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Background: Oral budesonide has been proven effective in short- and long-term treatment of collagenous colitis; however, symptom relapse frequently occurs after drug withdrawal. The aim of this study was to identify the risk factors for symptom relapse in patients with collagenous colitis after withdrawal of short-term budesonide therapy., Methods: One hundred twenty-three patients from 4 randomized controlled studies who achieved clinical remission after short-term treatment with budesonide (9 mg/d) were analyzed, including 40 patients receiving subsequent budesonide maintenance therapy (6 mg/d) for 6 months and 83 patients without active maintenance treatment. Variables available for analysis were age, sex, baseline stool frequency, duration of diarrhea, collagenous band thickness, and lamina propria inflammation. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated by Cox proportional hazard model., Results: The overall symptom relapse rate was 61%. By multivariate analysis, a baseline stool frequency >5 per day (HR, 3.95; 95% CI, 1.08-14.39), history of diarrhea >12 months (HR, 1.77; 95% CI, 1.04-3.03), and the absence of budesonide maintenance therapy (HR, 2.71; 95% CI, 1.37-5.38) were associated with symptom relapse. The time to relapse was shorter in patients with a baseline stool frequency >5 per day (56 versus 199 d, P = 0.024), as in those with history of diarrhea >12 months (56 versus 220 d, P = 0.009). Budesonide maintenance therapy delayed the time to relapse (56 versus 207 d, P = 0.005)., Conclusions: Our data demonstrate that a high stool frequency at baseline and a long duration of diarrhea are risk factors for symptom relapse in collagenous colitis, whereas budesonide maintenance therapy is a protective factor against symptom relapse.

The tibial nerve (TN) has three main terminal branches: the medial and lateral plantar nerves and the calcaneal branch (CB), which innervates the foot sole. The design and implantation of nerve cuff electrodes with separate channels for each of these three terminal branches would provide significant sensory information, which can be used in functional electrical stimulation systems to assist standing or to correct foot drop. Detailed quantitative anatomical data about fascicular size and separability of the terminal branches of TN are needed for the design and implantation of such cuff electrodes. Therefore, the branching pattern, the fascicular separability and the fascicular size of the TN posterior to the medial malleolar-calcaneal axis were examined in this study, using ten human TN specimens. The TN branching patterns were highly dispersed. For the CBs, multiple branches were identified in five (50%) of the specimens. For the TN, the bifurcation point was located within the tarsal tunnel in eight (80%) of the cases. The distance proximal to the medial malleolar-calcaneal axis for which the TN could be split ranged form 0 to 41 mm. Quantitative and qualitative data were obtained for the fascicular size and separability of the TN. Only the CB of the TN proved separable for a sufficient length for nerve cuff electrode implantation. The results suggest the use of a two-channel cuff with one common channel for the lateral and medial plantar nerves, having multiple electrodes for selective recording, and one channel for the CB.

Objective: To evaluate the efficacy and safety of long-term budesonide therapy for the maintenance of clinical remission in patients with collagenous colitis., Design: Randomised, placebo-controlled study with a 24-week, blinded follow-up period without any treatment., Setting: Three gastroenterology clinics in Denmark., Patients: Forty-two patients with histologically confirmed collagenous colitis and diarrhoea (more than three stools/day)., Interventions: Patients in clinical remission after 6 weeks' open-label therapy with oral budesonide (Entocort CIR capsules, 9 mg/day) received 24 weeks' double-blind maintenance therapy with budesonide 6 mg/day or placebo. Thereafter, patients entered the 24-week, blinded follow-up period., Main Outcome Measure: The proportion of patients in clinical remission (three or fewer stools/day) at the end of maintenance therapy., Findings: A total of 34 patients in remission at week 6 were randomly assigned to budesonide 6 mg/day (n = 17) or placebo (n = 17). After 24 weeks' maintenance treatment, the proportions of patients in clinical remission were 76.5% (13 of 17) with budesonide and 12% (2 of 17) with placebo (p<0.001). At 48 weeks (the end of the follow-up period, without any treatment) these values were 23.5% (4 of 17) and 12% (2 of 17), respectively (p = 0.6). The median times to relapse after stopping active treatment (6 plus 24 weeks in the budesonide group; 6 weeks in the placebo group) were 39 and 38 days, respectively. Long-term treatment with budesonide was well tolerated., Conclusions: Long-term maintenance therapy with oral budesonide is efficacious and well tolerated for preventing relapse in patients with collagenous colitis. The risk of relapse after 24 weeks' maintenance treatment is similar to that observed after 6 weeks' induction therapy.

