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It is generally assumed that molecules behave ergodically during chemical reactions, that is, reactivities depend only on the total energy content and not on the initial state of the molecule. While there are a few examples of nonergodic behavior in small (usually electronically excited) species, to date there have been no reports of such behavior in larger covalently bound species composed of several tens of atoms. Here, we demonstrate vibrational mode-selective behavior in a series of palladium catalysts. When we excite solvent-tagged gas-phase Pd catalysts with an infrared laser that is tuned to be resonant with specific molecular vibrations, depending on which vibration we excite, we can select different reaction pathways. We also demonstrate that this behavior can be “turned off” via chemical substitution.

Background and Aim: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. Methods: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN : TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. Results: The addition of 100–300 mg allopurinol daily and thiopurine dose reduction (17–50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11 643 (3 365–27 832) to 221 (55–844) pmol/8 × 108 red blood cells (RBC; P = 0.0005), increased 6-TGN from 162 (125–300) to 332 (135–923) pmol/8 × 108 RBC (P = 0.0005), and reduced the 6-MMPN : 6-TGN ratio from 63 (12–199) to 1 (0.1–4.5) (P = 0.0005). There was a significant reduction in steroid dose requirements at 12 months (P = 0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. Conclusions: In those with a high 6-MMPN : 6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

Background and Aim: The etiology of autoimmune hepatitis (AIH) is unknown, and limited epidemiological data are available. Our aim was to perform a population based epidemiological study of AIH in Canterbury, New Zealand. Methods: To calculate point prevalence, all adult and pediatric outpatient clinics and hospital discharge summaries were searched to identify all cases of AIH in the Canterbury region. Incident cases were recruited prospectively in 2008. Demographic and clinical data were extracted from case notes. Both the original revised AIH criteria and the simplified criteria were applied and cases were included in the study if they had definite or probable AIH. Results: When the original revised criteria were used, 138 cases (123 definite and 14 probable AIH), were identified. Prospective incidence in 2008 was 2.0/100 000 (95% confidence interval [CI] 0.8–3.3/100 000). Point prevalence on 31 December 2008 was 24.5/100 000 (95% CI 20.1–28.9). Age-standardized (World Health Organization standard population) incidence and prevalence were 1.7 and 18.9 per 100 000, respectively. Gender-specific prevalence confirmed a female predominance, while ethnicity-specific prevalence showed higher prevalence in Caucasians. 72% of cases presented after 40 years of age and the peak age of presentation was in the sixth decade of life. Conclusions: This is the first and largest population-based epidemiology study of AIH in a geographically defined region using standardized inclusion criteria. The observed incidence and prevalence rates are among the highest reported. The present study confirms that AIH presents predominantly in older women, with a peak in the sixth decade, contrary to the classical description of the disease.

Azathioprine and its initial metabolite, 6-mercaptopurine (6-MP), are associated with high rates of treatment cessation due to toxicity or inadequate response. Individualization of thiopurine dose based on concentrations of the active 6-thioguanine nucleotide (6-TGN) metabolites can help improve outcomes with this class. Some individuals, however, preferentially metabolize thiopurine drugs to the potentially hepatotoxic 6-methylmercaptopurine nucleotide (6-MMPN) metabolites rather than the 6-TGNs. For these patients, escalation in thiopurine dose is not likely to increase 6-TGN concentrations sufficiently but may lead to a disproportionate increase in exposure to the 6-MMPNs. We present three cases in whom thiopurine dose escalation based on clinical status and low 6-TGN concentrations (100-262 pmol/8 x 10 RBC) resulted in severe hepatotoxicity (liver failure in two cases) associated with unrecognized extremely high 6-MMPN concentrations of 26,000-40,000 pmol/8 x 10 RBC. These cases illustrate a risk with thiopurine dose adjustment based on monitoring of 6-TGN metabolites without also monitoring 6-MMPN.

