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Cystic Fibrosis Gene and Idiopathic Pancreatitis

The cystic fibrosis transmembrane conductance regulator (CFTR) functions

as a cyclic-AMP­regulated chloride channel essential in maintaining luminal

hydration in the ducts of many organs. Hence, mutations in the channel's gene

can lead to dysfunction in lungs, exocrine pancreas, sweat glands, and Wolffian

ducts, as manifestations of cystic fibrosis. Although the pancreatic involvement

usually does not resemble pancreatitis clinically, several observations suggest

that CFTR mutations may be responsible for some cases of chronic pancreatitis.

In both cystic fibrosis and chronic pancreatitis, the earliest pathologic

changes consist of ductal obstruction. Moreover, sweat tests may be abnormal in

patients with either condition.

The relation between CFTR mutations and idiopathic pancreatitis was

explored in 22 women and five men referred for evaluation of idiopathic

pancreatitis at Duke University and the University of North Carolina. The

investigators tested for 17 CFTR gene mutations and also for the 5T CFTR allele,

whose presence markedly reduces the level of functional gene product. Ten

patients (37%) had at least one such abnormality, for a mutation frequency

11-fold greater than expected. In three patients, both CFTR alleles were

affected, exceeding the expected frequency 80 fold. In another report,

investigators in Manchester, England, studied 134 consecutive patients with

chronic pancreatitis--53% of the cases were alcohol-related and 45% were

idiopathic. Testing for 22 CFTR mutations, the researchers identified a mutation

frequency nearly 2.5 times the expected figure. The frequency of the 5T allele

was twice as high as expected. The mutations were associated with idiopathic

rather than alcohol-related disease. In both the Manchester and North Carolina

studies, none of the patients had cystic fibrosis.

Cohn JA et al: Relation between mutations of the cystic fibrosis gene and

idiopathic pancreatitis. N Engl J Med 339:653, 1998; Sharer N et al: Mutations

of the cystic fibrosis gene in patients with chronic pancreatitis. Ibid:645;

Durie PR: Pancreatitis and mutations of the cystic fibrosis gene (editorial).

Ibid:687

Click here for Significance of Heterozygous Cystic Fibrosis Gene (Cystic

Fibrosis Transmembrane Conductance Regulator Mutations) In Idiiopathic

Pancreatitis.

Mutations of the Cystic Fibrosis Gene in Patients with Chronic

Pancreatitis

Sharer, M.R.C.P., Schwarz, Ph.D., Geraldine Malone, B.Sc.,

Howarth, M.Sc., Painter, M.R.C.P., Maurice Super, F.R.C.P., and Joan

Braganza, D.Sc.

Data gathered at http://content.nejm.org/cgi/content/full/339/10/645

ABSTRACT

Background The pancreatic lesions of cystic fibrosis develop in utero and

closely resemble those of chronic pancreatitis. Therefore, we hypothesized that

mutations of the cystic fibrosis transmembrane conductance regulator (CF TR )

gene may be more common than expected among patients with chronic pancreatitis.

Methods We studied 134 consecutive patients with chronic pancreatitis

(alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia

in 1, and idiopathic disease in 60). We examined DNA for 22 mutations of the CF

TR gene that together account for 95 percent of all mutations in patients with

cystic fibrosis in the northwest of England. We also determined the length of

the noncoding sequence of thymidines in intron 8, since the shorter the

sequence, the lower the proportion of normal CFTR messenger RNA.

Results The 94 male and 40 female patients ranged in age from 16 to 86

years. None had a mutation on both copies of the CF TR gene. Eighteen patients

(13.4 percent), including 12 without alcoholism, had a CF TR mutation on one

chromosome, as compared with a frequency of 5.3 percent among 600 local

unrelated partners of persons with a family history of cystic fibrosis

(P<0.001). A total of 10.4 percent of the patients had the 5T allele in intron 8

(14 of 134), which is twice the expected frequency (P=0.008). Four patients were

heterozygous for both a CF TR mutation and the 5T allele. Patients with a CF TR

mutation were younger than those with no mutations (P=0.03). None had the

combination of sinopulmonary disease, high sweat electrolyte concentrations, and

low nasal potential-difference values that are diagnostic of cystic fibrosis.

Conclusions Mutations of the CF TR gene and the 5T genotype are associated

with chronic pancreatitis.

