Heiner Mönig

Role of insulin-like growth factor-I (IGF-I) receptor, IGF-I, and IGF binding protein-2 in human colorectal cancers

The identification of novel autocrine/paracrine signaling pathways and possible markers represents an important component in the understanding of tumor growth control. In this study, we assessed the potential role of insulin-like growth factor-I (IGF-I), the IGF-I receptor (IGF-IR) and IGF binding protein-2 (IGFBP-2) in human colorectal cancer. Initial studies demonstrating increased IGF-I binding and IGF-IR density in human colon cancer tissue revealed that a component of iodinated (3-[125-I]iodotyrosyl) IGF-I (125I-ICGF-I) binding was not attributable to IGF-IR. Binding studies and Western blot analysis suggested that this second component of 125I-IGF-I binding could be due to IGFBP-2. Further analysis by a specific solution hybridization/RNase protection assay for IGF-IR mRNA levels, IGFBP-2 mRNA levels and in situ hybridization for IGFBP-2 localization, was carried out in nine patients with colon cancer. IGF-IR mRNA levels by RNAse protection assays were unchanged, whereas IGFBP-2 mRNA levels were increased 4-8-fold in patients with colon cancer compared to controls. Three patients with Dukes stage C disease had the highest levels of IGFBP-2 mRNA. In situ hybridization studies localized IGFBP-2 mRNA to malignant cells and not to the surrounding stromal cells, suggesting an autocrine role for IGFBP-2. The discrepancy between increased IGF-I binding, IGF-IR density, IGFBP-2 mRNA and the minimal modulation of the IGF-IR mRNA implies post-transcriptional regulation of IGF-IRs. Our results suggest that IGFBP-2 may be implicated in colon cancer metastases and prognosis. Its usefulness as a potential tumor marker should be further investigated.

Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide

SummaryThe effects of sulphaphenazole, cimetidine and primaquine on the disposition of antipyrine and tolbutamide in healthy volunteers have been investigated. The model substrates were administered simultaneously in order more clearly to define any selective effects of the potential inhibitors. Sulphaphenazole produced a significant increase in the half-life of tolbutamide (7.10 to 21.50 h) and a correponding decrease in its clearance (0.260 to 0.084 ml·min−1·kg−1). Clearance to hydroxytolbutamide (OHTOL) and carboxytolbutamide (COOHTOL) was also significantly decreased.In contrast, sulphaphenazole had no effect on the disposition of antipyrine. Administration of cimetidine did not significantly alter the disposition of either model drug. However, a 1.6-times higher dose of cimetidine did increase the half lives both of tolbutamide and antipyrine (6.21 to 9.04 h and 14.2 to 19.2 h, respectively) and decrease their clearance (0.226 to 0.148 and 0.50 to 0.31 ml·min−1 kg−1, respectively). Clearance to OHTOL and hydroxymethylantipyrine (HMA) was reduced.A single dose of primaquine had no demonstrable effect on tolbutamide disposition whereas the half-life of antipyrine was increased (12.1 to 15.0 h) and its clearance decreased (0.63 to 0.38 ml·min−1·kg−1). The partial clearance to HMA, 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was also significantly reduced.The two main inferences are first, that tolbutamide and antipyrine are metabolished by different forms of cytochrome P-450, and second that a battery of model substrates is needed to investigate the inhibitory effects of a drug in man.

Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy†

Nitrogen‐bisphosphonates (n‐BP), often referred to as aminobisphosphonates, are the most commonly prescribed drugs for the treatment of disorders of bone fragility. However, long‐term continuous treatment predisposes certain individuals to serious rare side effects, such as bisphosphonate‐associated osteonecrosis of the jaw (BAONJ). n‐BP use is known to unintentionally activate a subset of innate T cells called Vγ9Vδ2 T cells, but the consequence of this chronic immune stimulation has remained unexplored. The primary objectives of this study were to 1) determine the fate of Vγ9Vδ2 T cells in osteoporotic patients on n‐BP therapy as a function of time and type of therapy; 2) evaluate the proportion of Vγ9Vδ2 T cells in patients who had recently experienced n‐BP–associated ONJ. We found there is a notable loss of Vγ9Vδ2 T cells over time in osteoporotic patients on n‐BP therapy, particularly those on intravenous (iv) therapy (Spearman r = −0.55, p < 0.0001 iv; r = −0.3, p < 0.03 oral) (n = 68); no difference was observed in total T cells, monocytes, or granulocytes. Importantly, the observed negative effect on Vγ9Vδ2 T cells coincides with the reported route of administration and timing of the rare occurrence of BAONJ. Patients (n = 6) who had experienced BAONJ were all found to be significantly deficient in Vγ9Vδ2 T cells (median = 0.07%) in comparison to age‐ and sex‐matched treatment‐naïve controls (N = 11; median = 2.40%), U = 0, p = 0.001; this was the only consistent difference in the leukocytes assessed. All BAONJ cases had an underlying condition that further contributed to impaired immunity. We propose Vγ9Vδ2 T cells show a strong potential to serve as harbingers of possible adverse immune effects of n‐BP therapy, particularly in those patients already having a compromised immune system as they may be most vulnerable to the development of conditions such as BAONJ.

Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseases – implications for the euthyroid sick syndrome

Objective: To determine whether cytokine release or activation of the hypothalamo-pituitary-adrenal (HPA) axis is predominantly involved in the development of the euthyroid sick syndrome (ESS). Design: Prospective observational study. Setting: Intensive care unit at a tertiary care medical center in Germany. Patients: Nine patients with sepsis of different causes and eight patients with acute myocardial infarction. Interventions: None. Measurements and results: Immediately on admission and on day 7 the following parameters were determined: total thyroxine (T4), free thyroxine (FT4), total triiodothyronine (T3), thyrotropin (TSH), interleukin-1β (IL-1β), interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), serum cortisol and plasma adrenocorticotropin (ACTH). On admission, concentrations of all thyroid hormones and TSH were significantly lower in septic patients compared to non-septic patients, whereas all cytokines except IL-2 were significantly elevated in the sepsis group. By contrast, there was no difference in serum cortisol and plasma ACTH levels between the two groups. On day 7, T4 and T3 were still lower in the septic group, whereas IL-1β, sIL-2R and IL-6 were still elevated. Again, no differences were found with regard to cortisol and ACTH levels. Conclusions: Euthyroid sick syndrome occurs very early during the course of septic diseases. Significantly decreased levels of total T4, FT4, T3 and TSH in septic patients suggest central suppression of TSH as well as inhibition of thyroid hormone release in ESS. The HPA axis is activated in septic patients and in non-septic patients and does not contribute to the development of ESS.

Bioavailability and elimination of nitrendipine in liver disease.

SummaryTwenty one patients with liver disease (cirrhosis 11, chronic hepatitis 5 and acute hepatitis 5) and 6 healthy volunteers were given a single i.v. dose of nitrendipine 5 mg. Afterwords nitrendipine 20 mg once daily were administered orally for seven days.With the intravenous injection a significant increase in the AUC and elimination half-life of nitrendipine was found in patients with cirrhosis as compared to the normal volunteers. After chronic oral dosing, the area under the plasma concentration-time curve, AUC (0–24), was 94.5 ng ml−1 h and the plasma clearance CL was 1380.6 ml/min in the healthy controls; in patients with cirrhosis the AUC (0–24) h was significantly greater at 309.4 ng ml−1 h and CL had fallen to 686.6 ml/min. Considerable accumulation of nitrendipine was also found in the patients with chronic hepatitis. Nitrendipine could not be detected in urine from any of the subjects. Blood pressure and heart rate were not significantly influenced by the treatment in the various groups investigated. Antipyrine clearance in the patients with cirrhosis was correlated with the nitrendipine plasma clearance.Thus, accumulation of nitrendipine has been demonstrated in the patients with cirrhosis and chronic hepatitis.

