Örjan Norrgård

Intracranial aneurysms and heredity

The occurrence of intracranial aneurysms (IAs) in the families of 579 consecutive patients with subarachnoid hemorrhage (SAH), of whom 485 had verified IAs, was studied retrospectively. IAs occurred in the families of 6.7% of the IA patients, but only 0.4% of their siblings had IAs. However, there were differences between the familial and nonfamilial IA patients, indicating that the familial patients are a specific small subpopulation of IA patients. The familial patients were younger, often had multiple aneurysms, and had aneurysms frequently located on arteries other than those in the nonfamilial group.

Presence of a marked nonneuronal cholinergic system in human colon: Study of normal colon and colon in ulcerative colitis

Background: The body has not only a neuronal but also a nonneuronal cholinergic system. Both systems are likely to be very important, particularly in inflammatory conditions. The patterns and importance of the nonneuronal cholinergic system in patients with ulcerative colitis (UC) are largely unknown. Methods: The colons of UC and non‐UC patients were examined for expression patterns of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and the muscarinic receptor of the M2 subtype. Results: ChAT and VAChT immunoreactions and mRNA reactions for ChAT were detected in epithelial and endocrine cells, in cells in the lamina propria, and in blood vessel walls. Furthermore, a marked M2 immunoreaction was noted for epithelium, blood vessel walls, and smooth musculature. ChAT and VAChT immunoreactions were significantly higher in endocrine and epithelial cells, respectively, in non‐UC mucosa than in UC mucosa. On the other hand, there was a tendency toward higher M2 levels in epithelium of UC patients. Conclusions: There is a pronounced nonneuronal cholinergic system in the colon, which has previously been ignored when discussing cholinergic influences in UC. Furthermore, it is evident that certain changes in the nonneuronal cholinergic system occur in response to inflammation/derangement in UC. Cholinergic effects in the colon can be considered to be related not only to nerve‐related effects but also to effects of acetylcholine from nonneuronal local cells. Thus, the recently discussed phenomenon of a “cholinergic antiinflammatory pathway” in the intestine may have a pronounced nonneuronal component.

Colonic Neuroendocrine Peptide Levels in Patients with Chronic Idiopathic Slow Transit Constipation

The motility disorders in patients with slow-transit constipation have been attributed to a disturbance in the peptidergic innervation of the colonic enteric nervous system. The nature of this disturbance is, however, controversial. In the present study 7 patients with long-standing severe slow- transit constipation were included, and normal tissues from the colon of 6 patients, which had undergone colonectomy because of polyp, chronic diverticulitis, prolapsis and volvulus were used as controls. The concentrations of several neuroendocrine peptides were measured in tissue extracts by radioimmuno-assays. The level of pancreatic polypeptide was high in 2 patients and low in one patient. Peptide YY level was high in 3 patients and low in one patient, and that of neuropeptide Y was high in 4 patients. Somatostatin and vasoactive intestinal polypeptide levels were high in 3 patients and substance P concentration was low in 3 patients. Neurotensin level was high in one patient and low in another patient. Galanin concentration was low in 2 patients and high in one patient. Gastrin-releasing peptide level was high in one patient and that of enkephalin was high in 2 patients. All patients had altered concentrations of several neuroendocrine peptides except one, who had only a low level of galanin. It is concluded that patients with slow-transit constipation have disturbed neuroendocrine peptides in common, though the nature of this disturbance varies between patients and in most patients several neuroendocrine peptides were affected. This may explain the controversial results obtained in previous studies.

Co-existence of abdominal aortic aneurysms and intracranial aneurysms

SummaryThe occurrence of abdominal aortic aneurysms (AAAs) and intracranial aneurysms (IAs) in the same patient and in the same family was studied among 89 patients with AAAs and 485 patients with IAs. Among the AAA-patients two had IAs themselves and five had IAs in the family, whereas three IA-patients had AAAs themselves and eight had AAAs in the family. Moreover, one of the patients with both AAA and IA had a blood relative with AAA, and in six of the families with both types of aneurysms there were more than two subjects with aneurysms. The results indicate, that AAAs and IAs may have a common aetiologic factor.

