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OUR ANNUAL OXFORD MEETING

JULY 21st

2007

By Ivor Sweig1er

WE WOULD LIKE TO THANK the nearly fifty Members

and Carers who turned up for our Annual Meeting during a time

of torrential rain, when much of central England was under

water. Other Members attempted to make the Meeting, but could not

because of the bad roads. Fortunately,

the flood in Ocford only arrived after the

Meeting.

Dr. Chapman opened the Meeting by describing the major features of

P.S.C., but updating our knowledge.

P.S.C. is a male dominant, three to one, disease. How we diagnose this has

changed a little. The blood tests usually show a certain pattern, which we call

cholestatic, which means that you usually have a high alkaline phosphatase and

higher gamma GT. We rarely do liver biopsies now and they will become rarer in

future years. We find a serum antibody ANCA: it is present in about eighty per

cent of P.S.C. patients. But you also find it in other conditions so it is not

completely specific for P.S.C. It is of limited diagnostic use. This is how we

diagnose it in 2007, looking at the screen, there you see it on the screen, a

patient with ERCP; below we see the same patient with an MRCP. These show

typical images of the bile ducts which should be smooth. There are all these narrowings

~ dilatations. This is due to fibrosis ~ scarring of the liver tissue. The MRCP

on the bottom now gives you a very good picture. Technology improves from year

to year. MRCP is very much the gold standard. Where the diagnosis is doubtful

we use ERCP.  Basically MRCP is the way forward. With an MRCP you get ninety-three

per cent accuracy. You may find the MRCP a bit noisy and claustrophobic, (you

have to sit inside a machine), but it is non-invasive. You can not use it on

people who have bits of metal inside them, like for example a stent or a

pace-maker. So we still do ERCP from time to time for diagnostic purposes. ERCP

will be used for therapeutic purposes, stretching up a stricture, moving a bit

of sludge or putting in a tube. But most of you will end up having an ERCP at

some stage, for therapeutic reasons and not usually these days for a diagnostic

purpose.

SMALL DUCT P.S.C.

There

were three studies in 2002 one of which involved Oxford. One was from the Mayo Clinic, in America, one was from ourselves and Norway and one was from Stockholm in Sweden. Basically, they all showed

the same thing. In small duct P.S.C. you have abnormal blood tests, but the ERCP

or MRCP is normal. But if you do a liver biopsy it shows a picture consistent

with P.S.C. And that’s called small duct PS.C. The studies showed that

this is usually a gentle and more benign form of the disease which does not

progress. There were no cases at all of any bile duct cancer, there appeared to

be no benefit from taking Urso; maybe because you don’t need Urso for

small duct P.S.C. A. Bjornson, who was with me, went over to the Mayo Clinic

for three months last summer, he found from their work that what was true for

five years has also been true for ten years. This was seen in his data, the

Mayo Clinic’s and also our own work. That is 10 years data from three centres.

Just to remind you that P.S.C. mainly affects those aged twenty to fifty. But

we do see children and increasingly, more elderly patients, i.e. over the age

of fifty. We even see people with P.S.C. in their eighties and nineties. When I

first started studying this in 1976, we thought that this was always a very

serious condition in the context of a male patient with rip- roaring Colitis

and who was therefore very sick. As testified by looking at you in this room,

most patients are not jaundiced. The disease has been diagnosed in an IBD

clinic, and patients may have normal LFTs.

The chap you see on your right, on the screen, who has jaundice and is

sweating, is more unusual and perhaps has an end-stage condition.

In a paper from a study published in Stockholm this year, their experience

closely mirrors ours. We are increasingly seeing more elderly patients without

IBD, who are mostly doing extremely well. So it looks like, as we diagnose

things in a more sophisticated way, the spectrum is getting even more gentle

than we thought before. So if we take all these things into account, and

I’ve recently discussed this with Ivor, seventy-five per cent of patients

who are asymptomatic could be well many years after diagnosis, and I stick by

that. The prospect is much better than we thought it was in 1979. It remains

very variable and very difficult to predict, but some people can present very

few problems. With other people, of course, it can present problems. You may

start to get problems with pain on the right side you start to get itching and

fatigue, then you are symptomatic and the majority of patients will progress

slowly over the next ten to fifteen years. You may require a liver transplant

at some stage. So that’s the spectrum we are talking about. I know people

in this room who have been transplanted successfully and are a testament to how

good transplantation is. But the spectrum has changed a lot over the past

thirty years and is still changing as we speak. It has also become more common

than we thought. A recent study in 5outh Wales, and also studies in America, showed that about twenty

people per one hundred thousand of the population have P.S.C. and I suspect it

is more than that, (that gives a total P.S.C. population of around twelve

thousand - double previous estimates). Why do I think it is a random estimate?

