Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans.

Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease.

[Molecular and metabolic changes in human clear cell liver foci]. / Molekulare und metabolische Veränderungen in humanen klarzelligen Leberherden.

Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype are evident both in human hepatocellular carcinoma and in the rat model of insulin-induced hepatocarcinogenesis in the earliest preneoplastic lesions, i.e. clear cell foci (CCF) of altered hepatocytes. These CCFs have also been described in the human liver but characterization of molecular and metabolic changes are still pending. In this study, human sporadic CCFs were investigated in a collection of human non-cirrhotic liver specimens using histology, histochemistry, immunohistochemistry, electron microscopy and molecular pathological analysis. Human CCFs occurred in approximately 33 % of non-cirrhotic livers and stored masses of glycogen in the cytoplasm, largely due to reduced activity of glucose-6-phosphatase. Hepatocytes revealed an upregulation of the AKT/mTOR and the Ras/MAPK pathways, the insulin receptor, glucose transporters and enzymes of glycolysis and de novo lipogenesis. Proliferative activity was 2-fold higher than in extrafocal tissue. The CCFs of altered hepatocytes are metabolically and proliferatively active lesions even in humans. They resemble the well-known preneoplastic lesions from experimental models in terms of morphology, glycogen storage, overexpression of protooncogenic signaling pathways and activation of the lipogenic phenotype, which are also known in human hepatocellular carcinoma. This suggests that hepatic CCFs also represent very early lesions of hepatocarcinogenesis in humans.

Biomechanics of the Spine III. The Cranio-Cervical Junction.

By virtue of its unique anatomy and functions the cranial-cervical junction was excluded in previous reviews on the general biomechanics of the spine, being a world apart. The special design of the cranial-cervical (CCJ) junction responds to seemingly opposed necessities being at same time loose enough to allow a great variety of movements and strong enough to preserve the spinal cord and vertebral arteries and to resist the head weight and muscular action. The primary goal of the CCJ is to ensure the maximal mobility of the head for visual and auditory exploration of space. Like a cardan joint the CCJ allows simultaneous independent movements about three axes in order to repeat and extend eye movements under the control of vestibular receptors. Several muscular groups and a number of ligaments control the movements of the CCJ and ensure its stability. Although composed of two seemingly distinct joints the CCJ forms a unique functional complex whose stability is ensured by ligaments and bony restraints often operating on both joint components: the occipitoatlantal and atlantoaxial joints.

Human exposure to dioxins through diet in Italy.

We have measured the content of polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans (together defined as "dioxins") in 269 samples of food of animal origin collected through the regional veterinary services, covering the national territory. Quantification of the dioxins was accomplished by isotope dilution method, and toxic equivalents (TEQ) were calculated. The average daily food intake was obtained from two main sources: national data collected by the National Institute of Nutrition, and data from an ongoing cohort study on diet and cancer including 40,000 Italian subjects. The mean value of dioxins measured in food of animal origin was 0.144 +/- 0.266 pg-TEQ/g (range: 0.003-1.655 pg-TEQ/g). Fish was the item with the highest content. The estimated intake of dioxins with main food items of animal origin is presented. The major contribution to dioxins intake with food comes from cow milk and fish consumption. These results are in agreement with what observed in studies conducted in other countries, such as Germany, Finland, Japan, Spain, and are below the limits set by the European legislation.

Prevalence of Salmonella enterica and Listeria monocytogenes contamination in foods of animal origin in Italy.

The present survey collected and analyzed the results of routine testing for Salmonella enterica and Listeria monocytogenes on foods of animal origin submitted for official controls in Italy during 2001 to 2002. Salmonella was detected in 2.2% of 71,643 food samples examined, and the isolation rates ranged from 9.9% for raw poultry meat to less than 0.1% for dairy products. Isolation rates were also high in raw pork (4.9%) and processed meats (5.3%), which often involved pork. Low rates were observed in seafood (0.5%) and in ready-to-eat foods, such as grocery products (0.7%) and ice creams (0.1%). Serotyping showed that approximately 50% of the isolates belonged to the serotypes most commonly isolated from humans in Italy, thus confirming that most cases of human salmonellosis have a foodborne origin. Levels of L. monocytogenes were higher than what is accepted by the current regulation in 2.4% of 42,300 food samples. The positivity rates ranged from 10.3% in raw pork to none in eggs and egg products. Contamination rates were higher in other meat products (between 2 and 5%) and fish (6.5%) than in cheeses (1.1%) and other dairy products (0.6%). Routine control activities on the microbial contamination of foods can generate data with statistical and epidemiological value. Such data can be used as a basis for estimating the exposure of consumers to foodborne pathogens, following the trends of contamination over time, and evaluating the effects of control measures on the contamination of food.