NOD2 mutations are associated with Crohn's disease (CD) in Caucasian clinic-based cohorts. Data from population-based cohorts are limited. Clinic-based studies may overestimate this association. Genotype-phenotype relationships are yet to be assessed using the Montreal classification. We hypothesized that the NOD2-CD association would be weaker in a population-based cohort, and that the Montreal classification would strengthen genotype-phenotype associations.A population-based case-control study was performed including 91% of all people in Canterbury, New Zealand, with inflammatory bowel disease (IBD); NOD2 genotyping was performed and patients were phenotyped according to the Vienna and Montreal classification systems.The NOD2 genotype was available on 684 CD, 643 ulcerative colitis (UC), 36 indeterminate colitis/IBDU (IBD unclassified) patients, and 201 controls. Control frequencies for the 702W, 908R, and 1007fs alleles were 0.030, 0.012, and 0.010, respectively, compared with 0.074, 0.027, and 0.040 for CD. The 702W (P = 0.001) and 1007fs (P = 0.002) alleles were significantly associated with CD. Younger age of diagnosis (17 years) was associated with 1 (odds ratio (OR) 1.9 [95% confidence intervals 0.98-3.6]) or 2 (OR 6.5 [2.3-18.6]) NOD2 mutations compared with diagnosis40 years. Ileal disease was most strongly associated with NOD2 mutations (1 mutation OR 3.9 [2.4-6.3], 2 mutations OR 6.7 [2.4-18.5]). Penetrating disease was associated with NOD2 mutations using the Montreal but not the Vienna classification.The association between NOD2 mutations and CD was found to be weaker in our population-based cohort than in previous studies that used referral-based cohorts. Application of the Montreal classification led to a strengthening of the NOD2 genotype-phenotype association.

Patients with chronic ulcerative colitis and Crohn’s colitis have an increased risk of colorectal cancer. Because of this, surveillance colonoscopy is practiced. We aimed to describe the practice of surveillance colonoscopy in New Zealand, with comparison among specialties, and with practice internationally. New Zealand colonoscopists (both physicians and surgeons) looking after patients with inflammatory bowel disease were surveyed to evaluate attitudes about surveillance colonoscopy and ways in which colonoscopy results are interpreted. A postal survey assessed the colonoscopist’s understanding of how and why surveillance colonoscopy is undertaken and their interpretation of the results from such evaluations. Of the196 physicians and surgeons surveyed, 180 responded (92 percent). Sixty responses were excluded. Only 24 of 120 respondents (20 percent) correctly defined dysplasia. The median number of biopsies taken at colonoscopy was 17. Eighty of 120 (67 percent) and 77 of 120 (64 percent) doctors underestimate the risk of invasive malignancy if low-grade or high-grade dysplasia, respectively, is identified. The colectomy referral rate for dysplasia-associated lesion or mass was 115/120 (96 percent); that for high-grade dysplasia was 110/120 (92 percent); and that for low-grade dysplasia was 26/120 (22 percent). Thirty of 120 (25 percent) doctors offer patients the option of colectomy after 20 years of colitis. Seventy of 120 (58 percent) doctors sought the opinion of a second pathologist if dysplasia was found. There were differences in responses between specialist groups, with colorectal surgeons most likely to correctly define dysplasia and appreciate the significance of low-grade dysplasia. Many New Zealand colonoscopists have a poor understanding of the definition and importance of dysplasia associated with colitis. Although colectomy referral rates are higher in this study than in similar studies, low-grade dysplasia is often not referred for colectomy. Improved education may improve surveillance practice.

Summary Background : Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype. Aim : To compare the TPMT genotype frequencies in patients with inflammatory bowel disease who have had severe adverse effects to those who tolerate azathioprine or MP (controls). Methods : Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified. Patients with adverse effects, and controls, were invited to provide a peripheral blood sample for analysis of TPMT genotype. The genotype frequencies were then compared between the two groups. Results : Fifty-six patients were identified with adverse effects requiring cessation of therapy, of which 50 were genotyped. Reactions included allergic-type (25%), hepatitis (33%), nausea/vomiting (14%), bone marrow suppression (10%), pancreatitis (6%) and other (12%). Five of 50 patients with reactions had TPMT genotype *1/*3, one had *3/*3, and the rest had the wildtype genotype *1/*1. The patient with genotype *3/*3 had severe pancytopenia requiring hospitalization. Three of 50 controls had the *1/*3 genotype and the rest were *1/*1. Conclusions : The TPMT allele frequency in our population with inflammatory bowel disease is similar to that reported elsewhere. There was a slight trend for more frequent TPMT mutations in the patients with adverse reactions, but this was not statistically significant. Most patients with reactions did not have gene mutations.