Aims: To assess neuronal differentiation in oligodendrogliomas (ODGs)., Methods and Results: An electron microscopic and immunohistochemical study of 41 consecutive cases was performed. In all cases, tumour cells with neuritic structures were identified ultrastructurally, including synapses and neurosecretory granules. For the immunohistochemical identification of synaptophysin, monoclonal antibody clones 27G12, Snp88 and SY38 and a polyclonal antibody were compared in optimized protocols on slides from a spectrum of tissues and 16 ODGs. 27G12 gave the best signal-to-noise ratio, while SY38 gave the poorest. When 27G12 was applied on all 41 ODGs, widespread immunoreactivity was obtained in 100%. Among three antibodies to chromogranin compared similarly, clone LK2H10 and a polyclonal antibody gave identical patterns of immunoreactivity, whereas clone DAK-A3 gave weaker reactions. When LK2H10 was applied on all tumours, staining was found in 12 (29%). All tumours but one stained strongly for glial fibrillary acidic protein and all for synapsin I. Fluorescence in situ hybridization analysis showed a concomitant 1p/19q deletion in 12/16 ODGs., Conclusions: Our study provides evidence for widespread neuronal differentiation in ODGs, suggesting that these tumours may be derived from progenitor cells with limited commitment. Antibody selection and protocol optimization are mandatory for reliable immunohistochemistry results.

Pathological assessment of colorectal cancer resection specimens is the most significant prognostic indicator. This includes determination of TNM stage, tumour type and grade, status of resection margins, extramural vascular and perineural invasion, and molecular features such as defects in the mismatch repair system. The pathological assessment contributes significantly to the quality control of surgery and preoperative staging. Reporting should be standardized by using DSPAC's registration scheme for colorectal carcinomas.

Trichilemmal cysts (also named pilar cyst) derived from the outer root sheath of the deeper parts of the hair follicle can segregate dominantly, and are caused by a yet unknown gene. In order to identify candidate genes for this trait we have ascertained a Danish family with 38 persons (11 affected), and carried out a genome wide scan with 580 DNA micro-satellite markers to identify the locus for a gene, which we termed TRICY1 (for trichilemmal cysts). We found tight linkage to D3S1277 (Z = 4.63; theta(M = F) = 0.00), with flanking markers D3S2432 (Z = 1.59; theta(M = F) = 0.08), and D3S3685 (Z = 2.69; theta(M = F) = 0.08) spanning 10.3 Mb on chromosome 3p24-p21.2. We sequenced two candidate genes previously reported in inherited hair defects, CTNNB1 and MLH1 but failed to detect mutations in exons and intron-exon bounders., ((c) 2005 Wiley-Liss, Inc.)

Sequences of known 16S rRNA genes, derived from sequence analysis of cloned 16S rDNA, were used to design a specific oligonucleotide probe targeting spirochaetes of Brachyspira aalborgi lineages 2 and 3. The probe was used with fluorescent in situ hybridization to study the involvement of these organisms in human intestinal spirochaetosis. Seventeen human colonic biopsies from Norway and Denmark with intestinal spirochaetosis caused by Brachyspira-like organisms different from the type strain of B. aalborgi (lineage 1) were examined. Application of the probe gave a positive signal in two Norwegian biopsies, whereas the 15 other biopsies were hybridization-negative. The positive reaction visualized the spirochaetes as a fluorescent, 3-5 microm-high fringe on the surface epithelium, extending into the crypts. The study verified the presence of B. aalborgi lineages 2 and 3 and identified the bacteria as an aetiological agent of human intestinal spirochaetosis.

Background: Collagenous colitis is characterised by diarrhoea, lymphocytic inflammation, and a thickened subepithelial collagen layer in the colorectal mucosa. No standard treatment of the disease is established., Aims: To investigate the clinical and histological effect of oral budesonide (Entocort, AstraZeneca) in the treatment of collagenous colitis., Patients: Twenty patients with collagenous colitis (collagen layer >10 micro m) and diarrhoea (>4 stools/day and/or stool weight >200 g/day)., Methods: A randomised, double blind, placebo controlled trial of budesonide treatment. Patients were randomised to placebo or budesonide for eight weeks. Stool frequency and stool weight were registered before and after treatment. Sigmoidoscopy was performed before and after treatment, and biopsies at fixed locations were obtained for morphometric analysis., Results: Ten patients were randomised to budesonide and 10 to placebo. All 10 patients receiving budesonide had a clinical response compared with two in the placebo group (p<0.001). In the budesonide group, stool weight was reduced from 574 g/day to 200 g/day and stool frequency was reduced from 6.2/day to 1.9/day (p<0.01). The histological inflammation grade in the sigmoid mucosa and the thickness of the collagen layer were significantly reduced. A correlation between the grade of inflammation as well as collagen layer thickness and stool weight was found. No side effects were reported. Eight of 10 patients had relapse of symptoms within eight weeks after stopping treatment., Conclusions: Budesonide is a highly effective and well tolerated treatment of collagenous colitis. There is a high risk of relapse after stopping eight weeks of treatment.

We describe a case of Meckel's diverticulum containing ectopic gastric epithelium being the leading point in an ileoileal intussusception. This is usually an acute or subacute condition, but in this case the course was protracted and the case was misdiagnosed and treated as Crohn disease.

