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Biomedical subjects

N Ahmed

Publications and source records attributed to N Ahmed.

At least 37 records · Page 2Linked to original sources
PubMed2005

Rapid diagnosis of Helicobacter pylori infection in dyspeptic patients using salivary secretion: a non-invasive approach.

INTRODUCTION: Current guidelines that recommend Helicobacter pylori eradication treatment without endoscopy in selected patients underscore the importance of non-invasive testing. The accuracy of saliva as a non-invasive specimen was compared with that of invasive tests in pretreatment diagnosis of H. pylori infection. METHODS: One hundred patients undergoing gastroscopy were grouped into 80 symptomatic and 20 asymptomatic subjects and were investigated for the presence of H. pylori in saliva and stomach. Samples tested comprised saliva and gastric biopsies collected from each patient. Exclusion criteria were history of peptic ulcer, bleeding ulcer, cancer or recent use of antibiotics, proton pump inhibitors and non-steroidal anti-inflammatory drugs. Two sets of primers homologous to 534 bp fragment of H. pylori DNA, which have been shown previously to be highly specific and sensitive, were used for the polymerase chain reaction (PCR) amplification. RESULTS: 72 (90 percent) of the symptomatic group and 10 asymptomatic subjects were infected with H. pylori in the stomach as determined by histology and direct PCR amplification of biopsy DNA obtained from each subject. H. pylori DNA was identified in the saliva of 70 (87.5 percent) symptomatic subjects and 12 (60 percent) asymptomatic control subjects. CONCLUSION: High rates of detection using saliva as a specimen indicate that saliva of the infected person could serve as a reliable non-invasive alternative to detect the presence of H. pylori infection in comparison to the currently available standard diagnostic tests.

Adult↗
PubMed2004

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats.

AIMS/HYPOTHESIS: Cardiovascular disease in diabetes is linked to increased risk of atherosclerosis, increased levels of triglyceride-rich lipoproteins and enhanced hepatic lipogenesis. The hepatic hexosamine pathway has been implicated in signalling for de novo lipogenesis by the liver. In this study, we assessed if decrease of flux through the hexosamine pathway induced by high-dose thiamine therapy counters diabetic dyslipidaemia. METHODS: The model of diabetes used was the streptozotocin-induced diabetic rat with maintenance insulin therapy. Normal control and diabetic rats were studied for 24 weeks with and without oral high-dose therapy (7 and 70 mg/kg) with thiamine and benfotiamine. Plasma total cholesterol, HDL cholesterol and triglycerides were determined at 6-week intervals and hepatic metabolites and transketolase activity after death of the rats at 24 weeks. RESULTS: We found that thiamine therapy (70 mg/kg) prevented diabetes-induced increases in plasma cholesterol and triglycerides in diabetic rats but did not reverse the diabetes-induced decrease of HDL. This was achieved by prevention of thiamine depletion and decreased transketolase activity in the liver of diabetic rats. There was a concomitant decrease in hepatic UDP-N-acetylglucosamine and fatty acid synthase activity. Thiamine also normalised food intake of diabetic rats. A lower dose of thiamine (7 mg/kg) and the thiamine monophosphate prodrug benfotiamine (7 and 70 mg/kg) were ineffective. CONCLUSIONS/INTERPRETATION: High-dose thiamine therapy prevented diabetic dyslipidaemia in experimental diabetes probably by suppression of food intake and hexosamine pathway signalling but other factors may also be involved. Benfotiamine was ineffective.

Animals↗
PubMed2004

Proteomic-based identification of haptoglobin-1 precursor as a novel circulating biomarker of ovarian cancer.

