C-met protooncogene expression and its regulation by cytokines in the regenerating pancreas and in pancreatic cancer cells

BACKGROUND: Activation of the receptor c-met stimulates motility, mitosis, morphogenesis, processes involved in organ regeneration, or progression of malignancies. In the present study we investigated the expression of c-met protein in the regenerating pancreas and characterized the influence of cytokines on c-met expression. METHODS: Acute pancreatitis was induced in rats by cerulein injection. Rat acini and rat and human pancreatic cancer cells were stimulated with interleukin-1alpha (IL-1alpha), IL-6, tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-beta1 (TGF-beta1). C-met expression was analyzed by means of Western blotting and localization in pancreatic tissue by immunohistochemistry. RESULTS: C-met protein expression was significantly upregulated in the regenerating pancreas and localized in areas of regenerating tissue. Stimulation with cytokines resulted in a two- to threefold increase of c-met expression in vitro. CONCLUSION: Enhanced c-met expression after acute pancreatitis suggests that HGF/met has an important role in pancreatic regeneration, which is probably mediated by cytokines. This regulatory mechanism is also of importance in pancreatic cancer.     

Urinary excretion of N-methylhistamine as a marker of disease activity in inflammatory bowel disease

OBJECTIVE: Mast cells are thought to participate in the pathogenesis of inflammatory bowel disease (IBD). In this study, urinary excretion of N-methylhistamine (UMH), a stable metabolite of the mast cell mediator histamine, was evaluated as an indicator of disease activity in patients with IBD. METHODS: Urinary excretion of UMH (microg/mmol creatinine x m2 body surface area) was measured by radioimmunoassay in 55 controls, 56 patients with Crohn's disease, and in 36 patients with ulcerative colitis. Excretion rates were correlated with clinical, serological, and endoscopic disease activity, disease extent, and location. RESULTS: Urinary excretion of UMH was found to be significantly elevated in IBD. Patients with active Crohn's disease (7.1 +/- 4.2, p = 0.002 vs controls) and active ulcerative colitis (8.1 +/- 4.8, p = 0.02 vs controls) had higher rates of UMH excretion than patients in remission (6.3 +/- 3.8 and 5.2 +/- 2.3, respectively) or controls (4.6 +/- 1.9). In Crohn's disease and ulcerative colitis, a significant correlation of UMH excretion with clinical disease activity was obtained (Crohn's Disease Activity Index r2 = 0.58, Clinical Activity Index r2 = 0.57, p < 0.0001). Serologically, orosomucoid showed the best positive correlation with disease activity (Crohn's Disease Activity Index r2 0.80, Clinical Activity Index r2 = 0.86, p < 0.0001), but UMH excretion was found to reflect disease activity more accurately than C-reactive protein (Crohn's Disease Activity Index r2 = 0.46, Clinical Activity Index r2 = 0.42, p < 0.0001). No association between UMH excretion and disease type or localization could be found in Crohn's disease. However, UMH excretion correlated strongly with endoscopic severity of inflammation in Crohn's disease (Crohn's Disease Endoscopic Index of Severity r2 = 0.70, p < 0.0001) or disease extent in ulcerative colitis. CONCLUSIONS: Urinary excretion of the histamine metabolite UMH is enhanced in IBD. It appears to represent an integrative parameter to monitor clinical and endoscopic disease activity in IBD, which appears to be influenced most likely by mediators released from histamine-containing cells, such as intestinal mast cell subtypes.     