BACKGROUND Endoscopic biliary manometry is useful in the assessment of patients with types II and III sphincter of Oddi dysfunction, but it is time consuming and invasive. AIM To investigate the role of 99m Tc-DISIDA scanning, with and without morphine provocation, as a non-invasive investigation in these patients compared with endoscopic biliary manometry. SUBJECTS AND METHODS A total of 34 patients with a clinical diagnosis of type II (n=21) or III (n=13) sphincter of Oddi dysfunction were studied. Biliary scintigraphy with 100 MBq of 99m Tc-DISIDA was carried out with and without morphine provocation (0.04 mg/kg intravenously) and time/activity curves were compared with the results of subsequent endoscopic biliary manometry. RESULTS Eighteen (nine type II, nine type III) of the 34 (53%) patients had sphincter of Oddi basal pressures above the upper limit of normal (40 mm Hg). In the standard DISIDA scan without morphine, no significant differences were observed in time to maximal activity (Tmax) or percentage excretion at 45 or 60 minutes between those with normal and those with abnormal biliary manometry. However, following morphine provocation, median percentage excretion at 60 minutes was 4.9% in those with abnormal manometry and 28.2% in the normal manometry group (p=0.002). Using a cut off value of 15% excretion at 60 minutes, the sensitivity for detecting elevated sphincter of Oddi basal pressure by the morphine augmented DISIDA scan was 83% and specificity was 81%. Also, 14 of the 18 patients with abnormal manometry complained of biliary-type pain after morphine infusion compared with only two of 16 patients in the normal manometry group (p=0.001). CONCLUSIONS 99m Tc-DISIDA with morphine provocation is a useful non-invasive investigation for types II and III sphincter of Oddi dysfunction to detect those with elevated sphincter basal pressures who may respond to endoscopic sphincterotomy.

Genetic predisposition to haemochromatosis may be an important aetiological factor in some cases of Type 2 diabetes. Our aim was therefore to test the hypothesis that the haemochromatosis gene mutations Cys282Tyr and His63Asp are more prevalent in Type 2 diabetic patients compared with the Canterbury, New Zealand general population. We studied 230 consecutive patients referred to the Diabetes Services with age ≥30 years and considered to have Type 2 diabetes. DNA was extracted from whole blood and amplified by polymerase chain reaction prior to restriction fragment length polymorphism analysis. The frequency of the mutations was compared with that observed previously in 1064 subjects from the Canterbury general population by χ2 testing. Iron was measured by a colorimetric method, transferrin by rate nephelometry and ferritin by immunoassay. There were 2/230 (0.8%) Cys282Tyr homozygous subjects in the diabetic group compared with 5/1064 (0.5%) NS in the general population. Although there was a trend to lower incidence of Cys282Tyr heterozygosity in the diabetic group, there was no significant difference for any of the six genotype frequencies between the two groups. Haemochromatosis gene mutations Cys282Tyr and His63Asp are therefore not increased in Type 2 diabetics compared with the general population. Transferrin saturation was a sensitive marker (100%) of genetic haemochromatosis, although ferritin had low specificity (77.8%). Genetic susceptibility to haemochromatosis is not an important aetiological factor for diabetes, and targeted screening of diabetic patients for haemochromatosis is not indicated.

The aim of this study was to describe the natural history of gallbladder polyps. Thirty-eight subjects who had been previously identified as having gallbladder polyps in an epidemiologic study of gallstone prevalence in 627 diabetic subjects and matched controls were followed longitudinally. Follow-up sonograms were obtained on 33 and 22 of the 38 subjects at 2 and 5 years, respectively. Prevalence for gallbladder polyps in this population was 6.7%, with a marked male predominance (odds ratio 2.3). No statistical difference in prevalence was found between diabetic subjects and nondiabetic controls. Ninety percent of the polyps were less than 10 mm in diameter, with no polyp being larger than 12 mm. During the follow-up period no changes suggestive of malignant transformation were observed. In conclusion, we found that gallbladder polyps were relatively common and that few significant changes occurred over a 5 year period. In asymptomatic subjects in whom gallbladder polyps less than 10 mm in diameter are found incidentally, the likelihood of malignant transformation is low.

The aim of this study was to determine whether 12 months of therapy with Simvastatin, an HMG CoA reductase inhibitor, would dissolve gallstones. Twenty-seven subjects entered the study, all had a fasting oral cholecystogram, ultrasound examination, and fasting serum lipids prior to therapy. In addition, 22 subjects had their gallbladder ejection fraction, after CCK, determined by radionucleotide scanning. Eleven subjects had the cholesterol saturation index (CSI) of bile calculated before and at the end of 12 months of therapy. Of the 27 subjects, 26 completed 12 months of treatment with Simvastatin 20 mg daily. There was a significant fall in the total serum cholesterol (27%, P < 0.0001), LDL cholesterol (31%, P < 0.0001), triglyceride (34%, P < 0.0001) but no change in HDL after 12 months of therapy. Simvastatin treatment resulted in a 28% fall in the CSI of bile at the end of therapy (P < 0.01). The concentrations of individual bile acids did not change with therapy, and apart from a slight but significant increase in arachidonate, there were no other significant changes in the fatty acid composition of the biliary phospholipids. After 12 months of Simvastatin therapy there was a small decrease in the gallstone diameter but complete dissolution of gallstones was not achieved in any subjects. In conclusion 12 months of therapy with Simvastatin was effective in lowering the serum lipids and the CSI of bile but was not effective in dissolving gallstones.

