Role of insulin-like growth factor-1 in colon cancerogenesis: a case-control study

BACKGROUND: Our aim was to establish whether individuals who developed colon cancer have elevated blood levels of insulin-like growth factor-1 (IGF-1). METHODS: This was a case/control study in which 52 patients with colon cancer and a corresponding control group were investigated. Data on age, weight, height, and sex of subjects were recorded and levels of IGF-1 and growth hormone, as well as insulin and C-peptide levels, were measured in the morning before eating, 90 min after breakfast and again 90 min after lunch. RESULTS: We found significantly higher levels of IGF-1 in blood of colon cancer patients compared to the control group. No differences in the levels of growth hormone, insulin and C-peptide in blood were found between colon cancer patients and the control group. It was found that the increase of IGF-1 level was followed by a 3.15-fold increased risk for developing colon cancer. There were no differences in the levels of IGF-1 in blood in all three measurements in the group of colon cancer patients, whereas differences were found in the control group. We found differences in the levels of insulin and C-peptide in blood in all three measurements in both groups of patients. No differences were found in the levels of growth hormone in blood in all three measurements in both groups of patients. CONCLUSIONS: The results of this study suggest a positive correlation between the increased levels of IGF-1 and colon cancer and are thus consistent with the hypothesis that the level of IGF-1 plays an important role in the development of colon cancer.     

Dipeptidyl peptidase 8/9-like activity in human leukocytes

The proline-specific dipeptidyl peptidases (DPPs) are emerging as a protease family with important roles in the regulation of signaling by peptide hormones. Inhibitors of DPPs have an intriguing, therapeutic potential, with clinical efficacy seen in patients with diabetes. Until now, only recombinant forms of DPP8 and DPP9 have been characterized. Their enzymatic activities have not been demonstrated in or purified from any natural source. Using several selective DPP inhibitors, we show that DPP activity, attributable to DPP8/9 is present in human PBMC. All leukocyte types tested (lymphocytes, monocytes, Jurkat, and U937 cells) were shown to contain similar DPP8/9-specific activities, and DPPII- and DPPIV-specific activities varied considerably. The results were confirmed by DPPIV/CD26 immunocapture experiments. Subcellular fractionation localized the preponderance of DPP8/9 activity to the cytosol and DPPIV in the membrane fractions. Using Jurkat cell cytosol as a source, a 30-fold, enriched DPP preparation was obtained, which had enzymatic characteristics closely related to the ones of DPP8 and/or -9, including inhibition by allo-Ile-isoindoline and affinity for immobilized Lys-isoindoline.     

Heritability of levels of autoantibodies to thyroid antigens using the method of plotting regression of offspring on midparent (ROMP)

Only a few methods can be applied in a simple manner to estimate the genetic control of autoimmunity in humans. Here we examined the heritability of autoantibodies to two thyroid antigens; thyroglobulin (Tg) and thyroperoxidase (TPO, formerly known as thyroid microsomal antigen), using methods of regression of offspring on mid-parental values (ROMP). With the data sets available, affected and unaffected siblings were compared by this rapid screening method using results determined by hemagglutination (HA). The presence of both types of autoantibodies showed positive heritability in patients with Graves' thyrotoxicosis (TT), but it was not observed in chronic lymphocytic or Hashimoto's thyroiditis (CLT) patients. Since these assays have been extensively used over the years by most diagnostic and research laboratories, they should provide some insight as to which quantifiable parameters may be usefully accumulated to help select groups of patients and their families for further genetic study. ROMP may also be useful to determine the sequential appearance of different types of antibody in predicting disease onset in other family members, and in distinguishing maternal and paternal effects on imprinting. The method may be extended to study epitope spreading and other measures of disease progression.     

A familial inverted duplication 2q33-q34 identified and delineated by multiple cytogenetic techniques

We describe a unique family with two children having a delay in psychomotor development. In both children we identified an interstitial duplication dup(2)(q34q33) using multiple, complementary molecular cytogenetic techniques. Comparative genomic hybridisation (CGH) and array-CGH were used to determine the size and the location of the duplicated region, the orientation of the duplicated region was identified with fluorescence in situ hybridisation (FISH). Both parents demonstrated a normal karyotype and normal CGH and array-CGH-profiles. However, FISH on peripheral blood cells from the mother showed the inv dup(2) in 9% of metaphases and 19% of interphase nuclei. To our knowledge this is the first report of a mosaic carrier of duplication in the long arm of chromosome 2. The finding of chromosomal mosaicism of at least 19% in the mother increases the recurrence risk. The exact characterisation of the inv dup(2) with FISH probes enabled us to offer a reliable prenatal FISH test. Comparison of the clinical features of the two children with those of previously described cases supports the hypothesis that the characteristic facial phenotype is linked to the distal part of the 2q33-q37 region. This report illustrates that in case of two sibs with an identical structural chromosomal abnormality the possibility of parental chromosomal mosaicism must be thoroughly investigated.     

Is Sanfilippo type B in your mind when you see adults with mental retardation and behavioral problems?

Sanfilippo type B is an autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by deficiency of N-acetyl-alpha-D-glucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulfate. It is characterized by neurologic degeneration, behavioral problems, and mental decline. Somatic features are relatively mild and patients with this disorder can reach late adulthood. It is the most common subtype of MPS in the Netherlands and probably underdiagnosed in adult persons with mental retardation (MR). In order to increase knowledge on the adult phenotype and natural history in Sanfilippo type B, we present the clinical data of 20 patients with this disorder. Sixteen of them were followed for one to three decades. Six died between 28 and 69 years of age, mainly from pneumonia and cachexia; the surviving patients were 18-63 years old. Apart from the youngest, they had lost mobility at 36-68 years. Most had developed physical problems, in particular in the 4th-6th decade of life: cardiac disease (cardiomyopathy, atrial fibrillations), arthritis, skin blistering, swallowing difficulties requiring feeding by a gastrostomy tube, and seizures. The course of the disease was dominated in most of them by challenging behavioral problems with restlessness, extreme screaming and hitting, difficult to prevent or to treat pharmaceutically. Even in absence of knowledge of the history of an elderly patient with MR, the presence of behavioral problems should prompt metabolic investigation for MPS.     