Well, we have been taking Colitis patients who have normal LFTs and performing

MRCPs on them. We couldn’t do ERCPs in the past because there can be

complications with ERCP and it would not have been ethical. But now we can do

MRCPs which do no harm to patients. This has enabled us to examine patients who

have no evidence of P.S.C. We have found in about a fifth of sixty patients,

that the condition of ducts is consistent with having P.S.C. This raises all sorts of issues which I

won’t go into now, but it does leave us to suppose that P.S.C. is more common

than we previously thought.

About three-quarters of patients in Northern Europe with P.S.C. will have Ulcerative Colitis

or Crohn’s Disease. At Oxford we have about forty-eight patients with Crohn’s

Disease, quite a big group, and we are looking at them fairly closely. We are

looking at how often they need a colonoscopy and other factors as well. The

other thing that we are looking at is the characteristics of the type of IBD

you have with P.S.C. as opposed to patients who have IBD alone. The thinking

now is that it may be that the IBD with P.S.C. may be quite a separate disease

entirely to Ulcerative Colitis alone as we know it: with separate genes and it

behaves differently. We hope to sort this out with the genes study which

I’ll come back to later. How is it different? It involves the whole of

the colon but it tends to be very mild. Some sufferers here may disagree with

that. But it does appear to be milder than for those patients with Ulcerative

Colitis alone: less diarrhoea, less bleeding and less attacks. The back

passage, the rectum which is normally involved in Colitis is often not involved

in P.S.C. patients, and also, the changes outside the colon are quite

different. Patients who have Ulcerative Colitis without P.S.C., also tend to

get things like eye problems, joint problems, skin problems, which are rarer in

Ulcerative Colitis plus P.S.C. In Ulcerative Colitis with P.S.C. joint problems

usually appear to be rheumatoid arthritis, another autoimmune disease. It may

also be true that with P.S.C., after you have had a colectomy there is an

increased rate of pouchitis. This has been claimed but we haven’t found

this to be the case in Oxford. There was a paper published about ten years ago.

After thirty years of studying it, where are we in terms of understanding what

causes P.S.C.? It clearly has strong auto-immune factors. Those who get it have

a predisposition involving one particular gene, maybe more. There are clearly

environmental factors such as non-smoking.  How many in the room have P.S.C.

and smoke? (very few hands go up). It is quite clear that people who have P.S.C.

do not smoke. In the case of PBC, it is quite closely associated with smoking. P.S.C.

is associated with non-smoking. But if you look at P.S.C. patients without

Colitis, we are looking at nonsmokers. It does not mean, I hasten to add, that

you should all go and start smoking. Some time ago at the Mayo Clinic they gave

people nicotine patches to see if that would help their P.S.C. or the IBD. It

helped neither. What does smoking do to affect illnesses. Smoking does affect

blood flow, does affect mucus which can be protective of the gut and it also

affects the immune system. Any of these three factors could be playing a part,

or, some other factors. But it is a striking fact; our data does come from

patients, some of you here. And it fairly clearly shows the effect of

non-smoking.

So what could be triggering this process?

It means that if you have IBD, so the theory goes, you have a leaky colon which

doesn’t put up much of a barrier against bacteria that otherwise you

would normally have. It involves bacteria or possibly protozoa, crossing the

colon, then rising through the blood system by way of the portal vein to the liver where it can set up the reaction

called P.S.C. Another hypothesis which I tend to favour is that you have

antigens which are little proteins on the outside of cells which can attract

T-cells to them and this has been shown by work in Birmingham by Professor ’ group. Normally,

these T-cells, when they are made, are programmed, quite cleverly, to go back

to certain parts of the body. It is a very sophisticated system that we have,

and these cells have an address on them which says: you go back to the colon

when needed. Now for some reason in PS.C. the address is also put on the bile

ducts that therefore can attract those lymphocytes from the gut to the liver

where they should not be, and may well cause a reaction which causes problems

with the bile ducts. What actually causes these liver cells to express

lymphocytes, we do not know. It seems that two processes may be involved. That

roughly is where we are at the moment.