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In 1969, Paris et al.1 described two siblings who had the autosomal

recessive disease cystic fibrosis and whose father and paternal uncle and

grandfather had chronic calcific pancreatitis. Not only did this report hint at

a shared molecular basis for pancreatic damage in these two conditions,2 but it

also, since the children's mother was apparently unaffected, underlined the

importance of nature-nurture interactions in the pathogenesis of the sporadic

form of chronic pancreatitis.3

The presentation of chronic pancreatitis typically resembles that of acute

pancreatitis; subsequent attacks can be anticipated until all secretory

parenchyma is destroyed. Alcoholism is a major etiologic factor, exposure to

cigarette smoke and occupational exposure to volatile hydrocarbons independently

increase the risk,4,5 duct-obstructing lesions initiate a few cases, and there

may also be an underlying metabolic or autoimmune disorder. The cause of the

rare hereditary form has been identified as a mutation in the cationic

trypsinogen gene at locus 7q35.6 The disease is idiopathic in up to 40 percent

of affected patients in developed countries.

The exocrine pancreas is invariably affected in cystic fibrosis.7 The

lesion has been described as " basically a diffuse form of chronic

pancreatitis. " 8 The damage begins in utero7 and can be identified in neonates on

the basis of elevated blood concentrations of pancreatic enzymes, classically

trypsinogen. Pancreatic biopsy in the first year of life reveals interstitial

inflammation,9 but this is not found on postmortem examination after the failure

of pancreatic exocrine function. The progression of the disease is usually rapid

and painless; however, a few patients may have an attack of pancreatitis or

pancreatic calculi.

In 1989, the cystic fibrosis transmembrane conductance regulator (CF TR)

gene was identified at locus 7q31.10 This discovery led to the suggestion that

insufficiency of the CFTR protein may underlie the overlapping

clinicopathological facets of chronic pancreatitis and cystic fibrosis.2 As a

first step toward testing this hypothesis, we examined the frequency of CF TR

mutations in a cohort of patients with chronic pancreatitis.

Methods

Study Design

In a study of 600 unrelated partners of persons with a family history of

cystic fibrosis in the northwest of England, the rate of carriage of CF TR

mutations was 5.3 percent (95 percent confidence interval, 3.5 to 7.1

percent).11 Therefore, we calculated that a minimum of 106 patients with chronic

pancreatitis would have to be examined for the study to be able to detect, at a

power of 90 percent, a doubling of this frequency. Study of the attendance

register at the weekly pancreatobiliary clinic indicated that this target could

be met within six months. We decided at the outset that patients who were found

to have a CF TR mutation would undergo supplementary tests for atypical cystic

fibrosis12 and that their first-degree relatives would be offered the

opportunity to undergo screening for CF TR mutations.11

Patients

The study was approved by the hospital's ethics committee. Between January

1993 and June 1993, consecutive white patients with chronic pancreatitis were

enrolled after they gave informed consent. The diagnosis of chronic pancreatitis

was based on standard criteria: abnormalities on histologic analysis of biopsy

specimens, visible calculi on x-ray films, unequivocally abnormal findings on

endoscopic pancreatography,13 or impaired exocrine secretory capacity,

determined by the secretin-pancreozymin test (bicarbonate or enzyme output more

than 2 SD below the mean in normal subjects)13 or the p-aminobenzoic acid

excretion index (results more than 3 SD below the mean in normal subjects in our

version of this tubeless test, which uses bentiromide).14,15 Patients with a

periampullary lesion that obstructed duct drainage were excluded.

For the purposes of the study, alcoholism was defined as the daily intake

of at least 80 g of ethanol by men and at least 60 g of ethanol by women for two

years before the first symptom of pancreatitis, and cigarette smokers were

defined as those who smoked 10 or more cigarettes per day.5 Those who drank

lower amounts of alcohol were classified as nonalcoholics, and those who smoked

zero to nine cigarettes per day were classified as nonsmokers. Job histories

were also available, but we did not analyze these data because of the difficulty

of quantifying occupational exposure to hydrocarbon.6 All patients were taking

antioxidant supplements to control pain, and most had been taking them for about

five years. The rationale for antioxidant therapy has been discussed

previously.3,16,17,18 A frequent starting regimen consisted of six tablets

containing organic selenium, beta carotene, and vitamins C and E (Wassen,

Leatherhead, United Kingdom), and eight tablets of methionine ( Medical,

Horsham, United Kingdom) per day in divided doses, for total daily supplements

of 600 µg of organic selenium, 9000 IU of beta carotene, 0.54 g of vitamin C,

270 IU of vitamin E, and 2 g of methionine. Doses were adjusted after periodic

measurement of blood vitamin C, selenium, and glutathione.

