Report of an Amsterdam working group on Barrett esophagus.
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Barrett Esophagus↗
Biomedical subjects
A Bosma
Publications and source records attributed to A Bosma.
Choledochal cysts: age of presentation, symptoms, and late complications related to Todani's classification.
PURPOSE: The aim of this study was to compare presentation, complications, diagnosis, and treatment of choledochal cysts in pediatric and adult patients. METHODS: Forty-two patients were analyzed after subdivision into 3 groups: group A, less than 2 years (n = 10); group B, 2 to 16 years (n = 11); group C, greater than 16 years (n = 21). RESULTS: The cysts were classified as extrahepatic (n = 33), intrahepatic (n = 5), and combined (n = 4). Seventy-six percent of patients presented with abdominal pain, (20 of 21 group C), and 57% with jaundice, (10 of 10 group A). Cholangiocarcinoma occurred in 6 patients, 4 of whom had previously undergone internal drainage procedures. Excision of the extrahepatic cyst was performed in 27 of 37 patients. Five patients, of whom, 4 had cholangiocarcinoma, were beyond curative treatment at the time of diagnosis. Six patients had died at the closure of this study, 5 of them had carcinoma. CONCLUSIONS: Presenting symptoms are age dependent with jaundice prevailing in children and abdominal pain in adults. In view of the high risk of cholangiocarcinoma, early resection and not internal drainage is the appropriate treatment of extrahepatic cysts. Patients who had undergone internal drainage in the past still should undergo resection of the cyst.
Abdominal Pain↗
From genome to vaccine: in silico predictions, ex vivo verification.
Bioinformatics tools enable researchers to move rapidly from genome sequence to vaccine design. EpiMer and EpiMatrix are computer-driven pattern-matching algorithms that identify T cell epitopes. Conservatrix, BlastiMer, and Patent-Blast permit the analysis of protein sequences for highly conserved regions, for homology with other known proteins, and for homology with previously patented epitopes, respectively. Two applications of these tools to epitope-driven vaccine design are described in this review. Using Conservatrix and EpiMatrix, we analyzed more than 10000 HIV-1 sequences and identified peptides that were potentially immunostimulatory and highly conserved across HIV-1 clades. MHC binding assays and CTL assays have been carried out: 50 (69%) of the 72 candidate epitopes bound in assays with cell lines expressing the corresponding MHC molecule; 15 of the 24 B7 peptides (63%) stimulated gamma-interferon release in ELISpot assays. These results lend support to the bioinformatics approach to selecting novel, conserved, HIV-1 CTL epitopes. EpiMatrix was also applied to the entire 'proteome' derived from two Mycobacterium tuberculosis (Mtb) genomes. Using EpiMatrix, BlastiMer, and Patent-Blast, we narrowed the list of putative Mtb epitopes to be tested in vitro from 1600000 to 3000, a 99.8% reduction. The pace of vaccine design will accelerate when these and other bioinformatics tools are systematically applied to whole genomes and used in combination with in vitro methods for screening and confirming epitopes.
AIDS Vaccines↗
Incidence of benign lesions in patients resected for suspicious hilar obstruction.
BACKGROUND: The differentiation between benign and malignant strictures at the hepatic hilum is difficult. The aim of this study was to assess the clinical and radiographical features of hilar lesions in a series of patients resected for a presumed cholangiocarcinoma. METHODS: Of 132 consecutive patients undergoing resection for a suspicious lesion at the hepatic hilum, 20 (15 per cent) had a histopathologically proven benign tumour, diagnosed as chronic fibrosing or erosive inflammation, sclerosing cholangitis, or a granular cell tumour. All medical files and radiological examinations of the patients were reassessed. RESULTS: Clinical symptoms were considered suspicious in 16 of 19 patients. At ultrasonography only one of 16 patients had an unsuspicious examination. In 14 of 18 patients cholangiographic images were considered suspicious. Overall reassessment confirmed a suspicious lesion in all 20 patients. CONCLUSION: Because of the limitations of current diagnostic tools, a false-positive preoperative diagnosis of malignancy resulted in a 15 per cent resection rate of benign lesions in this series of suspicious hilar strictures.