Small bowel carcinoid tumor (SBC) is a rare disease of unknown etiology but with an age-, sex-, and place-specific occurrence that may indicate an occupational origin. A European multicenter population-based case-control study was conducted from 1995 through 1997. Incident SBC cases between 35 and 69 years of age (n = 101) were identified, together with 3335 controls sampled from the catchment area of the cases. Histological review performed by a reference pathologist left 99 cases for study; 84 cases and 2070 population controls were interviewed. The industries most closely associated (a twofold or more odds ratio [OR]) with SBC, taking into account a 10-year time lag after exposure were, among women, employment in wholesale industry of food and beverages (OR, 8.2; 95% confidence interval [CI], 1.9 to 34.9]) and among men, manufacture of motor vehicle bodies (OR, 5.2; 95% CI, 1.2 to 22.4), footwear (OR, 3.9; 95% CI, 0.9 to 16.1), and metal structures (OR, 3.3; 95% CI, 1.0 to 10.4). The identified high-risk occupations with an OR above 2 were shoemakers, structural metal preparers, construction painters and other construction workers, bookkeepers, machine fitters, and welders (men). The OR for regular occupational use of organic solvents for at least half a year was 2.0 (95% CI, 1.0 to 4.2). Exposure to rust-preventive paint containing lead was suggested as another potential occupational exposure (OR, 9.1; 95% CI, 0.8 to 107). This explorative study suggests an association between certain occupational exposures and SBC, but some of these associations could be attributable to chance. All findings should be regarded as tentative.

Objective: Little is known about the etiology of small bowel carcinoid tumor (SBC), but a few studies have pointed to certain medical and lifestyle factors as potential risk factors. This study aims to evaluate these findings and to identify new associations., Methods: A population-based European multicenter case-control study was conducted from 1995 through 1997. Incident histologically verified 35-69 year-old SBC cases (n = 99) and 3335 controls were recruited; 84 cases and 2070 controls were interviewed., Results: Ever being a smoker was associated with SBC (odds ratio = 1.9; 95% confidence interval 1.1-3.2) and increased risk estimates were seen for all smoking categories. SBC was associated with previous gallstone disease and ovariectomy, but only when these conditions occurred within two years prior to the SBC diagnosis. No association was seen for a history of cholecystitis, liver cirrhosis, ulcerative disease, or Crohn's disease. Intake of alcoholic beverages--as well as medical treatments with radioactive substances, hormones, or corticosteroid tablets--were not associated with SBC., Conclusions: This study indicates that tobacco smoking is a risk factor for SBC. The associations with gallstone and ovarian diseases may be due to enhanced medical surveillance during the early phase of the cancer disease.

Human intestinal spirochetosis, characterized by end-on attachment of densely packed spirochetes to the epithelial surface of the large intestines as a fringe has been associated with the weakly beta-hemolytic spirochetes Brachyspira aalborgi and Brachyspira (Serpulina) pilosicoli. In this study, fluorescent in situ hybridization with oligonucleotide probes targeting 16S or 23S rRNA of B. aalborgi, B. pilosicoli, and the genus Brachyspira was applied to 40 sections of formalin-fixed, paraffin-embedded intestinal biopsy specimens from 23 Danish and 15 Norwegian patients with histologic evidence of intestinal spirochetosis. Five biopsy specimens from patients without intestinal spirochetosis and three samples from pigs with experimental B. pilosicoli colitis were examined as well. In addition, the 16S ribosomal DNAs of two clinical isolates of B. aalborgi were sequenced, and a PCR procedure was developed for the identification of B. aalborgi in cultures. The genotypic characteristics of the two clinical isolates showed very high (99.5%) similarity with two existing isolates, the type strain of B. aalborgi and a Swedish isolate. Hybridization with the Brachyspira genus-specific probe revealed a brightly fluorescing fringe of spirochetes on the epithelia of 39 biopsy specimens, whereas 1 biopsy specimen was hybridization negative. The spirochetes in biopsy specimens from 13 Danish and 8 Norwegian patients (55.3%) were identified as B. aalborgi. The spirochetes in the biopsy specimens from the other 17 patients hybridized only with the Brachyspira probe, possibly demonstrating the involvement of as-yet-uncharacterized Brachyspira spirochetes in human intestinal spirochetosis.

Background: Crohn disease and biliary diseases have been associated with small-bowel adenocarcinoma (SBA). We examined how medical conditions affect the risk of SBA., Methods: A population-based European multicentre case-control study during the period 1995-97 including 95 histologically verified cases of SBA along with 3335 population controls; 70 cases (74%) and 2070 (62%) controls were interviewed about previous medical conditions., Results: Crohn disease was identified in two SBA cases (both located in ileum) and two controls; odds ratio (OR) 53.6 (6.0-477) (95% CI in parentheses). Only one case and no controls had had long-standing Crohn disease. Coeliac disease was associated with SBA (2 cases, 0 controls), but one of the cases was diagnosed at the same time as the SBA. Overall, people with a history of gallstones had no increased risk of SBA. The OR was exclusively increased during the 3-year period preceding the SBA diagnosis. Previous gallstone surgery, which may be a sign of severe gallstone disease, was not associated with SBA. Liver cirrhosis, hepatitis or medical treatments with radioactive substances or corticosteroid tablets were not associated with this disease. Cases with SBA had an increased prevalence of anaemia; OR 15.3 (2.5-92.1). An association between low educational level and SBA was found; OR 1.75 (1.0-3.0)., Conclusion: This study supports Crohn disease and coeliac disease being strong but rare risk factors for SBA. Previous gallstones were unrelated to SBA, and detection bias may account for the findings in earlier studies.

