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Background: Although the potential of biomarkers to aid in early detection of colorectal cancer (CRC) is recognized and numerous biomarker candidates have been reported in the literature, to date only few molecular markers have been approved for daily clinical use., Methods: In order to improve the translation of biomarkers from the bench to clinical practice we initiated a biomarker study focusing on a novel technique, the proximity extension assay, with multiplexing capability and the possible additive effect obtained from biomarker panels. We performed a screening of 74 different biomarkers in plasma derived from a case-control sample set consisting of symptomatic individuals representing CRC patients, patients with adenoma, patients with non-neoplastic large bowel diseases and healthy individuals., Results: After statistical evaluation we found 12 significant indicators of CRC and the receiver operating characteristic (ROC) curve of Carcinoembryonic antigen (CEA), Transferrin Receptor-1 (TFRC), Macrophage migration inhibitory factor (MIF), Osteopontin (OPN/SPP1) and cancer antigen 242 (CA242) showed additive effect. This biomarker panel identified CRC patients with a sensitivity of 56% at 90% specificity and thus the performance is sufficiently high to further investigate this combination of five proteins as serological biomarkers for detection of CRC. Furthermore, when applying the indicators to identify early-stage CRC a combination of CEA, TFRC and CA242 resulted in a ROC curve with an area under the curve of 0.861., Conclusions: Five plasma protein biomarkers were found to be potential CRC discriminators and three of these were additionally found to be discriminators of early-stage CRC. These explorative data in symptomatic individuals demonstrates the feasibility of the multiplex proximity extension assay for screening of potential serological protein biomarkers and warrants independent analyses in a larger sample cohort, including asymptomatic individuals, to further validate the performances of our CRC biomarker panel.

NAD+ is a co-enzyme for hydride transfer enzymes and an essential substrate of ADP-ribose transfer enzymes and sirtuins, the type III protein lysine deacetylases related to yeast Sir2. Supplementation of yeast cells with nicotinamide riboside extends replicative lifespan and increases Sir2-dependent gene silencing by virtue of increasing net NAD+ synthesis. Nicotinamide riboside elevates NAD+ levels via the nicotinamide riboside kinase pathway and by a pathway initiated by splitting the nucleoside into a nicotinamide base followed by nicotinamide salvage. Genetic evidence has established that uridine hydrolase, purine nucleoside phosphorylase, and methylthioadenosine phosphorylase are required for Nrk-independent utilization of nicotinamide riboside in yeast. Here we show that mammalian purine nucleoside phosphorylase but not methylthioadenosine phosphorylase is responsible for mammalian nicotinamide riboside kinase-independent nicotinamide riboside utilization. We demonstrate that so-called uridine hydrolase is 100-fold more active as a nicotinamide riboside hydrolase than as a uridine hydrolase and that uridine hydrolase and mammalian purine nucleoside phosphorylase cleave nicotinic acid riboside, whereas the yeast phosphorylase has little activity on nicotinic acid riboside. Finally, we show that yeast nicotinic acid riboside utilization largely depends on uridine hydrolase and nicotinamide riboside kinase and that nicotinic acid riboside bioavailability is increased by ester modification.

