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Objective Biomarkers for diagnosis and progression of osteoarthritis (OA) are lacking. This study was undertaken to identify circulating biomarkers for OA that could predict disease occurrence and/or progression to joint replacement. Methods Using the SomaScan platform, we measured 4,792 proteins in plasma from 37,278 individuals, of whom 12,178 individuals had OA and 2,524 had undergone joint replacement. We performed a case-control study for identification of potential protein biomarkers for hip, knee, and/or hand OA, and a prospective study for identification of biomarkers for joint replacement. Results Among the large panel of plasma proteins assessed, cartilage acidic protein 1 (CRTAC1) was the most strongly associated with both OA diagnosis (odds ratio 1.46 [95% confidence interval 1.41-1.52] for knee OA, odds ratio 1.36 [95% confidence interval 1.29-1.43] for hip OA, and odds ratio 1.33 [95% confidence interval 1.26-1.40] for hand OA) and progression to joint replacement (hazard ratio 1.40 [95% confidence interval 1.30-1.51] for knee replacement and hazard ratio 1.31 [95% confidence interval 1.19-1.45] for hip replacement). Patients with OA who were in the highest quintile of risk of joint replacement, based on known risk factors (i.e., age, sex, and body mass index) and plasma CRTAC1 level, were 16 times more likely to undergo knee replacement within 5 years of plasma sample collection than those in the lowest quintile, and 6.5 times more likely to undergo hip replacement. CRTAC1 was not associated with other types of inflammatory arthritis. A specific protein profile was identified in those patients who had undergone joint replacement prior to plasma sample collection. Conclusion Through a hypothesis-free approach, we identified CRTAC1 in plasma as a novel promising candidate biomarker for OA that is both associated with occurrence of OA and predictive of progression to joint replacement. This biomarker might also be useful in the selection of suitable patients for clinical trial enrollment.

The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF)

Pouchitis is the major long-term complication of restorative proctocolectomy for ulcerative colitis (UC). Allopurinol is a scavenger of oxygen-derived free radicals, which it is suggested play a role in the development of UC and pouchitis. The first aim was to test the hypothesis that the incidence of pouchitis can be reduced by prophylactic Allopurinol, and secondly to evaluate if Allopurinol influences the overall pouch function.273 patients with UC who were planned for proctocolectomy and ileal pouch-anal anastomosis at 12 centres in Sweden between October 1994 and June 1997 were offered the opportunity to participate. 184 patients (67%) were randomized to receive postoperative prophylactic Allopurinol 100 mg twice daily or placebo. All 273 patients had clinical and endoscopic follow-up at 1, 3, 6, 12, 18, 24 months after surgery.Of the 184 randomized patients, 94 were randomized to Allopurinol and 90 to placebo; 116 patients (63%) completed follow-up and the crude incidence of pouchitis among those patients fullfilling the protocol was 31% in the Allopurinol group and 28% in the placebo group (ns). The cumulative risk for a first attack of pouchitis was 30% and 26% after 24 months (ns). The overall pouch function improved over time and did not differ significantly between the two groups.Prophylactic Allopurinol did not reduce the risk of a first attack of pouchitis.

With the aid of specific monoclonal antibodies, an immunohistochemical technique has recently been developed for the detection of intratumoral thymidylate synthase (TS). This technique can be applied to paraffin-embedded material suitable for retrospective studies. In order to examine this technique further, the TS enzyme activity of lysates from frozen-stored colorectal cancer (CRC) specimens were compared with their immunohistochemical TS staining intensity (arbitrarily graded from 0 to 3). A statistically significant correlation between these two methods on a total of 25 tumour specimens (P< 0.001) was observed. The staining intensity in different areas of4S paraffin-embedded CRCs was examined. Sixty-seven per cent of the tumours were homogeneously stained (either grades 0–1 or 2–3), 33% showed a heterogeneity in TS staining. Increased TS expression correlated with more advanced Dukes' stage (P< 0.001). It is concluded that TS immunostaining intensity reflects TS enzyme activity in colorectal tumours and is well suited for paraffin-embedded material. The TS immunostaining pattern is heterogeneous in up to one-third of the tumours.