Screening for specific biomarkers of early-stage detection of ovarian cancer is a major health priority due to the asymptomatic nature and poor survival characteristic of the disease. We utilised two-dimensional gel electrophoresis (2DE) to identify differentially expressed proteins in the serum of ovarian cancer patients that may be useful as biomarkers of this disease. In this study, 38 ovarian cancer patients at different pathological grades (grade 1 (n=6), grade 2 (n=8) and grade 3 (n=24)) were compared to a control group of eight healthy women. Serum samples were treated with a mixture of Affigel-Blue and protein A (5 : 1) for 1 h to remove high abundance protein (e.g. immunoglobulin and albumin) and were displayed using 11 cm, pH 4-7 isoelectric focusing strips for the first dimension and 10% acrylamide gel electrophoresis for the second dimension. Protein spots were visualised by SYPRO-Ruby staining, imaged by FX-imager and compared and analysed by PDQuest software. A total of 24 serum proteins were differentially expressed in grade 1 (P<0.05), 31 in grade 2 (P<0.05) and 25 in grade 3 (P<0.05) ovarian cancer patients. Six of the protein spots that were significantly upregulated in all groups of ovarian cancer patients were identified by nano-electrospray quadrupole quadrupole time-of-flight mass spectrometry (n-ESIQ(q)TOFMS) and matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOFMS) as isoforms of haptoglobin-1 precursor (HAP1), a liver glycoprotein present in human serum. Further identification of the spots at different pathological grades was confirmed by Western blotting using monoclonal antibody against a haptoglobin epitope contained within HAP1. Immunohistochemical localisation of HAP1-like activity was present in malignant ovarian epithelium and stroma but strong immunostaining was present in blood vessels, areas with myxomatous stroma and vascular spaces. No tissue localisation of HAP1-like immunoreactivity was observed in normal ovarian surface epithelium. These data highlight the need to assess circulating concentration of HAP1 in the serum of ovarian cancer patients and evaluate its potential as a biomarker in the early diagnosis of ovarian cancer.

Biomarkers, Tumor↗
PubMed2004

Supportive care for patients with gastrointestinal cancer.

BACKGROUND: Supportive care has traditionally been given to optimise the comfort of patients and their ability to function, as well as to minimise the side-effects of anti-cancer treatments. The scope of modern comprehensive supportive care however is broadening and covers not only specific palliative treatment but non-tumour specific treatment such as social, psychological and spiritual support. In oncology, best supportive care (BSC) has been used as a comparator arm of randomised controlled trials in chemotherapy. However the BSC arm is usually not well defined and its evaluation is therefore difficult because of the heterogeneity of the definitions. A systematic review was undertaken of the evidence from all RCTs of gastrointestinal cancers (includes gastrointestinal/gastric, colorectal/colon cancer but excludes pancreatic cancer trials) which include a BSC/SC arm. OBJECTIVES: 1. To examine the effectiveness/outcomes of best supportive care interventions versus cancer therapies for gastrointestinal cancer trials;2. To determine whether trials containing best supportive care include a definition of this. SEARCH STRATEGY: Electronic databases, grey literature sources, citation searching and reference checking, handsearches of journals and discussion with experts were used to identify potentially eligible trials from both published and unpublished sources. SELECTION CRITERIA: RCTs comparing BSC/SC versus anticancer therapies in patients with gastrointestinal cancers. DATA COLLECTION AND ANALYSIS: Four RCTs were found and reviewed. Because of the heterogeneity of studies, a meta-analysis was not attempted. Data was extracted from the included papers and the quality of each included study was assessed using the Jadad 1996 and Rinck 1997 methods of assessing the quality of RCTs. MAIN RESULTS: Data from four trials (483 patients) were included. Due to the heterogeneity of studies (in terms of populations studied, the interventions used, the variety of outcomes and assessments used) it was not possible to make direct comparisons between the studies. The primary outcome in all four trials was survival, in spite of patients with advanced/metastatic gastrointestinal cancer having a poor prognosis, and the interventions being primarily palliative. REVIEWERS' CONCLUSIONS: Overall the results show that for most of the trials included in this review, certain forms of chemotherapy plus supportive care improve both survival and quality of life in patients with gastrointestinal cancer (gastric and colorectal cancers) compared to receiving supportive care alone. Trials involving BSC/SC in patients with advanced gastrointestinal cancer require careful evaluation. Oncologists and researchers alike should strive for improvements in trial design and reporting. Future trials should focus on clearer definitions of supportive care. The EORTC definition of supportive care can be used as a guide. BSC/SC trials should use standardised validated outcome measures for symptom control, quality of life, toxicity and other useful palliative measures.