Study of expression patterns and levels of neurotrophins and neurotrophin receptors in ulcerative colitis

Background: Neurotrophins may be involved in ulcerative colitis (UC). Yet, it is unclear whether if their effects should be blocked. Methods: In this study, the neurotrophins nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF) and their receptors were examined by immunohistochemistry, ELISA, and RT‐PCR. Results: BDNF immunoreaction was detected in nerve structures in particular, and NGF immunoreaction was detected in lamina propria cells. Cellular NGF immunoreaction was generally observed to be higher in the mucosa of UC patients than in the controls. In addition, UC patients demonstrated significantly higher p75 immunoreaction (P = 0.010) in lamina propria cells. The controls expressed significantly higher BDNF immunoreaction in the nerve structures than did UC patients (P = 0.000). However, the UC group showed marked interindividual variation in expression of neurotrophins and neurotrophin receptors. This included variation at the mRNA level for NGF. Differences with the controls were most pronounced in UC specimens demonstrating great infiltration of inflammatory cells and marked tissue derangement. Corticosteroid treatment seemed to affect neurotrophin production in lamina propria cells but not in nerve structures. These observations demonstrate that up‐regulation and down‐regulation of neurotrophins occur in different structural components in response to the disease process. Massive inflammation seemed to be correlated with decreased neurotrophin immunoreaction in nerve structures, but there was a tendency toward increased neurotrophin production in lamina propria cells. Conclusions: Our study shows that UC patients are not a uniform group in their expression of neurotrophins, a fact that should be considered when discussing therapeutic interventions.

Substance P and the neurokinin-1 receptor in relation to eosinophilia in ulcerative colitis.

Substance P (SP) has been implicated in the pathophysiology of ulcerative colitis (UC) and it has been suggested that blocking of its effect would be advantageous in this disease. Eosinophils have also been implicated in the pathophysiology of UC. In the present study, specimens from the sigmoid colon of UC patients were investigated by the use of antisera against SP and the neurokinin-1 receptor (NK-1R) and staining for demonstration of eosinophils. The degrees of SP innervation and NK-1R immunoreaction, as well as the levels of eosinophil infiltration, varied between different patients. Interestingly, NK-1R immunoreaction in the epithelium was often seen to be the most marked where there were numerous eosinophils in the underlying mucosa and where the mucosa showed a marked morphologic derangement. The observations suggest that there are marked fluctuations in effects of SP and eosinophils during the disease. The infiltrating eosinophils may be involved in the destruction of the mucosal tissue. Furthermore, for the majority of cases where there is marked derangement of the mucosa, it is apparent that there is an upregulation of the NK-1 receptor in the epithelium in parallel with the infiltration of the eosinophils.

Colonic endocrine cells in patients with carcinoma of the colon

Objective To investigate the colonic endocrine cells in patients with colon carcinoma in order to establish a possible abnormality. Patients Twelve patients with colon adenocarcinoma (eight women and four men; mean age 69 years; range 52–88 years) were studied. As controls, macroscopically and histologically normal tissues from the colon of 12 patients (eight women and four men; mean age 66 years; range 34–86 years) were examined. These patients suffered from polyps, prolapsus, chronic diverticulitis, volvulus or haemorrhoids Methods Macroscopically and histologically normal tissues from the colon of the patients, about 10 cm from the tumour, and of the controls were examined. Endocrine cells were immunostained with the avidin-biotin-complex method, and were quantified by computer image analysis using an automatic standard sequence analysis operation. Three parameters were used: (1) the number of endocrine cells per mm3 of epithelial cells; (2) the cell secretory index (CSI); and (3) the nuclear volume. Results The numbers of somatostatin- and serotonin-immunoreactive cells were significantly reduced in patients with colon carcinoma (P=0.03 and 0.009, respectively). There was no difference between patients and controls regarding the numbers of PYY- PP- and enteroglucagon-immunoreactive cells. The CSI of somatostatin- and serotonin-immunoreactive cells were significantly decreased. There was no difference in the CSI between the patients and controls regarding PYY PP- or enteroglucagon-immunoreactive cells. The nuclear volumes of PYY- and enteroglucagon-immunoreactive cells increased significantly in the patients. The nuclear volume of PP- somatostatin- and serotonin cells did not differ from those of the controls. Conclusion The present results support the assumption that a disturbance in the colonic neuroendocrine system occurs in patients with colon carcinoma, which might affect the development of the tumour. The decrease In the number and CSI of somatostatin cells may account for the decrease of the colonic content of this peptide observed previously in these patients. The decrease in the number and CSI of serotonin-immunoreactive cells in patients with colon adenocarcinoma might be a method by which the body defends itself against this mitogenic substance.

