An international call for a new grading system for cerebral and cerebellar cavernomas.

Surgical indications for cerebral cavernous malformations remain significantly center- and surgeon-dependent. Available grading systems are potentially limited, as they do not include epileptological and radiological data. A novel grading system is proposed for supratentorial and cerebellar cavernomas: it considers neuroradiological features (bleeding, increase in size), neurological status (focal deficits and seizures), location of the lesion and age of the patient. The score ranges from -1 to 10; furthermore, surgery should be considered when a score of 4 or higher is present. Based on neuroradiological characteristics, 0 points are assigned if the CCM is stable in size at different neuroradiological controls, 1 point if there is an increase in volume during follow-up, 2 points if intra- or extra-lesional bleeding <1 cm is present and 3 points if the CCM produced a hematoma >1 cm. Regarding focal neurological deficits, 0 points are assigned if absent and 2 points if present. For seizures, 0 points are assigned if absent, 1 point if present, but controlled by medications, and 2 points if drug resistant. We considered the site of the CCM, and in case of deep-seated lesions in a critical area (basal ganglia, thalamus) 1 point (-1) is subtracted, while for subcortical or deep cerebellar lesions 0 points are assigned, for CCMs in a cortical critical area 1 point is assigned and in case of lesions in cortical not in critical area or superficial cerebellar area, 2 points are assigned. As far as age is concerned, 0 points are assigned for patients older than 50 years and 1 point for patients younger than 50. In conclusion, a novel grading for surgical decision making in cerebral cavernomas, based on the experience of selected neurosurgeons, basic scientists, and patients, is suggested with the aim of further improving and standardizing the treatment of CCMs. The aim of this paper was also to call for both retrospective and prospective multicenter studies with the aim of testing the efficacy of the grading system in different centers.

Yersinia enterocolitica exploits different pathways to accomplish adhesion and toxin injection into host cells.

The current paradigm suggests that Yersinia enterocolitica (Ye) adheres to host cells via the outer membrane proteins Yersinia adhesin A (YadA) or invasin (Inv) to facilitate injection of Yops by the type III secretion system. In this process Inv binds directly to ß1 integrins of host cells while YadA may bind indirectly via extracellular matrix proteins to ß1 integrins. Here we challenged this paradigm and investigated the requirements for Yop injection. We demonstrate that Inv- but not YadA-mediated adhesion depends on ß1 integrin binding and activation, and that tight adhesion is a prerequisite for Yop injection. By means of novel transgenic cell lines, shRNA approaches and RGD peptides, we found that YadA, in contrast to Inv, may use a broad host cell receptor repertoire for host cell adhesion. In the absence of ß1 integrins, YadA mediates Yop injection by interaction with αV integrins in cooperation with yet unknown cofactors expressed by epithelial cells, but not fibroblasts. Electron microscopic and flow chamber studies revealed that a defined intimate contact area between Ye and host cells resulting in adhesion forces resisting shear stress is required for Yop injection. Thus, the indirect binding of YadA to a broad extracellular matrix (ECM) binding host cell receptor repertoire of different cell types makes YadA a versatile tool to ensure Yop injection. In conclusion, given the differential expression of the outer membrane proteins Inv and YadA in the course of Ye infection and differential expression of integrins by various host cell populations, the data demonstrate that Ye is flexibly armed to accomplish Yop injection in different host cell types, a central event in its immune evasion strategy.

Inhibition of nuclear factor-kappaB activation by IRFI 042, protects against endotoxin-induced shock.