Gastrointestinal Neoplasms↗
PubMed2004

Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a tap-like efflux pump.

BACKGROUND: One mechanism proposed for drug resistance in Mycobacterium tuberculosis (MTB) is by efflux of the drugs by membrane located pumps. We report a novel and definite association between drug resistance and transcription levels of a tap-like pump (Rv1258c) in a multi-drug resistant MTB patient isolate (ICC154) which possesses a unique genotypic signature. MATERIALS AND METHODS: The isolate ICC154 was tested for drug sensitivity. Over-expression of Rv1258c as a function of drug pressure was analyzed by RT-PCR and the strain was typed using fluorescent amplified fragment length polymorhism (FAFLP). RESULT: In the presence of rifampicin and ofloxacin, this isolate shows increased transcription of the gene Rv1258c. Genotypic fingerprinting revealed the presence of unique FAFLP markers. CONCLUSION: A clear association between drug resistance and overexpression of an efflux protein is evident from our studies. The presence of specific markers has implications in rapid identification of MDR clinical isolates and consequent disease management.

Anti-Bacterial Agents↗
PubMed2004

Video-assisted thoracic surgery: state of the art in trauma care.

The majority of chest-injured patients are managed with resuscitation and placement of chest tubes. Further interventions are required for complications or missed injuries. Video-assisted thoracic surgery (VATS) has become standard in elective surgery. Our purpose was to review the use of VATS in trauma. The literature and our experience support the use of VATS for specific indications. These indications are: (1) management of retained haemothorax; (2) management of persistent pneumothorax; (3) evaluation of the diaphragm in penetrating thoraco-abdominal injuries and management; (4) management of infected pleural space collections; and (5) diagnosis and management of on-going bleeding in haemodynamically stable patients. VATS for specific indications in trauma is associated with improved outcomes and decreased length of stay. VATS provides diagnostic and therapeutic benefit and should be included in the trauma surgeon's clinical armamentarium.

Diaphragm↗
PubMed2004

The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3).

Human bone marrow-derived mesenchymal stem cells (MSCs) represent an ideal source for cell therapy for inherited and degenerative diseases, bone and cartilage repair, and as target for gene therapy. The role of the combination of human parathyroid hormone (PTH) and vitamin D(3) in bone formation and mineralization has been established in several osteoblast cell culture studies. The aim of the present study was to evaluate the role of this hormonal combination alone and in the presence of bone morphogenetic protein-4 (BMP-4) or-6 (BMP-6) in inducing osteogenic differentiation of human MSC. Human MSC derived from adult normal bone marrow that are positive for CD29, CD44, CD105, and CD166 and negative for CD14, CD34, and CD45, were treated with the PTH and 1,25-dihydroxyvitamin D(3) in the presence and absence of recombinant human BMP-4 or BMP6. PTH and vitamin D(3) induced high levels of expression of two key markers of bone formation: osteocalcin and alkaline phosphatase by MSCs. BMP-6 but not BMP-4 increased osteocalcin expression induced by PTH and vitamin D(3). Both BMPs enhanced calcium formation in MSC cultures and this response was potentiated by PTH and vitamin D(3). The present results revealed a novel potent effect of PTH and vitamin D(3) plus BMPs in inducing bone development by human MSCs. These results may facilitate therapeutic utility of MSCs for bone disease and help clarify mechanisms involved in stem cell-mediated bone development.

Adult↗
PubMed2004

Systematic review of the problems and issues of accessing specialist palliative care by patients, carers and health and social care professionals.