Diabetics are known to have an increased prevalence of gallstones. The aim of this study was to investigate whether diabetics have increased gallbladder volumes that would predispose to stasis, nucleation of cholesterol crystals, and gallstone formation. The gallbladder volume of 271 diabetic subjects and 277 controls was determined by ultrasound using the ellipse formula. Gallbladder volume was also determined by the sum of the cylinders method in 143 cases with a strong correlation (r = 0.89) between the two methods. Using analysis of variance, gallbladder volume was influenced by both diabetic type (NIDDM = 33.68 cm3, IDDM = 26.84 cm3, controls = 29.05 cm3; P = 0.018) and the presence of gallstones (gallstones = 32.04 cm3, no gallstones = 27.58 cm3; P = 0.018). The variation in gallbladder volume between NIDDM, IDDM, and control subjects was influenced by the presence of gallstones (P = 0.024, interaction term from ANOVA). Significant differences (P < 0.001) were only found between NIDDM vs IDDM and NIDDM vs control in the nongallstone group (NIDDM = 34.33 cm3, IDDM = 25.08 cm3, control = 25.17 cm3). Males had significantly larger gallbladder volumes than females: 31.98 cm3 vs 27.74 cm3 (P = 0.023). After the inclusion of BMI, HDL cholesterol, triglyceride, and age in a statistical model with gender and diabetic type in those without gallstones, significant differences were still found between NIDDM and IDDM (P = 0.013) and NIDDM and controls (P = 0.005), demonstrating that NIDDM is an independent predictor for increased gallbladder volume.

The treatment of ulcerative colitis requires careful review of the medical and surgical options. The surgical procedure of choice is proctocolectomy with ileal pouch-anal anastomosis. This procedure removes the diseased mucosa, effectively curing the disease whilst maintaining the normal route of defecation and continence. Other surgical options that may be considered in selected patients include proctocolectomy with either a Brooke ileostomy or a Kock pouch, and abdominal colectomy with ileorectal anastomosis. The choice of operation requires consideration of the advantages and disadvantages of a particular procedure and must be tailored to an individual patient's needs and circumstances.

Background: The treatment of H. pylori-associated gastroduodenal disease is increasingly aimed at bacterial eradication which requires follow-up assessment of therapeutic effectiveness and re-infection. A simplified 37 kBq 14C-urea breath test for H. pylori infection has been developed. Methods: The 37 kBq 14C-urea breath test was compared with biopsy urease (CLO) and histological analyses of gastric biopsies obtained from 63 patients undergoing endoscopy. Results: The 30-min breath test correlated closely with biopsy findings, had a sensitivity of 100%, a specificity of 95% and a positive predictive value of 92%. Conclusions: The simplified, low-dose, 14C-urea breath test is a convenient, low-cost, transportable means of facilitating the management of H. pylori-associated diseases.

The diagnosis of graft-versus-host disease following liver transplantation may be delayed because the clinical and pathological features are nonspecific. We report the use of microsatellites to support a diagnosis of GVHD in a patient who developed fever and a skin rash 28 days after liver transplantation. The pattern of microsatellite alleles amplified from the peripheral blood on day 51 posttransplant indicated that recipient and donor DNA were present in approximately equal proportions. Microsatellite typing is a simple and rapid method to identify high levels of circulating donor DNA to support a diagnosis of GVHD following liver transplantation.

Haemochromatosis is now known to be a common genetic disorder, with a carrier rate of about 1 in 10 in populations of Northern European origin. With early diagnosis and treatment, life expectancy is normal, yet it remains underdiagnosed.

Caroli's disease is an uncommon congenital malformation involving the intrahepatic bile ducts. This paper reports two cases presenting with biliary tract infection. Diagnosis was established by non-invasive imaging and cholangiography. The infecting organisms were cultured from bile obtained by percutaneous aspiration and the results were used to direct antimicrobial therapy. The role of antibiotics and other management options in preventing recurrent infection is discussed.

The metabolic fate of the radioactive carbon in the 14C-urea breath test for Helicobacter pylori was investigated in 18 subjects. After ingestion of labelled urea, breath was sampled for 24 h, and urine was collected for 3 days. Subjects were designated high or low expirers on the basis of their breath counts, and this agreed well with H. pylori serologic analyses. When given 185 or 37 kBq of 14C-urea, 51% (SD = 16%, n = 11) of the label was recovered from the breath of high expirers, and 7% (SD = 3%, n = 7) from the breath of low expirers. The mean combined urinary and breath recovery for high expirers was 86% (SD = 7%), and for low expirers it was 97% (SD = 3%). It is concluded that the long-term retention of 14C from ingested 14C-urea is low. The results enable a more accurate estimation to be made of radiation exposure resulting from the 14C-urea breath test.

Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (20), which is indicative of a poor thiopurine response.Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared.The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol.In those with a high 6-MMPN:6-TGN ratio (20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

The etiology of autoimmune hepatitis (AIH) is unknown, and limited epidemiological data are available. Our aim was to perform a population based epidemiological study of AIH in Canterbury, New Zealand.To calculate point prevalence, all adult and pediatric outpatient clinics and hospital discharge summaries were searched to identify all cases of AIH in the Canterbury region. Incident cases were recruited prospectively in 2008. Demographic and clinical data were extracted from case notes. Both the original revised AIH criteria and the simplified criteria were applied and cases were included in the study if they had definite or probable AIH.When the original revised criteria were used, 138 cases (123 definite and 14 probable AIH), were identified. Prospective incidence in 2008 was 2.0/100,000 (95% confidence interval [CI] 0.8-3.3/100,000). Point prevalence on 31 December 2008 was 24.5/100,000 (95% CI 20.1-28.9). Age-standardized (World Health Organization standard population) incidence and prevalence were 1.7 and 18.9 per 100,000, respectively. Gender-specific prevalence confirmed a female predominance, while ethnicity-specific prevalence showed higher prevalence in Caucasians. 72% of cases presented after 40 years of age and the peak age of presentation was in the sixth decade of life.This is the first and largest population-based epidemiology study of AIH in a geographically defined region using standardized inclusion criteria. The observed incidence and prevalence rates are among the highest reported. The present study confirms that AIH presents predominantly in older women, with a peak in the sixth decade, contrary to the classical description of the disease.

Hemochromatosis is a common autosomal recessive disorder of iron metabolism occurring with a prevalence of 0.2–0.5% in Caucasian populations (1)(2)(3)(4)(5)(6). The disease is characterized by the excessive accumulation of dietary iron and a progressive rise in body iron stores, which may lead to serious clinical consequences, including cirrhosis, cardiac failure, diabetes, arthritis, and hepatocellular carcinoma. Treatment involves removal of the iron burden by regular venesection and leads to a normal life expectancy if implemented before the development of cirrhosis (7). Thus early detection and treatment are critically important. Recent identification of a hemochromatosis gene, ( HFE , initially termed HLA-H ) by Feder et al.(8) allows for early genetic diagnosis and greatly simplifies the screening of a family once affected individuals have been identified. The HFE gene encodes a protein similar in structure to MHC class I-type molecules (9) that interacts with the transferrin receptor to regulate iron absorption (10). Two mutations have been detected in the HFE gene. Most individuals with hemochromatosis (80–100%) are homozygous for the missense mutation C282Y. In addition, a small number of compound heterozygotes (heterozygous for both C282Y and H63D) may develop clinical iron overload (11)). Homozygosity for H63D is not clearly associated with hemochromatosis. A high prevalence of asymptomatic carriers of C282Y (13.2%) and H63D (24.3%) …

Thiopurine S-methyl transferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of the thiopurine immunosuppressants. To date, 22 variants have been identified that are predictive of decreased TPMT activity. In contrast, no molecular explanation has been found for the 1-2% of Caucasians who exhibit ultra-high TPMT activity. Here, we report the characterization of polymorphisms within a trinucleotide (GCC) repeat element of the TPMT promoter in two patients with inflammatory bowel disease exhibiting the highest TPMT activity from two testing centres. The first patient was heterozygous for a variant allele carrying seven GCC repeats [(GCC 7 ], whereas the second patient was heterozygous for a variant allele containing five GCC repeats [(GCC)5]. Fifty patients with inflammatory bowel disease with normal TPMT activity were all homozygous for six GCC repeats [(GCC) 6 ]. Of 200 healthy controls, five were found to be heterozygous for the (GCC) 7 variant. Within in vitro reporter gene assays, the mean luciferase activities of the (GCC) 6 , (GCC) 7 , and (GCC) 5 constructs were 8.0 ±0.26, 13.2 ±0.10 and 12.3 ±0.12, respectively. The significant increase in activity observed for (GCC) 5 and (GCC) 7 compared with (GCC) 6 (P-value ≤ 0.001) strongly suggests that alteration in the number of trinucleotide repeats is responsible for the ultra-high TPMT activity observed in these patients.

