Biomedical subjects
Publications and source records attributed to C Redaelli.
Phosphatidylinositol 3-kinase (PI3K) and serine/threonine protein kinase B (PKB or Akt) pathways regulate important cellular processes and are related to a number of human pathologies, such as cancer. The development of kinase inhibitors, with particular attention to small molecule analogues of natural phosphoinositides for pathway interruption and therapeutic applications will be reviewed.
BACKGROUND: Mortality rates associated with pancreatic resection for cancer have steadily decreased with time, but improvements in long-term survival are less clear. This prospective study evaluated risk factors for survival after resection for pancreatic adenocarcinoma. METHODS: Data from 366 consecutive patients recorded prospectively between November 1993 and September 2001 were analysed using univariate and multivariate models. RESULTS: Fifty-eight patients (15.8 per cent) underwent surgical exploration only, 97 patients (26.5 per cent) underwent palliative bypass surgery and 211 patients (57.7 per cent) resection for pancreatic adenocarcinoma. Stage I disease was present in 9.0 per cent, stage II in 18.0 per cent, stage III in 68.7 per cent and stage IV in 4.3 per cent of patients who underwent resection. Resection was curative (R0) in 75.8 per cent of patients. Procedures included pylorus-preserving Whipple resection (41.2 per cent), classical Whipple resection (37.0 per cent), left pancreatic resection (13.7 per cent) and total pancreatectomy (8.1 per cent). The in-hospital mortality and cumulative morbidity rates were 2.8 and 44.1 per cent respectively. The overall actuarial 5-year survival rate was 19.8 per cent after resection. Survival was better after curative resection (R0) (24.2 per cent) and in lymph-node negative patients (31.6 per cent). A Cox proportional hazards survival analysis indicated that curative resection was the most powerful independent predictor of long-term survival. CONCLUSION: Resection for pancreatic adenocarcinoma can be performed safely. The overall survival rate is determined by the radicality of resection. Patients deemed fit for surgery who have no radiological signs of distant metastasis should undergo surgical exploration. Resection should follow if there is a reasonable likelihood that an R0 resection can be obtained.
PURPOSE: To compare the development of the visual pathway in healthy preterm and full-term newborns using flash and patterned (both transient and steady-state) visual-evoked potentials (fVEP, pVEP-t, pVEP-ss). PATIENTS AND METHODS: Twenty-nine preterm newborns (28-35 weeks gestational age) were evaluated at four different times: at 3 months postnatal and corrected age, at 8 months postnatal and corrected age. They were matched with 92 term newborns tested at 3 and 8 months of life. RESULTS: The maximal perceived spatial frequencies in the groups were: 2 C/d at 3 months postnatal age, >2 C/d at 3 months corrected age and at 3 months at term, between 3 and 5C/d, >=5C/d at 8 months corrected age and at 8 months of life, respectively. The latencies of the P1 and P100 waves for the flash and the transient stimulation were, respectively, 192 ms and 207.9 ms at 3 months postnatal age, 144 ms and 137.7 ms at 3 months corrected age, 126.3 ms and 124.1 ms at 8 months postnatal age, 112.7 ms and 112.5 ms at 8 months corrected age, 137.3 and 110.1 ms at 3 months of life; and 122.3 and 100.5 ms at 8 months of life. DISCUSSION: In the preterm infants of 3 gestational months, the latencies of the fVEP are comparable to those of the 3-month-old full-term infants, although the pVEP-t latencies are still delayed at 8 months. In the fVEP; however, we noted a shorter latency in the preterm infants at 8 months corrected age compared to those of the full-term infants. This tendency inversion was also evidenced at the steady-state stimulation. CONCLUSIONS: As evidenced by our results, at 8 months of corrected age the preterm infants recovered the fVEP and pVEP-ss, but not the pVEP-t. Different results obtained with different visual-evoked stimulations suggest that similar neural pools are developed in not completely equal amounts of time.
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The binding of hemin to the primary site of human serum albumin (HSA) has been reinvestigated using UV-Vis, CD and NMR techniques. The major fraction of bound hemin contains a five-coordinated high-spin iron(III) center, but a minor fraction of the metal appears to be in a six-coordinated, low-spin state, where a 'distal' residue, possibly a second histidine residue, completes the coordination sphere. The reduced, iron(II) form of the adduct contains six-coordinated low-spin heme. The distal residue hinders the access to the iron(III) center of hemin-HSA to small anionic ligands like azide and cyanide and destabilizes the binding of neutral diatomics like dioxygen and carbon monoxide to the iron(II) form. In spite of these limitations, the hemin-HSA complex promotes hydrogen peroxide activation processes that bear the characteristics of enzymatic reactions and may have biological relevance. The complex is in fact capable of catalyzing peroxidative reactions on phenolic compounds related to tyrosine and hydrogen peroxide dismutation. Kinetic and mechanistic studies confirm that the low efficiency with which peroxidative processes occur depends on the limited rate of the reaction between hydrogen peroxide and the iron(III) center, to form the active species, and by the competitive peroxide degradation reaction.