OBJECTIVES: To determine the problems and issues of accessing specialist palliative care by patients, informal carers and health and social care professionals involved in their care in primary and secondary care settings. DATA SOURCES: Eleven electronic databases (medical, health-related and social science) were searched from the beginning of 1997 to October 2003. Palliative Medicine (January 1997-October 2003) was also hand-searched. STUDY SELECTION: Systematic search for studies, reports and policy papers written in English. DATA EXTRACTION: Included papers were data-extracted and the quality of each included study was assessed using 10 questions on a 40-point scale. RESULTS: The search resulted in 9921 hits. Two hundred and seven papers were directly concerned with symptoms or issues of access, referral or barriers and obstacles to receiving palliative care. Only 40 (19%) papers met the inclusion criteria. Several barriers to access and referral to palliative care were identified including lack of knowledge and education amongst health and social care professionals, and a lack of standardized referral criteria. Some groups of people failed to receive timely referrals e.g., those from minority ethnic communities, older people and patients with nonmalignant conditions as well as people that are socially excluded e.g., homeless people. CONCLUSIONS: There is a need to improve education and knowledge about specialist palliative care and hospice care amongst health and social care professionals, patients and carers. Standardized referral criteria need to be developed. Further work is also needed to assess the needs of those not currently accessing palliative care services.

Aged↗
PubMed2004

Sensory hypoinnervation in club foot.

We have compared the density of nerve fibres in the synovium in club foot with that of specimens obtained from the synovium of the hip at operations for developmental dysplasia. The study focused on the sensory neuropeptides substance P; calcitonin gene-related peptide; protein gene product 9.5, a general marker for mature peripheral nerve fibres; and growth associated protein 43, a neuronal marker for new or regenerating nerve fibres. In order to establish whether there might be any inherent difference we analysed the density of calcitonin gene-related peptide-positive nerve fibres in the hip and ankle joints in young rats. Semi-quantitative analysis showed a significant reduction in the number of sensory and mature nerve fibres in the synovium in club foot compared with the control hips. Calcitonin gene-related peptide (CGRP) positive fibres were reduced by 28%, substance P-positive fibres by 36% and protein gene product 9.5-positive fibres by 52% in club foot. The growth associated protein 43-positive fibres also seemed to be less in six samples of club foot. No difference in the density of CGRP-positive nerve fibres was observed in the synovium between ankle and hip joints in rats. The lack of sensory input may be responsible for the fibrosis and soft-tissue contractures associated with idiopathic club foot.

Animals↗
PubMed2004

Mammographic criteria for determining the diagnostic value of microcalcifications in the detection of early breast cancer.

OBJECTIVE: To evaluate the importance of microcalcifications in the detection of breast carcinoma in conventional mammography. METHODS: This prospective study was carried out at Aga Khan University Hospital (AKUH). Mammograms of 68 patients with microcalcifications were evaluated. Craniocaudal and oblique views of both breasts were acquired on routine basis with cone compression and magnified views when required. RESULTS: Among 68 patients with microcalcifications, 61 (89%) had clustered microcalcifications while 7 patients (10.29%) had scattered microcalcifications. Microcalcifications can occur in benign and malignant diseases. While evaluating clustered microcalcifications, few criteria have been established to determine malignant clustered microcalcifications, these include specific and nonspecific criteria. Among specific and statistically significant criteria for malignant microcalcifications, which were identified in this study, were irregularity of size, irregularity of density, linear or branched shape and Le Gal's type V distribution. In a cluster total number of >30 microcalcifications and at least 10 microcalcifications/cm2 of a cluster are also important in diagnosing a malignant cluster, but are included in nonspecific criteria because they can be present in benign diseases also. Scattered bilateral microcalcifications are usually present in benign breast diseases, but in this study, two patients with breast cancer had profuse bilateral scattered microcalcifications. CONCLUSION: This study shows that specific and statistically significant criteria for malignant microcalcifications, are irregularity of size, irregularity of density, linear or branched shape and Le Gal's type V distribution. Scattered bilateral microcalcifications are usually present in benign breast diseases, but irregular shape and development of new calcifications among diffusely scattered bilateral calcifications, on follow up study, should also raise suspicion for being malignant.