Background: Inflammatory bowel disease (IBD) has increased exponentially in industrialized nations over the last 50 years. Previous New Zealand studies have shown that IBD is less common than in other countries; however, clinical observations suggested a high incidence and prevalence of IBD in Canterbury, particularly Crohn's disease (CD). Aim: This study aimed to determine the descriptive epidemiology of IBD in Canterbury. Methods: Canterbury IBD patients, recruited using multiple strategies, gave informed consent, permission for clinical record review, completed a questionnaire, and were bled for DNA extraction as part of the Canterbury IBD Project. Cases were confirmed using standard criteria, and completeness of recruitment was validated using capture-recapture methods. Demographic and phenotypic data were extracted from case notes. One thousand four hundred twenty patients (715 CD, 668 ulcerative colitis [UC]) were recruited (>91% of Canterbury IBD patients). Results: In 2004, age-standardized (World Health Organization World Standard Population) IBD, CD, and UC incidence rates were 25.2, 16.5, and 7.6/100,000/year, respectively. The IBD, CD, and UC point prevalences on 1 June, 2005 were 308.3, 155.2, and 145.0/100,000, respectively. CD patients were more likely than UC patients to be female (61.4% vs. 47.1%) and to be younger (median age, 39.9 years vs. 43.7 years). The percent of IBD patients who were white was 97.5%. Conclusion: IBD is at least as common in Canterbury as in other western regions. CD incidence and prevalence are amongst the highest ever reported and are higher than for UC. IBD population characteristics are otherwise similar to other countries. The Canterbury IBD Project will be a valuable tool for future population-based IBD epidemiology and genetics research.

Purpose The thiopurine drugs, azathioprine and 6-mercaptopurine are effective in the treatment of inflammatory bowel disease (IBD). However, their use is limited by serious adverse effects that can lead to cessation of therapy. The incidence of these adverse effects has been reported to be approximately 9% but in Christchurch it was felt that the incidence was higher. Methods We searched our letter database to identify all patients with IBD who had received a thiopurine drug between 1996 and 2002. The case notes were then reviewed to identify those patients who had suffered an adverse effect that required cessation of the drug. Results From a total of 216 patients with IBD taking a thiopurine drug, 56 (25.9%) had an adverse reaction requiring cessation of the drug. Adverse effects included allergic-type (25%), liver test abnormalities (34%), nausea/vomiting (6%), bone marrow suppression (7%), pancreatitis (7%) and other (9%). Males were significantly more likely than females to have an allergic-type reaction (p=0.003). All adverse effects resolved with cessation of the drug, with a median of 7 days to resolution. Of the patients with liver test abnormalities on azathioprine, most were able to tolerate 6-mercaptopurine, however challenge with 6-mercaptopurine was not successful for most other patients. Conclusions In Canterbury, New Zealand, patients with IBD have a high rate of therapy-limiting adverse effects to thiopurine drugs. There is a significant gender bias for allergic-type adverse effects. Mechanisms for both these observations are not clear. Copyright © 2004 John Wiley & Sons, Ltd.

Background and Aims: Although coeliac disease is a common condition, the role of population screening is not clear. The aim of this study was to determine the prevalence and clinical significance of coeliac disease in the adult population of Christchurch, New Zealand. Methods: A total of 1064 adults randomly selected from the 1996 Christchurch electoral rolls were enlisted. The subjects were screened for coeliac disease using the anti-endomysial antibody test (EMA), and all those with positive tests were reviewed and underwent a small bowel biopsy. Results: Twelve of the 1064 persons tested (1.1%) were EMA positive and all had small bowel biopsy histology consistent with coeliac disease. Two of the 12 subjects were previously known to be EMA positive although neither had a small bowel biopsy. One additional subject with known and treated coeliac disease was also enrolled but was EMA negative. Thus, the overall prevalence of coeliac disease was 13 of 1064 subjects (1.2%, or 1 : 82), 10 of whom were newly diagnosed (0.9%, or 1 : 106) and three were previously known or suspected to have coeliac disease (0.3%, or 1 : 355). The prevalence in both sexes was similar. Nine of the 12 EMA-positive coeliac disease subjects identified by the use of screening reported symptoms, of which tiredness and lethargy were the most common. The subjects were of normal stature, although females tended to be lean. None of the subjects were anaemic, but four were iron deficient and four folate deficient. Five of the 12 had sustained bone fractures. Bone mineral density was reduced in males but not in females. Conclusions: The prevalence of coeliac disease in the adult population of Christchurch, New Zealand, is 1.2%. Unrecognized coeliac disease which was detected by population screening was three-fold more common than proven or suspected coeliac disease. Population screening may identify subjects who could benefit from treatment.