Objective: The proportion of Helicobacter pylori-negative duodenal ulcer disease appears to be increasing. Data on clinical outcome and prognosis in this subgroup are lacking., Methods: Two hundred seventy-six duodenal ulcer patients randomized, irrespective of H. pylori status, to either eradication therapy or maintenance omeprazole (double-blind, double-dummy design) for 1 yr were studied. Patients were followed up for a total of 2 yr, with visits performed every 2 months the first year and every 6 months the following year. Endoscopies for assessment of ulcer relapse were done at 6 and 12 months or in the event of symptomatic relapse. H. pylori status was assessed by culture, immunohistochemistry, and urea breath test at entry, at 6, 12, and 24 months or at failure. The primary endpoint was discontinuation, irrespective of reason. Patients were considered H. pylori negative if all three tests were negative. Patients were considered H. pylori-positive if any of the three diagnostic tests were positive. Study staff were blinded to H. pylori results., Results: Thirty-two (12%) patients were H. pylori negative at entry. There were no differences according to H. pylori status for a number of clinical and demographic characteristics. However, H. pylori-negative patients had a shorter history of ulcer symptoms and were more likely to be NSAID users (19% vs 1%, p < 0.001). Only 28% of the H. pylori-negative patients completed the study, as compared with 40% of H. pylori-positive patients (p = 0.0005). The main reasons for the poorer prognosis in H. pylori-negative patients were relapse of ulcer/ulcer not healed (35% vs 26%) and relapse of severe dyspepsia symptoms without ulcer relapse (16% vs 7%). H. pylori-negative patients randomized to eradication therapy left the study early compared with H. pylori-negative patients randomized to long-term omeprazole therapy. Outcome in omeprazole-treated patients did not differ according to H. pylori status (p = 0.3)., Conclusions: Clinical characteristics in H. pylori-negative and positive duodenal ulcer patients differ little. Clinical outcome over 2 yr is significantly poorer in H. pylori-negative patients, especially if treated empirically with eradication therapy. These results suggest that H. pylori infection should be assessed in all duodenal ulcer patients before treatment is decided.

Objectives: Because of the rarity of small bowel adenocarcinoma (SBA), little is known about the aetiology of this disease. This study aimed to identify occupational clustering of cases SBA as a systematic approach to new hypotheses on the aetiology of this disease., Methods: A European multicentre case-control study was conducted in 1995-7, inclusive. Incident cases aged 35-69 years with SBA (n=168) were recruited before acceptance by a pathologist. Altogether 107 cases and 3915 controls were accepted, of which 79 cases, 579 colon cancer controls, and 2070 population controls were interviewed., Results: The strongest industrial risk factors for SBA taking account of 10 years' exposure lag were dry cleaning, manufacture of workwear, mixed farming (women), and manufacture of motor vehicles (men). A significantly increased risk of SBA (odds ratio (OR) and 95% confidence interval (95% CI)) was found among men employed as building caretakers, OR 6.7 (1.7 to 26.0) and women employed as housekeepers, OR 2.2 (1.1 to 4.9); general farm labourers, OR 4.7 (1.8 to 12.2); dockers, OR 2.9 (1.0 to 8.2); dry cleaners or launderers, OR 4.1 (1.2 to 13.6); and textile workers (sewers or embroiderers), OR 2.6 (1.0 to 6.8). For the last four groups, together with welders OR 2.7 (1.1 to 6.6) (men) an exposure-response pattern was found when calculating the ORs for jobs held 1-5 years and >5 years, with never having held the job as reference. The ORs (95% CIs) for 1-5 years and >5 years were 4.3 (0.4 to 44.0) and 3.5 (0.9 to 13.7), 3.0 (0.3 to 26.2) and 4.3 (0.9 to 21.2), 4.6 (0.4 to 48.1) and 11.0 (2.0 to 60.4), 1.3 (0.2 to 11.0) and 5.8 (2.0 to 17.2), and 2.8 (0.3 to 23.8) and 4.6 (1.3 to 16.6), respectively, for each of these occupations. Among welders, people performing semiautomatic arc welding (MIG/MAG) were identified as a high risk group (OR 5.0 (1.3 to 19.6))., Conclusions: This explorative study suggests an increased occurrence of SBA in certain occupations, which needs further evaluation.

Objective: To discover whether tobacco smoking and intake of different types of alcoholic drinks are associated with small bowel adenocarcinoma (SBA)., Methods: A population-based European multi-center case-control study was conducted from 1995 to 1997., Results: After a histological review using uniform diagnostic criteria, 47 (33%) of the 142 identified cases of SBA were excluded due to reclassification as either tumors of the papilla of Vater (n = 22), stromal tumors, or metastases; 95 cases were accepted for study. In all, 70 cases of SBA together with 2070 controls matched by age, sex, and region were interviewed. A high intake (more than 24 g alcohol per day) of beer or spirits was associated with SBA, an odds ratio (OR) of 3.5 and 95% confidence intervals (CI) of 1.5-8.0 and 3.4 (95% CI 1.3-9.2), respectively). There was no association with wine intake or total alcohol intake. Tobacco smoking was probably unrelated to SBA., Conclusions: A high intake of beer or spirits seems to be a risk factor for SBA. Since this association was not seen for wine drinkers, protective components of wine may counterbalance a carcinogenic effect of alcohol on the small bowel. Alternatively, the result may be confounded by other factors, e.g. dietary factors.