BACKGROUND: The aim of our study was to investigate the effect of IRFI 042, a novel dual vitamin E-like antioxidant, on nuclear factor-kappaB (NF-kappaB) activation, TNF-alpha gene priming and on the release of the mature protein during endotoxin shock. METHODS: Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg(-1) of Salmonella enteritidis lipopolysaccharide (LPS). Survival rate, mean arterial blood pressure, serum TNF-alpha and plasma malondialdehyde (MAL) levels were investigated. We then evaluated in the liver TNF-alpha mRNA levels, NF-kappaB binding activity and the inhibitory protein IkappaBalpha. Moreover we studied in LPS stimulated (50 microg ml(-1)) peritoneal macrophages (Mphi), NF-kappaB activation, cytoplasmic IkappaB-alpha degradation, the message for TNF-alpha, and TNF-alpha and MAL levels. RESULTS: LPS administration reduced survival rate (0%, 72 h after LPS administration), decreased mean arterial blood pressure, augmented serum TNF-alpha (60+/-11 ng ml(-1)) and enhanced plasma malondialdehyde (MAL) levels (55+/-7.1 nmol l(-1)). LPS shocked rats also had increased TNF-alpha mRNA levels, augmented liver NF-kappaB binding activity in the nucleus and decreased levels of the inhibitory protein IkappaBalpha. In addition, in vitro LPS stimulation (50 microg ml(-1)) significantly induced NF-kappaB activation and cytoplasmic IkappaBalpha degradation in Mphi, enhanced TNF-alpha mRNA levels and increased Mphi TNF-alpha and MAL. Treatment with IRFI 042 (20 mg kg(-1), i.v., 5 min after endotoxin challenge) protected against LPS-induced lethality (90% survival rate 24 h and 80% survival rate 72 h after LPS injection, respectively), reduced hypotension, blunted plasma MAL (9.0+/-0.9 nmol l(-1)) and decreased serum TNF-alpha (15+/-3 ng ml(-1)). The antioxidant also inhibited the loss of IkappaBalpha protein from the hepatic cytoplasm, blunted the increased NF-kappaB binding activity in the liver and decreased hepatic liver mRNA for TNF-alpha. Furthermore 'in vitro' IRFI 042 (50 microM) significantly inhibited activation of NF-kappaB through inhibition of IkappaBalpha degradation, reduced the amount of TNF-alpha mRNA, decreased LPS-induced TNF-alpha release and blunted lipid peroxidation (MAL) in LPS stimulated Mphi. CONCLUSIONS: These data suggest that IRFI 042 blocks the activation of NF-kappaB, reduces TNF-alpha mRNA levels, and finally reverses endotoxic shock.

Evidence for a role of nuclear factor-kappaB in acute hypovolemic hemorrhagic shock.

BACKGROUND: In acute hypovolemic shock, a rapid systemic release of the inflammatory cytokine tumor necrosis factor (TNF-alpha) contributes to vascular failure. Nuclear factor kappaB (NF-kappaB) is an ubiquitous rapid-response transcription factor involved in inflammatory reactions and exerts its effect by expressing cytokines, chemokines, and cell adhesion molecules. The purpose of this study was to evaluate the role of NF-kappaB in acute hypovolemic hemorrhagic shock. METHODS: Hemorrhagic shock was induced in anesthetized male rats by intermittently withdrawing blood from an iliac catheter for 20 minutes (bleeding period) until mean arterial blood pressure (MAP) decreased and stabilized within the range of 20 to 30 mm Hg. Two minutes after bleeding was discontinued the rats received tacrolimus (100 microg/kg), an inhibitor of NF-kappaB activation, or its vehicle. We then evaluated survival rate and survival time, liver NF-kappaB activation by means of electrophoretic mobility shift assay, liver IkappaBalpha protein in the cytoplasm, hepatic TNF-alpha messenger RNA expression, plasma TNF-alpha, arterial blood pressure, and the contractile response of aortic rings to phenylephrine. RESULTS: Rats that underwent hemorrhagic shock died 28+/-2 minutes after bleeding was discontinued, experienced marked hypotension (MAP, 20-30 mm Hg), and had enhanced plasma levels of TNF-alpha (218 +/- 28 pg/mL 20 minutes after bleeding was discontinued). Aortas taken 20 minutes after bleeding was discontinued in rats that underwent hemorrhagic shock showed marked hyporeactivity to phenylephrine (1 nmol/L-10 micromol/L) compared with aortas harvested from sham shocked rats. Rats that underwent hemorrhagic shock also had increased levels of TNF-alpha messenger RNA in the liver. Furthermore, electrophoretic mobility shift assay showed that liver NF-kappaB binding activity increased in the nucleus, and Western blot analysis suggested that the levels of inhibitory IkappaBalpha protein in the cytoplasm decreased. Tacrolimus (100 microg/kg, administered 2 minutes after bleeding was discontinued) inhibited the loss of IkappaBalpha protein from the cytoplasm and prevented NF-kappaB binding activity in the nucleus. Moreover, tacrolimus increased survival time (118 +/- 7 minutes; P <.01) and survival rate (vehicle = 0 and tacrolimus = 90% 240 minutes after bleeding was discontinued), reverted the marked hypotension, decreased liver messenger RNA for TNF-alpha reduced plasma TNF-alpha (35 +/- 6 pg/mL), and restored the hyporeactivity to phenylephrine to control values. CONCLUSIONS: Our results suggest that acute blood loss (50% of the estimated total blood volume during a 20-minute period) causes activation of NF-kappaB and that tacrolimus, by inhibiting this transcription factor, protects against acute hypovolemic shock.