I am often asked whether PS.C. is an auto-immune disease. This means that the

body loses tolerances against its own organs.

There are very specific auto-immune diseases, where all of a sudden the body is

attacked by white blood cells and they may attack, for example, the thyroid

gland which will produce problems. I think it is not entirely clear that P.S.C.

is an autoimmune disease, but clearly immune factors are very important in this

disease. So that is the summation of about thirty years work in three minutes!

These days, you get more and more specialists. You can have a problem with your

ducts which will need an endoscopist. You can have problems with your ID and

you will need a gastroenterologist. If you are having problems with your liver,

then you will need to see an hepatologist. Then if you need a liver transplant,

you will need to see transplant surgeons. With the way it is going, certainly

in America and Germany, that means five different

doctors.  I am a jack-of-all-trades, and I do all of that, I am a dinosaur. So

you may find that you are being managed by a number of different doctors and

that can be a problem in care. P.S.C. is quite a complicated condition which

does require a number of different specialists, but it does need someone to

hold it together in terms of co-ordinating the treatment. My view is that that

should be hepatologists.

ON URSO

Just

to remind you that Urso is a naturally occurring bile-acid, which we all have

inside ourselves. Bile acids are produced in the liver and they do various

things. They make the food more soluble. Urso is a good bile acid because it is

not toxic to cells: it has a lot of good effects and it increases bile flow and

also ha5 good effects on the immune system as well. Just to remind you, the

high-dose Urso trials which 5ue Cullen took part in, is finally going off to

publication, though after four separate drafts. 5ome of you very kindly took

part in this study. During two years of treatment, three different doses were

used: Moderate: 10-15mg per kilo body weight; high: which was 20-25mg per kilo

body weight; Very High: 30-35mg per kilo body weight.

Surprisingly, there were no side-effects, even in the very high dose. There

were the improvements in the liver function tests, great improvements in the

moderate to high group and the Mayo prognostic score which gives you some idea

about how people are going to develop over time. Improvement in all three. Scar

tissue appeared to progress in the lower dose, improve in the very high dose,

but the numbers were very small. I think that the dose you should probably be

using is the 20-25mg.

There is a large study going on in at the Mayo Clinic, which should answer

that. There are very unlikely to be any new studies, so the American study is

likely to be the one that will be the most helpful. Most importantly, Urso is

likely to be cancer protective, against colon cancer and possible bile duct

cancer. We are probably looking in the future at combination studies, antibiotics

and immuno-suppressants. I would have done these studies now, but because of

the current regulations in Europe, it is virtually impossible for somebody like me to

do this study anymore, sadly.

We had a very successful P.S.C. symposium in Oxford just a few weeks ago. Dr. 5tiehl attended

and he told us about his approach which was to use balloon dilatation plus high

dose UP5O. Lvery year his patients have an LICP and he stretches all the

strictures in the bile ducts, which is quite a daunting prospect. Most people

don’t do that, but he claims good results with that technique.

I thought I’d just finish by telling

you about on-going research. Joy Worthington, (Dr. Chapman’5 research assistant),

is coming to the end of her three-year project: will tell us a little bit about

what she is doing. Thank-you also for supporting Joy’s past three months

with us. Our work on Crohn’s Disease will be published and we’ve

also analyzed our pouchitis study. And I’ve seen the results. And that

data will be coming out in the next year as well.

This is about patients who have had an operation for their Colitis and a pouch

is then made in the rectum. Some of you may have had this operation.  Our

results in Oxford appear to be quite good, much

better than previously published. I would like to mention a bit about the

genome study after Joy has told you about her research. We have done a fatigue

study. We’ve been scanning patients with an MRI scanner at St.

’s; it seems that there may be changes in the brain with people suffering

fatigue. So we are working on that as well.