HYPOTHESIS: Recent controlled clinical studies suggest a positive effect of early antibiotic treatment on late morbidity and mortality in severe acute pancreatitis. However, widespread use of antibiotics may lead to an increased number of fungal infections and multiresistant bacteria, thereby worsening the outcome of the disease. DESIGN: Single-center prospective study. SETTING: University hospital, gastrointestinal surgical service. PATIENTS: One hundred three patients with necrotizing pancreatitis seen consecutively in our service. INTERVENTIONS: In addition to standard treatment, patients with proven necrotizing pancreatitis received a prophylactic intravenous antibiotic treatment. Pancreatic infection was regarded as an indication for surgery. MAIN OUTCOME MEASURES: Pancreatic infection, microbiological findings, drug resistance, fungal infections. RESULTS: Thirty-three patients (32%) had infected necrosis. Gram-negative organisms were isolated from 19 patients (58%), Gram-positive organisms were isolated from 18 patients (55%), fungal organisms were isolated from 8 patients (24%), and multiresistant organisms were isolated from 3 patients (9%). In 7 patients (21%), the organisms cultured from the pancreatic tissue were resistant to the antibiotics given in for prophylaxis. Infection with multiresistant organisms or organisms resistant to the antibiotic used for prophylaxis, but not with fungal infection or Gram-positive or Gram-negative infection, was correlated with a negative outcome. CONCLUSIONS: Fungal infection under adequate treatment is not associated with a negative outcome. The occurrence of multiresistant organisms seems to be a rare finding (3 of 103 patients). Antibiotic prophylaxis is effective in preventing infection in necrotizing pancreatitis, but optimal choice and duration of administration of the antibiotic agent(s) need to be carefully determined to avoid the sequelae of multiresistant organisms.
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It has become evident in recent years that intracranial inflammation after traumatic brain injury (TBI) is, at least in part, mediated by activation of the complement system. However, most conclusions have been drawn from experimental studies, and the intrathecal activation of the complement cascade after TBI has not yet been demonstrated in humans. In the present study, we analyzed the levels of the soluble terminal complement complex sC5b-9 by ELISA in ventricular cerebrospinal fluid (CSF) of patients with severe TBI (n = 11) for up to 10 days after trauma. The mean sC5b-9 levels in CSF were significantly elevated in 10 of 11 TBI patients compared to control CSF from subjects without trauma or inflammatory neurological disease (n = 12; p < 0.001). In some patients, the maximal sC5b-9 concentrations were up to 1,800-fold higher than in control CSF. The analysis of the extent of posttraumatic blood-brain barrier (BBB) dysfunction, as determined by CSF/serum albumin quotient (Q(A)), revealed that patients with a moderate to severe BBB impairment (mean Q(A) > 0.01) had significantly higher intrathecal sC5b-9 levels as compared to patients with normal BBB function (mean Q(A) < 0.007; p < 0.0001). In addition, a significant correlation between the individual daily Q(A) values and the corresponding sC5b-9 CSF levels was detected in 8 of 11 patients (r = 0.72-0.998; p < 0.05). These data demonstrate for the first time that terminal pathway complement activation occurs after head injury and suggest a possible pathophysiological role of complement with regard to posttraumatic BBB dysfunction.
The synthetic complexes protohemin-6(7)-L-arginyl-L-alanine (HM-RA) and protohemin-6(7)-L-histidine methyl ester (HM-H) were prepared by condensation of suitably protected Arg-Ala or His residues with protohemin IX. HM-RA and HM-H were used for reconstitution of apomyoglobin from horse heart, yielding the Mb-RA and Mb-H derivatives, respectively, of the protein. The spectral, binding and catalytic properties of Mb-RA and Mb-H are significantly different from those of Mb. As shown by MM and MD calculations, these differences are determined by some local structural changes around the heme which are generated by increased mobility of a key peptide segment (Phe43-Lys47), containing the residue (Lys45) that in native Mb interacts with one of the porphyrin carboxylate groups. In the reconstituted Mbs this carboxylate group is bound to the Arg-Ala or His residue and is no longer available for electrostatic interaction with Lys45. The mobility of the peptide segment near the active site allows the distal histidine to come to a closer contact with the heme, and in fact Mb-RA and Mb-H exist as an equilibrium between a high-spin form and a major low-spin, six-coordinated form containing a bis-imidazole ligated heme. The two forms are clearly distinguishable in the NMR spectra, that also show that each of them consists of a mixture of the two most stable isomers resulting from cofactor reconstitution, as also anticipated by MM and MD calculations. Exogenous ligands such as cyanide, azide, or hydrogen peroxide can displace the bound distal histidine, but their affinity is reduced. On the other hand, mobilization of the peptide chain around the heme in the reconstituted Mbs increases the accessibility of large donor molecules at the heme periphery, with respect to native Mb, where a rigid backbone limits access to the distal pocket. The increased active site accessibility of Mb-RA and Mb-H facilitates the binding and electron transfer of phenolic substrates in peroxidase-type oxidations catalyzed by the reconstituted proteins in the presence of hydrogen peroxide.
