Cholecystokinin peptides and receptor binding in Alzheimer's disease

Summary Cholecystokinin (CCK) is a peptide that can be found in the cerebral cortex in high concentrations and is involved in learning and memory as well as neurodegenerative processes. Cortical brain samples from 9 patients with Alzheimer's disease and 9 matched control cases were studied with respect to the concentrations of various molecular forms of CCK and the CCK receptor binding characteristics. No differences were found between patients and controls in any of these measures. Significant correlations were found between the concentrations of CCK-8 sulphated and the three nonsulphated CCK peptides measured. In addition, the concentrations of CCK-4 and CCK-5 showed a highly significant and positive correlation.     

Risk of haematopoietic cancer in patients with inflammatory bowel disease

BACKGROUND AND AIMS: Several chronic inflammatory conditions are associated with an increased risk of lymphoma. Whether this applies to inflammatory bowel disease (IBD) is still unclear but of paramount interest, particularly in the safety evaluation of newer immunosuppressive drugs. Reports also indicate a possible increase in the risk of leukaemia in IBD. We therefore assessed the risk of haematopoietic cancers in a large cohort of patients with IBD.Subjects and METHODS: We performed a population based cohort study using prospectively recorded data, including 47 679 Swedish patients with Crohn's disease (CD) or ulcerative colitis (UC) assembled from regional cohorts of IBD from 1955 to 1990 (n = 8028) and from the Inpatient Register of 1964-2000 (n = 45 060), with follow up until 2001. Relative risks were expressed as standardised incidence ratios (SIR). RESULTS: Overall, we observed 264 haematopoietic cancers during follow up, which corresponded to a borderline significant 20% increased risk in both UC and CD. In UC, lymphomas occurred as expected (SIR 1.0, n = 87) but myeloid leukaemia occurred significantly more often than expected (SIR 1.8, n = 32). In CD, there was a borderline significant increased lymphoma risk (SIR 1.3, n = 65), essentially confined to the first years of follow up. Proxy markers of disease activity had little impact on lymphoma risk. CONCLUSION: On average, patients with IBD have a marginally increased risk of haematopoietic cancer. In UC, this is accounted for by an excess of myeloid leukaemia. In CD, a modest short term increase in the risk of lymphoma of unknown significance cannot be excluded but any long term risk increase seems unlikely.     

Increased risk of cancer in ulcerative colitis: a population-based cohort study

OBJECTIVE: There is an increased risk of colorectal cancer among patients with ulcerative colitis (UC). However, the overall and site specific cancer risks in these patients have been investigated to a limited extent. To study the association between UC and cancer, a population-based study of 1547 patients with UC in Stockholm diagnosed between 1955 and 1984 was carried out. METHODS: The patients were followed in both the National Cancer Register and the National Cause of Death Register until 1989. For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the UC disease cohort. RESULTS: A total of 121 malignancies occurred among 97 individuals as compared with 89.8 expected (standardized morbidity ratio [SMR] = 1.4; 95% confidence interval (CI), 1.1-1.6). Overall, an excess number of colorectal cancers (SMR, 4.1; 95% CI, 2.7-5.8), and hepatobiliary cancers in men (SMR = 6.0; 95% CI, 2.8-11.1) associated with primary sclerosing cholangitis, was observed. The risk of pulmonary cancer was decreased (SMR = 0.3; 95% CI, 0.1-0.9). In all, 91 extracolonic malignancies were observed, compared with the 82.3 expected (SMR = 1.11; 95% CI, 0.9-1.3). CONCLUSIONS: In UC patients, the overall cancer incidence is increased mainly because of an increased incidence of colorectal and hepatobiliary cancer. This increase is partly counterbalanced by a decreased risk of pulmonary cancer compared with that in the general population.     

Family history as a risk factor for colorectal cancer in inflammatory bowel disease

BACKGROUND & AIMS: Familial colorectal cancer (CRC) is a risk factor for CRC in healthy individuals and, as indicated by case-control studies, possibly in ulcerative colitis. Little is known about the cancer risk in familial inflammatory bowel disease (IBD). We assessed the significance of familial CRC, or IBD, on the risk for CRC in patients with IBD. METHODS: Population-based cohort study of 19,876 individuals with ulcerative colitis or Crohn's disease born between 1941 and 1995. Registry-based follow-up and assessment of familial CRC, and IBD. Risk of CRC assessed as incidence proportion ("absolute risk," IP) and relative risk (RR). RESULTS: Familial CRC was associated with a more than 2-fold risk of CRC (adjusted RR = 2.5, 95% confidence interval 1.4-4.4) and an increase in the IP of CRC at 54 years of age from 3.8% to 6.9%. Patients with a first-degree relative diagnosed with CRC before 50 years of age had a higher RR (9.2, 95% confidence interval 3.7-23) and the highest IP (29%). No association with familial IBD was observed. CONCLUSIONS: Information on family history of CRC may be a simple way to identify individuals with IBD at elevated risk of developing CRC.     