Mapping H5N1 highly pathogenic avian influenza risk in Southeast Asia

The highly pathogenic avian influenza (HPAI) H5N1 virus that emerged in southern China in the mid-1990s has in recent years evolved into the first HPAI panzootic. In many countries where the virus was detected, the virus was successfully controlled, whereas other countries face periodic reoccurrence despite significant control efforts. A central question is to understand the factors favoring the continuing reoccurrence of the virus. The abundance of domestic ducks, in particular free-grazing ducks feeding in intensive rice cropping areas, has been identified as one such risk factor based on separate studies carried out in Thailand and Vietnam. In addition, recent extensive progress was made in the spatial prediction of rice cropping intensity obtained through satellite imagery processing. This article analyses the statistical association between the recorded HPAI H5N1 virus presence and a set of five key environmental variables comprising elevation, human population, chicken numbers, duck numbers, and rice cropping intensity for three synchronous epidemic waves in Thailand and Vietnam. A consistent pattern emerges suggesting risk to be associated with duck abundance, human population, and rice cropping intensity in contrast to a relatively low association with chicken numbers. A statistical risk model based on the second epidemic wave data in Thailand is found to maintain its predictive power when extrapolated to Vietnam, which supports its application to other countries with similar agro-ecological conditions such as Laos or Cambodia. The model's potential application to mapping HPAI H5N1 disease risk in Indonesia is discussed.     

Jejunal tonometry for the diagnosis of gastrointestinal ischemia. Feasibility, normal values and comparison of jejunal with gastric tonometry exercise testing

BACKGROUND AND AIM: In most patients with chronic splanchnic syndrome the celiac artery is involved, enabling the use of gastric exercise tonometry as a diagnostic function test. In this study, we investigated the feasibility of combining gastric and jejunal exercise tonometry and determined the normal values. We investigated the potential diagnostic value of combining gastric with jejunal exercise tonometry. MATERIALS AND METHOD: Between 1998 and 2000, combined gastric and jejunal exercise tonometry tests were performed in a healthy volunteer and in patients suspected of chronic gastrointestinal ischemia. Using automated air tonometry, gastric (PgCO2) and jejunal PCO2 (PjCO2) were measured before, during and after 10-min of exercise. Luminal-arterial PCO2 gradients (DeltagPCO2 respectively DeltajPCO2) were calculated. In the patient cohort, final diagnosis of chronic ischemia was made by our institutional multidisciplinary working group on gastrointestinal ischemia. RESULTS: Jejunal tonometry was possible in 25 of 27 participants. The healthy volunteer was tested twice, yielding a total of 26 combined tests. Mean normal basal PjCO2 was 0.9 kPa higher than PgCO2. The calculated upper threshold (mean+2SD) of normal DeltajPCO2 was 1.4 kPa. In five of eight patients with chronic gastrointestinal ischemia gastric exercise tonometry was abnormal, in one, both gastric and jejunal tonometry were abnormal, in two only jejunal exercise tonometry was abnormal. CONCLUSION: Combined gastric and jejunal exercise tonometry is a feasible procedure that is relatively easy to perform. On the basis of this pilot study, jejunal tonometry seems to have a small additional value in the diagnosis of chronic gastrointestinal ischemia.     

Paced Respiration for Vasomotor and Other Menopausal Symptoms: A Randomized, Controlled Trial

BACKGROUND

Paced respiration has been internationally recommended for vasomotor symptom management, despite limited empirical evidence.

OBJECTIVE

To evaluate efficacy of a paced respiration intervention against breathing control and usual care control for vasomotor and other menopausal symptoms.

DESIGN

A 16-week, 3-group, partially blinded, controlled trial with 2:2:1 randomization and stratification by group (breast cancer, no cancer), in a Midwestern city and surrounding area.

PARTICIPANTS

Two hundred and eighteen randomized women (96 breast cancer survivors, 122 menopausal women without cancer), recruited through community mailings and registries (29 % minority).

INTERVENTIONS

Training, home practice support, and instructions to use the breathing at the time of each hot flash were delivered via compact disc with printed booklet (paced respiration intervention) or digital videodisc with printed booklet (fast shallow breathing control). Usual care control received a letter regarding group assignment.

MAIN MEASURES

Hot flash frequency, severity, and bother (primary); hot flash interference in daily life, perceived control over hot flashes, and mood and sleep disturbances (secondary). Intervention performance, adherence, and adverse events were assessed.