The Arabidopsis thaliana VTC2 gene encodes an enzyme that catalyzes the conversion of GDP-L-galactose to L-galactose 1-phosphate in the first committed step of the Smirnoff-Wheeler pathway to plant vitamin C synthesis. Mutations in VTC2 had previously been found to lead to only partial vitamin C deficiency. Here we show that the Arabidopsis gene At5g55120 encodes an enzyme with high sequence identity to VTC2. Designated VTC5, this enzyme displays substrate specificity and enzymatic properties that are remarkably similar to those of VTC2, suggesting that it may be responsible for residual vitamin C synthesis in vtc2 mutants. The exact nature of the reaction catalyzed by VTC2/VTC5 is controversial because of reports that kiwifruit and Arabidopsis VTC2 utilize hexose 1-phosphates as phosphorolytic acceptor substrates. Using liquid chromatography-mass spectroscopy and a VTC2-H238N mutant, we provide evidence that the reaction proceeds through a covalent guanylylated histidine residue within the histidine triad motif. Moreover, we show that both the Arabidopsis VTC2 and VTC5 enzymes catalyze simple phosphorolysis of the guanylylated enzyme, forming GDP and L-galactose 1-phosphate from GDP-L-galactose and phosphate, with poor reactivity of hexose 1-phosphates as phosphorolytic acceptors. Indeed, the endogenous activities from Japanese mustard spinach, lemon, and spinach have the same substrate requirements. These results show that Arabidopsis VTC2 and VTC5 proteins and their homologs in other plants are enzymes that guanylylate a conserved active site His residue with GDP-L-galactose, forming L-galactose 1-phosphate for vitamin C synthesis, and regenerate the enzyme with phosphate to form GDP.

Breast cancer is the leading type of cancer among women, and surgery is the primary treatment. The subacute phase of care after surgery has a significant impact on quality of life. This article explores the physical and psychological risk profiles of 240 women with early-stage cancer. Although several statistical models were designed for these data, the conclusions are based on the adjusted logistic regression model controlling for presurgical outcomes scores and all other demographics. Findings indicated that the physical risk profile included younger women (<55 years), unmarried, with a caregiver, and a college education. The psychological risk profile includes younger women (<55 years), unmarried, and with annual incomes under $75,000. These profiles will help practitioners anticipate the postsurgical supportive care needs of women with early-stage breast cancer.

Checkpoint with forkhead-associated and RING (Chfr) is a ubiquitin ligase (E3) that establishes an antephase or prometaphase checkpoint in response to mitotic stress. Though ubiquitination is essential for checkpoint function, the sites, linkages and ubiquitin conjugating enzyme (E2) specificity are controversial. Here we dissect the function of the two Chfr homologs in S. cerevisiae, Chf1 and Chf2, overexpression of which retard cell cycle at both G(1) and G(2). Using a genetic assay, we establish that Ubc4 is required for Chf2-dependent G(1) cell cycle delay and Chf protein turnover. In contrast, Ubc13/Mms2 is required for G(2) delay and does not contribute to Chf protein turnover. By reconstituting cis and trans-ubiquitination activities of Chf proteins in purified systems and characterizing sites modified and linkages formed by tandem mass spectrometry, we discovered that Ubc13/Mms2- dependent modifications are a distinct subset of those catalyzed by Ubc4. Mutagenesis of Lys residues identified in vitro indicates that site-specific Ubc4-dependent Chf protein autoubiquitination is responsible for Chf protein turnover. Thus, combined genetic and biochemical analyses indicate that Chf proteins have dual E2 specificity accounting for different functions in the cell cycle.

The first committed step in the biosynthesis of L-ascorbate from D-glucose in plants requires conversion of GDP-L-galactose to L-galactose 1-phosphate by a previously unidentified enzyme. Here we show that the protein encoded by VTC2, a gene mutated in vitamin C-deficient Arabidopsis thaliana strains, is a member of the GalT/Apa1 branch of the histidine triad protein superfamily that catalyzes the conversion of GDP-L-galactose to L-galactose 1-phosphate in a reaction that consumes inorganic phosphate and produces GDP. In characterizing recombinant VTC2 from A. thaliana as a specific GDP-L-galactose/GDP-D-glucose phosphorylase, we conclude that enzymes catalyzing each of the ten steps of the Smirnoff-Wheeler pathway from glucose to ascorbate have been identified. Finally, we identify VTC2 homologs in plants, invertebrates, and vertebrates, suggesting that a similar reaction is used widely in nature.

