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Biological responses are determined by information processing at multiple and highly interconnected scales. Within a tissue the individual cells respond to extracellular stimuli by regulating intracellular signaling pathways that in turn determine cell fate decisions and influence the behavior of neighboring cells. As a consequence the cellular responses critically impact tissue composition and architecture. Understanding the regulation of these mechanisms at different scales is key to unravel the emergent properties of biological systems. In this perspective, a multidisciplinary approach combining experimental data with mathematical modeling is introduced. We report the approach applied within the Virtual Liver Network to analyze processes that regulate liver functions from single cell responses to the organ level using a number of examples. By facilitating interdisciplinary collaborations, the Virtual Liver Network studies liver regeneration and inflammatory processes as well as liver metabolic functions at multiple scales, and thus provides a suitable example to identify challenges and point out potential future application of multi-scale systems biology.

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The aim of this work was to develop a spectrophotometric method for the measurement of salivary ß-galactosidase for the evaluation of oral malodor. A comparison between different methods for estimating oral malodor has been conducted on 94 healthy adult volunteers. For organoleptic measurements, the subjects were instructed to exhale briefly through the mouth at a distance of approximately 10 cm from the noses of two trained judges. The evaluation of ß-galactosidase activity was accomplished in unstimulated whole saliva of all participants through the colorimetric method and spectrophotometry. A significant association among spectrophotometric evaluation of ß-galactosidase and organoleptic measurements was assessed by Spearman correlations. Although colorimetric and spectrophotometric assessments of ß-galactosidases were estimated to have the same sensitivity, the last method is characterized by a higher specificity. The results suggest that the use of the UV-vis spectrophotometer increases the specificity of the evaluation of salivary ß-galactosidases.

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We investigated whether detection of fearful stimuli is independent from attention by using an iconic version of the Attentional Blink Task in arachnophobic individuals. A colored animal icon (Target) and a black spider or butterfly icon (Probe) appeared in close temporal proximity within a stream of distractors, at one of 4 possible time lags. In one task, Probe detection was required; in another one, Target identification was also requested. In this case, competition for attentional resources produces the so-called AB effect, that is the decrease of Probe perception as a function of lag. During spider-Probe detection, arachnophobics showed a reduced AB effect with respect to the butterfly-Probe session. Their spider detection scores were also greater than ratings obtained by non-phobic controls with both Probe types. Thus, fear appears to enhance the probability of consciously perceiving the stimulus even when attention is engaged by a previous demanding event. One may assume that spider-Probe is scarcely attention demanding because detection of threat in arachnophobics is increased by rapid amygdala activation of visual areas and/or facilitated by a strong arousal-induced noradrenergic cortical input. Alternatively, an attention capturing mechanism involuntary triggered by the phobic meaning of the stimulus could be hypothesized.

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This study reports major gastrointestinal (GI) complications among a group of 1611 patients following kidney transplantation. The immunosuppressive regimen changed somewhat during the course of the study but included azathioprine, prednisolone, antilymphocyte globulin, cyclosporine, tacrolimus, mycophenolate mofetil, and sirolimus. Perforations occurred in the colon (n=21), small bowel (n=15), duodenum (n=6), and stomach (n=4). Nearly 50% of the complications occurred while patients were being given high-dose immunosuppression to manage either the early postoperative period or acute rejection episodes. Of the 46 patients affected, 11 (24%) died as a direct result of the GI complication. This high mortality appeared to be related to the effects of the immunosuppression and the associated response to sepsis. Reduction of these complications may be achieved by improved surgical management, preventive measures, prompt diagnosis, and a reduced immunosuppressive protocol.

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Invasive growth is a complex biological program triggered by hepatocyte growth factor (HGF) through its tyrosine kinase receptor encoded by the Met proto-oncogene. The program involves-besides proliferation-cell dissociation, motility and invasiveness, controlled by intracellular signals impinging on PI3K and on the small G-proteins of the Rac/Rho family. The mechanism(s) unbalancing Rac/Rho activation are still not completely clarified. Here, we describe a functional link between HGF and Arhgap12, a gene encoding a previously uncharacterized protein of the RhoGAP family. We identified Arhgap12 as a transcriptional target of HGF, through a novel gene trapping strategy. We found that Arhgap12 mRNA and protein are robustly suppressed by HGF treatment, but not by serum. Arhgap12 displayed GTPase activating protein (GAP) activity towards Rac1 and, upon overexpression, impaired cell scattering, invasion and adhesion to fibronectin in response to HGF. Consistently, Arhgap12 silencing by RNA interference selectively increased the scatter and adhesion responses. These data show that HGF-driven invasive growth involves transcriptional regulation of a Rac1-specific GAP.