BACKGROUND: Clinically, intracellular type solutions are the most widely used solutions to preserve organs. The optimal ion composition of preservation solutions, however, is still unknown and extracellular-type solutions have frequently been superior to intracellular solutions in various experimental studies. MATERIALS AND METHODS: In this study, we measured extracellular (interstitial) electrolyte concentrations in rat livers, kidneys, hearts and lungs at 4 degrees C by means of microdialysis sampling. RESULTS: After 24 h cold ischaemia, [Na+]int and [K+]int were 104 +/- 25 mmol/l and 6.5 +/- 0.7 mmol/l in hearts, 92 +/- 12 mmol/l and 6.9 +/- 1.0 mmol/l in livers, 115 +/- 22 mmol/l and 6.3 +/- 0.9 mmol/l in kidneys and 87 +/- 17 mmol/l and 6.4 +/- 0.6 mmol/l in lungs. After preservation of organs in intracellular-type solutions, [Na+]int was significantly lower for each organ (range from 69 +/- 8 mmol/l to 73 +/- 20 mmol/l) and [K+]int was significantly higher (range from 8.0 +/- 1.7 mmol/l to 9.8 +/- 1.0 mmol/l). In no instance did the interstitial electrolyte concentration equilibrate with the intracellular electrolyte concentration. When the diffusion gradient from the vascular space to the interstitial space was calculated for Na+ and K+, a significantly higher barrier was found for K+ than for Na+ (P<0.001 and P<0.01 for hearts). CONCLUSIONS: These studies indicate that during cold storage of rat hearts, lungs, livers and kidneys, intra- and extracellular electrolytes do not equilibrate. Ion exchange stabilises at extracellular Na+ concentrations between 87 mmol/l and 115 mmol/l and K+ concentrations between 6.3 mmol/l and 6.9 mmol/l. Storage of organs in solutions with extracellular-type ion compositions might improve graft function and survival not only after lung and liver but also after heart and renal preservation.
Microperoxidase-8 (MP8) and microperoxidase-9 (MP9) have been covalently modified by attachment of proline-containing residues to the amino terminal peptide chain in order to obtain new peroxidase model systems. The catalytic activities of these derivatives in the oxidation of p-cresol by hydrogen peroxide have been compared to that of MP8. The presence of steric hindrance above the heme reduces the formation rate of the catalytically active species, while the reactivity is increased when the amino group of a proline residue is close to the iron. The modification of the catalyst affects the rate of degradation processes undergone by the heme group during catalysis. A bulky aromatic group on the distal side decreases the stability of the complex because it reduces the mobility of a phenoxy radical species formed during catalysis, while the presence of proline residues increases the number of turnovers of the heme catalysts before degradation. The complex Pro2-MP8 obtained by addition of two proline residues to MP8 exhibits the best catalytic performance in terms of activity and chemical stability.
The increasing knowledge of the anatomy and function of the liver made the surgical resection of liver metastases currently to the therapy of choice. Although liver metastasis is an advanced stage in tumor-progression, surgery achieves the best long-term results due to a better understanding of the carcinogenesis (i.e. micrometastases) and the prognostic risk factors. This study summarizes the results of 109 resections of colorectal and non-colorectal liver metastases during a period of 59 months at our department. Four different surgical techniques (extended hepatectomy vs. segmental resection vs. atypical resection vs. biopsy) were investigated. For resections a tumour-free resection margin of at least 10 mm was always attempted to achieve. The accumulated morbidity of all techniques together was 23%. Although the morbidity was higher for extended resections (Encephalopathy 16% vs. 2.3% for segmental resections, Liver insufficiency 23% vs. 4.7%), compared to the limited resection procedures, the long-term survival improved. The overall mortality was 2.7%. Survival was higher in patients with resection of colorectal than non colorectal metastases. Our results indicate that liver resection, under observance of the anatomical and functional margins (i.e. an adequate resection margin), is the only potentially curative therapy for liver metastases. An extensive formal resection, although inducing a higher perioperative morbidity, is superior to the limited resection techniques and results in an increased long-term survival. One reason is the increased probability of co-resection of preoperatively undetected local micrometastases.