This randomized controlled trial (n = 240) was designed to test the efficacy of a sub-acute home nursing intervention following short-stay surgery for breast cancer. Intervention participants received the in-home nursing protocol, whereas non-intervention participants received agency nursing care or no nursing care. Data, collected via questionnaire, telephone interview, and chart audit, included surgical recovery/self-care knowledge, functional status, anxiety, quality of life (QOL), and health service utilization. There were no significant group differences on postoperative functional status, anxiety, QOL, further surgeries, or complications. Intervention participants were more likely to receive instruction on surgical self-care (p

Objective: The narrow ICD-10 and DSM-IV definition of hypochondriasis makes it rarely used yet does not prevent extensive diagnosis overlap. This study identified a distinct hypochondriasis symptom cluster and defined diagnostic criteria., Method: Consecutive patients (N=1,785) consulting primary care physicians for new illness were screened for somatization, anxiety, depression, and alcohol abuse. A stratified subgroup of 701 patients were interviewed with the Schedules for Clinical Assessment in Neuropsychiatry and questions addressing common hypochondriasis symptoms. Symptom patterns were analyzed by latent class analysis., Results: Patients fell into three classes based on six symptoms: preoccupation with the idea of harboring an illness or with bodily function, rumination about illness, suggestibility, unrealistic fear of infection, fascination with medical information, and fear of prescribed medication. All symptoms, particularly rumination, were frequent in one of the classes. Classification allowed definition of new diagnostic criteria for hypochondriasis and division of the cases into "mild" and "severe." The weighted prevalence of severe cases was 9.5% versus 5.8% for DSM-IV hypochondriasis. Compared with DSM-IV hypochondriasis, this approach produced less overlap with other somatoform disorders, similar overlap with nonsomatoform psychiatric disorders, and similar assessments by primary care physicians. Severe cases of the new hypochondriasis lasted 2 or more years in 54.3% of the subjects and 1 month or less in 27.2%., Conclusions: These results suggest that rumination about illness plus at least one of five other symptoms form a distinct diagnostic entity performing better than the current DSM-IV hypochondriasis diagnosis. However, these criteria are preliminary, awaiting cross-validation in other subject groups.

The safety and efficacy of isoprinosine in HIV-infected individuals were assessed in a multicentre, randomized, double-blind, 24-week study phase, followed by an optional 24-week open treatment phase. The results of the double-blind phase have been reported separately. Of 866 HIV-seropositive individuals randomized, 832 were eligible for efficacy analysis. On completion of the double-blind phase, 596 patients started open treatment. All patients were evaluated with regard to progression to AIDS. Within 48 weeks, 10/412 patients (2.4%) assigned isoprinosine and 27/420 (6.4%) assigned placebo progressed to AIDS (p = 0.005; odds ratio: 2.8, 95% CI: 1.3-6.2). Intention-to-treat analysis showed identical results. No severe adverse reactions or toxicities were observed. We conclude that HIV-infected individuals without AIDS may be safely and effectively treated with isoprinosine.

The safety and clinical impact of isoprinosine in HIV-infected individuals were assessed in a multicentre, randomized, double-blind, 24-week study phase, followed by an optional 24-week open treatment phase. The results of the double-blind phase have been reported. Of 866 HIV-seropositive patients randomized, 832 subjects were eligible for efficacy analysis. On completion of the double-blind phase, 596 patients started open treatment. All patients were evaluated with regard to progression to AIDS and/or death. Within 48 weeks, 10/412 (2.4%) patients assigned isoprinosine and 27/420 (6.4%) patients assigned placebo progressed to AIDS (P = 0.005). Intention-to-treat analysis showed identical results. Viewing the open treatment phase in isolation revealed no difference in progression rates between those treated and those not receiving the drug, perhaps reflecting the higher proportion of patients receiving zidovudine or PCP prophylaxis in the latter group. No severe adverse reactions or toxicities were observed. We conclude that HIV-seropositive patients without AIDS may be safely and effectively treated with isoprinosine.