High prevalence of the CD14-159CC genotype in patients infected with severe acute respiratory syndrome-associated coronavirus

To investigate whether genetic factors of innate immunity might influence susceptibility and/or progression in individuals infected with SARS, we evaluated the CD14 gene polymorphism in 198 Hong Kong blood donors and 152 Hong Kong severe acute respiratory syndrome (SARS) patients who were previously genotyped for FcγRIIA polymorphisms. The prevalence of the CD14-159CC polymorphism was significantly higher in the patients with severe SARS than in the those with mild SARS or controls (31% versus 15% [mild SARS] or 20% [controls]; mild SARS: P = 0.029; odds ratio, 2.74; 95% confidence interval, 1.15 to 6.57; controls, P = 0.04; odds ratio, 2.41; 95% confidence interval, 1.05 to 5.54), and both CD14-159CC and FcγRIIA-RR131 are risk genotypes for severe SARS-CoV infection.     

The timing of sulfadiazine therapy impacts the reactivation of latent Toxoplasma infection in IRF-8−/− mice

The process of reactivation of latent infection with Toxoplasma gondii in immunosuppressed hosts is yet not fully understood. In the past, a number of murine models of reactivation in immunocompromised mice have been described using sulfadiazine to establish latent infection before withdrawal and subsequent reactivation. We studied the process of reactivation in brains of mice with a targeted mutation in the interferon-regulatory factor (IRF)-8 gene after withdrawal of sulfadiazine therapy. IRF-8^−/− mice were orally infected with five cysts of the ME 49 strain of T. gondii. To allow establishment of latent infection with cyst formation, mice were treated with sulfadiazine starting either 3, 5, 6, or 7 days postinfection. Sulfadiazine was withdrawn after 14–21 days to allow reactivation. We observed that timing of sulfadiazine therapy had a marked impact on the course of infection and reactivation. Mice treated late after infection (days 5–7) showed increased mortality and decreased time to death compared to mice treated early after infection (group A). In the blood of mice with late (days 5–7) but not early (day 3) initiation of treatment, T. gondii-specific deoxyribonucleic acid was detected by polymerase chain reaction. Using double staining with stage-specific antibodies, tachyzoites were detectable in brains of mice with late initiation of sulfadiazine treatment but rarely within cysts thus indicating continued invasion of parasites across the blood–brain barrier. Intracerebral cyst rupture or bradyzoite–tachyzoite conversion was not detectable in IRF-8^−/− mice when sulfadiazine therapy was initiated late after infection. These results indicate that continued invasion of tachyzoites rather than reactivation of latent cerebral infection impacts the course of infection in this model of reactivated toxoplasmosis. In conclusion, the timing of sulfadiazine therapy is of utmost importance for the course of infection in immunocompromised mice.     

The effects of COX-2 selective and non-selective NSAIDs on the initiation and progression of atherosclerosis in ApoE−/− mice

In this study, we investigated the effects of prolonged administration of the selective COX-2 inhibitors celecoxib and rofecoxib and the non-selective NSAID naproxen on the initiation and progression of atherosclerosis. ApoE(-/-) mice, as well as corresponding wild-type mice, were fed either a normal chow or a high fat Western diet with or without addition of the respective drugs over a period of 16 weeks. Thereafter, aortic lesion size, plasma lipid levels, and COX-2 expression in the plaques were determined. The results showed that neither the COX-2 selective inhibitors nor naproxen had a significant impact on the initiation and progression of atherosclerosis in diet-fed ApoE(-/-) mice, although both celecoxib and rofecoxib showed a tendency to reduce plaque size. This slight effect may be due to selective inhibition of COX-2 activity because the COX-2 expression was not altered in the plaque. Plasma lipid levels were also not significantly influenced by these drugs. Interestingly, in ApoE(-/-) mice that have been fed with normal chow, we found an increased incidence of plaque formation after treatment with celecoxib and rofecoxib, indicating that coxibs may promote the initiation of atherosclerosis. This effect was probably masked in diet-fed mice by the more pronounced effects of the high cholesterol diet. In conclusion, the reduction in diet-induced plaque size in animals fed a high fat diet and the promotion of atherosclerosis in mice on a normal diet indicate a dual role of the coxibs. In advanced stages of atherosclerosis, they may exert antithrombotic properties due to their COX-2 inhibiting activity, whereas in very early stages they may favor the initiation of atherogenesis. However, because these results were only observed in ApoE(-/-) and not in wild-type animals, coxibs may increase the risk of thrombosis in patients with a predisposition for thrombotic complications.     

From cure to palliation: agreement, timing, and decision making within the staff

Important issues in the transition from curative treatment to palliative care are agreement, timing, and decision making. A survey of 309 nurses and 415 physicians in Sweden showed that 61% of the nurses and 83% of the physicians thought agreement was current practice. None said that the decisions were made too early, but 19% of the nurses and 14% of the physicians thought that they often were made too late. Very few respondents stated that such decisions are changed, 0% and 1%, respectively. More than half of the informants made detailed comments on such transitions indicating that awareness and flexibility are desirable to make well-informed decisions. Three themes that emerged from the analysis concerning the decision to stop curative treatment and focus on palliative care were that the staff members should (if possible) make such decisions in agreement and should sometimes make the decisions earlier and that well-based reasons are required to make changes.