Abdominal Pain↗
Continuous or intermittent vascular clamping during hemihepatectomy in pigs: hyaluronic acid kinetics in the assessment of early microvascular liver damage.
OBJECTIVE: To assess the uptake of hyaluronic acid (HA) as a marker of microvascular damage in a model of hemihepatectomy in pigs having continuous or intermittent vascular inflow occlusion. DESIGN: Prospective, animal study. SETTING: Laboratory for experimental surgery, University hospital, The Netherlands. INTERVENTIONS: Total liver ischaemia was achieved during 90 minutes by continuous (n = 5) or intermittent (n = 5) occlusion of the portal vein and hepatic artery followed by 120 minutes of reperfusion. In a second series of pigs (n = 8) a left hemihepatectomy was added to the protocol. MAIN OUTCOME MEASURES: Uptake of exogenous HA was assessed before ischaemia and after 120 minutes of reperfusion, together with the galactose elimination capacity. Plasma activities of aspartate aminotransferase (AST), alanine amino transferase, and lactate dehydrogenase were measured and specimens of liver were obtained for histopathological examination. RESULTS: HA uptake was slightly reduced after reperfusion in unresected livers compared with uptake before ischaemia. After hemihepatectomy HA uptake after reperfusion was significantly reduced after both continuous and intermittent occlusion, but more HA was taken up after continuous occlusion (p = 0.02). Release of AST after reperfusion was increased only after hemihepatectomy. CONCLUSIONS: Microvascular damage, as assessed by HA uptake capacity, significantly contributed to normothermic ischaemia and reperfusion injury in porcine liver. Vascular inflow occlusion during 90 minutes in combination with hemihepatectomy resulted in less liver damage when vascular occlusion was continuous rather than intermittent.
Animals↗
Long-term survival after resection of proximal bile duct carcinoma (Klatskin tumors).
This retrospective study in 79 surgically treated patients with a proximal bile duct carcinoma revealed 12 patients with a median age of 59.5 years (range 21-73 years) who survived more than 5 years. These 12 patients were analyzed to identify specific patient characteristics for long-term survival. Fifteen patients died from postoperative complications and were excluded from this survival analysis. In relation with preoperative Bismuth classification, there were 3 (20%) long-term survivors of 15 patients with type I tumors and 9 (35%) long-term survivors of 26 patients with type II tumors. In the group of type III and IV tumors, there were no long-term survivors. Concerning the type of resection, 9 of 51 (18%) patients had long-term survival after local resection and 3 of 13 (23%) patients after local resection combined with hemihepatectomy. Complete tumor-free surgical specimen margins were found in only 4 of 64 cases (6%), among which only one patient survived more than 5 years. Negative proximal bile duct margins, absence of multifocality, and diploid tumors showed a significant correlation with long-term survival. There was no significant correlation between long-term survival and postoperative radiotherapy. Of the 12 long-term survivors, 5 died after 5 years: 2 had developed metastases and 1 a local recurrence; the other 2 died of a metastasis of an ovarian adenocarcinoma and cachexia, respectively. The remaining seven patients were still alive at the completion of this study. The mean survival of the 64 patients analyzed in this study (in which hospital mortality was excluded) was 33.7 months, with a median survival of 18.8 months. In conclusion, the preoperative Bismuth classification of the tumor, absence of multifocality, diploid-type tumors, and negative proximal bile duct margins at histopathologic examination were the only significant prognostic factors for long-term survival.
Adult↗
Prolonged continuous or intermittent vascular inflow occlusion during hemihepatectomy in pigs.