DNA Studies

We extracted DNA from buccal cells obtained by having the patients rinse

their mouths with 10 ml of 4 percent sucrose.19 The CF TR locus was examined for

the 22 mutations that together account for 95 percent of all such mutations in

patients with cystic fibrosis in the northwest of England.20 The

amplification-refractory mutation system Elucigene CF(4)m kit (Zeneca

Diagnostics, Macclesfield, United Kingdom) was used to detect the four most

common mutations: F508, G551D, G542X, and 621+1(GT)21; the polymerase chain

reaction, restriction-enzyme analysis, and allele-specific oligonucleotide

hybridization facilitated the detection of R560T, R117H, 1898+1(GA), R553X,

S549N, 1717-1(GA), N1303K, W1282X, E60X, 1154insTC, R347P, 3659delC, Q493X,

V520F, R334W, I507, 3849+10Kb(CT), and 1078delT. Low levels of CFTR protein may

result from a reduction in normal messenger RNA (mRNA), such as is associated

with a mutation in the noncoding sequence of thymidines in intron 8.22,23 This

sequence may contain five, seven, or nine thymidines (the 5T, 7T, and 9T

alleles, respectively); the shorter the sequence, the lower the proportion of

normal CFTR mRNA. The length of the intron 8 polyT region was determined by

oligonucleotide hybridization22 or direct sequencing.

Assessment for Atypical Cystic Fibrosis

Pulmonary spirometry and sinopulmonary radiography were performed whenever

possible. Studies of the transepithelial nasal potential difference24 were

undertaken in a subgroup of patients with a CF TR mutation and in comparable

groups of patients with chronic pancreatitis and normal subjects with no CF TR

mutations. The test involves the perfusion of a nasal mucosal electrode with

standard buffer, then with 100 µM amiloride in standard buffer to block the

epithelial sodium channel, then with 100 µM amiloride in low-chloride buffer to

stimulate chloride movement, and finally with 100 µM amiloride and 10 µM

isoproterenol in low-chloride buffer to increase intracellular cyclic AMP.

Pilocarpine iontophoresis25 was used to obtain sweat samples from the same

subgroups; a minimum of 100 mg of sweat was analyzed to determine sodium and

chloride concentrations. Several of the younger patients had already undergone

sweat testing at their initial presentation.

Statistical Analysis

A chi-square statistic with Yates' correction, a binomial distribution,

the Mann-Whitney U test, and Fisher's exact test were used as appropriate. All P

values were two-tailed. A P value of less than 0.05 was considered to indicate

statistical significance.26

Results

Characteristics of the Patients

The cohort of 134 patients included 71 with alcohol-related pancreatitis,

3 with a metabolic problem (2 with hyperparathyroidism and 1 with severe

hypertriglyceridemia), and 60 with idiopathic pancreatitis. There were 94 male

and 40 female patients. The age at onset of symptoms varied widely, from 5 to 81

years, as did age at the time of the study (16 to 86 years). Ninety-nine

patients smoked 10 or more cigarettes a day. Large-duct disease was identified

on the basis of an abnormal pancreatogram or radiographic evidence of calculi in

80 percent of the patients, and small-duct disease was identified on the basis

of histologic findings or impaired exocrine function in the others. An attack of

pancreatitis was the usual presenting symptom, and increasing pain was the usual

reason for referral.

DNA Studies

No patient had a mutation on both copies of the CF TR gene. Eighteen

patients (13.4 percent; 95 percent confidence interval, 8.2 to 20.4 percent) had

a CF TR mutation on one chromosome, as compared with 32 of the 600 unrelated

partners of persons with a family history of cystic fibrosis (5.3 percent; 95

percent confidence interval, 3.5 to 7.1 percent; P<0.001). The most common

mutation was F508 (Table 1), as is the case among patients with cystic fibrosis

in the northwest of England.20 The group of 18 patients with a CF TR mutation

were younger at presentation than the other 116 patients (P=0.03) and included

12 nonalcoholics. There was a higher frequency of CF TR mutations among patients

who were classified as nonsmokers than among those classified as smokers (28.6

percent vs. 8.1 percent, P=0.007), but there was no significant difference in

the frequency of mutations between alcoholics and nonalcoholics (8.5 percent vs.