We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of inosine pranobex (Isoprinosine) [corrected] in the treatment of patients with human immunodeficiency virus (HIV) infection but without manifest acquired immunodeficiency syndrome (AIDS). A total of 866 patients were enrolled in 21 centers in Denmark and Sweden. The patients were stratified in three groups according to their CD4+ cell count and randomly assigned to receive either inosine pranobex (1 g three times a day) (n = 429) or matching placebo (n = 437) for 24 weeks. Of the 831 patients who could be evaluated, AIDS developed in 17 in the placebo group as compared with 2 in the inosine pranobex group (P less than 0.001; odds ratio, 8.6 [95 percent confidence limits, 2.2 and 52.6]). There were no significant differences between the groups with respect to changes in CD4+ cell count or the development of other HIV-related conditions, with the exception of thrush, which developed in fewer patients in the inosine pranobex group (P = 0.05). No serious side effects were observed. We conclude that treatment with inosine pranobex delays progression to AIDS in patients with HIV infection. The duration of this beneficial effect, the optimal dose, and the mode of action of inosine pranobex remain to be clarified.

22 HIV-positive homosexual men were treated with fusidic acid tablets (500 mg t.i.d.) for a period of 2-12 months (mean 71/2). At entry, all had a CD4-count less than 500 X 10(6)/l, and/or a pokeweed mitogen lymphocyte proliferation response of less than 50% of 2 normal controls, and no overt opportunistic infections. No significant immunological changes were observed and no definite beneficial clinical effect. On the 10th-13th day of treatment, 12 of the patients developed fever and an itchy exanthema. The symptoms disappeared spontaneously in 9 patients. No hematological or biochemical side effects were seen. Thus, in this pilot study of fusidic acid therapy of HIV-infected men, no significant effect could be detected.

To study whether specific beta-adrenergic mechanisms contribute to the hypoglycaemic activation of gastrin and gastric acid secretion, the effects of racemic and dextroisomer propranolol (0.1 mg/kg, intravenously) were studied during insulin tests (0.2 IU/kg) in 13 persons. dl-Propranolol inhibited the gastrin response to hypoglycaemia markedly and more than the insignificant alteration observed after d-propranolol. Gastric acid response to hypoglycaemia was significantly reduced by dl-propranolol and not by d-propranolol. The findings demonstrate that non-beta-adrenergic effects of propranolol on the stomach are minor and that specific beta-adrenergic mechanisms are directly or indirectly involved in the hypoglycaemic stimulation of the stomach.

The secretion of gastric inhibitory polypeptide and of insulin was studied in patients with chronic relapsing pancreatitis and a healthy controls in the fasting state as well as after the oral intake of glucose. The basal levels of gastric inhibitory polypeptide were significantly lowered in patients with chronic relapsing pancreatitis compared with levels in normal persons, whereas the basal insulin levels were normal. The gastric inhibitory polypeptide response to orally administered glucose in patients with pancreatitis exhibited a paradoxic decline and was significantly lower than it was in normal persons. Patients with pancreatitis also had a diminished insulin response to glucose. The findings suggest that the feedback mechanisms between gastric inhibitory polypeptide and insulin, seen in normal persons, are not functioning in patients with chronic relapsing pancreatitis. The events which cause this are, at present, unknown.

Eight patients with biopsy-verified coeliac disease were investigated after remission on a gluten-free diet. A 50-g oral glucose load (OGTT) and an intravenous glucose infusion (IVGI) giving the same plasma glucose profile as the OGTT were carried out. The relation between gastric inhibitory polypeptide (GIP) plasma levels after oral glucose and the insulin release during OGTT and IVGI were studied. Plasma GIP concentration in the fasting state and the increase in plasma GIP during OGTT were significantly lower than in a group of eight healthy volunteers. However, the insulin potentiation during OGTT, the incretin effect, was normal. The results indicate the existence of other incretins than GIP. These are probably released from the distal small bowel in patients with coeliac disease.

Electrical spike potentials and intrauminal pressure variations were recorded from the human duodenum and distal ileum before and after i.v. administration of 80 log Ivy units of cholecystokinin. In the duodenum, quantitative calculations of motility gave identical values before and after drug administration, and results were identical in patients before and after cholecystectomy as well as in hernia patients without upper gastrointestinal disease. A decrease in amplitude of the spike potentials was observed in the duodenum during the first few minutes after drug administration in all groups. Recordings from the distal ileum in ileostomy patients showed a significant increase in motility after CCK administration whereas the spike potential amplitude was unchanged.