OBJECTIVE: To assess ischemia and reperfusion (I/R) injury in a hemihepatectomy model in pigs after prolonged continuous or intermittent vascular inflow occlusion in the liver. SUMMARY BACKGROUND DATA: Massive intraoperative blood loss during liver resections can be prevented by temporary vascular inflow occlusion, consequently leading to ischemia and reperfusion injury in the remnant liver. Previously, in a pig liver resection model in which only limited I/R injury was induced during brief (90 min) vascular inflow occlusion, the authors demonstrated reduced I/R injury after continuous (CNT) occlusion, compared to intermittent (INT). This liver resection study on pigs was undertaken to assess I/R injury after prolonged (120 min) CNT or INT occlusion. METHODS: In pigs (37.0 +/- 1.5 kg), liver ischemia during 2 hours was CNT (n = 6) or INT (n = 6) (eight subsequent periods of 12 min ischemia and 3 min recirculation), followed by 6 hours of reperfusion. A left hemihepatectomy (45.5% +/- 1.4%) was performed within the first 12 minutes of ischemia. No hepatic pedicle clamping or liver resection was performed in control experiments (n = 6). Microvascular damage was assessed by hyaluronic acid (HA) uptake capacity of the liver (parameter of early sinusoidal endothelial cell damage) and restoration of intrahepatic tissue pO2 during reperfusion. Hepatocellular damage was tested by plasma concentrations of aspartate aminotransferase (AST), alanine aminotransferase, and lactate dehydrogenase (LDH). RESULTS: Hyaluronic acid uptake after 6 hours of reperfusion, compared to preischemic uptake, was unaltered in the control group, but was significantly reduced in both resection groups. However, more HA was taken up after INT occlusion, compared to CNT (60.4% +/- 5.6% and 39.5% +/- 3.7%, respectively; ANOVA: p = 0.001). Intrahepatic tissue pO2 distribution after 6 hours of reperfusion more closely returned to preischemic configuration in the INT group than in the CNT group, indicating reduced microcirculatory disturbances after INT occlusion. Release of AST and LDH after 6 hours of reperfusion was significantly increased in both CNT and INT groups. Lower AST levels, however, were found after INT occlusion than after CNT occlusion (267.0 +/- 74.7 U/l and 603.3 +/- 132.4 U/l, respectively; p = 0.06). CONCLUSIONS: Intermittent hepatic vascular inflow occlusion during prolonged liver ischemia in pigs resulted in less microcirculatory and hepatocellular injury, compared to continuous occlusion. Intermittent clamping is preferable when prolonged periods of vascular inflow occlusion are applied during liver resections.
Animals↗
Occurrence of implantation metastases after resection of Klatskin tumors.
BACKGROUND: We found a high proportion of patients with implantation metastases during follow-up after resection of a proximal cholangiocarcinoma. A remarkable fact was that all these patients had undergone preoperative endoscopic retrograde cholangiopancreatography (ERCP) with placement of a stent. ERCP is frequently used in the assessment of the proximal extension of Klatskin tumors and is usually followed by stent insertion for biliary drainage. The aim of this study was to analyze the possible risk factors leading to implantation metastases in this series of patients. METHODS: Fifty-two patients who had undergone resection of a Klatskin tumor were divided into 2 groups, comparing patients who had had preoperative ERCP and stent placement (n = 41) and patients without preoperative drainage (n = 11). RESULTS: Eight patients developed implantation metastases within 1 year after resection, all of whom had undergone preoperative stent placement (8/41, 20%). None of the patients without preoperative stenting developed implantation metastases. In 22 patients bile samples were taken during operation. Sixteen (72.7%) patients had malignant cells and 4 (18.2%) patients atypical cells in the bile sample. There was no difference in cytology results between the 2 groups. CONCLUSION: This study suggests that preoperative ERCP with biliary drainage is associated with a higher frequency of implantation metastases after resection of Klatskin tumors. A properly planned prospective study, however, is needed to determine whether bile duct stenting in patients with resectable bile duct tumors is a true risk factor for the development of implantation metastases.
Bile Duct Neoplasms↗
Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma.