You may have been reading about this superdrug, Modafinil that students

have been using, for example, to keep awake for examinations. It has been used

for patients who suffer day-time sleepiness and / or narcolepsy. at

Newcastle, (a well-known PSC

researcher), has done a small trial with PBC patients and it does seem to be

effective. So that is a new possibility in reducing fatigue in P.S.C.  All I

can say is that anecdotally, it looks quite useful. We are exploring this at

the moment with some of our P.S.C. patients, and seeing how they do. We have

very provisional results, but at last maybe we have found something which makes

a difference to those suffering fatigue.

Joy, explained her current results with T-cells in both PBC and P.S.C. It does

require more blood cells from P.S.C. patients; so If you have some spare blood,

please give it to our “resident vampire”, before and after giving

them Modafinil, fatigue can be scored or measured, and this is also involved in

Dr. Chapman’s research in these areas, before and after giving them Modafinil.

He has also been looking at the blood of P.S.C. and PBC patients. In both

diseases patients have higher levels of manganese in the blood. It is too early

to say whether this is related to fatigue in these diseases and whether that

can lead on to any forms of treatment.

Dr. Chapman then briefly explained his genome project. This research enables us

to have trials involving thousands of patients but it costs millions of pounds.

You can take large amounts of DNA from a patient population and compare it with

the DNA of other populations. Particular genes may stand out as being potential

causes of the disease. This has been done with great publicity with IBD, particularly

Crohn’s Disease, where five candidate genes have been spotted, which were not

previously known about.

This has completely opened up the whole question of causes of IBD and also

potential treatments. Because of this I have spoken to two of the people

involved in this genome project, and we are planning to do a genome-wide

research into P.S.C. Theoretically you need 10,000 patients, but there are only

probably 6,000 patients with P.S.C. in Britain. We have compromised and said we need

1,000 patients, and perhaps half of these are receiving treatment. 5o our

master plan is to get P.S.C. patients by various routes. This is likely to

involve the major liver centres in the country: Edinburgh, Birmingham, ourselves. (Newcastle has signed up to this and so has Cambridge). In theory it would be

better if we tried to collect all the D11P in one place and that will be Cambridge. They will collect and store

it at a cost of £10 per patient. That’s quite a good deal. This is a big

undertaking, but I feel we can do it. Quite by chance I was approached by an European

group three weeks ago, which is doing exactly the same thing. This is a group

in Germany and Belgium. So this is quite a hot

topic. It will answer whether there are any genes involved which we haven’t

yet thought of, and that has certainly happened in Crohn’s Disease. And

it has completely altered the way in which we think of that disease and may

also answer whether IBD in F5.C. and IBD in non P.S.C. patients are different

diseases. Ivor has very generously asked me to think of some project or

equipment for which you could raise funds. My suggestion would be, if you are

agreeable, that that would be a very worthwhile way in which you could spend

your money to cover the cost of collecting and storing all the DNA we would

need. It would be 10,000 pounds for 1,000 patients. The total cost is likely to

be one to two million pound5. I am not asking you to pay that! The idea is that

we collect all the DNA and you would collect all the clinical profiles of these

patients. Then we hope to involve the Wellcome Trust, which has financed

previous projects, and we are told on good authority, that the trust would look

upon this very favourably. But we have to get the DI1I in place first. Even if

they don’t fund it this would be a great resource for P.S.C. research.

QUESTIONS AND ANSWERS

A patient

said that he was surprised that on taking high dose URSO his fatigue seemed to

improve.

Well, I am delighted but sadly, Urso seems to have very little effect on symptoms.

There is a thing called itching of pregnancy which some ladies in the audience

may have had. And Urso which does improve bile flow has a good effect on that.

But that isn’t an effect with people who have P.S.C. (Two of our Members

have also reported considerable improvement in their fatigue in taking high

dose Urso).

QUESTION: Is there a connection between Arthritis

and P.S.C?

ANSWER: There is an arthritis that is related to active

Ulcerative Colitis, without P.S.C., it involves a stiffness in the hands and

that goes along with diarrhea in Colitis. Find there is a particular genetic

fingerprint. But that occurs only more rarely in P.S.C. where we find some of

our P.S.C. patients may suffer from Rheumatoid Arthritis. This is a specific

auto-immune condition which also damages the joints of the hands.

Ivor mentioned that two questions have come from the American PSCers,

athan and Joanne H. have asked the following: — They are very much interested in your

fatigue research. One of them says this: “One thing that I would mention

is that since P.S.C. causes a significant amount of sleep disturbance it is

hardly surprising that it causes fatigue. There may be other things that

contribute to the causes of fatigue as well, but for me, I certainly have more

problems with fatigue when I was sleeping poorly. I wonder if these researchers

have thought to include that in their consideration of the causes”.