19.0 percent, P=0.12).

Table 1. Characteristics of 18 Patients with Chronic

Pancreatitis and a Mutant CF TR Allele. Click here to view this table.

Analysis of the polyT sequence identified the 5T allele in 14 of 134

patients, or 10.4 percent (95 percent confidence interval, 5.8 to 16.9 percent);

the frequency is 5.0 percent in the general population22 (P=0.008). It was

present in 4 of the 18 patients with a CF TR mutation and in 10 (all males) of

the other 116 patients (22.2 percent vs. 8.6 percent, P=0.10). The

clinicopathological features of the patients with chronic pancreatitis

classified according to whether they had a 5T allele or a CF TR mutation alone

or in combination are summarized in Table 2. On the basis of the work of Chillón

et al.,27 it is likely that the CF TR mutation and the 5T allele were on

opposite chromosomes.

Table 2. Characteristics of Patients with Chronic

Pancreatitis According to Whether They Had a CF TR Mutation or a 5T Allele Alone

or in Combination.

Click here to view this table

Assessment for Atypical Cystic Fibrosis

None of the 18 patients with a CF TR mutation alone or in combination with

a 5T allele met the diagnostic criteria for cystic fibrosis when all the

evidence was considered.12 A review of family histories revealed cystic fibrosis

in close relatives of two unrelated patients. Subsequent screening identified

the disease in the outwardly healthy infant son of another patient.

There were no sinopulmonary symptoms or signs or radiologic abnormalities

in 133 patients. The one exception was a 76-year-old woman (Patient 17 in Table

1) who was a former smoker with the F508/ - (9T/7T) genotype and mild

bronchiectasis but without colonization by pseudomonas strains. Spirometry was

possible in 109 patients, including all 18 with a CF TR mutation. Evidence of

obstruction (ratio of forced expiratory volume in one second to forced vital

capacity, <70 percent) was found in 4 of the 18 patients with a CF TR mutation

(22.2 percent) and in 23 of 91 patients with no CF TR mutations (25.3 percent).

The former group included three patients who smoked at least 10 cigarettes daily

(Patients 14, 15, and 16 in Table 1) and a nonsmoker with a history of

hyperparathyroidism (Patient 17 in Table 1).

Nasal potential-difference tests (Figure 1) were interpreted with

reference to published studies,24 after we confirmed that the pattern was

abnormal in patients with classic cystic fibrosis by testing two such patients

(data not shown). As compared with the mean (±SE) value in 12 normal subjects

with no CF TR mutations (-7.2±0.7) , the base-line value was significantly lower

in the subgroup of patients with a CF TR mutation (-10.5±1.2, P=0.02) but not in

the subgroup with no CF TR mutations (-8.1±0.5). However, no patient had a value

that was diagnostic of cystic fibrosis (approximately -50 mV)12 and the results

in our two patients with cystic fibrosis were close to this value (-48 and -56

mV). Moreover, the patterns and gradients of responses to the various perfusates

were similar in the three subgroups. Only one of the four patients who were

heterozygous for both a CF TR mutation and the 5T allele agreed to be tested

(Patient 10 in Table 1). His base-line value was the lowest recorded (-17.6 mV),

and it changed to -11.8 mV after exposure to amiloride - representing a change

of 32.9 percent, as compared with approximately 70 percent in patients with

cystic fibrosis12 - and changed to -20.7 mV with a low-chloride perfusate and to

-22.5 mV after exposure to isoproterenol.

Figure 1. Mean (+SE) Values for Nasal Potential-Difference

Measurements in 12 Normal Subjects, 12 Patients with Chronic Pancreatitis and No

CF TR Mutations, and 11 Patients with Chronic Pancreatitis and a CF TR Mutation.

