Maximal-intensity exercise does not fully restore muscle pyruvate dehydrogenase complex activation after 3 days of high-fat dietary intake.

BACKGROUND & AIMS: Exercise activates muscle pyruvate dehydrogenase complex (PDC), but moderate intensity exercise fails to fully activate muscle PDC after high-fat diet [1]. We investigated whether maximal intensity exercise overcomes this inhibition. METHODS: Quadriceps femoris muscle biopsy samples were obtained from healthy males at rest, and after 46 and 92 electrically-evoked maximal intermittent isometric contractions, which were preceded by 3 days of either low- (18%) or high- (69%) isocaloric dietary fat intake (LFD and HFD, respectively). RESULTS: The ratio of PDCa (active form) to total PDCt (fully activated) at rest was 50% less after HFD (0.32 ± 0.01 vs 0.15 ± 0.01; P < 0.05). This ratio increased to 0.77 ± 0.06 after 46 contractions (P < 0.001) and to 0.98 ± 0.07 after 92 contractions (P < 0.001) in LFD. The corresponding values after HFD were less (0.54 ± 0.06; P < 0.01 and 0.70 ± 0.07; P < 0.01, respectively). Resting muscle acetyl-CoA and acetylcarnitine content was greater after HFD than LFD (both P < 0.05), but their rate of accumulation in the former was reduced during contraction. Muscle lactate content after 92 contractions was 30% greater after HFD (P < 0.05). Muscle force generation during contraction was no different between interventions, but HFD lengthened muscle relaxation time (P < 0.05). Daily urinary total carnitine excretion after HFD was 2.5-fold greater than after LFD (P < 0.01). CONCLUSIONS: A bout of maximal intense exercise did not overcome dietary fat-mediated inhibition of muscle pyruvate dehydrogenase complex activation, and was associated with greater muscle lactate accumulation, as a result of lower PDC flux, and increased muscle relaxation time.

Immunological profiling of haemodialysis patients and young healthy individuals with implications for clinical regulatory T cell sorting.

With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients.

Medicine adaptive pathways to patients (MAPPs): using regulatory innovation to defeat Eroom's law.

Eroom's Law is, literally, Moore's law in reverse. The pharmaceutical sector invests $50 billion annually in research for new medicines but, "the number of new drugs approved per billion US dollars spent has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms". Pharmaceutical companies have invested enormous sums in new molecular entities (NME) in the areas of unmet medical need identified by the World Health Organization (WHO), but the approval rates from phase I are only 7% for cardiovascular disease, dropping to 4% for Alzheimer's disease. The increasing cost of research & development (R&D) is not only a factor of research management quality, but also indicative of an industry trying to address therapeutic areas that have incredibly complex biological mechanisms with budget-crushing failure rates. Medicine adaptive pathways to patients (MAPPs) build on the stratification breakthroughs of personalized medicine to facilitate new types of clinical trials that adapt to a given patient's response. At their core, MAPPs will have a limited commercial marketing authorization for a patient group who has access to new therapeutic agents while validating additional clinical endpoints at the same time. This gives MAPPs a theoretical ability to run trials that fulfil both the efficacy requirements for authorization and the effectiveness needs of national health technology assessments (HTA) simultaneously, providing patients with needed therapies in the most efficient timescale and trial size possible. In order to move science forward and meet these daunting medical challenges for patients, new collaborative approaches to testing the efficacy and effectiveness of new improved medicines such as MAPPs should be embraced by regulators in close partnership with patients, payers, and practitioners. To not do so puts the entire healthcare value chain, and the future health of patients, at risk.

Self-expandable metal stents as a new treatment option for perforated duodenal ulcer.

Primary stenting and drainage has been shown to be an effective and safe way to treat esophageal perforations and anastomotic leaks after gastric bypass surgery. We present a case series of eight patients with perforated duodenal ulcers treated with covered self-expandable metal stents (SEMS). The first two patients received their stents because of postoperative leakage after initial traditional surgical closure. The following six patients had SEMS placed as primary treatment due to co-morbidities or technical surgical difficulties. Endoscopy and stent treatment in these six patients was performed at a median of 3 days (range, 0 - 7 days) after initial symptoms. Six patients had percutaneous abdominal drainage. Early oral intake, 0 - 7 days after stent placement, was possible. All patients except one recovered without complications and were discharged 9 - 36 days after stent placement. This series indicates that primary treatment with SEMS and drainage might be an alternative to surgery in patients with perforated ulcer disease.