The frequency of ovarian cysts in patients with Crohn's disease (CD) or ulcerative colitis (UC) is believed to be higher than in the normal population, but this aspect has not been studied hitherto. The prevalence of ovarian cysts in the normal population is unknown. By ultrasonic scanning, we studied the frequency of ovarian cysts in 61 patients with CD, 64 with UC, and in 100 controls. The findings were positive in 3 out of 61 with CD, 5 of 64 with UC, and in 2 of 100 controls. There is a tendency to a higher frequency of ovarian cysts in patients with inflammatory bowel diseases than in the normal population, but no statistically significant difference.

Rectal biopsy samples from 22 healthy control subjects, 54 patients with ulcerative colitis, and 34 with Crohn's disease with involvement of the colon or rectum were investigated in a stereomicroscopic study. Samples were stained as whole mounts with Alcian Green before the stereomicroscopic examination. In ulcerative colitis, biopsies almost constantly showed changes in the mucosal surface pattern, including irregular, enlarged crypt openings filled with exudate, granulated and bulging surface, and patchy localization of the goblet cells. There was a close correlation between the stereomicroscopic findings and the clinical disease activity, the sigmoidoscopic findings, and the histologic activity. Apart from the stereomicroscopic observation of small superficial erosions in one fourth of the biopsies, no changes of diagnostic value were observed in Crohn's disease.

To study the beta-adrenergic contribution to the hypoglycaemic stimulation of gastric acid and gastrin release the effect of an equal and extensive beta-adrenergic blockade with three drugs was studied. Propranolol was investigated in 12, pindolol in 22, and practolol in 11 patients. Fasting concentration of gastrin serum and spontaneous acid secretion were not reduced by the drugs. Propranolol eliminated the gastrin response to hypoglycaemia, pindolol reduced it, and practolol caused no alteration. The hypoglycaemic acid response was reduced by all three drugs, propranolol reduced the response to one-half and was the strongest inhibitor, practolol the weakest. It is concluded that beta-adrenergic receptors may be of major importance for the hypoglycaemic stimulation of the stomach, but the receptors respond differently from the receptors in the heart.

Twelve morbidly obese patients and 17 patients treated for obesity by jejunoileal shunt operation were studied. A 50-g oral glucose load (OGTT) and an intravenous glucose infusion were carried out to study a) the relation between the plasma gastric inhibitory polypeptide (GIP) levels after oral glucose and the type of jejunoileal bypass performed and b) the importance of endogenous GIP as an incretin in man. The GIP release during OGTT and incretin effect were normal in the obese patients. After jejunoileal shunt, measuring 48 cm and with a ratio of 3:1 between the jejunal and ileal segments, the GIP release and the incretin effect were significantly reduced. Incremental increase in plasma GIP and OGTT was significantly correlated to the incretin effect in these patients. After jejunoileal shunt with the reverse ratio of proximal and distal intestine the incretin effect was significantly higher in spite of a comparable GIP release. Five patients after ileoascendostomia for familial hypercholesterolemia had significantly supernormal GIP release during OGTT but normal incretin effect. The findings indicate the insulinotropic effect of GIP and are in accordance with the concept that incretins other than GIP are released from the distal intestine.

