficiency doubled the risk of subsequently developing Alzheimer's disease. Recently the much larger and longer Framingham community based study confirmed that a raised plasma homocysteine concentration doubled the risk of developing Alzheimer's and non-Alzheimer's dementia.

Neurochemical Aspects - Concentrations of folate in serum and cerebrospinal fluid decline and those of plasma homocysteine rise with age, which contributes to the apparently high incidence of the vitamin deficiency in geriatric and psychogeriatric populations. Low concentrations of folate in serum, red cells, and cerebrospinal fluid are associated with depression and dementia in a wide range of clinical neuropsychiatric settings, as is raised plasma homocysteine.

There is also increasing evidence of an association between plasma homocysteine and vascular disease, and the increased risk of dementia, including Alzheimer's disease, associated with raised plasma homocysteine may be mediated by a vascular or possibly a neurotoxic mechanism.

Mood and some cognitive functions may be related to methylation processes in the brain. With respect to depression, this hypothesis is supported by the similar effect of S-adenosylmethionine to that of folates on mood, and by the influence of folates and S-adenosylmethionine on monoamine metabolism, which is also incriminated in depression. The lowest concentrations of folate and S-adenosylmethionine in cerebrospinal fluid are found in dementia, including Alzheimer's disease.

British Medical Journal June 22, 2002;324:1512-1515

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U.S. LETS DRUG TIED TO DEATHS BACK ON MARKET
By Denise Grady - New York Times

For the first time, the Food and Drug Administration is allowing a drug to go back on the market after it was removed for safety reasons.

The drug, Lotronex, a prescription treatment for irritable bowel syndrome, will be available again in several months.

Lotronex was taken off the market in November 2000, less than 10 months after it was approved, because it was linked to severe intestinal problems and several deaths. GlaxoSmithKline, based in Britain, withdrew the drug voluntarily at the F.D.A.'s request when the two could not reach an agreement on marketing restrictions intended to reduce adverse reactions.

But thousands of patients protested the withdrawal, saying Lotronex was the only treatment to have aided them. Their pleas helped to persuade the agency and manufacturer to find a way to reinstate it.

Lotronex will return, the agency said - with restrictions. The new rules leave considerable responsibility with doctors, pharmacists and patients to use it correctly and to watch for early signs of intestinal problems, which can be fatal.

Dr. Victor Raczkowski, deputy director of the F.D.A. office that evaluates gastrointestinal drugs, said that the return of Lotronex was "not part of any overall F.D.A. strategy to bring back withdrawn drugs." Rather, he said, it wa s a unique case in which the agency took an unusual action to help desperate patients who had no other effective treatment.

Before Lotronex was pulled from the market, a month's supply cost $175. A GlaxoSmithKline spokeswoman said the price would rise because of the costs attached to the new marketing plan.

GlaxoSmithKline's shares rose 2.8 percent in London trading yesterday.

Lotronex was the first drug shown to be effective specifically for irritable bowel syndrome. When it was first marketed, some financial analysts predicted Lotronex would become a blockbuster treatment for GlaxoSmithKline. But it did not get the chance to become one and is unlikely to do so now, some analysts say, because of the restrictions.

At its sales peak, about 275,000 people used Lotronex. But it was withdrawn after 70 patients developed severe constipation or ischemic colitis, a lack of blood flow to the bowel. Some needed surgery. Three deaths were linked to Lotronex use.

More reports came in later. The F.D.A. said yesterday that as of March 8, it had been notified of 84 cases of ischemic colitis and 113 cases of serious complications from constipation. Of those with ischemic colitis, 54 were hospitalized, 11 needed surgery and 2 died. Of the constipation cases, 83 were hospitalized, 34 had surgery and 2 died.

Even so, many other Lotronex users said that they had essentially been homebound by pain and severe diarrhea, and that Lotronex had enabled them to live normal lives for the first time in years.

Doctors who studied the drug said it greatly helped some patients, did little or nothing for many, and greatly harmed others. But it was impossible to predict into which group a patient would fall.

Under the new rules set by the F.D.A., doctors who want to prescribe Lotronex will have to enroll in a program run by GlaxoSmithKline that requires them to "self attest" that they know how to diagnose and treat irritable bowel syndrome, how to prescribe Lotronex and how to recognize and treat complications.

The doctors must also agree to explain the drug's risks and benefits to patients, give them the company's informational pamphlet and report serious adverse effects to GlaxoSmithKline or the F.D.A.

Any doctor can get into the program by self attesting. Those who do not feel qualified to prescribe the drug can take an as yet undeveloped course from GlaxoSmithKline.

Patients who want Lotronex must sign an agreement acknowledging its risks, which include a 1-in-1,000 chance of serious constipation problems and a 1-in-350 chance of ischemic colitis. Patients must also pledge to call their doctors immediately if they develop any symptoms considered to be dangerous, including constipation, new or worse bowel pain or blood in their stools.

Doctors in the program will be given special stickers to apply to prescriptions for Lotronex, and the drug's labeling will alert pharmacists not to fill prescriptions that lack stickers. Pharmacists will also be instructed not to allow refills or prescriptions that are telephoned or faxed in, to insure that patients keep in contact with their doctors.