KEY RESULTS

There were no significant group differences for primary outcomes at 8-weeks or 16-weeks post-randomization. Most intervention participants did not achieve 50 % reduction in vasomotor symptoms, despite demonstrated ability to correctly do paced respiration and daily practice. Statistically significant differences in secondary outcomes at 8 and 16 weeks were small, not likely to be clinically relevant, and as likely to favor intervention as breathing control.

CONCLUSIONS

Paced respiration is unlikely to provide clinical benefit for vasomotor or other menopausal symptoms in breast cancer survivors or menopausal women without cancer.     

Use of granulocyte macrophage colony stimulating factor in children after orthotopic liver transplantation

Background/Aims: Bacterial infections complicate the course of up to 80% of pediatric liver transplant recipients, and in some case, neutropenia, surgical complications and/or antibiotic resistance prevent successful control of sepsis. The aim of the present study was to evaluate the safety and efficacy of granulocyte macrophage colony stimulating factors (GM-CSF) in treating neutropenia following pediatric orthotopic liver transplantation.Methods: Among a cohort of 430 pediatric orthotopic liver transplantation recipients, 13 children (12 months to 15 years, median 2 years, 10 males) received 15 courses of GM-CSF, 5 μg · kg⁻¹ · d⁻¹ subcutaneously, during their post-transplant course. In nine cases, the initial neutrophil count was below 1000/mm³. Ten patients were infected. Three received GM-CSF for severe sepsis without neutropenia. The mean duration of treatment was 16.3 days (range 4–49).Results: In all but one neutropenic patient the neutrophil count increased above 1500/mm³ and the mean neutrophil count increased from 1392±1912/mm³ (range 130–7170, median 640) to 4508±2459/mm³ (range 350–9630, median 4390) (p<0.01). Only one neutropenic patients (FK506 related) failed to respond to treatment. No rejection episode was induced by treatment, no side effects were noted, and patients with sepsis were cured.Conclusion: In these patients, GM-CSF was safe, it achieved a significant increase in neutrophilic count, and was beneficial in patients with severe bacterial infections. This compound may prevent infectious complications in neutropenic patients and may benefit patients with severe sepsis with or without neutropenia.     

Adult liver transplantation: UCL experience.

OBJECTIVE: To evaluate the impact of standardized operative and peri-operative care on the outcome of liver transplantation in a single center series of 395 adult patients. METHOD AND MATERIAL: Between February 1984 and December 31, 1998, 451 orthotopic liver transplantations were performed in 395 adult patients (> or = 15 years) at the University Hospitals St-Luc in Brussels. Morbidity and mortality of the periods 1984-1990 (Gr I--174 pat.) and 1991-1998 were compared (Gr II--221 pat.). During the second period anti-infectious chemotherapy and perioperative care were standardized and surgical technique changed from classical orthotopic liver transplantation with recipients' vena cava resection (and use of veno-venous bypass) towards liver implantation with preservation of the vena cava (without use of bypass). Immunosuppression was cyclosporine based from 1984 up to 1996 and tacrolimus based during the years 1997 and 1998. Immunosuppression was alleviated during the second period due to change from quadruple to triple and even double therapy and due to the introduction of low steroid dosing and of steroid withdrawal, once stable graft function was obtained. Indications for liver grafting were chronic liver disease (284 pat--71.9%), hepatobiliary tumor (52 pat--13.2%), acute liver failure (40 pat--10.1%) and metabolic disease (19 pat--4.8%). Regrafting was necessary because of graft dysfunction (21 pat), technical failure (12 pat), immunological failure (18 pat) and recurrent viral allograft disease (5 pat); three of these patients were regrafted at another institution. Follow-up was complete for all patients with a minimum of 9 months. RESULTS: Actuarial 1, 5 and 10 years survival rates for the whole group were 77.9%, 65.7% and 58.3%. These survival rates were respectively 77.3%, 69.7%, 62.5% and 73.2%, 59.6% 51.4% for benign chronic liver disease and acute liver failure; those for malignant liver disease were 80.6%, 44.3% and 36.7%. Early (< 3 months) and late (> 3 months) posttransplant mortalities were. 14.4% (57 pat) and 21.2% (84 pat). Early mortality lowered from 20% in Gr I to 9.4% in Gr II (p < 0.02); this was due to a significant reduction during the second period of bacterial (99/174 pat.--56.9% vs 82/221 pat.--37.1%), fungal (14 pat.--8% vs 7 pat.--3.2%) and viral (87 pat.--50% vs 49 pat.--22.2%) infections (p < 0.05) as well as of perioperative bleeding (92 pat.--52.9% vs 39 pat.--17.6%--p < 0.001). Late mortality remained almost identical throughout the two periods as lethal outcome was mainly caused by recurrent allograft diseases, cardiovascular and tumor problems. Morbidity in these series was important considering that almost, half of the patients had a technical complication, mostly related to bleeding (131 pat--33.2%) and biliary problems (66 pat--16.7%). Retransplantation index was 1.1 (54 pat.--14%). Early retransplantation mortality was 24%; it lowered, although not yet significantly, during the second period (8/25 pat.--32% vs. 5/29 pat.--17.2%). CONCLUSION: Despite a marked improvement of results, liver transplantation remains a major medical and surgical undertaking. Standardization of operative and perioperative care, less haemorraghic surgery and less aggressive immunosuppression are the keys for further improvement.     