We designed and performed a multicenter clinical trial to determine the relationship between measurements of the level of the enzyme aspartate aminotransferase (AST) in gingival crevicular fluid (GCF) to other measures used to detect periodontal disease and monitor outcome of treatment, including pocket depth and gingival inflammation. 32 periodontitis patients were enrolled at the University of Washington, Seattle, 30 at the University of Florida, Gainesville, and 34 at the University of Illinois, Chicago. 10 periodontally normal control subjects were enrolled at each location. 8 diseased and 4 healthy sites were designated for study in each patient and 8 healthy sites designated in each control subject. Measures of disease included pocket depth, severity of gingival inflammation, and GCF volume. AST levels were measured using the PerioGard test kit. Clinical measurements were made and GCF samples harvested and tested 2x before and 2x after therapy consisting of scaling and root planing under local anesthetic. Specific design and other issues are discussed, including selection of patients and control subjects, sample size, selection of experimental test sites, methods for assessment of diseased and therapeutic improvement, harvesting of GCF and selection of appropriate biostatistical methods for data analysis. Demographics of the patient populations at the 3 locations are reported. As expected, therapy induced only negligible changes in the measures of disease at healthy sites in control subjects, and relatively minor improvement in healthy sites in patients. In contrast, statistically significant improvement relative to pretreatment baseline status in all 3 measures of disease was observed for diseased sites at all 3 study locations with all p-values less than 0.0002. The magnitude of improvement was comparable to that reported previously by others. The % of PerioGard-positive sites decreased significantly between the screening baseline and both post-treatment visits for patients at all 3 locations, with p values of 0.0001 to

Purposes of this study were 1) to estimate in humans, using 14C-labeled propionate, the rate of hepatic gluconeogenesis relative to the rate of Krebs cycle flux; 2) to compare those rates with estimates previously made using [3-14C]lactate and [2-14C]acetate; 3) to determine if the amount of ATP required for that rate of gluconeogenesis could be generated in liver, calculated from that rate of Krebs cycle flux and splanchnic balance measurements, previously made, and 4) to test whether hepatic succinyl-CoA is channeled during its metabolism through the Krebs cycle. [2-14C]propionate, [3-14C]-propionate, and [2,3-14C]succinate were given along with phenyl acetate to normal subjects, fasted 60 h. Distributions of 14C were determined in the carbons of blood glucose and of glutamate from excreted phenylacetylglutamine. Corrections to the distributions for 14CO2 fixation were made from the specific activities of urinary urea and the specific activities in glucose, glutamate, and urea previously found on administering [14C]-bicarbonate. Uncertainties in the corrections and in the contributions of pyruvate and Cori cyclings limit the quantitations. The rate of gluconeogenesis appears to be two or more times the rate of Krebs cycle flux and pyruvate's decarboxylation to acetyl-CoA, metabolized in the cycle, less than one-twenty-fifth the rate of its decarboxylation. Such estimates were previously made using [3-14C]lactate. The findings support the use of phenyl acetate to sample hepatic alpha-ketoglutarate. Ratios of specific activities of glucose to glutamate and glucose to urinary urea and expired CO2 indicate succinate's extensive metabolism when presented in trace amounts to liver. Utilizations of the labeled compounds by liver relative to other tissues were in the order succinate = lactate > propionate > acetate. ATP required for gluconeogenesis and urea formation was approximately 40% of the amount of ATP generated in liver. There was no channeling of succinyl-CoA in the Krebs cycle in the hepatic mitochondria.

Several studies have suggested that the intratumoral level of thymidylate synthase (TS) in colorectal tumors correlates with survival. We have studied the correlation between TS expression in primary rectal cancer and locoregional recurrence, distant metastases, and survival. TS enzyme levels were evaluated immunohistochemically using the specific monoclonal antibody TS 106 in paraffin-embedded tumors from 243 patients who had undergone primary surgery for rectal cancer during the years 1980-1993. All patients were included in prospective randomized trials aimed at determining the clinical value of a short preoperative course of local radiation therapy (five doses of 5 Gy each). With a median follow-up of 94 months (range, 43-202 months), it was observed by multivariate analysis that Dukes' stage and TS expression were independent prognostic markers of locoregional recurrence (P0.001 and P = 0.038, respectively) distant metastasis (P0.001 and P = 0.011, respectively) disease-free survival (P0.001 and 0.014, respectively), and overall survival (P0.001 and 0.020, respectively). By multivariate analysis, preoperative irradiation therapy showed a borderline improvement in locoregional recurrence (P = 0.051). No other factors, such as age, sex, differentiation of the tumor, or p53 expression, were noted to be independent prognostic factors for clinical outcome in these patients. We concluded that the intratumoral expression of TS in primary rectal cancer is an independent prognostic factor for locoregional recurrence, distant metastases, disease-free survival, and overall survival. Patients with low intratumoral TS expression had a significantly better outcome than those with high TS expression.