Measurement of Waist Circumference at Four Different Sites in Children, Adolescents, and Young Adults: Concordance and Correlation with Nutritional Status as well as Cardiometabolic Risk Factors

Background: This study investigates the concordance of four waist circumference (WC) measurement sites, and examines their relationships with nutritional status and cardiometabolic risk. Subjects and Methods: In 91 females / 89 males (6.1–19.9 years; 12.2% overweight), WC was assessed beneath the lowest rib (WCR), 4 cm above the umbilicus (WC4), above the iliac crest (WCC), and midway between WCR/WCC (WCM). ‘Overwaist’ was defined as a WC > 90th age-/sex-specific percentile. Pubertal stage was assessed according to Tanner. Body composition (air-displacement plethysmography), blood pressure, lipid profile, glucose/insulin levels, and HOMA-IR (homeostasis model assessment of insulin resistance) were measured. Results: Medians of WCs (cm) for females/males were WCR (64.4/69.5) < WC4 (64.6/70.2) < WCM (67.1/71.2) < WCC (71.5/ 74.2). Although closely related to each other (all r > 0.93; p < 0.001), paired comparisons revealed differences between WCs in their magnitudes which was stronger for females than males. Prevalence of ‘overwaist’ differed according to measurement site in females/males: WCR (13.2/15.7%) < WC4 (14.3/ 19.1%) < WCM (18.7/22.5%) < WCC (37.4/30.3%). After adjusting for age and pubertal status, WCs were closely related to body mass index (BMI) (all r > 0.86; p < 0.001), percent fat mass (%FM; all r > 0.61; p < 0.001), and comparably associated with cardiometabolic risk factors. However, stronger correlations were found for i) WCR vs. WC4 with BMI in males (r = 0.93 vs. 0.91; p < 0.05), ii) WCC vs. WC4 with %FM in females (r = 0.67 vs. 0.61; p < 0.05), iii) WCC vs. WCR with triglycerides in females (r = 0.29 vs. r = 0.22; p < 0.05), and iv) WCC (r = 0.36) vs. other WCs (r = 0.30–0.32) with low-density lipoprotein cholesterol (LDL-C) in males (p < 0.05). Conclusion: WCs measured at different sites were closely correlated with BMI and %FM as well as comparably associated with cardiometabolic risk factors. However, different WCs had different magnitudes, which was more obvious in females and led to discordant results with respect to ‘overwaist’ and risk assessment.

Expression of functional prolactin and its receptor in human colorectal cancer

Abstract Background and aims. Ectopic production of prolactin has been reported for several tumors, and elevated prolactin plasma levels have been detected in colorectal cancer patients. However, the role of prolactin in colorectal cancer remains unclear. We therefore compared expression patterns of prolactin and its receptor in normal and neoplastic colonic mucosa of the same patient with noncancer controls and determined mitogenic effects in vitro. Materials and methods. mRNA and protein expression was analyzed by semiquantitative RT-PCR and western blotting. Localization of ligand and receptor in tissues was investigated by immunohistochemistry. Mitogenic effects of prolactin on colorectal cancer cell lines (Caco-2, HT-29, LoVo) were assayed by [3H]thymidine incorporation. Results. mRNA expression of prolactin was detected in 13% of normal and 27% of cancer specimens, with the highest levels seen in moderately differentiated tumors. Receptor mRNA was amplified from the majority of normal (96%) and cancer (94%) samples with an overexpression seen in tumor tissues. Protein expression of prolactin was detected in cancer tissues only, with the highest levels seen in moderately differentiated tumors. Receptor protein expression was correlated with the RT-PCR data, showing up to fourfold overexpression in tumor tissues. Staining for both ligand and receptor was observed in epithelial cells. DNA synthesis was significantly stimulated by prolactin in all cell lines reaching 167–197% of unstimulated controls. Conclusion. Expression of prolactin, overexpression of prolactin receptors in colorectal cancers, and mitogenic effects of prolactin suggest a role for this hormone in a subgroup of colorectal cancers, which is presumably mediated by paracrine/autocrine pathways.

