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 x 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.

Pronounced substance P innervation in irradiation-induced enteropathy--a study on human colon.

The immunohistochemical expression of various neuropeptides, including substance P (SP), and the substance P receptor (SPR), was examined in irradiation-induced enteropathy in man. Samples from irradiated and non-irradiated patients operated on for rectal carcinoma were examined. The samples were from the sigmoid and corresponded macroscopically to non-cancerous sigmoid colon. There was a marked atrophy, ulcerations and inflammatory reactions in the irradiation-influenced mucosa. In this mucosa, there was a very pronounced innervation of varicose nerve fibers showing SP-like immunoreactivity (LI). The degree of SP-LI in the ganglionic cells of the submucous plexus was increased as compared to non-irradiated patients. There were only few or no nerve fibers showing immunoreaction for other neuropeptides examined (CGRP, enkephalin, NPY) in the irradiation-influenced mucosa. A marked SPR immunoreaction was detected in cells in the lamina propria which were interpreted as representing polymorphonuclear leukocytes. The marked expression of SP in the irradiation-damaged mucosa and the presence of SPR immunoreactive leukocytes suggest that SP is highly involved in the inflammatory reactions that occur in response to radiotherapy. The observations also suggest that SP, but not NPY, CGRP and enkephalin, has an important role in the reorganisation processes that take place in the mucosa in irradiation-induced enteropathy.

Abnormal colonic endocrine cells in patients with chronic idiopathic slow-transit constipation.

BACKGROUND: The aim of the present study was to investigate the colonic endocrine cells in patients with slow-transit constipation, to ascertain the presence of a possible abnormality. METHODS: Ten patients with chronic slow-transit constipation were investigated. As controls, macroscopically and histologically normal tissues from the colon of 12 patients were examined. These patients had polyps, prolapsis, chronic diverticulitis, volvulus, and haemorrhoids. The endocrine cells were stained by immunocytochemistry and quantified by computerized image analysis. RESULTS: There were significantly fewer enteroglucagon- and serotonin-immunoreactive cells in patients with chronic slow-transit constipation. There was no statistically significant difference between patients and controls with regard to the number of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and somatostatin-immunoreactive cells. The cell secretory indexes (CSI) of enteroglucagon- and somatostatin-immunoreactive cells were significantly decreased. There was no statistically significant difference in the CSI between the patients and controls with regard to PYY-, PP-, and serotonin-immunoreactive cells. CONCLUSION: The changes in colonic endocrine cells in patients with slow-transit constipation may be one cause of the decreased motility in the colon and consequent development of constipation.

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

Vasoactive intestinal peptide (VIP) is known to modulate inflammatory reactions, to have trophic effects, and to contribute to diarrhea and has been implicated as an important factor in several inflammatory conditions in the human gut. The aim of the present study was to investigate the effects of irradiation on the expression of VIP in the colon of patients operated on for adenocarcinoma. Some of the patients had received preoperative irradiation (25 Gy) within one week before the operation. Specimens of sigmoideum, 10 cm cranial to the margin of the cancer, were examined, by using antiserum against VIP and immunohistochemistry. There were numerous nerve fibers showing VIP-like immunoreactivity in the damaged mucosa, including the regions showing ulcerations. There was a higher degree of expression of VIP in the ganglion cells in the submucous plexuses in irradiated than nonirradiated patients. The study shows that there is a marked immunohistochemical expression of VIP concomitant with the occurrence of inflammatory and repair processes in the irradiation-damaged human colonic mucosa.

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.

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.

Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms.

Detailed DNA sequencing of the triple-helical domain of type III procollagen was carried out on cDNA prepared from 54 patients with aortic aneurysms. The 43 male and 11 female patients originated from 50 different families and five different nationalities. 43 patients had at least one additional blood relative who had aneurysms. Five overlapping asymmetric PCR products, covering all the coding sequences of the triple-helical domain of type III procollagen, were sequenced with 28 specific sequencing primers. Analysis of the sequencing gels revealed only two nucleotide changes that altered the structure of the protein. One was a substitution of threonine for proline at amino acid position 501 and its functional importance was not clearly established. The other was a substitution of arginine for an obligatory glycine at amino acid position 136. In 40 of the 54 patients, detection of a polymorphism in the mRNA established that both alleles were expressed. The results indicate that mutations in type III procollagen are the cause of only about 2% of aortic aneurysms.