Intratumoral thymidylate synthase (TS) expression and M(r) 53,000 phosphoprotein (p53) overexpression were studied immunohistochemically in sections from stored paraffin-embedded primary colorectal cancers in 70 patients who had undergone surgery during the years 1987-1990. These cancers were classified according to Dukes' stage A-D, using monoclonal antibodies TS 106 and DO-7. In patients with Dukes' stage A-C tumors, univariate analyses showed that there was a significant correlation (P = 0.048) between disease-free survival and TS expression and between TS expression and time to death with colorectal cancer (P = 0.038). In patients with Dukes' stage A-D tumors, overall survival was correlated to TS expression (P = 0.015), Dukes' stage (P0.001), and level of tumor differentiation (P = 0.044) but not to p53 overexpression. Patients with low intratumoral TS expression survived significantly longer than patients with high expression. Cox multivariate analysis showed that Dukes' stage (P0.001) and TS expression (P = 0.043) could independently serve as prognostic factors for time to death with colorectal cancer in patients with Dukes' stage A-D tumors.

Subcutaneous administration of low doses of recombinant interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) on an out-patient basis has been reported not to significantly compromise the response frequency compared to intravenous IL-2 in patients with renal cell carcinoma and melanoma. As part of an ongoing program to develop a biotherapeutic concept in patients with colorectal carcinoma (CRC) we studied the clinical effects of such a regimen in 15 patients with metastatic CRC. The daily dose of IL-2 varied between 4.8-14.4 x 10(6) U/m2 and of IFN-alpha between 3-6 x 10(6) U/m2. The cycle length was 6 weeks. The course was repeated every 8 weeks until disease progression. Maximum 4 cycles were administered. Maintenance therapy was given to responding patients once a week every month. No patient showed a major response (CR or PR). Six patients had a stable disease ranging from 3 months to 18 months with a median duration time of 5 months. The median survival of all patients was 13 months. The main adverse reactions were fever, chills, anorexia and shortness of breath. No treatment related deaths occurred. 6/14 patients developed abnormal concentration of serum levels of thyroid hormones. It is concluded that the present treatment schedule using IL-2 and IFN-alpha in advanced CRC seemed not to be of clinical benefit.

Three different 5-fluorouracil (5-FU)-interferon-α-2b (IFN)-containing regimens were designed for treatment of patients with advanced colorectal cancer. 87 patients with a Karnofsky index ≥70 were included in three sequential non-randomised phase II trials. Regimen A consisted of 5-FU (750 mg/m 2 /day) given as a continuous infusion on days 1–5 followed by weekly 1-h intravenous infusions until week 8. IFN (5 MU) was given subcutaneously on days 1, 3 and 5 followed by injections (9 MU) every second day until week 8. The cycle was then repeated. Regimen B consisted of 5-FU (750 mg/m 2 /day) given as a continuous infusion on days 1–5 followed by 5-min intravenous injections on days 12 and 19. IFN (3 MU) was given subcutaneously on days 1–5 followed by injections (5 MU) on days 11–13 and 18–20. The cycle was repeated every fourth week. Regimen C consisted of 5-FU (750 mg/m 2 /day) given as a continuous infusion on days 1–5. IFN (3 MU) was given subcutaneously on days 1–5. The cycle was repeated every third week. The objective response rates (complete response (CR) and partial response (PR)) after approximately 4 months of therapy or longer were as follows: regimen A ( n = 27) 22% (2 CR, 4 PR), regimen B ( n = 33) 42% (4 CR, 10 PR) and regimen C ( n = 27) 22% (1 CR, 5 PR). The corresponding response figures for previously untreated patients were regimen A 50%, regimen B 64% and regimen C 38%. Response durations varied from a few weeks up to 142 + weeks. Toxicities were generally mild and reversible, and the treatments were convenient for the patients and cost effective since the 5-day infusions could be given by a portable pump without hospitalisation. Our results are in agreement with those of others showing that 5- FU IFN combinations can be highly effective in advanced colorectal cancer, and that a number of factors such as doses, dose intensities, infusion rates and timing of the two drugs may be crucial for the anti-tumour activity of this drug combination.