The normal subjects were 8 men and 4 women with a median age

of 37 years (range, 20 to 64), the 12 patients with chronic pancreatitis and no

CF TR mutations were 8 men and 4 women with a median age of 47 (range, 23 to

68), and the 11 patients with chronic pancreatitis and a CF TR mutation were 6

men and 5 women with a median age of 39 (range, 21 to 79). The points represent

readings taken at 15-second intervals with the mucosal electrode initially

perfused with Krebs' HEPES buffer to obtain a base-line reading, then with 100

µM amiloride in standard buffer, amiloride in low-chloride buffer, and amiloride

together with 10 µM isoproterenol in low-chloride buffer. There is a brief

disjunction of data points 30 to 45 seconds after the perfusion of each solution

because this interval equates to the dead space of the equipment and the

response time of the epithelium. As compared with the value in the normal

subjects (-7.2 ±0.7), the base-line value was significantly lower in the

patients with a CF TR mutation (-10.5 ±1.2, P=0.02) but not in the patients with

no CF TR mutations (-8.1 ±0.5).

Click here to view table in larger version (20k)

Sweat tests showed a stepwise increase in electrolyte concentrations, with

the normal subjects having the lowest concentrations and the patients with a CF

TR mutation the highest concentrations (Figure 2). There was no significant

change in electrolyte concentrations in five patients who were examined twice,

at presentation and again for the study, while receiving antioxidant therapy. A

sweat chloride concentration of at least 60 mmol per liter, which is suggestive

of cystic fibrosis,12 was found in three patients, one with a normal CF TR

genotype and two with a CF TR mutation but normal results on spirometry and

nasal potential-difference tests (Patients 8 and 15 in Table 1). Alcoholism, but

not cigarette smoking, as defined in this study, may have contributed to this

outcome (mean chloride concentration, 51 mmol per liter in eight patients with

alcoholism and 37 mmol per liter in 18 patients without alcoholism, irrespective

of the CF TR genotype; P=0.02).

Figure 2. Sweat Chloride and Sodium Concentrations in 17

Normal Subjects, 13 Patients with Chronic Pancreatitis and No CF TR Mutations,

and 13 Patients with Chronic Pancreatitis and a CF TR Mutation.

The normal subjects were eight men and nine women with a

median age of 36 years (range, 20 to 64), the patients with chronic pancreatitis

and no CF TR mutations were nine men and four women with a median age of 45

(range, 23 to 68), and the patients with chronic pancreatitis and a CF TR

mutation were six men and seven women with a median age of 39 (range, 21 to 79).

The horizontal lines indicate the means.

Click here to view table in larger version (11k)

Male patients with cystic fibrosis frequently have azoospermia,12 as was

found in a patient (Patient 1 in Table 1) who has been described previously in

another context.28 Of the other nine male patients, four are fathers, one had

normal results on semen analysis, and four declined to undergo semen analysis.