The vagal influence on gastroduodenal content of gastrin was studied in duodenal ulcer patients. Endoscopic biopsies were assayed for total concentrations of gastrin, and fractionated for measurements of gastrin components before and after total vagotomy. Antral concentration was 17-0 +/- 2-0 mug gastrin/g mucosa (mean +/- s.e.m.) in 52 unoperated patients compared with 25-2 +/- 3-2 mug in 32 vagotomized patients. In 14 patients studied before and 3 months after vagotomy antral content was almost doubled (10-9 +/- 2-3 and 20-4 +/- 2-9 mug respectively). In the duodenal bulb the concentration was 2-4 +/- 0.3 mug in 37 unoperated patients and 2-2 +/- 0.4 mug in 19 vagotomized patients. In 6 patients in whom measurements were made throughout the duodenum, gastrin concentrations were slightly but significantly lower 3 months after vagotomy. Fractionations of pooled homogenates on Sephadex G-50 showed that gastrin component III (gastrin-17) made up 95 per cent of the antral gastrins before and after operation. In the duodenum component III constituted more than half of the gastrins preoperatively, but only one-third postoperatively. The total amount of gastroduodenal gastrin was considerably increased by vagotomy, and it is well established that in serum the gastrin concentration is also higher postoperatively. The most likely implication of these findings is that in man the vagus, directly or indirectly, suppresses gastrin production.

The in vitro function of neutrophil granulocytes from 11 patients with Crohn's disease was studied. Nitroblue tetrazolium reduction test results were normal in all patients. Increased intracellular survival of Staphylococcus aureus, impaired glucose-1-14C metabolism of the granulocytes at rest and during phagocytosis, and reduced and delayed staphylococcus-induced granulocyte chemiluminescence response were recorded in the patients with Crohn's disease, a defect that may be involved in the pathogenesis of the chronic granulomatous inflammatory response in this disease.

We encountered two cases of acquired zinc deficiency. In one of the patients the state was due to alcoholism with liver cirrhosis and pancreatitis, and in the other patient it was attributed to a small intestine bypass operation for obesity. The skin symptoms included hair loss, acrodermatitis, and widespread eczema craquelé (asteatosis). The cutaneous manifestations of zinc deficiency seem to constitute a characteristic syndrome that might be helpful in recognizing manifest zinc-deficient states in man.

The importance of beta-adrenergic and cholinergic mechanisms to the circadian rhythm of gastrins in serum was studied in 15 healthy volunteers. The subjects were investigated during peroral treatment with 1) a beta-adrenergic blocking drug (propranolol), 2) an anticholinergic drug (glycopyrron), 3) both drugs, and 4) without treatment. Gastrin concentrations were measured with an antiserum that measures all four main components of gastrin in serum, and with a gastrin-17 specific antiserum. A circadian rhythm was observed with both antisera. The total immunoreactivity in serum increased from 39 pg per ml +/- 3 (mean and S.E.M.) in the morning to a peak at 2300 (77 +/- 7), followed by a nadir at 0400 (38 +/- 2). The circadian rhythm was maintained during administration of the drugs, but the concentrations of component III (gastrin-17) were reduced by beta-adrenergic blockade, while the anticholinergic treatment increased the concentrations of the other gastrin components. The inhibition of gastric secretion of acid by anticholinergics is presumably due to an action on the parietal cells; according to this study, the inhibition is connected by an increased gastrin stimulus. Beta-adrenergic blockade, on the other hand, seems to reduce the gastrin stimulus and might be of therapeutical interest in duodenal ulcer disease.

To study the role played by vagal activity for the gastrins in peripheral blood, the mean pattern during feeding was studied in 16 duodenal ulcer patients before and after selective (n=8), or truncal vagotomy (n=8). Two normal subjects were studied with and without atropine during hypoglycaemic activation of the vagus. Gastrins were fractionated by gel chromatography. Serum gastrin was almost exclusively made up of gastrin component II (gastrin 34-like) and III (gastrin 17-like). Both components rose after feeding but the major increase was incomponent III. Total gastrin concentrations rose after vagotomy but no qualitative changes were seen. During hypoglycaemia a marked increase in gastrin component III and a lesser increase in component II was found. This pattern was not changed by atropine. It is concluded that the vagus plays little or no role for a selective release of the various gastrins. Furthermore there is no indication that the higher serum levels after vagotomy consist of gastrins of a lesser biological activity.