PURPOSE: To perform an analysis of the results obtained with radiotherapy in patients with either resectable or unresectable cholangiocarcinoma of the proximal bile ducts. Emphasis will be paid to analyse the role of radiotherapy, particularly brachytherapy. PATIENTS AND METHODS: Between 1985 and 1997, 109 patients received radiotherapy. In 71 patients (group I) tumor resection was combined with postoperative irradiation in 52 patients and pre- plus post-operative irradiation in 19 patients. Among this group, 41 patients had a boost of 10 Gy to the biliodigestive anastomosis using intraluminal brachytherapy. Median total dose was between 50-55 Gy. The other 38 patients (group II) had an unresectable tumor at laparotomy (16 patients) or were considered primary unresectable because locoregional tumor extension (22 patients). Brachytherapy boost through a nasobiliary approach was given to 19 patients (22-25 Gy). The median total dose varied between 60 to 68 Gy. Mean follow-up was 25 +/- 23 months. RESULTS: In group I, the survival rates at 1, 3, and 5 year were 84%, 37%, and 24%, respectively. Median survival was 24 months. Sixteen patients did live longer than 4 years. Analysis of prognostic factors among resected patients showed the tumor differentiation grade, microscopically involved margins other than the upper (hepatic) and lower (choledocus) resection parameters analysed, only the total dose had influence on margins, and elevated alkaline phosphatase as factors which significantly influence survival. From the different radiotherapy prognosis, patients receiving a total dose above 55 Gy had a shorter survival. It is important to note that patients receiving brachytherapy boost did not have a better survival than patients treated with external beam irradiation alone. Preoperative radiotherapy did not have impact on survival but recurrences in the surgical scars were not observed as compared to 15% recurrences if preoperative radiotherapy was not given. In group II the median survival was 10.4 months. Survival rates at 1 and 2 year were 43% and 10%, respectively. The only significant prognostic factor found was if unresectability was defined primarily or during laparotomy. As it was the case in group I, brachytherapy boost did not have influence on prognosis as compared to external beam irradiation alone. Observed late complications consisted of duodenal stenosis, upper digestive tract bleeding and cholangitis. Probably these complications were not only attributable to radiotherapy, as tumor relapse was also present in the majority of the cases. CONCLUSIONS: The role of radiotherapy either as adjuvant or as primary treatment remains to be demonstrated in prospective randomised studies. From our results, it seems that high radiation doses could be dangerous and could detriment prognosis. Brachytherapy boost was not superior to treatment with external beam irradiation alone.
Adult↗
[Treatment of 8 patients with an acute hemorrhage in a hepatocellular adenoma at the Academic Medical Center, Amsterdam].
OBJECTIVE: Evaluation of the early management and treatment of patients with an acute haemorrhage in a hepatocellular adenoma. DESIGN: Descriptive. SETTING: Academic Medical Centre (AMC), Amsterdam, the Netherlands. METHOD: In the period 1989-1996, eight women with an acute haemorrhage in a hepatocellular adenoma were treated in the AMC. Four had an intrahepatic bleeding which initially was treated conservatively. The other four patients arrived with a haemoperitoneum for which laparotomy was immediately performed: in three, the haemorrhage was stopped by gauze tamponade and in one, the tumour was removed by bisegmental resection. In all seven initially not subjected to resection, the tumour was removed later by partial hepatectomy. RESULTS: The condition stabilized in all patients after initial conservative treatment or after laparotomy and gauze tamponade. The tamponade gauzes were removed after 48 hours. The definite treatment, after 2-4 months, consisted of right-sided hemihepatectomy (four patients), left-sided hemihepatectomy and (bi)segmental resection (three). Three patients showed postoperative complications: infected haematoma, bile leakage and a non-infected subphrenic haematoma. In half the patients, the pathological diagnosis was not certain owing to the effects of the recent bleeding. In one patient, a highly differentiated hepatocellular carcinoma could not be excluded. CONCLUSION: Patients with a haemorrhage in a hepatocellular adenoma without signs of rupture should be treated conservatively. An effective and safe first treatment of an unstable patient with haemoperitoneum is laparotomy and staunching of the bleeding by gauze tamponade. This management is feasible in every general hospital, following which the patient may be referred to a specialized centre for further diagnosis and treatment. It is advisable to remove the tumour surgically after about three months.