CF TR Genotype and the Pancreatic Phenotype

Among patients with cystic fibrosis, mutations have been described that

result in pancreatic insufficiency (e.g., F508), necessitating enzyme

supplementation, or in disease that does not affect pancreatic function to the

same extent (e.g., R117H),29 but no such clinical differences were discernible

in our patients (Table 2). We do not know whether antioxidant supplementation,

which controlled pain sufficiently in all but one patient, who underwent distal

pancreatectomy after referral because a tumor was thought to be present, altered

the natural history of chronic pancreatitis.3

Discussion

Our investigation had three linked objectives: to assess whether, because

certain features of pancreatic involvement overlap in chronic pancreatitis and

cystic fibrosis,2 CF TR mutations are more common than would be expected among

patients with chronic pancreatitis; to determine whether patients with a

mutation had an atypical form of cystic fibrosis12; and to seek clues to the

possible role of CF TR mutations in the development of chronic pancreatitis.3

In a cohort of 134 patients, we found that the frequency of a CF TR

mutation was nearly 2.5 times as high as expected and that the frequency of the

5T allele was twice as high as expected. CF TR mutations were associated with

idiopathic rather than alcohol-related disease, as was the case in preliminary

reports by others,30,31,32 and there was a high rate of mutations among

nonsmokers or those who smoked fewer than 10 cigarettes a day. A diagnosis of

atypical cystic fibrosis was not justified in these patients,12 but a few

patients had a partial pattern of extrapancreatic involvement compatible with

this diagnosis, and a more extensive molecular genetic analysis might have

identified other such patients. However, on the basis of our findings, we

conclude that chronic pancreatitis should be added to the list of conditions in

which a mutant CF TR gene has pathogenetic importance. This list includes

congenital absence of the vas deferens,27 nasal polyposis,33 diffuse

bronchiectasis,34 and bronchopulmonary allergic aspergillosis in adults.35

There is a fundamental difference between our findings and those reported

in patients with congenital absence of the vas deferens.27 Among patients with

congenital absence of the vas deferens, 19 percent had a CF TR mutation in both

copies of the gene without a 5T allele on either chromosome (a genotype that is

calculated to reduce the percentage of normal CFTR mRNA to less than 3 percent

of normal), and 34 percent had a 5T allele with a CF TR mutation on the opposite

chromosome or were 5T homozygotes (genotypes that would result in a reduction of

functional CFTR mRNA to between 8 and 12 percent of normal).23,27 In contrast,

none of our patients with chronic pancreatitis had two CF TR mutations, 11

percent had a CF TR mutation and no 5T allele, and 3 percent had both a CF TR

mutation and a 5T allele. These data suggest that CF TR mutations are a

sufficient explanation for the problem with the development of the vas deferens

in at least 50 percent of affected persons but that the relation between CF TR

mutations and the development of chronic pancreatitis is more subtle.

Ductal obstruction is generally regarded as the initiating event in both

chronic pancreatitis and cystic fibrosis. However, this theory is undermined by

several observations,2,3,13,36,37 as well as by histologic evidence to the

contrary.7,8,9,28 We favor an alternative explanation wherein the acinar cell is

a direct target2,3,38 and the damage is amplified when bicarbonate-producing

epithelium is affected in a manner that reduces the pH within the intra-acinar

space and lumen of ductules.39 The involvement of the CFTR protein in

intracellular-vesicle targeting, movement of macromolecules, and membrane

recycling,37,40 over and above its role in ion transport, is central to this

concept.

The sweat studies in our patients were not meant to be definitive but

rather to document the findings in a newly characterized subgroup with a CF TR

mutation, since increased sweat electrolyte concentrations have been reported in

patients with alcohol-related chronic pancreatitis.41,42 We found that the

electrolyte concentrations were independent of CF TR mutations, although

concentrations were higher in patients with a mutation (Figure 2). It is

impossible to assess the meaning of the lower base-line values for nasal

potential difference in the patients with a CF TR mutation, because several ion

channels contribute to the result.43

In conclusion, our study identifies mutations of the CF TR gene as a risk

factor for chronic pancreatitis. Further studies are needed to explain why

chronic pancreatitis does not develop in the majority of persons with a CF TR

mutation and to examine the relation between a CF TR mutation and a mutation in

the cationic trypsinogen gene.44

Abstracts of this work were presented at a meeting of the British Society

of Gastroenterology, Manchester, United Kingdom, September 18-20, 1996, and the

International Conference on Cystic Fibrosis, Jerusalem, Israel, June 17-21,

1996.

We are indebted to Zeneca Diagnostics for the amplification-refractory

mutation system kits, to Dr. L.P. Hunt for statistical advice, to Dr. K.

Southern for instruction on nasal potential-difference methods, to Mr. D.

Marland for sweat electrolyte analyses, to Ms. S. and Ms. B. Bosch for

respiratory spirometry, to Ms. T. for CFTR screening, to Mrs. S. Postill

for nursing assistance, and to Ms. T. Knott for secretarial help.

Source Information

From the Pancreato-Biliary Unit (N.S., J.P.) and University Department of

Medicine (J.B.), Manchester Royal Infirmary; and the Regional Genetic Service,

Royal Manchester Children's Hospital (M. Schwarz, G.M., A.H., M. Super) - both

in Manchester, United Kingdom.

Address reprint requests to Dr. Braganza at Manchester Royal Infirmary,

Oxford Rd., Manchester M13 9WL, United Kingdom.

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Related Letters:

Correction: Mutations of the Cystic Fibrosis Gene in Patients with Chronic

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Malats N., Real F. X., Sharer N. M., Schwartz M. J.

Extract | Full Text

N Engl J Med 1999; 340:1592-1593, May 20, 1999. Correspondence

Mutations of the Cystic Fibrosis Gene and Pancreatitis

Ren C. L., Sharer N., Schwartz M., Cohn J. A., Silverman L. M., Knowles M.

R.

Extract | Full Text

N Engl J Med 1999; 340:238-239, Jan 21, 1999. Correspondence

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I hope this finds you and yours well

Mark E. Armstrong

casca@...

www.top5plus5.com

PAI NW Rep

ICQ #59196115

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