Endoscopic sutured closure of a gastric natural orifice transluminal endoscopic surgery access gastrotomy compared with open surgical closure in a porcine model. A randomized, multicenter controlled trial.

BACKGROUND AND STUDY AIMS: In natural orifice transluminal endoscopic surgery (NOTES) procedures it is essential to be able to perform secure closure of the access perforation. The aim of this study was to compare endoscopically sutured closure of a gastric access gastrotomy using the tissue apposition system (TAS), with closure via laparotomy in a randomized multicenter study. METHODS: A total of 32 pigs (18 - 42 kg) were used in this study. The gastric NOTES access was created using a needle knife and a 20-mm balloon. Following transgastric pelvic peritoneoscopy, the endoscope was withdrawn into the stomach. The animals were then randomized to endoscopic closure or laparotomy with surgical closure. Procedure time, recovery time, and weight gain were measured. At necropsy, adhesions, abscesses or peritonitis were recorded. RESULTS: Of the 32 pigs, 29 survived 14 days without complications. All endoscopic and all open surgical closures were secure at postmortem. On average two suture pairs were used for endoscopic closure. Surgical closure was quicker (12.5 vs. 20.1 minutes). Recovery time and postoperative weight gain were similar for both groups. Two pigs in the endoscopic group died: one of gastric dilatation, without leakage from the gastrotomy; another was euthanized due to rectal prolapse. In the laparotomy group one pig was euthanized after 7 days due to abdominal wound dehiscence. At necropsy there were significantly more intra-abdominal adhesions in the laparotomized group. CONCLUSION: This randomized controlled study of endoscopic and surgical closure of a gastrotomy made for transperitoneal access for NOTES procedures suggests that both techniques are comparable in technical closure rates, postoperative recovery, and prevention of peritonitis. There were fewer adhesions in the endoscopic group.

Transgastric peritoneoscopy and appendectomy: thoughts on our first experience in humans.

We present a series of three patients operated on by means of natural-orifice transgastric peritoneoscopy, including one appendectomy. A standard double-lumen gastroscope was used together with standard endoscopic tools. In all patients abdominal access through the gastric wall was smooth using a needle-knife/guide-wire/balloon technique. The whole abdominal cavity could be visualized and the appendix was found in two patients. In one patient the procedure was converted to laparoscopic appendectomy and in one to open surgery. In the third patient transgastric appendectomy was performed. The gastric access site was closed with the T-tag technique. Patients were allowed to drink and eat as soon as they woke up. Postoperatively patients were followed clinically and with standard laboratory tests daily until discharged. One patient (converted to open surgery) had a serious complication (pneumothorax). The transgastric approach to the abdominal cavity was shown to be feasible, but significant technical problems remain to be resolved.

Heating of carbon dioxide during insufflation alters the peritoneal fibrinolytic response to laparoscopic surgery : A clinical trial.

BACKGROUND: Laparoscopic surgery is evolving rapidly. It involves the creation of a pneumoperitoneum, mostly using carbon dioxide. Cooling of the peritoneum, due to insufflation, might traumatize the peritoneum and disturb peritoneal fibrinolysis, important in peritoneal healing processes. The current study was performed to elucidate the effects of the temperature of insufflation gas on the peritoneal fibrinolytic response to laparoscopic surgery. METHODS: Thirty patients scheduled for laparoscopic cholecystectomy were randomized in two groups: one group in which the pneumoperitoneum was created with carbon dioxide at room temperature, and one wherein carbon dioxide at body temperature was used. Peritoneal biopsies were taken at the start and at the end of surgery. Tissue concentrations of tPA antigen, tPA activity, uPA antigen, and PAI-1 antigen were measured using ELISA techniques. RESULTS: Peritoneal PAI-1 antigen levels were significantly higher at the end of the procedure in patients operated with carbon dioxide at room temperature (p < .05). A slight, but not significant, decrease in tPA antigen and activity was observed in both groups during the procedure. Peritoneal concentrations of uPa antigen did not change during the procedure. CONCLUSIONS: The temperature of carbon dioxide used for insufflation of the abdominal cavity affects peritoneal biology. Cooling of the peritoneum by unheated carbon dioxide causes increased peritoneal PAI-1 levels, important in peritoneal healing processes.

Effect of acidosis on expression of mesothelial cell plasminogen activator inhibitor type-1.