Santorini's duct : risk factor for acute pancreatitis or protective morphologic variant? Experiments in rabbits

Background and aims: Gallstone pancreatitis is assumed to result from stone passage through the choledochoduodenal junction. Stone impactions may either result in the obstruction of the pancreatic duct or occur below the confluence of the biliary tract and the pancreatic duct and, thus, may favour bile reflux into the pancreatic duct. We studied effects of a patent Santorinis duct upon secretory flow and pancreas morphology under both conditions. Methods: A catheter in the distal rabbit pancreatic duct created a second outlet for pancreatic juice and, thus, mimicked a patent Santorinis duct. A second catheter was introduced into the proximal pancreatic duct and into the common bile duct. This catheter mimicked a common channel behind a papillary obstruction. Clamping of this catheter mimicked a stone obstruction of the pancreatic duct. A catheter in the cystic duct allowed for the infection of bile with 107 Escherichia coli bacteria/ml. The flow direction of bile and pancreatic juice was directly observed. Pancreatic histology was analysed after 24 h. Results: Pancreatic duct obstruction produced an oedema of the gland. Creation of a patent Santorinis duct prevented development of the histological changes caused by pancreatic duct obstruction. In rabbits in which a common channel obstruction was mimicked, Santorinis duct produced flow of bile along the pancreatic duct system. Flow of sterile bile along the duct did not cause pancreatic inflammatory lesions. Bile that was infected with E. coli bacteria produced an acute interstitial‐oedematous pancreatitis. Conclusions: (1) A patent Santorinis duct protects the gland from the effects of main pancreatic duct obstruction; (2) Santorinis duct promotes biliary pancreatic reflux during obstruction of the common channel and subsequent development of pancreatitis caused by infected choledochal secretions; (3) Santorinis duct may thus be both a protective morphological variant and a risk factor for pancreatitis dependent upon the site of stone impaction within the choledochoduodenal junction.

Thyroid autoantibodies and thyroid dysfunction during treatment with interferon-α for chronic hepatitis C

Interferonα(2a or 2b) is increasingly used for treatment of chronic hepatitis C virus (HCV) infection. Recent reports suggested a correlation between increases in thyroid autoantibodies and the development of thyroid dysfunction during interferon-α therapy. In this study, we analyzed thyroid hormones and antithyroid antibodies at monthly intervals in 53 patients who received interferon α for chronic active hepatitis C infection. Of five patients with initially elevated levels of antithyroid peroxydase antibodies (anti-TPO), the antibodies increased further in two of them. Ten patients, who started interferon therapy with normal antibody levels, developed elevated anti-TPO antibodies for limited times during treatment. Levels of anti-TPO antibodies showed a marked fluctuation, and only three patients had increased anti-TPO antibodies persisting for longer than 3 mo. Antithyroglobulin antibodies appeared in four patients, all of whom were also positive for anti-TPO antibodies. No changes in TRAB levels were observed. All of these patients with elevated antithyroid antibodies remained in an euthyroid state. One patient with normal antithyroid antibodies developed thyroiditis with severe thyrotoxicosis after 9 wk of interferon therapy. These findings suggest that the induction of antithyroid antibodies during treatment with interferon-α does not indicate clinical relevant thyroid dysfunction. Routine measurement of antithyroid antibodies during interferon-α therapy does not seem to be mandatory.

Iodine absorption in patients undergoing ERCP compared with coronary angiography

BACKGROUND Systemic absorption of iodinated contrast material occurs during endoscopic retrograde cholangiopancreatography (ERCP), the clinical significance of which has not yet been determined. METHODS Urinary iodine excretion was measured before and after coronary angiography (n = 20) and ERCP (n = 12). Thyroid hormone levels were determined before iodine load and after 6 and 24 weeks. RESULTS Before coronary angiography, iodine excretion was 101 +/- 38.3 micromol/mol creatinine and increased to 865. 10(5) +/- 721. 10(5) micromol/mol on the next day (p </= 0.001). After 6 weeks, it was still elevated (167 +/- 88.8 micromol/mol, p < 0.01). Before ERCP, iodine excretion was 115 +/- 60.3 micromol/mol and reached a peak of 5.3. 10(5) +/- 4.9. 10(5) micromol/mol (p < 0.001). Six weeks later, it had returned to baseline. Two patients in the coronary angiography group but none in the ERCP group had suppressed thyrotropin after 6 weeks. CONCLUSIONS The systemic iodine load during ERCP is approximately 0.6% of the iodine load during coronary angiography. Therefore routine measurement of thyroid hormones before ERCP is not recommended.