Sucralfate prophylaxis of fluorouracil-induced stomatitis.

AIMS AND BACKGROUND: Various attempts have been made to prevent 5-fluorouracil-induced stomatitis, with unsatisfactory results. Sucralfate is an aluminum hydroxide complex of sulfated sucrose commonly used in the treatment of gastroduodenal ulcers. We used the compound in a phase II study to reduce and minimize the stomatotoxicity of 5-fluorouracil chemotherapy administered in a multiple-day schedule. METHODS: Fifty-two patients entered the study, and 129 cycles of chemotherapy were evaluated. Seven patients refused sucralfate rinses for taste intolerance. RESULTS: A low level of stomatotoxicity was recorded: grade 2 stomatitis was observed after 14 cycles (10.8%) and grade 3 after 3 cycles (2.3%). CONCLUSIONS: Sucralfate administration could have a role in the prevention of 5-fluorouracil-induced stomatitis.

Stem cell factor and interleukin-6, alone or in combination with granulocyte colony-stimulating factor, do not affect the growth of solid tumor cell lines.

Hematopoietic growth factors (HGFs) are glycoproteins that control hemopoiesis. They have potential usefulness in a range of clinical conditions including the treatment of patients with myelosuppression induced by chemotherapy. Among HGFs, Stem Cell Factor (SCF) and Interleukin 6 (IL-6) are attracting interest for their capacity to stimulate early hematopoietic progenitors. Furthermore, their use in combination with late-acting growth factors with a more lineage-restricted potential (such as granulocyte colony-stimulating factor, G-CSF) might be expected to offer optimal marrow stimulation and usefulness in clinical oncology. Since non-hematopoietic malignant cells may express receptors for HGFs and respond to these peptides in vitro, we investigated clonal growth 3H-thymidine incorporation and cell cycle analysis by flow cytometry of 5 human solid tumor cell lines under the influence of SCF and IL-6 with or without G-CSF. Our experiments show that these cytokines have no effects on the proliferative capacity of the cell lines tested. Based on our and previously reported data, the use of these HGFs can be considered safe in cancer patients.

[Transposition of upper permanent canine and premolar. Orthodontic, surgical and conservative solutions]. / Trasposizione del canino e del premolare permanenti superiori: soluzioni ortodontiche, chirurgiche, conservative.

According to the bibliography and their personal experiences, the Authors take into account the transposition of the canine and first premolar, in order to discuss their causes and consider the different therapeutical possibilities. Three clinical cases are here treated.

[Relationship of orthodontics and periodontal support]. / Rapporti tra ortodonzia e supporto parodontale.

The Authors, in the light of available data in the published literature and using their own personal experience as a basis, examine the relationship existing between orthodontia and periodontology, giving prominence to the more immediate and dynamic aspects of the comparison. An obvious cause-and-effect relationship often links the position of the teeth and the periodontal pathology; if this relationship is understood by the orthodontist, it can guide him in his choice of treatment, both where curative treatment is required but also, and more importantly, where prevention can be provided. Emphasis is placed on how serious can be the damages caused to the periodontium where the monitoring of the bacterial plaque and of the inflammation which it brings about is not sufficiently constant. Certain programs of treatment are proposed which, using orthodontal methods, can make a substantial contribution to solving periodontal problems, the kind of problems which are hard to control when traditional methods are used.