Acute Disease↗
Bacterial translocation from the biliary tract to blood and lymph in rats with obstructive jaundice.
BACKGROUND: The disruption of the hepatocyte tight junctions observed in biliary obstruction suggests altered permeability of the blood-bile barrier. In this study the role of biliary obstruction and increased biliary pressure on the translocation of bacteria from biliary tract to bloodstream and lymphatic system were evaluated. MATERIALS AND METHODS: Rats underwent distal bile duct ligation (BDL, n = 33) for two weeks or a sham celiotomy (n = 21). Seventeen of the 33 BDL rats underwent subsequent biliary decompression by a choledochojejunostomy (CJ). Two weeks after the final operation, a laparotomy was performed again and the CBD, the thoracic duct, and the caval vein were canulated. Next, a suspension containing 10(8) Escherichia coli/ml was retrogradely infused in the CBD for 5 min at 5 or 20 cm H2O above the secretory biliary pressure. RESULTS: A higher biliary infusion pressure resulted in a significant increase of cfu E.coli per milliliter of blood in all the three groups (Sham, BDL, CJ). BDL rats showed significantly more bacterial translocation to the bloodstream than the shams. After biliary decompression, translocation normalized to the control levels. At 5 cm H2O infusion pressure only one lymph culture was positive (CJ group). At 20 cm H2O overpressure, nine lymph cultures were E.coli positive (P = 0.03). These were found mainly in groups with a nonobstructed bile duct (Sham and CJ 40% vs BDL 10%). CONCLUSION: Translocation of bacteria from biliary tract to bloodstream increased at higher intrabiliary pressures. Longstanding bile duct obstruction was an independent determinant for cholangiovenous reflux. Bacterial translocation to the lymphatic system did not parallel translocation to the bloodstream, although in the nonobstructed biliary tract, increased bacterial translocation to the lymphatic system was pressure related.
Animals↗
Prognostic value of cell proliferation (Ki-67 antigen) and nuclear DNA content in clinically resectable, distal bile duct carcinoma.
BACKGROUND: The aim of this study was to investigate the prognostic value of cell proliferation (Ki-67 antigen) and DNA content in patients resected for distal bile duct carcinoma (DBDC). METHODS: Formalin-fixed tumor specimens of 35 patients with resected DBDC and a long-term clinical follow-up were analyzed. MIB-1 antibody was used for Ki-67 antigen detection to determine the proportion of proliferating cells. DNA content was measured using flow cytometry. RESULTS: A significant correlation was found between a low MIB-1 index (<20%) and survival (P <.05). Of the 35 tumor specimens, 34 specimens were evaluable by flow cytometry: 22 carcinomas were diploid (65%), and 12 were aneuploid (35%). The median DNA index of aneuploid tumors was 1.36 (range, 1.09 to 1.76). No correlation of DNA-ploidy with survival time was found. CONCLUSION: In contrast to DNA-ploidy pattern, Ki-67 antigen expression showed prognostic significance in resectable DBDC. A Ki-67 positive ratio of > or =20% was associated with decreased survival time.
Adult↗
Synaptic transmission in the rat dentate gyrus after adrenalectomy.