The new plan also cuts the dose in half, to one milligram a day.

Lotronex was first approved for women with chronic diarrhea from irritable bowel syndrome, but it is now recommended only for a narrower group: women with very severe cases that have not responded to other drugs. The group amounts to less than 5 percent of all people with irritable bowel syndrome, and is estimated to be about 185,000 women.

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NEW ANTI INFLAMMATORY DRUGS DAMAGE YOUR BONES

Some painkilling drugs may delay or even prevent the healing of fractures. The main concern is the new generation of non-steroidal anti-inflammatory drugs (NSAIDs). Both drugs, Vioxx and Celebrex, are often used to ease the pain of broken bones.

But for over 20 years there have been occasional reports of impaired bone healing in patients taking NSAIDs. The issue may have escaped attention because the older generation of NSAIDS, such as ibuprofen and indomethacin, only appear to delay healing by a few weeks instead of blocking it. Interestingly, aspirin is one of the few NSAIDs that appears to kill pain without this side effect.

Ibuprofen and indomethacin delay bone healing by about one to two weeks in rats, which is the equivalent to slowing it down by 25 to 50 per cent in humans. None of the rats treated with Vioxx managed to heal their bones. In those treated with Celebrex, none managed to completely heal their bones but about half had some form of bone regrowth.

Traditional NSAIDs inhibit the enzymes cox-1 and cox-2. Cox-2 catalyses the production of hormone-like chemicals known as prostaglandins involved in inflammation, while cox-1 has a variety of roles not specific to the inflammatory response. Since the new generation of NSAIDs such as Celebrex block cox-2 almost exclusively, it was hoped they would have fewer side effects.

But it now seems that cox-2 may be crucial in helping bone-forming stem cells and growth factors do their work.

Journal of Bone and Mineral Research June, 2002 17:963

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FAT FREE FOODS WILL SABOTAGE YOUR WEIGHT-LOSS EFFORTS

The introduction of more than 5,000 low-fat and non-fat foods over the past decade has contributed to an epidemic of obesity in America, the American Heart Association (AHA).

The trouble comes when people think they can eat unlimited amounts of reduced-fat cookies, frozen yogurt and cakes. While these foods contain less fat than their full-fat versions, they tend to have more sugar and can be even higher in calories.

Choosing fresh produce and other fiber-rich foods allows a person to eat a large volume for relatively few calories because it promotes a feeling of fullness.

The advice from health experts comes at a time when rates of obesity are unprecedented in the US and other countries. While Americans have followed the government's advice and reduced fat intake in the past half-century, they continue to pack on the pounds.

Studies have shown that the rate of obesity has doubled in the US in the last 20 years while the number of people with type 2 diabetes, a disease that can result from excess weight, increased by one-third during the 1990s. Children as young as 10 are now being diagnosed with type 2 diabetes, formerly known as adult-onset diabetes because it affected people in their 40s and older.

The AHA's statement recommends that individuals who want to lose weight and maintain a healthy body weight follow the US government's food guide pyramid and pay particular attention to portion sizes. A serving of meat, for instance, is just 3 ounces or roughly the size of a deck of cards. A half-cup of pasta is equivalent to a serving of carbohydrate. Circulation June 11, 2002;10.1161/01

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EXPERTS QUESTION SAFETY OF ARTHRITIS DRUG
By Salynn Boyles - WebMD Medical News Reviewed By Michael Smith, MD

Sales of the arthritis drug Celebrex topped $3 billion last year, mainly because it is believed to be a safer choice than traditional anti-inflammatory drugs. But its safety is now being called into question with the revelation that a key study showing its superiority omitted critical data.

The published report of the Celebrex Long Term Arthritis Safety Study (CLASS), sponsored by the drug's manufacturer, concluded that people taking Celebrex for six months had lower rates of stomach and intestinal ulcers than those taking two older arthritis drugs - diclofenac and ibuprofen. But the study actually lasted for a year, and the summary ignored later data showing no safety advantage for the newer drug.

"Within a year of the publication of this trial, sales of Celebrex increased by almost a billion dollars," arthritis researcher Peter Juni, MD, of Switzerland's University of Berne tells WebMD. "The economic incentives to manipulate trial data are huge. We are not talking about thousands of dollars here, or even millions. We are talking about billions."

In a newly published editorial, Juni argues that the CLASS authors essentially got away with manipulating their data, even though the incident was reported in The Washington Post and several medical publications.

"[The study] may still be relied on by many doctors without reference to these flaws," he wrote in the June 1 issue of the British Medical Journal. "In our experience most still believe the findings published originally."

Celebrex was the first drug of its kind -- called Cox-2 inhibitors -- to be approved. Vioxx followed shortly thereafter and Bextra hit the market in late 2001. These drugs are widely believed to cause fewer stomach ulcers and stomach bleeding than traditional arthritis treatments. In his editorial, Juni calls for an independent review of all studies evaluating the safety of the Cox-2 drugs.