Background—Haemochromatosis is associated with mutations in the HFE gene but the significance of these mutations in the general population is unknown.Aims—To determine the frequency ofHFE gene mutations in the general population, their effect on serum iron indexes, and their role in screening for haemochromatosis.Methods—Deoxyribonucleic acid (DNA) from 1064 randomly selected subjects was analysed for the C282Y and H63D mutations in the HFE gene. Serum iron, transferrin saturation, and ferritin were measured and individuals with increased iron indexes were investigated to confirm or exclude a clinical diagnosis of haemochromatosis.Results—Mutations were identified in 409 individuals (38.4%) with heterozygote (carrier) frequencies of 13.2% and 24.3% for the C282Y and H63D mutations respectively. Heterozygosity for either mutation significantly increased serum iron and transferrin saturation but despite a similar trend for ferritin, this was only significant for C282Y homozygotes. Five individuals (0.47%) were homozygous for the C282Y mutation, three of whom had haemochromatosis confirmed by liver biopsy (0.28%). The other two C282Y homozygotes would not have been detected by phenotypic screening alone.Conclusions—HFE mutations are present in 38.4% of the population, affect serum iron indexes, and are important determinants of iron status. The population frequency of genetically defined haemochromatosis (C282Y homozygosity) is approximately one in 200 and is higher than the prevalence of clinically apparent haemochromatosis.

It has recently been suggested that the hepatic iron concentration can be used to predict the response to interferon in patients with chronic hepatitis C. An hepatic iron concentration greater than 1100 microg/g appears to identify a group of patients that are unlikely to respond to alpha-interferon. It is not known whether this relationship can be explained by associated variables such as age, gender or disease severity or whether the hepatic iron concentration itself influences the response to interferon. Furthermore, the hepatic iron concentration is of no value in discriminating responders from non-responders in patients with hepatic iron concentrations less than 1100 microg/g. The possibility of improving response rates to interferon by pretreatment venesection needs to be explored but currently only limited data are available. Venesection results in a significant fall in the serum transaminases but the preliminary results regarding the efficacy of subsequent interferon therapy are unclear. Until the results of prospective controlled trials are available it is concluded that the available evidence does not support venesection before interferon therapy for chronic hepatitis C.

The gene responsible for hereditary haemochromatosis (HH) has recently been identified. One mutation in this gene, termed HFE, has been found in all Australian HH patients. We previously identified a predominant HH ancestral haplotype covering 4.5Mb at 6p21.3, and showed that patients with two copies of this haplotype express a more severe form of the disorder. One key question to now be resolved is why haplotype related variation in phenotypic expression of HH is present if all patients tested have the same HFE mutation. A cos-mid resource covering the 4.5Mb HH ancestral haplotype region was obtained. These cosmids provide the material for the completion of a transcript map of this region, and will assist the identification of candidate modifiers of HFE expression.

We have constructed a yeast artificial chromosome (YAC) contig over the candidate hemochromatosis gene region. This contig comprises 16 YACs from the CEPH, Washington University, and ICI YAC libraries and covers 4.5 Mb at 6p21.3-6p22. The complete contig has been restriction mapped, enabling the precise relationship between the YACs to be determined and the mapping of a total of 12 STSs. Nine of these are highly polymorphic STSs that are closely linked to hemochromatosis; this series includes D6S265 and D6S1260, which comprise the most proximal and distal markers linked to HC. This is the first YAC contig that spans the hemochromatosis candidate region, and it provides valuable resource material for the cloning of this and other genes in the region distal to the MHC class I complex.

D6S265 is a polymorphic dinucleotide repeat, mapped within 70 kb centromeric of HLA-A, on chromosome 6p21.3. While genotyping families for genetic linkage analysis, allele non-amplification resulting in apparent non-Mendelian inheritance was observed at the D6S265 locus in 15 individuals, on chromosomes carrying the HLA-A25 and HLA-A26 antigens. The D6S265 locus was sequenced in a variant individual homozygous for allele non-amplification, and in a non-HLA-A25/-A26 individual, homozygous for D6S265 allele 1. Five base changes were identified in the reverse primer binding region of the variant individual, effectively preventing annealing of the 3' primer to the template.