Granule cells in the rat hippocampal dentate gyrus contain intracellular receptors for the adrenal hormone corticosterone. Activation of these receptors seems essential for granule cell viability, since removal of the adrenal gland (adrenalectomy) results within three days in apoptotic-like degeneration of granule cells. In the present study we used extracellular in vitro recording methods to study the synaptic transmission in the dentate gyrus of adrenalectomized animals, in sham-operated controls and adrenalectomized rats treated with a low dose of corticosterone. We found that particularly three days after adrenalectomy orthodromic field responses in the dentate gyrus were reduced in amplitude. Corticosterone-treated rats did not show this impairment of synaptic transmission. Antidromically-evoked field responses were also reduced after adrenalectomy, which indicates that postsynaptic cell properties rather than signal transduction in the synapses are under steroid control. Responses to paired pulse stimulation were only marginally affected, suggesting that interneuronal networks may be less affected by the hormones than the principal cells. These electrophysiological data indicate that adrenalectomy induced apoptotic-like degeneration in the hippocampal dentate gyrus is clearly associated with impaired processing of incoming information.
Adrenalectomy↗
[Pre- and postoperative irradiation in the treatment of resectable Klatskin tumours].
Proximal bile duct carcinoma (Klatskin tumour) is infrequent and difficult to treat. In principle, surgery is indicated. The usefulness of irradiation after resection is controversial in the literature. This article describes the experiences gained in the Academic Medical Centre of Amsterdam with pre- and postoperative irradiation of resectable Klatskin tumours. Preoperative irradiation (10.5 Gy) is administered to devitalize detached tumour cells in the bile, to prevent implantation metastases after resection. Postoperative irradiation has been administered since 1986 according to protocol. An analysis of 71 patients, of whom 48 had been irradiated after resection while 23 had not, showed a statistically significant prolongation of survival in the group irradiated postoperatively. Radiotherapy was administered externally (55 Gy) or in combination with internal radiotherapy (45 Gy external, 10 Gy internal). For internal irradiation, the source of radiation (Iridium-192) was introduced along the bile duct anastomoses via the soma formed by the blind end of the Roux-Y jejunal loop used for bile duct reconstruction. Since internal irradiation in combination with external irradiation caused more complications, while there was no difference of survival from patients only irradiated externally, the complete postoperative irradiation is currently being given from the outside. Pre- and postoperative irradiation may contribute to the success of the treatment of the resectable Klatskin tumour.
Bile Duct Neoplasms↗
Effects of adrenalectomy on Ca2+ currents and Ca2+ channel subunit mRNA expression in hippocampal CA1 neurons of young rats.
Previously it was found that the amplitude of Ca currents in CA1 hippocampal neurons increases after adrenalectomy (ADX) of young adult rats. Preliminary data suggested that this effect of ADX is age-dependent. In the present study we therefore investigated the effect of ADX on Ca currents in three age groups: rats that were 1, 3, or 6 months old. It appeared that ADX of the youngest age group resulted in a selective enhancement of sustained, high threshold Ca currents. By contrast, ADX of the oldest rats enhanced only the low threshold, transient Ca current amplitude. The age dependency of the ADX-induced effects can be explained by developmental changes in Ca current properties in the adrenally intact rats with which ADX animals were compared. Data from acutely dissociated cells, which lack most of their dendrites, suggest that the ADX-induced changes of Ca current properties are at least partly targeted at currents generated in the distal dendrites. No significant changes were observed with age or after ADX for the mRNA expression of the alpha 1D Ca channel subunit, which forms the ionpore of the sustained high threshold L-type Ca channel. We can therefore presently not exclude that the altered amplitude of Ca current with age and ADX is due to changes in ion channel function rather than in the total number of these channels.
Adrenalectomy↗
Incidence and clinical findings of benign, inflammatory disease in patients resected for presumed pancreatic head cancer.