Lp(a) lipoprotein in patients with arterial insufficiency of the lower extremities.

The serum concentration of Lp(a) lipoprotein was determined in 66 patients with peripheral arterial insufficiency of the lower extremities (PAI) and 164 controls. The mean level was higher among the patients than among the controls (236 +/- 248 vs. 129 +/- 159 mg/l, p = 0.01), and values above 300 mg/l were more common among the patients (22/66 vs. 21/164, p less than 0.001). The difference between the 26 female patients and the 94 female controls was statistically significant (280 +/- 268 vs. 118 +/- 141 mg/l, p less than 0.001), but not the difference between the 40 male patients and the 70 male controls (208 +/- 235 vs. 142 +/- 182 mg/l). A high Lp(a) lipoprotein level was not associated with a high LDL-cholesterol level, and there was no significant correlation between the serum levels of Lp(a) lipoprotein and triglycerides++, total cholesterol or HDL-cholesterol. The results indicate, that high Lp(a) lipoprotein levels may be a risk factor for PAI in women.

Nephrectomy in unilateral chronic pyelonephritis. A long-term follow-up study.

In order to study the effectiveness of unilateral nephrectomy as a treatment for chronic unilateral pyelonephritis, 15 consecutive patients who had undergone this operation were followed up. The patients had been operated on 8.9 years (mean) earlier. All of the 15 patients had had recurrent urinary tract infections prior to the operation, 11 of them had had pyelonephritis for between 1 and 19 (mean 6.7) years. One patient only had had a verified episode of urinary tract infection during the follow-up period. All 15 patients were hypertensive prior to the operation. At the time of follow-up, 7 patients were normotensive without drugs, and 2 were normotensive with a reduced dosage of antihypertensives. The mean systolic blood pressure went down from 180 to 150 mm Hg, and the mean diastolic pressure from 109 to 88 mm Hg. This operation can thus be recommended in selected cases of unilateral chronic pyelonephritis with hypertension.

Ultrasonographic screening of the abdominal aorta among siblings of patients with abdominal aortic aneurysms.

To evaluate the prevalence of abdominal aortic dilatations among asymptomatic brothers and sisters of patients with abdominal aortic aneurysms (AAAs), an ultrasonographic screening study was performed. One hundred and two siblings of patients operated on for AAAs at two Swedish hospitals were invited to attend, and 87 of them (35 men and 52 women) from 32 different families, accepted the invitation. Their median age was 63 years (range 39-82 years). Aortic dilatation was diagnosed in ten of the brothers (29 per cent) and three of the sisters (6 per cent). In ten cases (eight men and two women) there was a localized dilatation caudal to the coeliac axis, and in three a general dilatation of the abdominal aorta with the diameter at the coeliac axis greater than 29 mm. None of the aortic dilatations had been known before this study was performed. The conclusion is that the prevalence of asymptomatic aortic dilatations among brothers of patients with AAAs seems to be high and that this group should be selected for further screening studies.

HLA antigens, blood groups and serum protein groups in patients with intermittent claudication.

HLA (A and B) antigens, blood group systems (AB0, Rh, MNSs P, Kell, Lewis and Duffy) and serum group systems (Hp, Tf, Pi, C3 and C4) were studied in patients with intermittent claudication (IC) and controls. HLA antigen A 28 was significantly more common, and blood group 0 was significantly less common among the patients than among the controls. A comparison between patients with IC and those with abdominal aortic aneurysms showed a significant difference between these two groups concerning the MN blood groups.

High concentrations of Lp(a) lipoprotein in serum are common among patients with abdominal aortic aneurysms.