BACKGROUND: Abdominal mesothelial cells are exposed to carbon dioxide during laparoscopy. Previous data indicate that carbon dioxide increases release and expression of plasminogen activator inhibitor type-1 (PAI-1) and induces acidification. METHODS: To assess the impact resulting from a range of pH, human mesothelial cells were exposed to culturing media balanced to pH levels of 6.0 to 8.0 for 90 min. Samples from cell media were withdrawn at several time points. Concentrations of PAI-1 and PAI-1 activity were measured using enzyme-linked immunoassay techniques. To focus on the effect of clinically relevant pH, cells were subjected to pH 6.4 and 7.4. Samples were withdrawn for PAI-1 assessments and for PAI-1 mRNA analyses. RESULTS: During exposure to various levels of pH, PAI-1 secretion and activity were variable. However, 5 h after exposure, greater concentration and activity of PAI-1 were observed in acidified cultures. More PAI-1 mRNA was isolated after exposure of cells to a pH of 6.4, apparently indicating transcriptional regulation. CONCLUSIONS: Mesothelial cells seem to respond to acidification by an increased release and production of PAI-1 in vitro.

Carbidopa pretreatment improves image interpretation and visualisation of carcinoid tumours with 11C-5-hydroxytryptophan positron emission tomography.

PURPOSE: Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) as tracer is a promising imaging instrument in the management of patients with neuroendocrine tumours (NETs). However, high radioactivity concentrations in the urinary collecting system sometimes produce image reconstruction artefacts that can make detection of small NETs difficult. As a means to decrease urinary excretion of radioactivity and thereby improve image quality, we examined the effect of pretreatment with carbidopa (CD), a peripheral inhibitor of aromatic amino acid decarboxylase (AADC), which converts 5-HTP to serotonin (5-hydroxytryptamine, 5-HT). METHODS: Six patients with midgut carcinoid metastases were examined with 11C-5-HTP PET before and 1 h after oral administration of 100 or 200 mg of CD. RESULTS: There was a fourfold significant reduction of tracer uptake in the urinary collecting system after CD administration (p=0.0277, n=6), with a mean standard uptake value (SUV) of 155+/-195 before CD and 39+/-14 after CD. In tumour lesions there was a significant increase in SUV after CD administration (p<0. 0001, n=18), with a mean SUV of 11+/-3 before CD and 14+/-3 after CD. There was no difference between the doses (100 and 200 mg) of CD in this respect. In all patients, image interpretation and tumour detection were markedly improved after CD administration. CONCLUSION: We conclude that CD premedication improves 11C-5-HTP PET image quality and facilitates detection of NET lesions. Because of the similarity of metabolic pathways, this method could probably be applied to improve PET imaging using other tracers like 18F-DOPA and 11C-DOPA.

Bacterial vaginosis. Transmission, role in genital tract infection and pregnancy outcome: an enigma.

Whether bacterial vaginosis (BV) is acquired from an endogenous or an exogenous source is subject to controversy. Despite findings of an association between sexual behaviour and BV, some data indicate that BV is not a sexually transmitted infection in the traditional sense, while other data indicate that BV is an exogenous infection. A third aspect of BV is its tendency to go unnoticed by affected women. All of this will have a strong impact on how physicians view the risks of asymptomatic BV. This review focuses on whether or not BV should be regarded as a sexually transmitted infection (STI), its role in postoperative infections and pelvic inflammatory disease (PID), and on whether or not treatment of BV during pregnancy to reduce preterm delivery should be recommended. The reviewed studies do not lend unequivocal support to an endogenous or exogenous transmission of the bacteria present in BV. For women undergoing gynaecological surgery such as therapeutic abortion, the relative risk of postoperative infection is clearly elevated (approx. 2.3-2.8). A weaker association exists between BV and pelvic inflammatory disease. Data on treatment of BV as a way of reducing preterm delivery are inconclusive and do not support recommendations for general treatment of BV during pregnancy. The discrepant associations between BV and preterm birth found in recent studies may be explained by variations in immunological response to BV. Genetic polymorphism in the cytokine response--both regarding the TNF alleles and in interleukin production--could make women more or less susceptible to BV, causing different risks of preterm birth. Thus, studies on the vaginal inflammatory response to microbial colonization should be given priority.

Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography.