Unconjugated monoclonal antibodies (MAb) and granulocyte macrophage-colony stimulating factor (GM-CSF) may induce tumor regression in patients. Antibody-dependent cellular cytotoxicity (ADCC) is considered to be one of the effector functions of MAb. Human peripheral blood mononuclear cells (PBMC) preincubated with GM-CSF and used as effector cells in an 18h ADCC assay with SW948 (human colorectal carcinoma cell line) as target cells and MAb 17-1A induced significant increase in the lytic capacity of the effector cells. Based on these findings the therapeutic effect of the combination of mouse MAb 17-1A (IgG2a) against colorectal carcinoma (CRC) cells and GM-CSF was evaluated in 20 patients with metastatic CRC. The patients received GM-CSF (250 micrograms/m2/day s.c.) for 10 days and a single i.v. infusion of MAb 17-1A (400 mg) at day 3 of the cycle. The cycles were repeated with an interval of one month. Four cycles were given. ADCC as well as Fc-receptor bearing mononuclear cells increased significantly during therapy. Two patients achieved CR (10%). One patient had an MR (5%) and a further three patients were considered to have SD > 3 months (15%). The two CR patients are still in CR, 35+ and 30+ months respectively after initiation of therapy. Patients with an ADCC activity at start of therapy above the median value of the total patient material survived significantly longer than those patients with an ADCC reactivity below this value (p = 0.002).

To quantify intrahepatic Krebs cycle metabolism, phenyl acetate, excreted in urine as a glutamine conjugate, was given to healthy subjects infused with [3-14C]lactate. They were studied after 60 h of fasting and when given glucose after an overnight fast. Distributions of 14C in glutamate from urinary phenylacetylglutamine and blood glucose were determined. Corrections to the distributions because of the fixation of 14CO2 formed from the [3-14C]lactate were determined by administering [14C]bicarbonate. Comparisons of distributions in glucose and glutamate support the assumption that the glutamate distributions reflect those in hepatic alpha-ketoglutarate. From the distributions in glutamate, the extent of exchange of labeled with unlabeled carbons and relative flow rates in the cycle in liver were estimated. Dilution of 14C by 12C in the cycle was found in the fasted but not the fed state. In the fasted state, pyruvate carboxylation was estimated to be at least twice the rate of Krebs cycle flux and the rate of pyruvate's decarboxylation less than 1/25 the rate of its carboxylation. In the fed state, the rate of decarboxylation was estimated to be between one-sixth and one-half the rate of carboxylation. The rate of conversion of oxalacetate to fumarate in both states appeared to be greater than 6 times the rate of Krebs cycle flux.

The haemostatic effect of terlipressin (triglycyl-lysine vasopressin; Glypressin) on bleeding from oesophageal varices was evaluated in a placebo-controlled, double-blind, randomized clinical trial. Patients with clinically suspected liver cirrhosis were included in the study if they had been admitted to hospital with an extensive haemorrhage within the last 24h before diagnostic endoscopy. The patients randomized after stratification for severity of liver disease. Terlipressin or placebo was administered as intravenous bolus injections every 4th h during a period of 24 to 36 h or until the clinical course necessitated active intervention (failure or withdrawal). Sixty patients entered the study; 31 patients were allocated to receive terlipressin, and 29 patients to receive placebo. Bleeding from varices was arrested in 28 of the 31 receiving terlipressin, as compared with 17 of the 29 receiving placebo (p less than 0.01). Patients receiving active drug required significantly fewer blood transfusions (p less than 0.05). Most of the side effects were classified as mild and were registered in the terlipressin group.