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PURPOSE: Although at present nonabsorbable meshes are the preferred material for tension-free hernioplasty, some problems with their use have yet to be addressed (i.e., chronic pain and infections). In order to address these disadvantages, a collagen-based material, the porcine small-intestinal submucosa mesh (Surgisis Inguinal Hernia Matrix, Cook Surgical, Bloomington, IN, USA), has recently been developed for hernia repair. METHODS: With the aim of investigating the clinical safety and effectiveness of Surgisis IHM inguinal hernia repair, we report our experience of 45 consecutive hernioplasties with a medium-term follow-up. The surgical technique for the use of this material in hernioplasty is described in detail. RESULTS: Although some local (i.e., seromas) and general (i.e., hyperpyrexia), complications appeared in the immediate postoperative period (all of them disappeared spontaneously), no rejection or infection was observed after operations. At the 2-year follow-up, a low degree of pain and discomfort and no recurrences were observed. CONCLUSIONS: We conclude that the Surgisis IHM hernioplasty is feasible with promising results and, from a clinical perspective, seems safe and effective.

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Many theories of hypnotic responding have proposed that differences in hypnotic trait rely on differences in frontal attentional functions. Evidence of hypnotizability-related attentional abilities are, however, very scant. This study was designed to investigate the relationship between hypnotizability and executive control components of attention in the spatial domain. We chose the Attention Network Test that enables to analyze alerting, orienting and executive control functions by measuring reaction times (RTs) to targets cued for different locations in space. According to Posner theory, alerting, orienting and executive control effects were found in both groups. No differences between highly susceptible (Highs) and low susceptible individuals (Lows) on executive control functions were found. However, in Highs alerting was significantly smaller than in Lows and Highs were significantly faster than Lows in the no and central cue conditions. These findings suggest that Highs would be endowed with a basal higher efficiency in achieving and maintaining their readiness to respond to incoming stimuli. This relation between hypnotizability and alerting, is discussed in terms of a possible more efficient noradrenergic activity driven by frontal attentional systems.

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Overexpressed or activated hepatocyte growth factor receptor, encoded by the MET proto-oncogene, was found in the majority of colorectal carcinomas (CRCs), whose stepwise progression to malignancy requires transcriptional activation of beta-catenin. We here demonstrate that a functional crosstalk between Met and beta-catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts beta-catenin tyrosine phosphorylation and dissociation from Met, and upregulates beta-catenin expression via the phosphatidylinositol 3-kinase pathway in conditions that mimic those found by the invading and metastasizing cells. Additionally, a transcriptionally active form of beta-catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the beta-catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic beta-catenin. In the mirror experiments, either Met or beta-catenin knocking down also reduces their protein level. In biological assays, beta-catenin knocking down abrogates the HGF-induced motile phenotype, whereas active beta-catenin fosters ligand-independent cell scattering. Met and beta-catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and beta-catenin pathways are mutually activated in CRC cells. This might generate a self-amplifying positive feedback loop resulting in the upregulation of the invasive growth properties of CRC cells.

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BACKGROUND: Complicated hernias often involve contaminating surgical procedures in which the use of polypropylene meshes can be hazardous. Prostheses made of porcine dermal collagen (PDC) have recently been proposed as a means to offset the disadvantages of polypropylene meshes and have since been used in humans for hernia repairs. The aim of our study was to evaluate the safety and efficacy of incisional hernia repair using PDC as a mesh in complicated cases involving contamination. METHODS: A prospective study of hernia repair of complicated incisional hernias with contamination using PDC grafts was carried out at the Department of General, Emergency and Transplant Surgery of St Orsola-Malpighi University Hospital. RESULTS: From January 2004 up to the writing of this article, seven patients were treated for complicated incisional hernias with a PDC prosthesis. In six out of seven patients a bowel resection was carried out. There were not surgical complications. Morbidity was 14.2%. No recurrences and wound infections were observed. CONCLUSIONS: Incisional hernioplasty using PDC grafts is a potentially safe and efficient approach in complicated cases with contamination.