Preliminary experience with anterior cervical microdiscectomy and interbody titanium cage fusion (Novus CT-Ti) in patients with cervical disc disease.

BACKGROUND: Although the use of intervertebral fusion after anterior microdiscectomy in cervical disc disease remains controversial, a new surgical device is proposed for use in intervertebral fusion instead of bone graft. METHODS: This retrospective study at the Department of Neurosurgery, Cardarelli Hospital, Naples, from January 1993 to December 1998, compares the results of surgery on 58 patients with anterior microdiscectomy and intervertebral bone graft fusion (Group A) (ADIBG) with a group of 52 patients who underwent anterior microdiscectomy and intervertebral titanium cage fusion (Group B) (ADITC) in cervical radiculopathy and spondylotic myelopathy. In both groups a "radical discectomy" was performed under the operating microscope. In group A, interbody fusion was performed with autologous tricortical bone graft. In group B, a new type of titanium device (Novus CT-Ti) was used (Sofamor Danek Group). RESULTS: There was no collapse or extrusion of the device and no complications at the donor site (the bone fragments used to fill the cage were taken from osteophytes or vertebral body fragments). The use of this device provides immediate stabilization, reduces or eliminates pain, promotes bone fusion between the vertebrae adjacent to the cage by allowing bone growth through the cage, reestablishes and maintains the intervertebral space, reduces the average hospitalization time, and allows a quicker return to work. CONCLUSIONS: Patients who underwent ADITC did well and benefited from the surgery. Those who underwent ADITC did better than those who underwent ADIBG in regard to function, relief from pain, and complications. Early and good stability of the cervical spine seems to be the main advantage of using titanium cages.

A new instrumentation for posterior stabilization of cervical traumatic instability.

BACKGROUND: Twenty-six patients underwent application of a new posterior plating system (CIDEF SYSTEM) for the alignment and the stabilization of C3-C7 cervical unstable fractures from January 1992 to December 1993. METHODS: The osteosynthesis apparatus employs posterior articular screw fixation and plate application. Indications for surgery were the presence of neurological damage and cervical column instability. Operative techniques included decompressive and exploratory laminectomy in 20 cases and an articular resection in six cases of posterior superior articular fractures. A one-stage operation with an anterior approach, designed to remove anterior compression from herniated discs, or bone fragments, was also performed in four cases. Three cervical motion segments were immobilized in 15 of the treated cases; four in nine; and five in two. All patients were studied pre- and postoperatively with plain radiographs and computed tomography. Pre- and postoperative examinations demonstrated no alteration in neurological status. RESULTS: At a mean follow-up period of 47 months, no evidence was found of infection, rejection of the materials used, or mechanical failure of the plates and screws; all patients with incomplete lesion showed improvement in neurological function. Four patients tetraplegic at admission expired from systemic complications (one from pulmonary embolism; one from Disseminated Intravascular Coagulopathy; one for sepsis; and one from myocardial infarction). All patients were immobilized for at least 4 months with a Philadelphia collar. No injury to the neural or vascular structures contiguous to the cervical spine has occurred. CONCLUSIONS: The authors' experience suggests that the new system offers ease and versatility of application, restoration of vertebral alignment, enhanced spinal stability and is useful in the treatment of urgent and rather complex traumatic lesions of the lower cervical spine.

The postero-lateral approach in the treatment of post-traumatic canalar stenosis of the thoraco-lumbar spine.