In October, 2007, a 24-year-old woman was seen in our internal-medicine clinic. She had Rett’s syndrome, an X-linked neurodevelopmental disorder, and was brought up by a professional carer. Once she became ineligible for paediatric community care, she had no longer received regular specialist review. She was brought to us because she was no longer walking, having learnt to do so at 10 years of age; having been aware of other people, and able to signal basic needs, she was communicating only by brief eye contact with her carer. Initially, her deterioration (which had lasted several months) had been thought to refl ect the natural history of Rett’s syndrome. The patient also had longstanding gastrointestinal refl ux, which had been severe enough to stop her eating. Fundoplication, and a percutaneous feeding gastrotomy, had little eff ect, so she was fed by percutaneous jejeunostomy, with a preparation designed as a complete diet. Her body-mass index remained around 16 kg/m2. On examination, the patient was pale, with no observable subcutaneous fat. Blood tests revealed macrocytic anaemia (haemoglobin concentration 77 g/L; mean cell volume 131 fL), and neutropenia (0·1×109 cells per L); the platelet count was normal, as were results of other blood tests, including tests of kidney, liver, and thyroid function, and concentrations of iron, vitamin B12, and folate. A bone marrow aspirate from the posterior iliac crest contained few haemo poietic precursors. Histo pathological analysis showed replacement of haemo poietic and fat cells with amorphous material (fi gure). We concluded that haemopoietic tissue had undergone gelatinous trans formation to ground substance. This change is seen in protein-calorie malnutrition; how ever, the cytopenias were uncharacteristically severe for this diagnosis. At our laboratory, we routinely measure con cen trations of selected proteins: the caerulo plasmin concen tration was only 0·03 g/L (normal range 0·15–0·6 g/L). We wondered whether our patient’s neuro developmental delay might be caused by Wilson’s disease, especially since, unlike 70% of people with Rett’s syndrome, she seemed to have no mutation of the MECP2 gene. Her serum copper concentration was 1·9 μmol/L (normal range 11–26 μmol/L). A random urine sample contained no detectable copper; calculated free copper was 0·05 μmol/L (>4 μmol/L in active Wilson’s disease). A Google search, with the terms “anemia”, “neutropenia”, and “copper”, yielded reports that copper defi ciency causes neutropenia and (usually macrocytic) anaemia, without aff ecting platelet numbers. A sternal bone-marrow aspirate showed normal numbers of cells; however, many erythroid and myeloid progenitors contained vacuoles, and we saw many sideroblasts. All these changes were characteristic of copper defi ciency. We gave the patient a blood transfusion, and zinc-free copper chloride (PharmaLab, Lane Cove, Australia), 2 mg daily, for 5 days. Before the copper chloride became available, we administered granulocyte colony-stimulating factor (300 μg daily, for 5 days). On discharge, 16 days after admission, the patient’s neutrophil count had increased to 6·7×109 cells per L; she was communicating as she had before her deterioration, and could walk a few steps independently. Later, we briefl y repositioned the feeding tube in the duodenum, but recurrence of gastrooesophageal refl ux required us to return it to the jejunum. Our patient needs intra venous copper every 6 weeks to prevent cytopenias, and still has a mild macrocytosis. However, when last seen by us, in October, 2008, she had returned to sheltered employment, and was able to sit on a horse unaided. Causes of copper defi ciency include severe weight loss, gastric surgery, malnutrition, and zinc poisoning. Copper defi ciency causes myeloneuropathy, and can mimic subacute combined degeneration. Less commonly, it causes anaemia and neutropenia, sometimes mis diagnosed as myelodysplastic syndrome. Our patient’s haematological abnormalities were more severe than previously described, presumably due to gelatinous degeneration of bone marrow. Copper is absorbed primarily in the duodenum, where it competes with zinc—but our patient’s nutrition, although containing adequate copper, was delivered to the jejeunum. Unlike most patients with copper-defi ciency myeloneuropathy, our patient regained lost function: we speculate that some of her decline was caused by anaemia.

OBJECT to determine the prevalence of antibodies to hepatitis C virus in selected groups of patients with chronic liver disease. METHODS serum specimens were obtained from 39 patients with chronic liver function abnormalities of uncertain cause (group A), from 15 patients with autoimmune chronic active hepatitis (group B) and from 10 patients with chronic hepatitis B (group C). In an extension of the study, serum was collected from sexual partners of patients found to be HCV seropositive. A second generation ELISA assay (Abbott) was used to analyse the specimens. RESULTS ten patients (26%) in group A were seropositive, one (7%) in group B and three (30%) in group C. Risk factors for infection included blood transfusion in three, intravenous drug use in six (including the only positive patient in group B) and both factors in another patient. Only one of the 10 sexual partners tested was positive but this subject was also an intravenous drug user. CONCLUSIONS hepatitis C virus is a significant cause of chronic liver disease in Christchurch. Important risk factors include blood transfusion and intravenous drug use although sporadic cases occur. Transmission to sexual partners is uncommon. The second generation assay does not appear to give false positive results in autoimmune chronic active hepatitis.