Background: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition., Methods: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/ day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was discontinuation of treatment, irrespective of reason., Results: Two hundred and seventy-six patients were randomized (139 in the eradication treatment group). In the maintenance phase there were no differences in the reporting of dyspeptic symptoms or in premature withdrawal. In the passive follow-up phase only five patients in the eradication therapy group discontinued owing to relapse of dyspeptic symptoms or ulcer, compared with 51 patients initially randomized to long-term omeprazole. There were no differences in reflux symptoms or in the development of reflux oesophagitis., Conclusions: Eradication therapy and long-term omeprazole are equally effective in controlling dyspeptic symptoms and reflux in duodenal ulcer patients with healed ulcers. One-quarter of the duodenal ulcer patients who start eradication therapy continue to be symptomatic or fail therapy for other reasons over a 2-year period. Eradication therapy does not increase the risk of reflux in ulcer patients.

Objective: Collagenous colitis was first described in 1976. It is a rare disorder and the long-term course and prognosis of the disease are unknown. The aim of this study was to evaluate the course of the disease more than 5 years after the diagnosis., Design: A retrospective follow-up of patients with collagenous colitis diagnosed during the period 1979-1990., Methods: All examinations performed at the time of diagnosis were reviewed and the clinical courses of the patients were determined by evaluation of the medical records. At a follow-up visit in 1996 complete histories were obtained and conventional laboratory tests were performed., Results: Two men and 22 women aged 20-82 years with collagenous colitis were identified. At the time of diagnosis, extensive investigation did not reveal other gastrointestinal diseases. At the time of follow-up, six patients had died from diseases unrelated to collagenous colitis, 10 patients suffered from chronic or intermittent diarrhoea, and four patients had been without gastrointestinal symptoms for the last 2-10 years. None of the patients developed colorectal cancer or chronic inflammatory bowel disease. Four patients were lost to follow-up., Conclusion: Collagenous colitis is a benign disease, most often with a chronic course. No association with other gastrointestinal diseases was found.

A 38 year-old male was admitted to hospital with somnolence, flaccid paralysis of the extremities, arterial hypertension, oedema, severe hypokalemia and rabdomyolysis. The course was complicated with respiratory and kidney failure. It became apparent that the symptoms were caused by the ingestion of 200 g of licorice daily for ten weeks together with a thiazide diuretic for two weeks.

Background: We examined the fiber type composition of the articular branches of the tibial nerve in human cadavers. Our primary motivation was to assess the suitability of these nerve branches for making neural recordings by using an interface, such as a nerve cuff electrode or a microelectrode array. Articular branches of the tibial nerve innervate primarily the posterior joint capsule of the knee (Gardner, 1948. Anat. Rec, 101:109-130); the main branch corresponds anatomically to the posterior articular nerve (PAN), which has been studied extensively in animals such as the cat., Materials and Methods: By using light microscopy, we counted the numbers of myelinated fibers in articular branches of the tibial nerve removed from eight cadavers. Unmyelinated fibers were counted in the same specimens by using electron microscopy, and the percentage of unmyelinated fibers was calculated., Results: We found on average 2,280 myelinated fibers in the main articular branch and 279 fibers in individual capsular ramifications. Myelinated fiber diameter histograms showed either bimodal (peaks at 3-4 and 9 microns) or unimodal (peak at 3-4 microns) distributions, depending on the specimen. These histograms were similar in appearance for both the individual capsular ramifications and the main articular branch of the tibial nerve. Numbers of unmyelinated fibers ranged from 4,176 to 5,200 in the main tibial nerve branch (average percentage of unmyelinated fibers = 69.6%) and from 750 to 2,250 in the individual capsular ramifications (average percentage of unmyelinated fibers = 78.5%)., Conclusions: The percentage of unmyelinated fibers is comparable to that found in articular nerves in other species. We discovered that the main articular branch of the tibial nerve contains a branch projecting distal to the knee joint capsule; therefore, the best location for placement of a neural recording interface to record from capsular afferents appears to be the well-defined ramifications of the articular branch that penetrate the joint capsule. Branches that contain only these ramifications are 0.5-1.0 mm in diameter and, on average, have 658 myelinated axons, which should be a sufficient number from which to record.