We report the case of focal nodular hyperplasia-like nodular hepatic lesions, that developed in the liver of a 35-year-old Caucasian female who required orthotopic liver transplantation for Budd-Chiari syndrome. The rapid development of focal nodular hyperplasia-like lesions in a severe hepatic vascular disorder and in the absence of cirrhosis may represent an additional argument in favor of the vascular origin of focal nodular hyperplasia. The pathogenesis of the nodules is not clear, but pathological arterialization of the liver in hepatic vein thrombosis may be a candidate mechanism.
Giant liver hemangiomas are defined as hemangiomas with a diameter of more than 4 cm. They often require surgery due to bleeding tendencies or local compression. Between 1994 and 1998 we operated 11 patients with giant hemangiomas (median diameter 5.8 cm, range 4-12.5 cm). Average age was 50 years (range 23-85 years). 6 patients complained of pain, 1 patient sustained a bleeding. 7 hemangiomas were enucleated, 2 segmentally resected, 1 patient underwent a hemihepatectomy. 1 patient suffered from a bile leakage. Mortality was 0%. We conclude that clinically symptomatic liver hemangiomas can be safely resected. In a right sided localisation a enucleation has the best parenchyma sparing effect, in left sided locations a segmentectomy or bisegmentectomy can be performed with little blood loss.
The authors report a case of bilateral uveitis following Mycoplasma pneumoniae pneumonia verified by IgM and rising IgG antibodies against the organism. Uveitis is a rare manifestation of Mycoplasma pneumoniae pneumonia and since it is a common pathogen, it should be considered in the differential diagnosis, even in the absence of respiratory symptoms or neurological findings. Immunobiological hypotheses are briefly discussed.
BACKGROUND: Tumour vascularisation is a determinant of the development of metastases. AIMS: To measure blood flow in normal stomach and gastric adenocarcinomas by laser Doppler flowmetry and correlate blood flow with vascularisation after immunohistochemical staining of resected specimens for CD31 and von Willebrand factor. PATIENTS: Twenty two undergoing resection for gastric adenocarcinoma and 10 undergoing cholecystectomy. RESULTS: Mean (SD) gastric blood flow was 208 (35) perfusion units (PU) in patients undergoing cholecystectomy and 190 (75) PU in the undiseased part of the stomach in patients with gastric adenocarcinoma. Gastric blood flow was higher in the border of gastric adenocarcinomas (322 (120) PU, p<0.01 v normal stomach) but lower in the centre (74 (27) PU, p<0.01 v normal stomach and tumour border). Blood flow was higher in tumours staged T>/=3 than in those staged T<3. Blood vessel density in normal stomach was 41 (8) stained cells/field viewed and was 1. 9-3.4 times higher in gastric adenocarcinomas. CONCLUSION: Laser Doppler flowmetry is a valuable tool for studying the pathophysiological alterations of malignant blood flow in the human stomach in vivo.
The purpose of this study was the evaluation of retinal abnormalities during a treatment with natural interferon (IFN-alpha for chronic hepatitis C. Retinal hemorrhages and optic disk edema were found in a 40-year-old woman during IFN-alpha therapy. The disk edema and retinopathy resolved after the INF was discontinued. Although retinal abnormalities correlated with IFN therapy have been described recently by some authors, the pathogenesis is still unclear. Anterior ischemic optic neuropathy occurring in a patient treated with IFN is a probable complication of the therapy.
Experimental chronic pancreatitis is associated with microcirculatory disturbances but can also be induced or aggravated by perfusion changes. Microcirculatory alterations in human chronic pancreatitis are poorly defined. In this clinical study we investigated pancreatic microcirculation in the normal human pancreas and in chronic pancreatitis by laser Doppler flowmetry. Laparotomy was performed on 13 patients with nonpancreatic disease and on nine patients with chronic alcoholic pancreatitis for pancreatic head resection. Blood flow was measured over the pancreatic head, the uncinate process, over the mesenteric vein, the pancreatic corpus, and over the pancreatic tail by laser Doppler flowmetry. Blood flow was highest in the head of a normal pancreas with a mean of 436 +/- 34 perfusion units (PU), 399 +/- 43 PU in the uncinate process, 286 +/- 30 PU in the pancreatic corpus, and 351 +/- 46 PU in the tail of the pancreas. In the normal pancreas, lowest blood flow was measured over the mesenteric vein (228 +/- 23 PU). In chronic pancreatitis, blood flow in the pancreas was significantly decreased across the whole pancreas (p < 0.01). Furthermore flow-wave pattern was altered in chronic pancreatitis as compared with the normal pancreas. The normal human pancreas has a spatial variation in blood flow, correlating with the pancreatic arterial blood supply. In the chronically inflamed human pancreas, blood flow is significantly diminished, with a lower flow toward the pancreatic head.