The effect of a long acting somatostatin analogue SMS 201-995 on stomal effluents in patients with severe short bowel syndrome was investigated in a double blind placebo controlled balance study. Six patients, five with Crohn's disease and one with radiation enteropathy were studied. Five patients had a jejunostomy and one an ileostomy. The patients had a normal food intake, but because of severe malabsorption had received home parenteral nutrition for several years. Faecal mass was reduced (p less than 0.005) and intestinal net sodium absorption was increased (p less than 0.005) by intravenous infusion of SMS 25 micrograms/h. Net absorption of potassium, calcium, magnesium phosphate, zinc, nitrogen and fat was not influenced. Subcutaneous injections of 50 micrograms SMS every 12 hours had a similar effect on net intestinal absorption of sodium and water. Four patients continued with a five to six months open follow up study when subcutaneous SMS in the same dose was administered by the patients at home. The effect on faecal sodium loss persisted, but in one patient faecal mass gradually increased and finally exceeded pretreatment values. SMS may decrease net absorption of water and sodium following reduced secretion of digestive juices rather than by increasing absorptive capacity. SMS may be useful as an antidiarrhoeal drug in patients with high output jejuno- or ileostomies, but in patients who need permanent parenteral nutrition the effect is too small to significantly alter management.

Complement factor H (beta-1H globulin) is an important regulatory protein which inhibits the spontaneous complement activation via the alternative pathway. We describe a 15-year-old girl without any detectable factor H in plasma. She has had two episodes of meningococcal disease, but is otherwise completely healthy. Secondary to the factor-H deficiency, the levels of factor B, properdin, C3, and C5-C9 were strongly reduced due to spontaneous in vivo activation of the alternative complement pathway. Plasma C3dg was strongly elevated in spite of the factor-H deficiency; apparently erythrocyte CR1 substitutes for factor H in C3 degradation. Neither C3 nor complement lesions were demonstrable on her erythrocytes which did, however, show increased, spontaneous haemolysis in vitro in citrate plasma, but not in serum. The patient is a single child and her parents, who are unrelated and healthy, had half-normal levels of factor H. This reduction of factor H is sufficient to cause increased, spontaneous activation of the alternative pathway.

The normal mucosal surface morphology in the rectum has been described by investigation of 15 rectal biopsies using a semimacroscopic technique. The structures of the mucosal surface were rendered visible by staining the biopsies as whole mounts with Alcian Green. A regular pattern of the crypt openings was found, and the goblet cells were observed in and just around the crypt openings. The density of crypt openings was calculated as the number of crypt openings per square millimetre (104 +/- 23 openings per mm2, mean and S.D.). Histologic examinations of the same biopsies were performed, and the density of crypt tubules was calculated from serial, horizontal sections (130 +/- 34 tubules per mm2, mean and S.D.). The ratio of crypt openings/crypt tubules was 1:1.25, indicating some branching of the mucosal glands in the rectum.

Fifteen patients in whom various parts of the small intestine had been resected because of Crohn's disease or mesenteric thrombosis and 10 healthy volunteers were studied. A 50-g oral glucose load (OGTT) and an intravenous glucose infusion giving the same plasma glucose profile as the OGTT were carried out to study (a) the relation between the plasma gastric inhibitory polypeptide (GIP) levels after oral glucose and the length and nature of the intestinal residues and (b) the importance of endogenous GIP as an incretin in man. The magnitude of the increase in plasma GIP after oral glucose load was positively correlated to the length of residual jejunum. The incretin effect was positively correlated to the length of residual intestine. Patients with preserved ileal residues had larger incretin effects than patients with less than 150 cm jejunal residues and no ileal residues, although the integrated increases in plasma GIP after oral glucose were equal. Compared with healthy volunteers, the patients with more than 150 cm residual jejunum had significantly higher increases in plasma GIP and normal incretin effects. The GIP release and the incretin effect in patients with preserved ileal residues were normal. The incretin effect of the patients with less than 150 cm jejunum was significantly subnormal in spite of a normal GIP release. These findings indicate that the upper intestine releases GIP after oral glucose and that other as yet unknown intestinal hormonal factors act as incretins in concert with GIP.