The serum concentrations of Lp(a) lipoprotein was determined in 57 patients with abdominal aortic aneurysms (AAAs) and in 56 controls. Twentynine of the AAA-patients also suffered from other cardiovascular diseases and eleven had brothers and sisters with AAAs. Lp(a) was significantly higher among the AAA-patients than among the controls (22.3 +/- 24.3 vs 12.6 +/- 20.4 mg/dl, p less than 0.01). The 28 AAA-patients without other cardiovascular diseases had a somewhat higher Lp(a) in serum than the other AAA-patients, but this difference was not statistically significant (26.4 +/- 28.4 vs 18.5 +/- 19.3 mg/dl). The 11 AAA-patients with AAAs in the family didn't differ from the other AAA-patients concerning Lp(a) in serum. Several genetic markers were also studied, and the seven Kell-positive AAA-patients had a significantly lower Lp(a) in serum than the 47 Kell-negative AAA-patients (7.0 +/- 10.3 vs 25.7 +/- 25.2 mg/dl, p less than 0.05).

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.

Co-existence of abdominal aortic aneurysms and intracranial aneurysms.

The 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.

Genetic markers in patients with intracranial aneurysms.

HLA antigens, blood group systems (ABO, Rh, MNSs, P, Kell, Lewis and Duffy) and serum group systems (Hp, Tf, Gc, Pi, Bf, C3 and C4) were studied in a series of patients with intracranial aneurysms. A significantly increased frequency of HLA antigen A28, a significantly decreased frequency of HLA antigen B40, and a significantly decreased frequency of complement factor C4 B2 was found among the patients when compared with controls from the same geographic area.

Abdominal aortic aneurysms: distribution of elastin, collagen I and III, and intermediate filament proteins desmin and vimentin--a comparison of familial and nonfamilial aneurysms.

The aortic walls of patients with abdominal aortic aneurysms (AAA) and of healthy controls were examined for elastin, collagen I and III, and the intermediate filament proteins desmin and vimentin by immunohistochemical, enzyme histochemical, and routine histological techniques. The morphology of the aneurysmatic walls varied considerably from case to case, but many pathological changes were seen in all cases, e.g., extensive atherosclerotic plaques in the intima, prominent alterations in amount and organization of the elastic lamellae in the media, and an increase of connective tissue. Both collagen I and III were present in all the aneurysmatic walls. The smooth muscle cells in all the aortic walls showed a marked heterogeneity with respect to the morphological appearance, the enzyme histochemical features, and the content of desmin and vimentin. Vimentin occurred in some intimal, medial muscle, and adventitial cells of both the controls and the AAA patients. Desmin occurred in some of the intimal, medial, and adventitial muscle cells of both the controls and the AAA patients. All the cells with desmin in the intima and media also contained vimentin. Thus, smooth muscle cells in the walls of both the normal human abdominal aorta and aneurysms contained either vimentin, desmin, or both. This variability may be explained by the presence of different phenotypes of smooth muscle cells and could be of significance for the development of atherosclerosis and aneurysms. Of special interest was the finding that 5 of the 24 AAA patients studied had blood relatives with the same disease, suggesting a hereditary influence. However, no systematic differences between the morphological appearance of the aneurysmatic walls in familial and nonfamilial AAA could be detected.

Familial aortic aneurysms: serum concentrations of triglyceride, cholesterol, HDL-cholesterol and (VLDL + LDL)-cholesterol.

Patients with abdominal aortic aneurysms (AAAs) have been compared with healthy controls with respect to the serum concentrations of triglyceride, cholesterol, HDL-cholesterol and (VLDL + LDL)-cholesterol. The concentrations of triglyceride and (VLDL + LDL)-cholesterol in serum were higher in the patients than in the controls, while the concentration of HDL-cholesterol in serum was lower in the patients than in the controls. There was no statistically significant difference in the serum concentration of total cholesterol between the patients and the controls. Twelve patients had first degree relatives (brothers, sisters and/or parents) with AAAs and six patients had second degree relatives (cousins or brothers and sisters of the parents) with AAAs. There was no statistically significant difference between the patients who had first degree relatives with AAAs and the patients without AAAs in the family in the serum concentrations of triglyceride, cholesterol, HDL-cholesterol and (VLDL + LDL)-cholesterol.