METHODS: Twenty-four cases of unstable thoraco-lumbar fractures with significant canalar stenosis were operated in the Emergency Neurosurgical Unit of the Cardarelli Hospital from November 1989 to October 1991. The surgical technique was the combined transpedicular (TPA) and transarticular (TAA) postero-lateral approach, posterior osteosynthesis and arthrodesis. The average follow-up was 20 months. RESULTS: No evidence of implant breakage or pseudoarthrosis was detected. CONCLUSIONS: The authors affirm recalibration of the posterior wall by direct impaction, epidural hemostasis, removal of extruded disc fragments and dural repair are the advantages offered by this technique without compromise the contsrist stability. This approach represents an alternative to single posterior and combined anterior-posterior approaches in the management of the thoraco-lumbar fractures with severe canal stenosis.

Surgical treatment of subdural empyema: a critical review.

Between 1990 and 1992 six cases of subdural empyema were surgically treated at the Neurosurgical Division of Emergency Department of Cardarelli Hospital in Naples. Three cases were associated with paranasal sinusitis and three cases with otitis media. Headache and fever were the presenting symptoms in all cases; in only two cases they were associated with seizures and altered mental status. CT scans showed convexity low density collections in five cases and multilocalized pus collection in one; concurrent paranasal or mastoid infections were visualized as well. The organisms responsible for the subdural empyema were Peptococcus in four cases, Streptococcus and anaerobius in the other two cases. In five cases surgical treatment consists in pus drainage by selective burr hole and placement of a subdural small silicon tube for local antibiotic therapy. In one case with a loculated diffuse empyema, craniotomy was performed in order to provide a better access to all the localizations. In all cases drainage of the wound and intravenous antibiotic therapy were used. Paranasal sinus drainage or mastoidectomy performed by the otolaryngologist when a localized collection of pus was present, grave a quicker regression of symptoms. A full recover of the original neurological status was achieved in all cases; a 20 months mean followup confirms the results.

Non invasive recording of CO2 cerebrovascular reactivity in normal subjects and patients with unilateral internal carotid artery stenosis.

CO2 cerebrovascular reactivity has been recorded in 12 healthy volunteers and 10 patients with unilateral > 70% extracranial internal carotid artery (ICA) stenosis, using non invasive techniques. The relative changes of middle cerebral artery blood flow velocity (VMCA) and velocity waveform pulsatility (PIMCA) after that hypocapnia was induced by spontaneous hyperventilation were recorded. 35.5% average VMCA reduction and 63% PIMCA increment of basal values was produced in healthy subjects after hyperventilation. The percentage variation of CO2 Reactivity Index (RI), expressed in terms of VMCA (V-RI) and PIMCA (PI-RI), per mmHg change in pCO2, presents a good right-left side correlation (r = 0.82 and r = 0.83 respectively) in healthy subjects, while a dissociation between V-RI and PI-RI was found in our patients. A significant reduction of PI-RI was also recorded in the group of patients on the side of ICA stenosis. From our data CO2 reactivity index recorded in terms of PI seems to allow a better separation between pathology and normality, without the need to assume a close relationship between velocity and blood flow under the condition considered. Furthermore, PI-RI seems to be a valid index in the evaluation of some attribute pertaining to the distal vascular bed.

A new instrumentation system for the reduction and posterior stabilization of unstable thoracolumbar fractures.

An innovative instrumentation and stabilization system was used for the treatment of unstable thoracolumbar fractures. The new osteosynthesis apparatus employs pedicle screw fixation, plate application, and a mechanical device for dynamic reduction in stable posterior fixation. Sixteen patients were treated with this operative technique that included a decompressive laminectomy, an arthropedunculectomy, and the removal of vertebral canal bone fragments. In most patients, three vertebral bodies, rather than four or five, were immobilized. All patients were studied pre- and postoperatively with plain radiographs and computed tomography. Pre- and postoperative examinations demonstrated no alteration in neurological status. All patients, however, with incomplete lesions showed improvement in neurological function at a mean follow-up period of 12 months. The authors' experience suggests that the new system offers ease and versatility of application, restoration of vertebral alignment through mechanical reduction, and enhanced spinal stability. The new system, moreover, enables the reduction of lateral dislocation.