Adult↗
PubMed2003

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells.

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.

Colonic Neoplasms↗
PubMed2003

Impact study of the introduction of low-dose epidural (bupivacaine 0.1%/fentanyl 2 microg . mL(-1)) compared with bupivacaine 0.25% for labour analgesia.

We conducted a retrospective analysis of the obstetric effects of introducing a low-dose epidural regimen for epidural analgesia in labour. Before this, all women in our unit requesting epidural analgesia for labour received intermittent boluses (10 mL) of 0.25% bupivacaine. After the introduction of the low-dose service in March 2000, intermittent boluses (10 mL) of 0.1% bupivacaine with fentanyl 2 microg . mL(-1) were given. The records of 300 women were examined, 150 who had received the standard regimen before the introduction of the new service and 150 women afterwards. The groups were compared for outcome of labour, quality of analgesia and any adverse events related to the epidural analgesia. There was a significant reduction in the low-dose group in the number of women requiring instrumental delivery (41% vs. 29%, P = 0.04). The need for indwelling bladder catheters was also reduced in the patients receiving the low-dose regimen (21.3% vs. 4.7%, P < 0.001). Duration of analgesia was longer in patients receiving bupivacaine 0.25% (mean minimum time between boluses 42.25 +/- 33.8 vs. 24.37 +/- 19.8 min, P < 0.001). The need for further anaesthetic intervention was higher with the low-dose regimen (24% vs. 34%, P = 0.037). Maternal satisfaction was high in both groups (95 and 97%, respectively). We conclude that the introduction of a low-dose regimen of epidural analgesia for labour reduces the incidence of instrumental deliveries. It also decreases the incidence of bladder catheterisation during labour, but the need for anaesthetic intervention may be greater.

Journal Article↗
PubMed2003

Removal of advanced glycation end products in clinical renal failure by peritoneal dialysis and haemodialysis.

AGEs (advanced glycation end products) accumulate markedly in the plasma of human subjects with renal failure. We investigated the efficiency of removal of AGEs from the circulation by PD (peritoneal dialysis) and HD (haemodialysis) therapy. Free AGEs were measured by LC-MS/MS in blood plasma before dialysis, in dialysis fluid effusate after a 2-12 h dwell time in the peritoneal cavity of PD subjects, and in the HD dialysate before and after HD therapy. In clinical uraemia, the concentrations of free AGEs in blood plasma were increased up to 50-fold. For example, levels of MG-H1 (methylglyoxal-derived hydroimidazolone) were: normal controls, 110+/-46 nM; PD subjects, 1876+/-676 ( P <0.01); HD subjects, 5496+/-1138 nM ( P <0.001). In PD subjects, the AGE concentration in the effusate increased with increasing dwell time, reaching a maximum at a concentration higher than that in plasma for some AGEs at 4-12 h. This may reflect AGE formation in the peritoneal cavity. In HD, AGE concentrations in HD fluid were decreased markedly from the start to the end of a dialysis session, except that levels of the methylglyoxal-derived AGEs N (epsilon)-(1-carboxyethyl)lysine and MG-H1, and of pentosidine, remained 5-fold higher than control levels. Inadequate clearance of free AGEs may be linked to the increased risk of cardiovascular disease in patients with renal failure.

Glycation End Products, Advanced↗
PubMed2003

Quantitative screening of protein biomarkers of early glycation, advanced glycation, oxidation and nitrosation in cellular and extracellular proteins by tandem mass spectrometry multiple reaction monitoring.