Neuroendocrine tumors (NETs) can be small and situated almost anywhere throughout the body. Our objective was to investigate whether whole-body (WB) positron emission tomography (PET) with (11)C-5-hydroxytryptophan (5-HTP) can be used as a universal imaging technique for NETs and to compare this technique with established imaging methods. Forty-two consecutive patients with evidence of NET and a detected lesion on any conventional imaging (six bronchial, two foregut, 16 midgut, and two thymic carcinoids; one ectopic Cushing's syndrome; four gastrinomas; one insulinoma; six nonfunctioning endocrine pancreatic tumors; one gastric carcinoid, one paraganglioma; and two endocrine-differentiated pancreatic carcinomas) were studied. The WB-(11)C-5-HTP-PET examinations were compared with WB-computed tomography (CT) and somatostatin receptor scintigraphy (SRS). Tumor lesions were imaged with PET in 95% of the patients. In 58% of the patients, PET could detect more lesions than SRS and CT and equal numbers in 34%, whereas in three cases, SRS or CT showed more lesions. In 84% (16 of 19 patients), PET could visualize the primary tumor compared with 47 and 42% for SRS and CT, respectively. The surgically removed PET-positive primary tumor sizes were 6-30 mm. To conclude, this study indicates that WB-(11)C-5-HTP-PET can be used as a universal imaging method for detection of NETs. This study also shows that WB-(11)C-HTP-PET is sensitive in imaging small NET lesions, such as primary tumors, and can in a majority of cases image significantly more tumor lesions than SRS and CT.

Developments in PET for the detection of endocrine tumours.

Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. (18)F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [(11)C]-5-hydroxytryptophan and [(11)C]-L-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[(18)F]-fluorodopamine and [(11)C]-hydroxyephedrine for phaeochromocytomas, and [(11)C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.

Demonstration of high monoaminoxidase-A levels in neuroendocrine gastroenteropancreatic tumors in vitro and in vivo-tumor visualization using positron emission tomography with 11C-harmine.

BACKGROUND AND AIMS: A majority of neuroendocrine gastroenteropancreatic (GEP) tumors can be detected by conventional radiological methods and scintigraphic techniques. Still there are problems to visualize small tumor lesions and non-functioning tumors. The aim of this study was to investigate some of the monoamine processing pathways of neuroendocrine GEP-tumors and try to find a new tracer substance for in vivo characterization and visualization by Positron Emission Tomography (PET). SUBJECTS AND METHODS: Autoradiography of tumor sections from 8 midgut carcinoids (MGC) and 8 endocrine pancreatic tumors (EPT) was performed with (11)C-labeled tracers for serotonin and dopamine transporters, serotonin HT2A-, dopamine D1- and muscarinic receptors and for monoamine oxidase A (MAO-A). The in vitro results initiated PET studies with (11)C-Harmine in 4 patients with MGC and 7 patients with EPT (one insulinoma, two glucagonomas and four non-functioning EPT). RESULTS: The MAO-A-ligand Harmine expressed specific in vitro binding of 87 +/-21% for MGC and 125 +/- 50% for EPT, compared to reference tissue (rat brain, 100%). All other substances showed relatively low specific binding. (11)C-harmine-PET could visualize tumors in all patients. The mean standardized uptake value (SUV) for MGC was 7.5 +/- 3.9 and for EPT 12.9 +/- 2.7, whereas the SUV of normal liver, intestine and pancreas were 3.1 +/- 0.5, 3.4 +/- 1.2 and 8.9 +/- 3.0 respectively. CONCLUSIONS: This study demonstrates in vitro and in vivo that neuroendocrine GEP-tumors are characterized by a high MAO-A-expression, thereby adding to the similarities of neuronal and neuroendocrine tissue. It also indicates a possible application for (11)C-harmine as a new PET-tracer for neuroendocrine GEP-tumors with the potential to visualize also non-functioning EPT's.

CO2 promotes plasminogen activator inhibitor type 1 expression in human mesothelial cells.

BACKGROUND: Previous observations have indicated that CO2 insufflation increases peritoneal plasminogen activator inhibitor type 1 (PAI-1) expression. METHODS: Primarily cultured human peritoneal mesothelial cells were exposed to either flowing or pressurized CO2 for 90 min. Unexposed cultures served as controls. Samples of cell culture media were taken at 0, 5, and 24 h after exposure to measure media pH, PAI-1, and tissue-type plasminogen activator (t-PA) protein release. Simultaneous samples were taken to measure PAI-1 and t-PA mRNA expression. RESULTS: Mesothelial cells exposed to flowing CO2 released more PAI-1 than those exposed to pressurized CO2 ( p < 0.001) and controls ( p < 0.001). Cells exposed to flowing CO2 had an increased PAI-1 mRNA expression at 5 h. CONCLUSIONS: CO2 increased mesothelial cell PAI-1 expression involving a transcriptional mechanism. These findings might provide a mechanism for adhesion formation and cancer progression following laparoscopic surgery.

