Prevalence of Borrelia Burgdorferi sensu lato genomospecies and of the human granulocytic ehrlichiosis (HGE) agent in Ixodes ricinus ticks collected in the area of Monti Lepini,Italy

Ticks are obligate hematophagous arthropods that are parasites in every class of vertebrates in most regions of the world. They are also considered to be important vectors for the transmission of human infectious diseases. In the present study we used polymer chain reaction (PCR) amplification analysis to determine the prevalence of Borrelia burgdorferi and Ehrlichia phagocytophila, the agents of, respectively, Lyme borreliosis and human granulocytic ehrlichiosis, among ticks inhabiting the area of Monti Lepini, a wild area located in the Latium Region of Italy. A total of 141 I. ricinus ticks (125 nymphs and 16 adults) were collected in the studied area. Total DNAs were extracted from I. ricinus nymphs (pooled in groups of five) and from individual adults. The DNA samples were examined for the presence of B. burgdorferi sensu lato and E. phagocytophila by PCR using two specific pairs of oligonucleotides that specifically amplify distinct DNA regions of the 16S rRNA genes of the two species. The prevalence of vectors infected with B. burgdorferi s. l. was 16% in pooled nymphs samples, and 12.5% in adult ticks, while E. phagocytophila was found only in pooled nymphs samples (8%). Three genomospecies were identified, namely Borrelia afzelii, Borrelia garinii, and Borrelia valaisiana, in samples found positive for B. burgdorferi s. l. No sample was found positive for Borrelia burgdorferi sensu stricto.     

Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice

Tumor vasculature is hyperpermeable to macromolecules compared to normal vasculature; however, the relationship between tumor hyperpermeability and tumor progression is poorly understood. Here we show that a cell-permeable peptide derived from caveolin-1, termed cavtratin, reduces microvascular hyperpermeability and delays tumor progression in mice. These antipermeability and antitumor actions of cavtratin occur in the absence of direct cytostatic or antiangiogenic effects. Cavtratin blocks microvascular permeability by inhibiting endothelial nitric oxide synthase (eNOS), as the antipermeability and antitumor actions of cavtratin are markedly diminished in eNOS knockout mice. Our results support the concepts that hyperpermeability of tumor blood vessels contributes to tumor progression and that blockade of eNOS may be exploited as a novel target for antitumor therapy.     

Pyogenic discitis revealing infrarenal aortic prosthetic graft infection impinging on the left ureter

Coexistence of aortic lesions and discitis is uncommon but potentially fatal if the diagnosis is not made promptly. We report the case of a 71-year-old patient with an infected prosthetic graft of the abdominal aorta impinging on the left ureter and accompanied with lumbar discitis. This triad has not been reported previously. Other unusual features in this patient were the circumstances of onset and the development of the infection in a vascular prosthetic graft. The medical and surgical treatment is discussed.     

Docetaxel and epirubicin in advanced breast cancer

In an International Breast Cancer Study Group phase I/II program, 70 patients with advanced breast cancer received up to eight courses of 75 mg/m2 docetaxel combined with 90 mg/m(2) epirubicin, every 3 weeks. G-CSF was not administered prophylactically. Grade 4 neutropenia occurred in 88% of cycles that were not supported by G-CSF. However, febrile neutropenia affected only 24% of cycles. It occurred after the first cycle in 56% of cases and was managed by oral antibiotics in 52% of cases. When supportive G-CSF was administered, the incidence of febrile neutropenia fell to 3% and grade 4 neutropenia to 41%. Only 6% of patients experienced a greater than 20% reduction in left ventricular ejection fraction and no severe, irreversible cardiotoxicity was observed. The overall response rate (RR) was 66% and median time to progression was 4.5 months. The RR was similar in patients with prior adjuvant chemotherapy and patients with predominantly visceral disease. These data and those of comparable series suggest that the combination of epirubicin and docetaxel is tolerable and active, and that it should be further developed clinically.     

Distribution and activity of transglutaminase in rat brain carcinogenesis and in gliomas

Tissue transglutaminase is a calcium-dependent enzyme which may influence cell morphology, cytoskeletal processes and membrane functions. During rat brain carcinogenesis induced by transplacental administration of N-ethyl-N-nitrosourea to BD IX rats, cytosolic tissue transglutaminase activity was increased by about 140% at 30 days of extrauterine life and returned towards the control values at 3–5 months. In the particulate fraction, enzyme activity progressively increased, reaching values similar to those present in the developed gliomas. Tissue transglutaminase activity in gliomas had a behavior inverse to that observed in controls, with a decrease (about 50%) in the cytosol and a marked increase (380%) in the particulate fraction, indicating a redistribution of enzyme activity.     

Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo

Histamine, vascular endothelial growth factor, acetylcholine, oestrogen as well as fluid shear stress activates a mechanism that recruits heat shock protein 90 to the endothelial nitric oxide synthase. The interaction between Hsp90 and eNOS enhances the activation of the enzyme in cells and in intact blood vessels leading to NO production. Intraplantar administration of carrageenan (50 microl paw(-1)) to mice causes an oedema lasting 72 h. Geldanamycin (0.1, 0.3, 1 mg kg(-1)), a specific inhibitor of Hsp-90, that inhibits endothelium-dependent relaxations of the rat aorta, mesentery and middle artery inhibits carrageenan-induced mouse paw oedema in a dose dependent manner. Co-administration to mice of dexamethasone (1 mg kg(-1)) with geldanamycin (0.3 mg kg(-1)) at anti-inflammatory dose causes a loss of the total anti-inflammatory effect of each agent alone. RU 486 (10 mg kg(-1)), a well known glucocorticoid receptorial antagonist, does not inhibit oedema formation but prevents the anti-inflammatory action of dexamethasone (1 mg kg(-1)). Similarly, RU 486 prevents the anti-inflammatory action of geldanamycin (0.3 mg kg(-1)). In conclusion we have described for the first time that geldanamycin, an inhibitor of Hsp90 dependent signal transduction, is anti-inflammatory in vivo implying that Hsp90 is critical for pathways involved in carrageenan-induced paw oedema. In addition the ability of GA to block NO release and reduce oedema formation suggests a therapeutic rationale for specific inhibitors of Hsp90 as potential anti-inflammatory drugs.     

Proposing phase I studies: Patients', relatives', nurses' and specialists' perceptions

Purpose:As of now the primary objective of studies on informedconsent in phase I trials has been to assess patients' expectations andreasons for participation. We have previously shown that the quantity ofinformation provided through a procedure of subsequent oral interviews withpatients was adequate while the attention paid by the physician to theemotional needs and concerns of patients was not. We wanted therefore toassess and compare the perceptions of the information provided about theinvestigational study of patients, relatives, the research nurse and theinvestigator responsible for the phase I trial and the impact this informationhad on the patients' level of anxiety and depression. Patients and methods:The participation to a phase I study wasproposed to patients through two subsequent interviews, the latter attendedalso by patients' relatives, the research nurse and the investigatorcoordinating the phase I trial. After the second interview, attendees wererequested to complete a questionnaire assessing the principal reason forparticipating in the study and the informative, emotional and interactivedimension of the information. Patients were also requested to complete theHospital Anxiety and Depression (HAD) scale before and after the secondinterview. Results:The completed questionnaires of 31 of 42 patients wereretrieved and analysed. The possibility to benefit from the study wasindicated as the main reason for participating by 59% of the patientswhile it was judged to be the case in 78% and 86% of thepatients by the nurse and the investigator, respectively. The information wasjudged to be clear and sufficient in almost all cases by all attendees, whilethe investigator judged that a lower percentage of patients felt at ease andcould express their main worries during the interview, had been helped andwere less worried after it than it was judged by the nurse and the relatives.Patients' state of anxiety and depression was not adversely affected by theinformation provided. Conclusions:Informing patients on the option of receiving aninvestigational treatment within a phase I study is feasible and can be donein a way felt appropriate by patients and relatives, nursing and medicalprofessionals. Providing information in an appropriate manner does notincrease patients' anxiety and depression. Divergence between the aims andinterests of the investigators and patients might explain the difference inthe evaluation of physician, a problem which could perhaps be partiallyovercome by the application of innovative phase I designs.     

The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells.

The mechanism by which L-glutamine (L-Gln) inhibits the release of endothelium-derived relaxing factor from bovine aortic cultured endothelial cells was investigated. The intracellular concentration of L-arginine (L-Arg) in Arg-depleted endothelial cells was inversely related to the level of L-Gln. Removal of L-Gln from the culture medium (usually containing L-Gln at 2 mM) abolished the inhibitory effect of the culture medium on L-Arg generation. L-Gln (0.2 and 2 mM) but not D-Gln inhibited the generation of L-Arg by both Arg-depleted and nondepleted endothelial cells. L-Gln did not interfere with the uptake of L-Arg or the metabolism of L-Arg-L-Phe to L-Arg but inhibited the formation of L-Arg from L-citrulline (L-Cit), L-Cit-L-Phe, and NG-monomethyl-L-arginine. L-Gln also inhibited the conversion of L-[14C]Cit to L-[14C]Arg by Arg-depleted endothelial cells. However, L-Gln did not inhibit the conversion of L-argininosuccinic acid to L-Arg by endothelial cell homogenates. Thus, L-Gln interferes with the conversion of L-Cit to L-Arg probably by acting on argininosuccinate synthetase rather than argininosuccinate lyase. L-Gln also inhibited the generation of L-Arg by the monocyte-macrophage cell line J774 but had no effect on the conversion of L-Cit to L-Arg by these cells. As the release of endothelium-derived relaxing factor from cultured and non-cultured endothelial cells is limited by the availability of L-Arg, endogenous L-Gln may play a regulatory role in the biosynthesis of endothelium-derived relaxing factor.     

Diamine oxidase activity in a model of multistep hepatocarcinogenesis

Treatment of rats with a complete hepatocarcinogenic regimen (diethylnitrosamine, 2-acetylaminofluorene and partial hepatectomy) produced a prolonged stimulation of diamine oxidase activity in liver, which showed early and persistent preneoplastic nodules. Diethylnitrosamine or partial hepatectomy tested separately caused a transient increase in enzyme activity. Early nodules, which were positive for gamma-glutamyltransferase activity, and hepatomas showed diamine oxidase activity of approximately 5- and 13-fold that of control liver, respectively. These results indicate an activation of terminal catabolism of polyamines in preneoplastic nodules and in hepatomas.