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INTRODUCTION: We present a novel approach to the treatment of membranous duodenal stenosis (MDS). To our knowledge this is the first paper to describe balloon dilatation for this entity. MATERIAL AND METHODS: Four children, 2 boys and 2 girls, aged between 8 and 28 days, underwent duodenal balloon dilatation. Balloon dilatation was performed under general anaesthesia using standard angiography balloons per os. Balloon diameters ranged from 6 to 14 mm. RESULTS: All balloon dilatations were successful. None of the procedures showed procedural or post-procedural complications. None of the patients subsequently required surgical intervention. To date all children are doing well. DISCUSSION: The initial experience with balloon dilation of MDS showed a 100% success rate, without procedural or post-procedural complications. The results obtained in this small group of patients suggest that the use of balloon dilatation in cases of MDS may be a safe technique that can be readily performed by an experienced interventional radiologist.

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While polypropylene mesh remains the preferred prosthesis material for hernioplasties, there are some problems with infections, intestinal obstruction and fistulization, and migration particularly in immunodepressed patients. A new degradable and reabsorbable material, the porcine small intestinal submucosa (Surgisis) has been developed for hernia repairs in humans. This prospective study evaluated the safety and efficacy of Lichtenstein hernioplasty using the Surgisis inguinal hernia matrix soft-tissue graft as a mesh in ten immunodepressed subjects. Six subjects were HIV-positive in the immunodepressive phase, and the other four had undergone transplantation (three kidney, one liver). There were no intraoperative or postoperative complications, recurrences, or wound infections. Thus Lichtenstein's hernioplasty using the Surgisis inguinal hernia matrix soft-tissue graft in immunodepressed patients promises safety and efficacy.

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The gallbladder volvulus is a very rare but extremely dangerous event. Described for the first time by Wendel in 1898, it affects more frequently the female sex, particularly in old age. The clinical case of a patient affected by this pathology, personally observed, is presented and the initial symptoms, diagnostic procedures and surgical intervention are described in detail. The anatomical and physiological backgrounds that permit the gallbladder to twist on its axis are analysed and finally the importance of an early diagnosis to avoid the complications of a bilious peritonitis is underlined. In any case the definite diagnosis is made more frequently during surgical intervention. An early intervention allows a rapid resolution of the clinical picture preventing the perforation of the viscus into the peritoneal cavity and the complication of a bilious peritonitis besides the spreading of the biliary stones into the abdominal cavity.

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A deficiency in uroporphyrinogen decarboxylase (UROD) enzyme activity, the fifth enzyme of the heme biosynthetic pathway, is found in patients with sporadic porphyria cutanea tarda (s-PCT), familial porphyria cutanea tarda (f-PCT), and hepatoerythropoietic porphyria (HEP). Subnormal UROD activity is due to mutations of the UROD gene in both f-PCT and HEP, but no mutations have been found in s-PCT. Genetic analysis has determined that f-PCT is transmitted as an autosomal dominant trait. In contrast, HEP, a severe form of cutaneous porphyria, is transmitted as an autosomal recessive trait. HEP is characterized by a profound deficiency of UROD activity, and the disease is usually manifest in childhood. In this study, a strategy was designed to identify alleles responsible for the HEP phenotype in three unrelated families. Mutations of UROD were identified by direct sequencing of four amplified fragments that contained the entire coding sequence of the UROD gene. Two new missense mutations were observed at the homoallelic state: P62L (proline-to-leucine substitution at codon 62) in a Portuguese family and Y311C (tyrosine-to-cysteine substitution at codon 311) in an Italian family. A third mutation, G281E, was observed in a Spanish family. This mutation has been previously described in three families from Spain and one from Tunisia. In the Spanish family described in this report, a paternal uncle of the proband developed clinically overt PCT as an adult and proved to be heterozygous for the G281E mutation. Mutant cDNAs corresponding to the P62L and Y311C changes detected in these families were created by site-directed mutagenesis. Recombinant proteins proved to have subnormal enzyme activity, and the Y311C mutant was thermolabile.

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Patients undergoing a composite graft replacement of the aortic root with reimplantation of the coronary ostia (Bentall procedure) are at risk for late prosthetic heart valve dysfunction: approximately 10% of the patients are expected to experience this complication at 10 years. Therefore, replacement of the prosthetic valve is indicated. This procedure involves technical problems related to the manipulation and the reconstruction of the composite graft without distortion of the coronary arteries. We describe a simple surgical approach to treat these particular patients.