11C-harmine as a potential PET tracer for ductal pancreas cancer: in vitro studies.

Our objective was to find a tracer in diagnosing human pancreatic cancer using positron emission tomography (PET). For this purpose in vitro test of pancreatic tissues with autoradiography was used. Autoradiography was performed with (11)C-harmine (a MAO-A-inhibitor) with and without competitive inhibition. Tissue preparations were obtained from normal human pancreas and pancreatic cancer. The uptake was compared with rat brain or pig brain, tissues with high expression of MAO-A. Nine autoradiography studies on 16 samples from five different human pancreatic cancers gave a significant level of specific binding of (11)C-harmine in 13, and 3 samples did not give a significant level of specific binding of (11)C-harmine. All 16 samples were analysed with autoradiography. Compared with rat brain, the uptake in the human cancers varied between 9 and 43% except for one tissue preparation which had a too low value for measurement. This study shows expression of MAO-A in human pancreatic cancer. This is readily characterised in vitro. The potential use of (11)C-harmine in the diagnosis of pancreatic cancer using PET might be limited, but further PET studies are necessary.

Peritoneal response to pneumoperitoneum and laparoscopic surgery.

BACKGROUND: It is generally believed that laparoscopic surgery inflicts less trauma to the peritoneum than open surgery. Local peritoneal fibrinolysis is a critical factor in adhesion development. The objective was to investigate fibrinolytic changes in the peritoneum during laparoscopic and open surgery. METHODS: At laparotomy (n = 10) peritoneal biopsies were taken at opening of the abdomen and just before closure. At laparoscopy (n = 12) opening peritoneal biopsies were taken after carbon dioxide insufflation, and closure biopsies just before exsufflation. Tissue concentrations of tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1) and the resulting tPA activity were assayed. RESULTS: Concentrations of tPA in peritoneal tissue declined during operation in both groups, but significantly so only in the laparotomy group (- 53 per cent; P = 0.01). PAI-1 levels were higher in opening biopsies from the laparoscopy group (P = 0.004). There was an increase in PAI-1 concentration during laparotomy, but not during laparoscopy. At the end of the operation, there was no difference between the groups. The resulting tPA activity did not differ between groups at opening or closure. In both groups there was a significant decline during operation (laparotomy: - 59 per cent, P = 0.02; laparoscopy: - 63 per cent, P = 0.01). CONCLUSION: These findings indicate that the peritoneal response to open and laparoscopic surgery is similar. The initial rise in peritoneal PAI-1 concentration during laparoscopy suggests an adverse effect of carbon dioxide insufflation, which might affect peritoneal repair.

Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas.

BACKGROUND: Considerable numbers of patients with low-grade gliomas experience an early malignant course and may benefit from aggressive treatment. These patients are difficult to identify using established prognostic factors. A retrospective study was performed to determine whether the (11)C-methionine uptake in tumor is a survival factor in adult patients with supratentorial gliomas classified as World Health Organization Grade 2. METHODS: The authors identified 89 patients with histologically confirmed low-grade gliomas in whom an (11)C-methionine positron emission tomography (PET) scan had been performed as part of the diagnostic tumor investigation from 1983 to 1998. Clinical data were collected, and the PET scans were re-evaluated according to a fixed protocol. The (11)C-methionine uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analyses. RESULTS: At the end of the study, 49 patients (55.1%) had died. The median overall survival was 5.7 years. Low methionine uptake was significantly favorable in the multivariate survival analysis (P = 0.04) along with oligodendroglioma (P = 0.003). In the histologic subgroups, (11)C-methionine uptake was an important survival factor among patients with astrocytomas (P = 0.05) and oligodendrogliomas (P = 0.03). Tumor resection was a favorable prognostic factor in patients with high methionine uptake (P = 0.01) but not in patients with low uptake. CONCLUSIONS: Baseline (11)C-methionine PET is a prognostic indicator in patients with low-grade gliomas. The results imply that PET is a valuable tool in the clinical management of these patients and may assist in the selection of patients for therapy.

PET with 11C-deuterium-deprenyl and 18F-FDG in focal epilepsy.