Glucocorticoid receptor mRNA in patients with ulcerative colitis: a study of responders and nonresponders to glucocorticosteroid therapy

BACKGROUND AND AIMS: Up to 30% of patients with severe-to-moderate attacks of ulcerative colitis (UC) respond poorly to glucocorticosteroid (GCS) treatment. The reason for this unresponsiveness is unknown. AIM: Our aim was to evaluate possible differences in glucocorticoid receptor (GR) density in peripheral leukocytes and effects of low-dose GCS treatment on GR density and on the hypothalamic-pituitary-adrenal axis in UC patients who had received high-dose GCS treatment due to a moderate or severe attack. Eleven UC patients in remission who were responders (Rs) to previous GCS treatment were compared with 10 patients who failed GCS therapy and had a colectomy (nonresponders. NRs). Ten healthy individuals served as controls. METHODS: Quantitation of GR mRNA by a solution hybridization assay in peripheral leukocytes and a low-dose adrenocorticotropin hormone stimulation test was performed before and after low-dose dexamethasone (DEX) treatment for 14 days. The glucocorticoid-responsive gene for metallothionein IIa (MTIIa) was also analyzed by a solution hybridization assay in peripheral leukocytes. RESULTS: Overall, basal GR mRNA levels were higher in patients than in controls (p < 0.0001). There were no significant differences between NRs and Rs. None of the groups down-regulated their GR mRNA levels in response to DEX treatment. Basal and stimulated cortisol levels decreased significantly only among NRs after DEX (p = 0.012 and 0.0093). MTIIa levels were lower in NRs as compared with Rs, both in mononuclear (p = 0.0059) and in polynuclear leukocytes (p = 0.030). CONCLUSION: Patients with UC in remission exhibit higher levels of GR mRNA in peripheral leukocytes. We speculate that this may be secondary to an underlying up-regulation of proinflammatory factors also present in patients in clinical remission. Differences in GR mRNA levels per se thus may not be important for the ability of patients with UC to respond to GCS treatment. The hypothalamic pituitary adrenal axis was suppressed by low-dose DEX treatment only in NRs, possibly indicating that steroid-resistance is not a generalized phenomenon. Lower levels of MTIIa in NRs may indicate a diminished efficiency of GR regulation in steroid-refractory patients.     

Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system.

Gamma-Trace was purified in large amounts from urine and used for the production of a specific rabbit antiserum. An enzyme immunoassay for quantitation of gamma-trace was developed using the pure protein as a primary standard. Its sensitivity was approximately 30 microgram/l. An enzyme amplified single radial immunodiffusion was developed as well. Its sensitivity was approximately 0.3 mg/l. These assays allowed quantitation of gamma-trace in normal human biological fluids. The following results were obtained (mean +/- SD): cerebrospinal fluid: 5.8 +/- 2.2 mg/l, plasma: 1.1 +/- 0.42 mg/l, saliva: 1.8 +/- 0.88 mg/l and urine: 0.095 +/- 0.057 mg/l. Plasma samples from patients with advanced renal failure revealed gamma-trace values up to 13 times the normal mean plasma value. The results indicate a production of gamma-trace in the central nervous system and that the protein is primarily catabolized by the kidney.     

Antimyosin scintigraphy in patients with acquired and hereditary muscular disorders

Scintigraphy with indium-111 labelled antimyosin has an established role in the evaluation of cardiac muscle damage. This antibody has been shown to cross-react with myosin in skeletal muscle. We therefore studied the usefulness of this method for the detection of skeletal muscle lesions in rhabdomyolysis, myositis and hereditary muscular dystrophies. All nine patients with rhabdomyolysis had focal uptake of antimyosin antibody which correlated with the clinical findings of soft tissue damage. However, a number of symptomless lesions were also detected by immunoscintigraphy. In rhabdomyolysis the target to non-target uptake ratios varied from 1.3 to 7.6. Diffuse uptake of antibody in skeletal muscle was observed in all three patients with polymyositis-dermatomyositis and in 12 out of 13 patients with muscular dystrophies. In myositis the intensity of antibody accumulation correlated reasonably well with the magnitude of oedema detected by magnetic resonance imaging (MRI). Most patients with Becker type or non-X-chromosomal muscular dystrophies showed slight or moderate uptake of antibody, mainly in the lower extremities. In these patients more antibody accumulated in the calves than in the thighs, whereas the findings on MRI were more prominent in the thighs than in the calves, presumably because of the better preserved muscle bulk in the calves. We conclude that antimyosin scintigraphy can be used for the detection of muscle lesions not only in acquired muscle diseases but also in hereditary muscular disorders, and that immunoscintigraphy provides information on muscle disease activity not obtainable with MRI.