BACKGROUND: The differentiation between cancer and benign disease in the pancreatic head is difficult. The aim of this study was to examine common features in a group of patients that had undergone pancreatoduodenectomy for a benign, inflammatory lesion misdiagnosed as pancreatic head cancer. METHODS: Among 220 pancreatoduodenectomies performed on the suspiscion of pancreatic head cancer, an inflammatory lesion in the pancreas or distal common bile duct was diagnosed in 14 patients (6%). Of these patients, all preoperative clinical information and radiologic images (ultrasound, endoscopic retrograde cholangio-pancreaticography [ERCP]) were critically reassessed. For each examination, the suspicion of cancer was scored on a 0/+/++ scale. RESULTS: Clinical presentation (pain, weight loss, jaundice) raised a suspicion of cancer in 12 patients. On ultrasound, a tumor (mean size: 2.8 cm) was found in the pancreatic head in 13 patients; 12 of 14 ultrasound examinations raised a suspicion of cancer. ERCP showed a distal common bile duct stenosis (length: 1 to 4 cm), stenosis of the pancreatic duct (length: 1 to 5 cm), or a "double duct" stenosis, suspicious for cancer in 13 evaluable patients. The overall index of suspicion was + in seven patients and ++ in seven patients, confirming the initial interpretation of preoperative data. CONCLUSION: When undertaking pancreatoduodenectomy for a suspicious lesion in the pancreatic head, it is necessary to expect at least a 5% chance of resecting a benign, inflammatory lesion masquerading as cancer.
Cholangiopancreatography, Endoscopic Retrograde↗
Rat ferritin-H: cDNA cloning, differential expression and localization during hepatocarcinogenesis.
Elevated serum ferritin levels, especially of the H subunit, accompany many clinical malignancies. By using the subtraction-enhanced display technique, we have recently isolated several cDNA clones which are over-expressed in rat hepatocellular carcinoma induced by diethylnitrosamine. One 830-base-pair clone was 88% similar to human ferritin-H cDNA and encoded a 182 amino acid protein which is 97% homologous to human ferritin-H chain. Hepatic mRNA levels of ferritin-H were increased markedly at the early stage of diethylnitrosamine-induced hepatocarcinogenesis in the rat (6 weeks) and appeared more than 10-fold overexpressed as the tumour progressed. In contrast, hepatic ferritin-H mRNA remained constant during liver regeneration after a 70% partial hepatectomy. In situ hybridization showed that over-expression of ferritin-H was exclusively localized to preneoplastic foci, to tumour nodules and to tumour cells invading blood vessels. These findings suggest that ferritin-H is a highly conserved protein, its over-expression during tumour development is phenotypically correlated with tumour initiation and/or progression, and it is useful as an early marker for hepatocellular carcinoma.
Animals↗
Addition of felodipine to metoprolol vs replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade. Results of the Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Working Group on Cardiovascular Research, The Netherlands (WCN).
AIMS: The study aimed to compare the addition of felodipine to metoprolol, and of the replacement of metoprolol by felodipine, with continuation of metoprolol, in patients with angina pectoris despite optimal beta-blockade. METHODS AND RESULTS: The study was double-blind, parallel, randomized and controlled, and comprised 363 patients from 27 outpatient cardiology clinics in the Netherlands. The patients had angina and positive bicycle exercise tests despite optimal beta-blockade (resting heart rate < 65 beats.min-1). Randomization was to three treatment groups: continuation of metoprolol (control), addition of felodipine to metoprolol, and replacement of metoprolol by felodipine. Exercise tests were repeated after 2 and 5 weeks. The main outcome measure was: exercise result after 5 weeks, compared with baseline, between-group comparison of changes vs control. There were no significant differences in exercise duration and onset of chest pain vs control. The addition of felodipine increased time until 1 mm ST depression (43 s, 95% confidence interval 20-65 s), and decreased both ST depression at highest comparable work load (0.46 mm, 95% confidence interval 0.19-0.72), and maximal ST depression (0.49 mm, 95% confidence interval 0.23-0.74). Exercise results after replacement of metoprolol by felodipine were not different from control, apart from a significant increase in rate pressure product. Significantly more patients experienced adverse events in the felodipine monotherapy group. CONCLUSION: Combination of metoprolol and felodipine is to be preferred to felodipine monotherapy in patients who have signs and symptoms of myocardial ischaemia despite optimal beta-blockade.
Adolescent↗