New aspects concerning ulcerative colitis and colonic carcinoma: Analysis of levels of neuropeptides, neurotrophins, and TNFalpha/TNFreceptor in plasma and mucosa in parallel with histological evaluation of the intestine

Background: The levels of neuropeptides, neurotrophins, and TNFalpha (TNF&agr;)/TNF receptor in plasma and mucosa for patients with ulcerative colitis (UC) and colonic carcinoma, and concerning plasma also for healthy controls, were examined. Moreover, the relationships between the different substances and the influence of mucosal derangement on the levels were analyzed. Methods: The levels of VIP, SP, CGRP, BDNF, NGF, and TNF&agr;/TNFreceptor1 were measured using ELISA/EIA. Results: Patients with UC demonstrated the highest levels of all analyzed substances in plasma, with the exception of BDNF. However, there were differences within the UC group, patients treated with corticosteroids, and/or nonsteroid antiinflammatory/immunosuppressive treatment having higher plasma levels than those not given these treatments. Patients with colonic carcinoma showed higher SP and TNFreceptor1 levels in plasma compared to healthy controls. Concerning mucosa, the levels of almost all analyzed substances were elevated for patients with UC compared to noncancerous mucosa of colonic carcinoma patients. There were correlations between many of the substances in both plasma and mucosa, especially concerning the 3 neuropeptides examined. There were also marked associations with mucosa derangement. Conclusions: Via analysis of correlations for the respective patients and via comparisons between the different patient groups, new and original information was obtained. Interestingly, the degree of mucosal affection was markedly correlated with tissue levels of the substances and the treatments were found to be of importance concerning plasma but not tissue levels of these. Combined plasma analysis of neuropeptides, neurotrophins, and TNFreceptor1 may help to distinguish UC and colonic carcinoma patients.

Early increase and later decrease in VIP and substance P nerve fiber densities following abdominal radiotherapy: a study on the human colon

Purpose : The neuropeptides substance P (SP) and vasoactive intestinal peptide (VIP) mediate physiologic activities in the intestine, not least in relation to motility and inflammatory processes. Neuropeptides are up-regulated and play particular importance during tissue stress. This paper aims to quantify mucosal and smooth muscle SP, VIP and total innervation in human colon in short- and long-term perspectives after abdominal irradiation. Materials and methods : Colon specimens from 23 irradiated or non-irradiated patients were investigated with immunohistochemistry and computerized image analysis. Plasma levels of SP and VIP in 15 additional patients receiving radiotherapy were analyzed. Results : At 4-7 days after irradiation (5 ×5 Gy), the overall innervation, and also VIP and SP nerve fiber densities, were increased in both mucosa and circular muscle layer. In contrast, 5-6 weeks as well as several years after irradiation, the VIP and SP nerve fiber densities were decreased. No peptide changes were revealed in plasma. Conclusions : The degree of VIP and SP intestinal innervation was increased after radiotherapy in the short-term perspective but it decreased in the long-term. In the short-term, SP may have pro-inflammatory and VIP anti-inflammatory effects and the peptides may have trophic effects and be related to the occurrence of motor changes. It cannot be excluded that the decrease in VIP and SP neuronal supply seen in the long-term may contribute to intestinal malfunction.

Irradiation induces marked immunohistochemical expression of vasoactive intestinal peptide in colonic mucosa of man.

Vasoactive intestinal peptide (VIP) is known tomodulate inflammatory reactions, to have trophiceffects, and to contribute to diarrhea and has beenimplicated as an important factor in severalinflammatory conditions in the human gut. The aim of thepresent study was to investigate the effects ofirradiation on the expression of VIP in the colon ofpatients operated on for adenocarcinoma. Some of thepatients had received preoperative irradiation (25 Gy)within one week before the operation. Specimens ofsigmoideum, 10 cm cranial to the margin of the cancer,were examined, by using antiserum against VIP and immunohistochemistry. There were numerous nervefibers showing VIP-like immunoreactivity in the damagedmucosa, including the regions showing ulcerations. Therewas a higher degree of expression of VIP in the ganglion cells in the submucous plexusesin irradiated than nonirradiated patients. The studyshows that there is a marked immunohistochemicalexpression of VIP concomitant with the occurrence of inflammatory and repair processes in theirradiationdamaged human colonic mucosa.