Thirty-three patients (seventeen females and sixteen males), six with complete and twenty-seven with abortive forms of Melkersson-Rosenthal syndrome (MRS) have been studied. Only patients with histologic granulomatous involvement were included in the study. The onset of MRS occurred predominantly during the second decade of life; the disease had a median duration of 6 1/2 years and a range of 6 months to 31 years. Recurrent lip swelling gradually turning into a permanent enlargement was the dominating sign, but changes in the buccal, palatal, sublingual, and gingival mucosa were frequently recorded as well. Peripheral facial paralysis occurred in 20 percent of the patients and plicated tongue in 40 percent. Laboratory investigations showed no specific changes. The elimination of odontogenic infectious foci was followed by regression or disappearance of the swellings in eleven of sixteen patient, suggesting a pathogenic mechanism. The present study does not seem to justify resections of the swellings when exacerbations are still occurring. A conservative approach is recommended.

The importance of beta-adrenergic receptor activity for ulcer formation was studied. In rats fasted for 48 hours, ulcers in the rumen were produced constantly after 17 hours of pyloric ligation. d,1,Propranolol in doses of 1 to 30 mg/kg given 4 times during 12 hours caused a dose-dependent inhibition of ulcer formation. The ulcero-protective potency of d,1,propranolol was about 20 times that of d,propranolol. No explanation of the ulcero-protective effect was observed when the gastric acid secretion was studied after 17 hours. Serum gastrin concentration after 17 hours of ligation was in all animals less than 5 pmol per liter, i.e. below one-third of the normal fasting value. For all pharmacological effects apart from beta-adrenergic blockage, d,1, and d,propranolol do not differ, while the results presented here suggest that intact beta-adrenergic receptor activity is important for the development of gastric ulcers in the pylorus-ligated rat. The mechanism behind the ulcero-protective effect of beta-adrenergic blockage remains to be solved.

Factors influencing spontaneous survival in 49 patients with liver metastases after cancer in colon/rectum were evaluated. In addition the same evaluation was performed in 12 patients treated with 5-Fluoro-uracil systemically of intraarterially in the hepatic artery. Alkaline phosphatases, elevated more than 4 times normal values, elevated serum alanine aminotransferase, or jaundice are all unfavorable prognostic signs in the spontaneous group. In the 5-Fluoro-uracil treated group only elevated serum dilirubin had the same unfavorable prognostic sign. Even though it seems to be an increased survival time in the 5-Fluoro-uracil treated group it is concluded that metastases to the liver from cancer in colon/rectum assume to be more or less resistent to 5-Fluoro-uracil.

To study the physiological importance of epinephrine and norpinephrine for gastrin release and gastric secretion of acid the effect of intravenous infusions was investigated. Two doses were used (5 and 50 mg per kg per minute in one hour), the low dose of epinephrine and both doses of epinephrine (n=20) stimulated gastrin release and acid secretion, whereas the high dose (n=8) stimulated the gastrin release strongly, but did not change acid secretion. Norepinephrine in the low dose (n=11) caused a very small increase in gastrin release and no change in acid secretion, whereas the high dose (n=11) inhibited acid secretion without any change in gastrin concentration. No postoperative change was observed in the release of gastrin by both doses of epinephrine after truncal vagotomy in sex and seven patients with duodenal ulcer. It is concluded that epinephrine and norepinephrine both may be of importance in the physiological regulation of gastrin release and gastric acid secretion.

Identical clinical and histopathological features of the oro-facial swellings in Melkersson-Rosenthal syndrome (M.R.S.) and Crohn's disease (C.D.) exist. In order to disclose a possible relation between these two granulomatous diseases and to evaluate the necessity of extensive screening for C.D. in cases of M.R.S., 16 patients with complete or abortive forms of M.R.S. were examined. However, no clinical, radiological or biochemical findings indicated such a relationship. It is concluded that in patients with M.R.S. extensive examinations for C.D. are not justified in absence of associated gastrointestinal symptoms.