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Purtscher's retinopathy is a retinal lesion associated with different diseases such as cardiac aneurism, thoracic compression, bone fractures, post-trauma, pancreatitis and eclampsia. It consists in the appearance of white patches and retinal hemorrhage encircling an apparently normal optic disk. There is some controversy about its pathogenesis, but a probable cause for the development of this affection might be leukocyte emboli activated by complement. We present the case of a patient who developed a Purtscher's like retinopathy while he was being treated for pancreatitis.

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La retinopatía de Purtscher es una afección ocular secundaria a diversas enfermedades como aneurisma cardíaco, compresión torásica, fracturas óseas, post traumática, pancreatitis y preeclampsia. Consiste en la aparición de múltiples parches blancos y hemorragias retinales, rodeando un disco óptico de apariencia normal. Su patogenia es discutida aunque se acepta que podría ser causada por la embolia de leucocitos activados por el complemento. Se presenta el caso de un paciente que durante el curso de una pancreatitis desarrolla una lesión compatible con esta retinopatía

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BACKGROUND: Transesophageal echocardiography (TEE) is a useful means in the diagnosis of acute aortic dissection (AD), owing to its very high sensibility and specificity. In this study, TEE was performed to assess post-surgical evolution. PATIENTS: Between 1982 and 1991, 119 pts. were operated on in our institution for AD (De Bakey I and II type): 87 pts. underwent replacement of the ascending aorta with a composite tubular graft bearing a mechanical valve; 26 had a simple tubular graft and 6 had aortic reconstruction. Sixty-eight of 72 discharged pts. were followed for up to 9.5 years (mean 4.5 +/- 2.6). Nine years after surgery actuarial survival of discharged pts. was 75%. Seven pts. died after a mean period of 3.4 years from surgery: only one died from postoperative complication (dehiscence of proximal anastomosis), none for aortic rupture distal to the graft. TEE was performed in 32 of these pts. and in other two operated on elsewhere, after 4.4 +/- 2.7 years from surgery; before the operation, type I AD was diagnosed in 23 pts. and type II in 11 pts. RESULTS: In 10/11 pts. with type II AD the aortic arch and the descending aorta looked normal; in one patient a localized intimal flap was found up to the arch. The descending aorta diameter was somewhat higher than in normal subjects (25.2 +/- 2.8 vs 21.9 +/- 3.7 mm), but in only one case was it beyond 2DS (32 mm). In all type I pts. an intimal flap persisted distal to the graft, along the whole thoracic aorta. Within the false lumen a flow was detected by color-Doppler in 14/23 pts. (61%), and spontaneous echo-contrast was noted in 14 pts. (61%). A thrombus was observed in 7 pts. (30%) and it was generally localized; in only one case it was extensive with total obliteration of the false lumen. In 16 pts. (70%) communications between the two lumina were found. The descending aorta diameter ranged from 25 to 53 mm, and mean value was higher than in normal subjects (34.2 +/- 6.2 vs 21.9 +/- 3.7 mm). CONCLUSIONS: In most pts. with type II AD, surgery can be a definitive treatment, as the remaining aorta keeps to normal size and appearance. In type I AD, operation is only palliative, as the dissection persists: the false lumen is often perfused through one or more communications with the true lumen and seldom its obliteration is noted. The persistence of dissection does not necessarily seem to be an ominous finding, as the survival of the study population was high and no patient died from aortic rupture. Nevertheless, long-term prognosis can be affected by aorta dilation that often (but not always) follows the persistence of wall dissection. For its high reliability, easy feasibility and low cost TEE is a very useful method for following up patients operated on for AD and for detecting those who are at higher risk of aortic rupture because of lumen dilation.

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The treatment of symptomatic chronic obstructive peripheral arteriopathies is a difficult task since it requires the prolonged administration of drugs which are often unable to correct the various pathogenetic factors reponsible for the disability. The authors, on the basis of recent studies demonstrating the rheological and vasoactive as well as metabolic activities of levocarnitine propionyl, have decided to use this substance in the treatment of arteriopathics affected by intermittent claudication. Levocarnitine propionyl administered orally to 142 arteriopathics affected by intermittent claudication was responsible for a marked increase in initial as well as absolute walking distances. It is particularly important to note that these clinical results were obtained primarily due to the metabolic activities of levocarnitine propionyl.

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