Chromosome aberrations and cytogenetic intratumor heterogeneity in chondrosarcomas

Clonal chromosome aberrations identified after short-term culture are presented for 13 chondrosarcomas; in 5 cases both the primary tumors and local recurrences were studied. The stemline chromosome number was hypodiploid or hyperhaploid in 9 tumors. The most frequent numerical anomalies were, in falling order of frequency, loss of chromosomes Y, 10, 13, and 6, and gain of chromosomes 7 and 20. No recurrent structural rearrangement was found, but chromosome bands 5q13, 1q21, 7p11, and 20q11 were each involved in three different rearrangements. Karyotypic heterogeneity was assessed in two different ways: as the presence of more than one clone in one sample and as the presence of different clones in different samples from the same surgical specimen. Clonal karyotypic evolution was demonstrated in 6 of the 7 cases in which two or more samples could be investigated. All 6 showed intersample heterogeneity. Intrasample heterogeneity was found in only 5 of the 28 samples with aberrations. By comparing the incidences of the nonrandomly occurring aberrations in stemlines and sidelines in the heterogeneous tumors, it was possible to conclude that loss of chromosome 13 and rearrangement of band 5q13 were early events in the clonal evolution.Abbreviation EMC extraskeletal myxoid chondrosarcoma     

Mammalian Erv46 localizes to the endoplasmic reticulum-Golgi intermediate compartment and to cis-Golgi cisternae

Yeast endoplasmic reticulum (ER) vesicle protein Erv46p is a novel membrane protein involved in transport through the early secretory pathway. Investigation of mammalian Erv46 (mErv46) reveals that it is broadly expressed in tissues and protein-secreting cells. By immunofluorescence microscopy, mErv46 displays a crescent-shaped perinuclear staining pattern that is characteristic of the Golgi complex. Quantitative immunoelectron microscopy indicates that mErv46 is restricted to the cis face of the Golgi apparatus and to vesicular tubular structures between the transitional ER and cis-Golgi. Minor amounts of mErv46 reside in ER membranes and later Golgi cisternae. On Brefeldin A treatment, mErv46 redistributes to punctate structures that costain for ERGIC53. Depletion of mErv46 protein by RNA interference caused no apparent structural changes in the intermediate compartment or Golgi complex. These findings place mErv46 in a group of itinerant proteins that cycle between the ER and Golgi compartments such as ERGIC53 and the p24 proteins.