Epidermal growth factor (EGF) is present in large amounts in the urine, but the effects of systemically administered EGF on the urinary tract have not been described previously. In the present paper, we describe a potent growth induction of EGF on the urinary tract. Goettingen minipigs were treated with solvent (n = 5), EGF 30 micrograms/kg/day (n = 6) for 4 weeks, or EGF 30 micrograms/kg/day for 5 weeks followed by 3 weeks of recovery (n = 5). The ureters and bladders were examined by routine histology and electron microscopy and were immunostained for proliferating cell nuclear antigen. Four weeks of EGF treatment increased the median cross sectional area of the ureter fourfold with growth of all wall layers. The urothelium was widened from 5 cell layers in the controls to 10 in the EGF-treated animals. Proliferating cell nuclear antigen immunostaining revealed an increased mitotic activity in the basal zone of the urothelium. In the luminal zone, glycoconjugates accumulated in goblet cells, in cells with intracytoplasmic lumina, and beneath the luminal cell membrane in the umbrella cells. Our studies present a new experimental approach to growth induction of the urinary tract. The findings implicate the EGF system in regulating urothelial growth and glycoconjugate biosynthesis.

Two premature siblings described herein had clinical features comparable to the fetal akinesia-hypokinesia deformation sequence (Pena-Shokeir syndrome) with polyhydramnios, intrauterine growth retardation, pulmonary hypoplasia, short umbilical cord and lethality. Autopsy revealed no thoracal or abdominal viscera anomalies and examination of the brain, spinal cord and peripheral nerves did not disclose any pathological changes. Light microscopy, immunohistochemistry and electron microscopy of skeletal muscles demonstrated immature muscles with some fibril disorganisation and abnormal immunoreactivity for actin and desmin. Subsequent molecular genetic analysis revealed a maternal diagnosis of myotonic dystrophy. The retarded growth and maturation of skeletal muscle observed in the presented cases correspond with previous findings in neonatal myotonic dystrophy. A well-defined myopathy can thus result in the fetal akinesia-hypokinesia deformation sequence.

We have recently discovered that prolonged systemic administration of epidermal growth factor (EGF) induces a remarkable growth of all wall layers of the urinary tract in minipigs. In the present paper, we report the most pronounced changes induced by 4 weeks of systemic EGF challenge in two pigs treated for four weeks with either solvent or EGF (30 micrograms/kg/day), respectively. The EGF treated ureter was longer and thicker with an approximately four fold increase in diameter. All wall layers were enlarged. The urothelium was increased from 5 to 10 cellular rows with basal hyperplasia and an increased number of goblet cells and cells with intracytoplasmic lumina in the luminal half. In the muscular coat, the bundles of hypertrophied cells and intervening connective tissue were enlarged. The present paper suggests a possible in vivo approach to increase the amount of tissue needed in reconstructive surgery of the urinary tract.

To investigate the frequency of Helicobacter pylori and gastritis in asymptomatic adults, 30 healthy volunteers underwent upper endoscopy. Biopsy specimens were obtained from the corporeal and antral mucosa of the stomach. The specimens were examined by light microscopy for gastritis and the occurrence of H. pylori. In 12 subjects signs of gastritis were noted at endoscopy, but only in 7 of them was this diagnosis confirmed histologically. No other abnormalities were observed by the endoscopist. Histologic examination was normal in 17 subjects, but in 13 subjects (43%) inflammation was found in the gastric specimens. Ten had inflammation both in the corpus and in the prepyloric specimens, and in six of these subjects H. pylori was discovered. H. pylori was only found in subjects with inflammation in both the corpus and the antrum. Subjects with gastritis were slightly older than subjects with normal gastric mucosa (median age, 47 versus 37 years; not significant). In the group of subjects with gastritis, persons with H. pylori were older than those without (median age, 53.5 versus 36 years; p = 0.05). The results of our study indicate that gastritis is present before colonization with H. pylori occurs. This could imply that H. pylori is not the cause of gastritis but that the presence of gastritis is a prerequisite for colonization of the bacterium in the stomach.

To evaluate the prognostic influence of blood transfusion in cancer patients, transfusion data were reviewed on 468 radically operated patients (260 Dukes' B and 208 Dukes' C) with carcinoma of the rectum and the rectosigmoid. Data on whole blood and packed red blood cell transfusions were recorded together with a number of clinical, pathological and histochemical characteristics. The endpoint used was death with cancer. All patients were followed for 2-7 years or until time of death. Univariate statistical methods revealed a highly significant trend towards worsened prognosis with increasing volume of transfusion blood. However, this effect was insignificant when multivariate statistical methods were employed: patients receiving whole blood or packed red blood cell transfusions did no worse than expected from their clinico-pathological characteristics. It is concluded that in this series the observed association between transfusion status and prognosis is adequately explained by a multivariate prognostic model including well-established prognostic factors.

The ultrastructure of spirochetes obtained from rectal biopsies of patients with intestinal spirochetosis was studied by means of negative staining and ultrathin sectioning. The cells were sigmoidal with tapered ends, 2 to 6 microns long, with a wavelength of 2 microns. Four flagella were inserted at each end of the cells. The maximal cell width was about 0.2 microns. The spirochetes were cultured on tryptose soy blood agar plates. They were anaerobic and grew, although very slowly, at 37 to 38.5 degrees C in an atmosphere of 5% CO2-95% H2. Two types of colonies could be distinguished. The growth characteristics and the morphology of the isolated spirochetes differ from those of previously isolated spirochetal strains. Consequently, it is proposed that the present strains constitute a new genus, Brachyspira, of the family Treponemataceae. The type species is Brachyspira aalborgi, the type strain of which is 513A (NCTC 11492).