Glycation of proteins forms fructosamines and AGEs (advanced glycation end products). Oxidative and nitrosative stress leads to the formation of oxidative and nitrosative modifications. The modified amino acid residues formed in these processes are biomarkers of protein damage: some are risk markers and some may be risk factors for disease development. We developed a method for the concurrent quantitative measurement of 16 biomarkers indicative of protein glycation, oxidation and nitrosation damage using LC-MS/MS (LC with tandem MS detection). Underivatized analytes were detected free in physiological fluids and in enzymatic hydrolysates of cellular and extracellular proteins. Hydroimidazolones were the most important glycation biomarkers, and methionine sulphoxide was the most important oxidative biomarker quantitatively; 3-nitrotyrosine was the biomarker of nitrosation. Quantitative screening showed high levels of AGEs in cellular protein and moderate levels in protein of blood plasma. Levels of 3-nitrotyrosine were typically 100-fold lower than this. The major glycation adducts in blood plasma had high renal clearances in normal healthy human subjects, whereas methionine sulphoxide and 3-nitrotyrosine had low renal clearances due to further metabolism. Physiological AGEs in blood plasma were eliminated from the circulation in the kidney and not in the liver. LC-MS/MS peptide mapping was also used to locate the protein biomarkers. These studies reveal that advanced glycation is a significant modification of cellular and extracellular protein. The enzymatic defences against glycation, antioxidants and proteasomal protein degradation inside cells are probable factors regulating biomarker levels of cellular protein.

Biomarkers↗
PubMed2003

Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats.

The accumulation of AGEs (advanced glycation end products) in diabetes mellitus has been implicated in the biochemical dysfunction associated with the chronic development of microvascular complications of diabetes--nephropathy, retinopathy and peripheral neuropathy. We investigated the concentrations of fructosyl-lysine and AGE residues in protein extracts of renal glomeruli, retina, peripheral nerve and plasma protein of streptozotocin-induced diabetic rats and normal healthy controls. Glycation adducts were determined by LC with tandem MS detection. In diabetic rats, the fructosyl-lysine concentration was increased markedly in glomeruli, retina, sciatic nerve and plasma protein. The concentrations of N (epsilon)-carboxymethyl-lysine and N (epsilon)-carboxyethyl-lysine were increased in glomeruli, sciatic nerve and plasma protein, and N(epsilon)-carboxymethyl-lysine also in the retina. Hydroimidazolone AGEs derived from glyoxal, methylglyoxal and 3-deoxylglucosone were major AGEs quantitatively. They were increased in the retina, nerve, glomeruli and plasma protein. AGE accumulation in renal glomeruli, retina, peripheral nerve and plasma proteins is consistent with a role for AGEs in the development of nephropathy, retinopathy and peripheral neuropathy in diabetes. High-dose therapy with thiamine and Benfotiamine suppressed the accumulation of AGEs, and is a novel approach to preventing the development of diabetic complications.

Animals↗
PubMed2003

Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas.

BACKGROUND AND AIMS: We tested the hypothesis that the actual or predicted consequences of mutations in the cystic fibrosis transmembrane regulator gene correlate with the pancreatic phenotype and with measures of quantitative exocrine pancreatic function. METHODS: We assessed 742 patients with cystic fibrosis for whom genotype and clinical data were available. At diagnosis, 610 were pancreatic insufficient, 110 were pancreatic sufficient, and 22 pancreatic sufficient patients progressed to pancreatic insufficiency after diagnosis. RESULTS: We identified mutations on both alleles in 633 patients (85.3%), on one allele in 95 (12.8%), and on neither allele in 14 (1.9%). Seventy six different mutations were identified. The most common mutation was DeltaF508 (71.3%) followed by G551D (2.9%), G542X (2.3%), 621+1G-->T (1.2%), and W1282X (1.2%). Patients were categorized into five classes according to the predicted functional consequences of each mutation. Over 95% of patients with severe class I, II, and III mutations were pancreatic insufficient or progressed to pancreatic insufficiency. In contrast, patients with mild class IV and V mutations were consistently pancreatic sufficient. In all but four cases each genotype correlated exclusively with the pancreatic phenotype. Quantitative data of acinar and ductular secretion were available in 93 patients. Patients with mutations belonging to classes I, II, and III had greatly reduced acinar and ductular function compared with those with class IV or V mutations. CONCLUSION: The predicted or known functional consequences of specific mutant alleles correlate with the severity of pancreatic disease in cystic fibrosis.

Child↗