While highly critical of the CLASS authors, arthritis researcher Chris Hawkey tells WebMD that the findings still suggest a safety advantage for Celebrex. In a separate BMJ editorial, Hawkey noted that the failure of the study could have had more to do with the design of the trial than with inadequacies in the drug itself.

He notes that a large and widely reported trial that he was involved in showed an unequivocal advantage for Vioxx over traditional arthritis drugs in terms of safety. Hawkey is a professor in gastroenterology at University Hospital Nottingham, England.

"When you take all of the available data into account, it is pretty clear that for gut safety, these two drugs are better than earlier drugs," he tells WebMD. "But they are probably the same with regard to other side effects." In fact, in April 2002, the FDA officially approved Vioxx as being safer on the stomach than traditional anti-inflammatory drugs. Currently, the makers of the other Cox-2 inhibitors are not able to say this.

Like traditional anti-inflammatory drugs, the Cox-2 drugs have been associated with an elevated risk of swelling and high blood pressure. This is particularly problematic because both arthritis and high blood pressure are common among the elderly. But Hawkey says new drugs are being developed that may offer arthritis treatment without these side effects.

"These drugs offer promise, but they are still in very early trials," Hawkey says. "But they may one day offer a better treatment option for older patients with arthritis and high blood pressure."

This decision to use an anti-inflammatory drug is obviously a complicated one -- and one that needs to be made between you and your doctor. Research continues and, we hope, should be able to settle the Cox-2 inhibitor safety question once and for all.

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LIPITOR CHOLESTEROL MEDICATION USERS VERSUS PFIZER INC.

A number of legal actions are being pursued against Pfizer Inc., the manufacturer of the cholesterol-lowering drug Lipitor (atorvastatin), to recover for liver or kidney damage suffered by patients prescribed Lipitor. Like other drugs in its class (the statins), Lipitor can cause elevated liver enzymes. In clinical trials, this occurred in 0.7 percent of the patients, but the rate was much higher for those taking the 80 mg dose. Another serious side effect of Lipitor and other statins is a condition called rhabdomyolysis, in which muscle cells break down and release potentially toxic cell contents into the bloodstream.

Symptoms of rhabdomyolysis include muscle pain, tenderness and weakness--most commonly in the calves and lower back. Malaise, fever, dark urine, vomiting and nausea can also be symptoms. The most feared consequence of rhabdomyolysis is acute kidney failure, occurring in 30-40% of the cases.

Some of the warning signs of liver failure are nausea, vomiting, abdominal pain, fatigue, loss of appetite, dark urine, and generalized skin discoloration.

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ALTERNATIVE RELIEF FOR ARTHRITIS?-MOST PROMISING STUDY YET
BY Mary Harris ABC News Medical Unit

B O S T O N, Nov. 15 - The newest hope for people with a common form of arthritis is not a drug, but an over-the-counter nutritional supplement.

It's a new alternative therapy for osteoarthritis - cheaper than traditional prescription therapy, available over the counter, and almost devoid of side effects, according to research made public today at the American College of Rheumatology's annual scientific sessions in Boston.

The therapy involves a nutritional supplement called glucosamine, and it is being studied on osteoarthritis, the gradual deterioration of cartilage that cushions bones in the joints. Osteoarthritis accounts for about half of all arthritis cases, with symptoms including joint pain concentrated in the knees and hips. If untreated, many osteoarthritis patients eventually will face total joint replacement, or disability.

The research unveiled today comes from the University of Liege in Belgium. It involved an international team randomly assigning 212 patients with osteoarthritis of the knee to take either glucosamine or a placebo daily for three years. Every four months, scientists surveyed the patients to measure the pain and discomfort associated with their osteoarthritis. Researchers also took regular knee X-rays to monitor the disease's progression.

The results show that while the patients in the placebo group saw their symptoms worsen slightly, including joint narrowing, the patients taking glucosamine improved, and their joints did not narrow.

Glucosamine therapy for arthritis has drawn so much interest that other major studies are under way, including one at the University of Utah, which received a $6.6 million grant in September from the National Institutes of Health. But the research presented today is one of the first long-term studies of glucosamine use for arthritis; most previous research has followed patients for no more than a few months.

In addition, while most osteoarthritis research focuses on relieving symptoms and pain, this is one of the first studies to demonstrate how glucosamine works-by keeping the joints from narrowing.

"This news affects a great number of patients," says Dr. Daniel Clegg, the University of Utah professor of medicine directing the clinical trials funded by the new NIH grant. "It would be very intriguing to have a dietary supplement that affects not only the pain [of osteoarthritis] but changes the course of the disease."

Glucosamine is a natural substance found in and around the cells of cartilage. Researchers hypothesize that it may help repair and maintain cartilage, inhibit inflammation, and stimulate growth of cartilage cells.

They also emphasize that while these preliminary results are encouraging, further research is needed, on larger groups.

Mary Harris, based in Boston, is a researcher for the ABCNEWS Medical Unit.

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Good Health to All !!!!!

Jack Nicholas
Newsletter Editor
Cornishpro@aol.com
Issue 2002 7/20/2002-16