ANSWER: Well they have. They do go to some lengths to exclude

that. Obviously, if you are itching and you can’t sleep you are going to

be fatigued, but that’s a sort of normal fatigue. We are talking about

quite a different kind of phenomenon: the kind of fatigue associated with P5.C.

is not really the same as the fatigue referred to there. This fatigue has a central

effect and it is something going on within the brain. It is not reduced by

liver transplantation, which would be the scenario you quote. If you are

itching and therefore not sleeping, that kind of thing would be cured by

transplantation. So these are different kinds of fatigue and there are

different causes.

AND THE SECOND question from America: — “I would ask about the symptoms of

abdominal pain: upper right quadrant pain, bloating similar in GERD symptoms,,

plus itching. These are such frequent P.S.C. related symptoms and I would ask

if there was any recent or ongoing research into better symptom management in

relation to improved quality of life for any of these symptoms.”

ANSWER: Well I don’t think that all of these are in fact

P.S.C. symptoms. The right upper quadrant pain certainly is and sometimes that

can go along with blockage of bile ducts in a stricture and there may be a

worsening of jaundice and itching. That can be dealt with by opening the

stricture with a stent or balloon endoscopy. Or in the worst case scenario,

even a liver transplant if things get very bad. The other symptoms mentioned

such as bloating and heartburn are not due to P.S.C. They are due to ref1ux

which is commonly found in forty to fifty per cent of the population anyway. I

lecture on reflux to students and I ask how many of them had reflux and about

forty per cent of them put up their hands. These are medical students aged

about twenty-five. So reflux is not a symptom of P.S.C. But I would take the

pain in the upper right quadrant fairly seriously. We would probably use E.R.C.P

to think about relieving any blockage that we find. And looking at the Liver Function

Tests as well.

A QUESTION about ileostomy: A patient was told that if he’s

had an ileostomy, after nine years he shouldn’t get any P.S.C.

ANSWER: Dr. Chapman said that was complete nonsense.

P.S.C. can occur up to twenty years after you’ve had your colon out.

A QUESTION about the nature of fatigue in

P.S.C.

ANSWER: What I was talking about in relation to fatigue in P.S.C.

is a specific syndrome of being so tired that you are unable to lead a normal

life. This is separate from other forms of fatigue, it isn’t unique to P.S.C.,

it also occurs in PBC. For example because the bile doesn’t flow properly

it tends to result in something deposited in the brain. This very likely causes

the fatigue. We are making some progress in this and it may be possibly

connected with manganese being the reason. When we look at our scans of P.S.C.

patients there is excess manganese. It is all provisional and I haven’t analyzed

all the results yet. This isn’t related to the stage of P.S.C. You can

have very mild P.S.C., normal LFTs, but still have bad fatigue. It is a great

conundrum as to why this should be. Thirty-five per cent of PBC patients will

have such fatigue, perhaps a little less in P.S.C. It can be disabling and it

appears to be cured by liver transplantation. Blocked bile ducts could

certainly make things worse.

In answer to a question from a patient about his gall bladder operation: Dr.

Chapman said, any form of cholestatic disease will get an increase in gallstones in the gall bladder. And some

people with P.S.C. will actually

form sludge, pigment sludge within the bile ducts themselves. It’s not

that uncommon, it does happen. This usually worsens any jaundice and fever.

It’s usually treated with a Sphincterotomy: cutting the ends of the bile

ducts and putting a balloon through and trying to remove the sludge. The gall

bladder can be involved in P.S.C. If you have a gall bladder with polyps then

the gall bladder is usually removed.

QUESTION: Does sunlight help

with Itching? I was on holiday in Spain and the Itching disappeared.

ANSWER: That’s right, ultraviolet light (U.V.), does

help. 8ut it’s a difficult thing to do on a regular basis and as soon as

you stop, the itching comes back. So you have to keep going into the sunlight

which is a good excuse to have a lot of holidays! There have been studies and

it does work. But it’s not terribly practical. Sun-bed may be a good

idea, but by and large you can control itching with medications. In P.S.C. you

have to be careful to make sure that blocking in the bile ducts is not the

cause of the itch.