Results obtained during the first 5 years of a randomized study of postoperative radiotherapy (50 Gy) are presented. Criteria for randomization were fulfilled in 494 of 861 patients with Dukes' B and C tumors, when the trial was closed. Severe complications from radiotherapy approximated 10%. Probability of survival without local failure within 24 months was significantly higher after radiotherapy in patients with Dukes' C tumors, and the time of local failure was delayed 1 year. Patients with Dukes' B tumors had no benefit from radiotherapy. Risks of distant metastases and death were not influenced by radiotherapy in the main groups. Plasma-CEA measurements were evaluated blindly, and radiotherapy changed the critical levels of CEA for detection of recurrent cancer. It was concluded that patients with Dukes' C tumors may benefit from radiotherapy and plasma-CEA levels are influenced by radiotherapy, which may be important, when these are used in screening for recurrent cancer.

A case of so-called collagenous colitis is described. This entity, featured clinically by watery diarrhea, is characterized histologically by a 50-60 micrometer fibrous layer immediately beneath the surface epithelium. Ultrastructural changes in the endothelial cells and the basement membranes of the superficial capillaries of the colonic lamina propria, as well as concentric collagenous encasement of these capillaries, are described.

Pyrophosphate and capsular chondromatosis were demonstrated histologically in 15 cases, 14 of which also exhibited local deposition of amyloid. A systematic examination of the joint capsule in 57 consecutive hip replacement operations for osteoarthritis revealed these changes in 6 of the cases (10.5 per cent). Microscopic examination which was done if intraarticular calcifications were grossly visible at operation, showed the same changes in 8 knees, 4 with osteoarthritis and 4 with meniscal disease. The changes were also seen in the menisci. Only one patient was suffering from chronic, polyarticular pyrophosphate arthritis. In the other cases neither change had been expected a priori, and the patients had no signs of systemic articular disease or amyloidosis. Most of them were elderly, but in good health.

In a consecutive material consisting of 24 stomachs resected due to adenocarcinoma, intestinal metaplasia occurred in 21. Gastrin-producing cells (G-cells) were found to be distributed in a sporadic manner in antra with intestinal metaplasia. Not a single G-cell could be demonstrated in areas with metaplasia, while in the nonmetaplastic areas the distribution of the G-cells corresponded to that of the middle part of the mucosa. This means, that an error can occur when determining the quantity of G-cells, and can explain the previous controversial results regarding the density of G-cells. Enteroglucagon containing cells (GLI-cells) on the contrary were demonstrated in areas with intestinal metaplasia in antra of 19 of the stomachs showing intestinal metaplasia but never in the nonmetaplastic mucosa. This indicated that metaplasia also includes the endocrine cells. The identification of the G-cells and the GLI-cells was carried out by means of indirect immunoperoxidase technique combined with alcian blue pH 2,6-PAS staining.

The intraosseous pressure of the femoral head and greater trochanter was measured during 146 Charnley hip replacement operations. In 108 hips with primary osteoarthritis the pressure in the femoral head averaged 49.6 and in the greater trochanter 31.6 mmHg. The pressures in the greater trochanter were significantly lower than those in the femoral head. There was no sex difference, and the pressures were independent of age. The intraosseous pressure in the femoral head varied appreciably with a dispersion which did not significantly differ from the normal distribution. There was a faintly positive correlation between the mean blood pressure and the intraosseous pressure. No relationship was found between the pressure in the femoral head and the radiological severity of the osteoarthritis or between the intraosseous pressure and the duration of symptoms, severity of rest pain, walking ability, range of motion or degree of bone density at the site of measurement. The haemodynamic conditions in bone depend upon blood flow and resistance. Variations in these two factors determine the actual intraosseous pressure. As a consequence intraosseous pressure measurement as the only evaluation of the haemodynamic conditions is of limited value. The vascular factor in osteoarthritis needs further clarification.

A prospective investigation of 188 patients with cancer of the rectum and rectosigmoid colon with synchronous liver metastases is described. The mean survival time for 183 patients who did not receive any treatment for the liver metastases was six months and only one survived for longer than 37 months. After extirpation of the primary tumour, the most significant prognostic factors were etrahepatic metastases, enlarged liver on account of metastases and more than three liver metastases. Serum basic phosphatases had the greatest significance among a series of laboratory tests. In the sub-groups with the best possible prognoses, the mean survival time was 12 months. 25% five-year survival has been described in the literature following resection of the liver in patients with a maximum of three metastases, no other metastases and age under 70 years. Provided this holds true, liver surgery will be a therapeutic possibility in at least 100 patients per annum in Denmark with synchronous liver metastases and 25 of these will be cured. This figure requires an improved programme for the diagnosis of synchronous liver metastases than at present and the same high frequency of extirpation of the primary colorectal cancer on a national basis which was achieved in the present material.