OBJECTIVES: This study compares positron emission tomography (PET) using 11C-deuterium-deprenyl (DED) with PET using 18F-fluorodeoxyglucose(18F-FDG) for examining epileptogenic regions in patients with focal epilepsy. MATERIAL AND METHODS: Twenty-three patients undergoing evaluation for epilepsy surgery were subjected to PET with DED. Fourteen patients had mesial temporal lobe epilepsy (TLE) and 9 patients had seizures of neocortical origin. In addition, 6 healthy control subjects were examined. Pixel-by-pixel analysis was used to generate graphical images of tracer distribution volume (intercept) and the accumulation rate (slope). Asymmetries with respect to relative intercept and slope were compared in patients with temporal lobe epilepsy (TLE), in patients with extra-temporal lobe epilepsy (exTLE), and in the control subjects. The results were compared with 18F-FDG-PET. RESULTS: Among the patients with TLE, significant differences between the epileptogenic and the contralateral lobe were found with DED intercept and FDG-uptake. No significant differences were found with DED slope. The exTLE and the control groups showed no significant differences between sides or lobes. CONCLUSIONS: This study indicates that PET with 11C-deuterium-deprenyl is a useful method for identifying TLE and is equivalent to PET with 18F-FDG in this sense. The method has little localizing value in seizures originating from neocortical structures.

Overproduction of transforming growth factor-beta1 (TGF-beta1) is associated with adhesion formation and peritoneal fibrinolytic impairment.

BACKGROUND: Reduction in peritoneal fibrinolytic capacity and increased transforming growth factor-beta1 (TGF-beta1) production are associated with adhesion development. This study investigated the expression of TGF-beta1 in peritoneal tissue, and possible correlation with components of the fibrinolytic system locally in peritoneal tissue. MATERIALS AND METHODS: Peritoneal samples were taken from 22 patients at relaparotomy. Samples of adhesions were collected from 10 patients. The patients were categorized into different groups depending on the quantity and the quality of adhesions. TGF-beta1 and components of the fibrinolytic system in tissue extracts were assayed using enzyme-linked immunosorbent assays. RESULTS: The concentration of active TGF-beta1 in peritoneal samples from patients with extensive adhesions was double (P <.01) that of healthy subjects, but the total levels of TGF-beta1 were similar (P =.63). In adhesion tissue, both active (P <.003) and total (P <.008) TGF-beta1 concentrations were more than twice as high as unaffected peritoneum. There was a significant correlation between the concentration of plasminogen activator inhibitor type 1 in peritoneal samples with active TGF-beta1 (P <.03, r = 0.693) and adhesion tissue with total TGF-beta1 (P =.001, r = 0.872). The other components of the fibrinolytic system did not correlate significantly with TGF-beta1. CONCLUSIONS: These data indicate that an overexpression of TGF-beta1 is associated with adhesion formation, possibly through a mechanism involving local regulation of plasminogen activator inhibitor type 1.

Analysis of 76Br-BrdU in DNA of brain tumors after a PET study does not support its use as a proliferation marker.

76Br-bromodeoxyuridine has previously been suggested as a PET tracer to characterize proliferation potential. However, in animal studies a large fraction of the tissue radioactivity is due to 76Br-bromide, which remains extracellular for extensive periods and contributes significantly to the level of radioactivity. The present project aimed at investigating whether in human brain tumors, sufficient amounts of 76Br-bromodeoxyuridine would be incorporated into DNA, to motivate further attempts with this tracer. Eight patients with brain tumors: 3 meningiomas, 2 astrocytoma grade IV, 1 astrocytoma oligodendroglioma grade II-IV and 2 metastases, were examined with PET and 76Br-BrdU on three occasions: immediately after injection of the tracer, at 4-6, and at 18-20 hours after administration. After the first PET study, diuresis was introduced and maintained for about 12 hours. About 20 hours after tracer administration, 200 mg/m(2) bromodeoxyuridine was administered to 7 patients median 5.8 (range 1-22) hours prior to operation allowing the immunohistochemical analysis of the proliferation potential. During the operation, tumor samples were taken and radioactivity in DNA extracted and measured. The uptake of radioactivity was higher in the tumors than in brain parenchyma. However, in the operative samples only 1-27% (average: 9%) of the radioactivity was found in the DNA fraction. The plasma radioactivity remained high throughout the study with only minimal signs of elimination by the diuresis. 76Br-BrdU is extensively metabolized to 76Br-bromide, and only a minor fraction of the radioactivity is found in the DNA fraction, making it unlikely that this tracer can be used for assessment of proliferation potential.