QUESTION: How likely is it that P.S.C. will come back after

transplantation?

ANSWER: Quite high, we are talking about figures of around

twenty-five to thirty per cent after five years. Find probably, fifty per cent

after ten years. 5ome people will get it back without any problems, so it

doesn’t mean that they need to be re-transplanted necessarily. ut this

does happen with other liver diseases including PBC.

QUESTION: question about regeneration of the liver.

ANSWER Yes, it is true that the liver is an amazing organ,

it can regenerate even after severe damage. Take away half of the liver and it

will grow back to its previous size. There’s a story from the Greek

classical legend of Promethius. He gave knowledge of fire to humans and as a

punishment from Zeus was placed on top of a mountain; every day an eagle would

come and eat a piece of his liver. But then every day the liver grew back

again. The Greeks knew about this.

QUESTION: A question

about Professor Habib’s approach in regenerating the liver by implanting

stem cells.

ANSWER: Professor Habib has taken several patients with very

advanced liver disease, who may have required a liver transplant and injected

them with stem cells. We were asked to take part In a trial; we haven’t

done so. I can’t see this

type of treatment used for P.S.C. in the next ten years.

At the end of the meeting some envelopes were given out for those who would

like to take part in Dr. Chapman’s genome project. We were urged to

consider giving DNA.

At the end of the

Meeting, - Dr. Chapman was presented with a cheque for

£9,000 to pay the last three

months of his assistant’s salary.  For the first time we have managed to give

Dr. Chapman a substantial sum of money for his research. The Chairman explained

that there was a lot of blood, sweat and tears in achieving this amount. In Wales there was

the sponsored ten-mile race in Aberystwyth, a number of other people completed

sponsored events including a walk up Ben Nevis in a

Blizzard, and there have been some very generous contributions. This is the

first time we have been able to collect a substantial amount of money for P.S.C.

research.

OUR ANNUAL GENERAL MEETING, 2007

After

the refreshments break, the 2007 Meeting. The Chairman began by giving a little

history of the group. Which was founded in 1994, by Deborah . And from a

handful of Members she built it up to a Membership of around 300. In the seven

or so years since she resigned from the Chairmanship, we haven’t done a

great deal better, although we have managed to raise the Membership to 400.

Then last year we stopped sending Newsletters to over fifty Members, who have

never paid their subscriptions, did not answer our letters of reminder, and, we

therefore assumed that they no longer wanted the Newsletter. That has reduced

our numbers down to about three hundred and forty Members. We do see it as part

of our function to reach as many P.S.C. patients as possible. We believed that

there are around sin/seven thousand P.S.C. sufferers in the United Kingdom,

although, perhaps only half of these may be receiving treatment. As we have

heard, the national figure may well be over 12,000 and even more. There are

people who have P.S.C. and may never know it. But we shouldn’t be

satisfied with current numbers: that would make us a static organization. There

is strength in numbers although we know that we can never be a large organization.

We would like your help in trying to increase Membership.

What we do at present is to send our Newsletters to twenty-five or so

gastroenterologists/hepatologists. We ask these doctors to tell their P.S.C.

patients of our existence. This doesn’t appear to have produced any

result. It’s unclear as to whether or not these doctors actually read the

Newsletters. We try to put posters in liver units. We’re also recruiting a number

of Members through our Website. We have some spare posters and business cards.

If you can help us, please take some. We also manage to recruit some Members

through the British Liver Trust.

FUND-RAISING

For the first time we have been successful in raising a substantial sum of

money for Dr. Chapman’s Research efforts. We really owe it to Dr. Chapman

to give him the maximum available support. He is not only a very caring doctor

as people in this audience will testify, but he is also the country’s

pre-eminent P.S.C. Researcher, if not in the world. He needs funds to continue

his research and we have dedicated ourselves to raising £10,000 for his latest

genome-wide research which he has told us about. We would therefore like to ask

all those who can, to re-double their efforts in the run-up to Christmas. Like

PBC, but perhaps more so, P.S.C. remains the ‘Cinderella’ of liver

diseases. We will never receive priority from government funding. Although our

group is small, we can try to make a difference.

Jackie (who leads our fund-raising efforts), gave a report on her

efforts and suggested new ideas and areas for fund-raising.