Mucosal biopsy specimens from 300 consecutive patients with symptoms requiring sigmoidoscopy were examined for spirochetosis by light and electron microscopy. Colorectal spirochetosis was detected in 15 of the patients (5%). Apart from the spirochetal infestation, the mucosa appeared normal with no inflammatory reaction. The spirochetes were eliminated upon treatment with neomycin and bacitracin, but the symptoms of the patients remained unchanged. It is concluded that in the present material, colorectal spirochetosis was without clinical significance.

Pleomorphic (giant cell) carcinomas have been described in the lungs, thyroid, pancreas, and gallbladder. Two pleomorphic carcinomas of the small bowel and two of the large bowel are presented. On light microscopic study, the carcinomas were solid, without squamous or glandular differentiation. The tumors were composed of the following three cell types: gemistocytic (giant) cells, smaller polygonal cells, and spindle cells, with identical immunohistochemical reactions. A panel of monoclonal and polyclonal antibodies was applied. All tumors were found to coexpress keratin and vimentin. A positive reaction for neuron-specific enolase (NSE) was found in three tumors and a positive reaction for chromogranin was found in one tumor. On electron microscopic study, intracytoplasmic whorls of intermediate filaments were seen in the perinuclear area. Dense core "neurosecretory" granules were rarely seen. Intestinal pleomorphic carcinomas are histologically identical to pulmonary giant cell carcinomas. The prognosis is poor due to early tumor spread, with only a few months of postoperative survival. The pleomorphic carcinomas have some of the differentiation characteristics of carcinoid tumors and are best regarded as poorly differentiated variants of neuroendocrine carcinomas.

A series of 681 surgically removed appendices were examined for spirochetes. Five hundred seventy-four appendices were removed because of suspected acute appendicitis; the rest were removed per occasionem. One hundred six of the former were histologically normal, whereas 421 showed acute appendicitis. The remaining 47 specimens showed a variety of other pathological conditions, for example, tumors and diverticula. Spirochetes were found in 13 (12.3%) of the appendices removed from patients clinically suspected to suffer from acute appendicitis, but whose appendices were otherwise histologically normal (pseudoappendicitis). Only 3 patients (0.7%) with histologically confirmed acute appendicitis (p less than 0.05) did show spirochetes in their appendices. Of the 107 patients who had their appendices removed per occasionem, 2 patients (1.9%) had spirochetosis (p less than 0.05). The ultrastructure of the spirochetes obtained from appendices with spirochetosis was studied by means of negative staining and ultrathin sectioning. The morphology of these spirochetes was very similar to that of Brachyspira aalborgi, a spirochete recently isolated from rectal biopsy specimens obtained from patients with colorectal spirochetosis.

The design, and complications seen during the first 2 years, of a randomized trial of postoperative radiotherapy for rectosigmoid cancer Dukes' B and C are presented and discussed. It is concluded that the present complication rate-below 10% in 221 patients-permits continuation of the intake, which is planned to include 550 patients, to demonstrate a possible increase in crude 5-year survival by 15% (60-75% in Dukes' B and 25-40% in Dukes' C), on the basis of a 0·01 significance level and a probability that the experiment will be successful of 0·90.

Intestinal metaplasia in the non-tumour bearing parts of the gastric mucosa was demonstrated in 24 cases in a material consisting of 27 consecutive patients operated for carcinoma of the stomach. Two mucin histochemical types of intestinal metaplasia could be identified. 1) "Small intestinal type" which was present in all 24 cases, and which was by far the most dominating type. 2) "Colonic type" which occurred in small foci in the gastric mucosa of 11 cases, and which was significantly more frequent in stomachs bearing tumours of presumed intestinal histogenesis, than in those bearing tumours of presumed non-intestinal histogenesis.

When a patient presents with acute diarrhoea, the most important question is whether it represents the first episode of chronic inflammatory bowel disease (CIBD) or acute self-limited colitis (ASLC). The early changes in the rectal mucosa of patients with ASLC have been claimed to be highly diagnostic, the presence of an unspecific inflammatory infiltrate in the lamina propria and the absence of disturbances in the crypt architecture being the characteristic features. Thirty-two patients who in the period 1980-1984 presented with their first episode of acute diarrhoea and whose rectal mucosa showed these histologic features were followed up for 1.5-7 years. Forty-one per cent of the patients were finally classified as having ASLC and 28% as having diseases other than CIBD or ASLC. Thirty-one per cent eventually developed CIBD. Thus the features claimed to be diagnostic of ASLC could not predict the final outcome of the disease in patients presenting for the first time with acute diarrhoea. The histologic interpretation can provide significant information in these patients but should never replace a careful clinical judgement and, if doubt remains, further observation of the patients.

The histologic finding of basal-layer hyperplasia and papillosis as consequences of gastroesophageal reflux still constitute an area of controversy. Consequently, a prospective study of symptoms and endoscopy and biopsy interpretation was undertaken in 200 patients consecutively submitted to upper endoscopy, whereof 12 were excluded. Complete agreement among all three variables was found in half of the patients and harmony between two of the variables in one fourth. In the last fourth the outcome was positive in one variable only, equally distributed among the symptoms, endoscopy, and histology. It is concluded that histology is of considerable value in gastroesophageal reflux disease.