Ischaemic colitis was not diagnosed until laparotomy in five cases. In two it was secondary to hypotension and multiple organ failure, in two it was atherosclerotic, and one had polycythemia vera. The diagnosis should always be considered in patients with abdominal distension--with or without diarrhoea and abdominal pain--so that treatment may be instituted before the onset of peritonitis.

The present investigation was carried out to study some aspects of the recolonization of a subgingival microbiota following subgingival instrumentation in sites with deep pockets. 16 patients were recruited for the study. From each patient 4 inflamed gingival sites with deep pockets were selected. These sites were examined for plaque, overt gingivitis, bleeding on probing and probing depth. Samples of the subgingival microbiota were obtained and examined in the darkfield microscope and in a Neubauer chamber. Following the Baseline examination the teeth of all 4 jaw quadrants were carefully scaled and planed. Subgingival instrumentation was carried out under local anesthesia and required between 2-4 appointments. The patients were subsequently divided into 2 groups (Groups A and B) consisting of 9 and 7 subjects, respectively. During the first 16 weeks of maintenance the patients of Group A were not supervised regarding their self-performed plaque control measures and they accumulated supragingival plaque. The patients of Group B, however, were during these 16 weeks recalled once every 2 weeks for professional tooth cleaning. In addition they rinsed twice daily with a 0.2% solution of chlorhexidine digluconate. Reexaminations including assessments of the same parameters as those studied at Baseline were performed after 2, 4, 8, 12 and 16 weeks. After the 16-week examination the patients of Group A received a new sequence of subgingival scaling and root planing. During the subsequent 16 weeks the patients of Group A were also recalled for professional tooth cleaning. They were reexamined 18, 20, 24, 28 and 32 weeks after the Baseline examination. Subgingival scaling followed by carefully supervised oral hygiene measures resulted in a marked improvement of periodontal conditions. This improvement was accompanied by a pronounced and sustained reduction in the motile segments of the subgingival microbiota. In the presence of supragingival plaque (Group A), however, a subgingival microbiota containing large numbers of spirochetes and motile rods was soon (4-8 weeks) reestablished. A small number of sites with deep pockets (greater than or equal to 8 mm) was not substantially reduced in depth following subgingival instrumentation. In these sites which were kept free from supragingival deposits a subgingival microbiota with a large proportion of motile bacteria soon recurred.

Cholecystokinin (CCK) was used in a randomized double-blind trial to evaluate its effect on post-operative paralytic ileus. Sixty patients were admitted to the study. The return of postoperative intestinal motility was registered with subjective and/or objective methods. No differences were found between the CCK group and the placebo group.

A case of gastric carcinoid tumor in a patient with pernicious anemia is presented. From a pathophysiological point of view, the treatment of choice, i.e. endoscopic removal or gastric resection, is discussed.

A patient with massive hematemesis due to an aorto-oesophageal fistula is presented. An aorto-oesophageal fistula is mostly a fatal disease. In the literature it is pointed out that recognition of the clinical syndrome with midthoracic pain, massive arterial hemorrhage and exsanguination after a symptom-free interval might ameliorate the prognosis. In the reported patient the correct diagnosis was not immediately suspected. The patient, however, survived a long operation and exsanguination without any major postoperative complications or sequelae.

Increasing doses of MAb 17-1A (mouse IgG2A) have been given for therapy of patients with metastatic colorectal carcinoma (n = 28). Serum half-life (T beta 1/2) of MAb 17-1A after a single infusion was about 24 h. A constant serum level of MAb 17-1A could be maintained for a long time period by infusions every 2-3 days. Patients received 500 mg 3 days a week for 12 weeks (total dose 12 g). Side effects were mild and dose related but never required medical intervention except for three times (out of 243 infusions) when allergic reactions appeared. All patients developed IgM and IgG antibodies. Two patients experienced immune complex-related symptoms. Six out of 22 evaluable patients (27%) had objective evidence of tumor cell regression/lysis. One of these achieved a complete remission. Median survival for all patients was 12 months, for responding patients 19 months and for non-responding 11 months. 5/17 patients were studied for the development of anti-anti-idiotypic antibodies (Ab3). The presence of Ab3 in serum correlated favourably to the clinical outcome of the disease.