Deep venous thrombosis and neoplastic pathology: our experience in emergencies

Deep vein thrombosis incidence is 1/1000 per year; it is associated with many risk factors which is considered as "thrombophilic states". Its pathogenesis is complex, caused by alterations of hemostasis system. Many studies have established the relation between cancer and subsequent venous thromboembolism, confirming the relationship of neoplastic cell interaction with coagulation system. Forty-seven patients admitted to the hospital from 1987 to 1996 with symptomatic clinically proved deep vein thrombosis were included in a retrospective study. Routine examination at the time of diagnosis of deep vein thrombosis revealed an occult cancer in 8 out of 47 patients; 9 out of 47 patients were admitted in hospital with vein thrombosis and known cancer. The aim of this study is to suggest the best, first treatment of vein thromboembolism in emergency to avoid the dangerous pulmonary embolism complication. The patients affected with deep vein thrombosis and cancer were elderly (over 70 years old, in mean); the neoplasia was of digestive system (8/17) in advanced metastatic stage there was cancer familiarity in 7 out of 47 patients. The high risk of pulmonary embolism associated to deep vein thrombosis suggests the importance of early starting the anticoagulant therapy and placing caval filter.     

Split tolerance to a viral antigen expressed in thymic epithelium and keratinocytes

When expressed as a transgene from the keratin 14 (K14) promoter in an MHC class II-deficient mouse, I-Ab expressed in thymic cortical epithelium promotes positive but not negative selection of I-Ab-restricted CD4+ T cells (Laufer, T. M. et al., Nature 1996. 383:81-85). Transgenic mice expressing the E7 protein of human papilloma virus 16 from the K14 promoter were studied to determine the consequence of expression of a cytoplasmic/ nuclear protein from the K14 promoter. K14E7-transgenic mice express E7 in the thymus and skin without evidence for autoimmunity to E7. Repeated immunization of FVB(H-2q) or F1(C57BL/6JxFVB) mice with E7 elicited similar antibody responses to the defined B cell epitopes of E7 in K14E7-transgenic and non-transgenic animals. In contrast, for each genetic background, a single immunization with E7 elicited demonstrable T cell proliferative responses to the major promiscuous T helper epitope of E7 in the transgenic but not the non-transgenic animals. Further, E7-immunized non-transgenic F1 (FVBxC57BL/6J) animals developed strong E7-specific cytotoxic T lymphocyte (CTL) responses and were protected against challenge with E7+ tumors, whereas similarly immunized K14E7-transgenic animals had a markedly reduced CTL response to E7 and no E7-specific tumor protection was observed, although the antibody and CTL response to ovalbumin was normal. Expression of E7 protein as a transgene from the K14 promoter in the skin and thymus thus induces E7-specific tolerance in the cytotoxic T effector repertoire, together with expansion of the E7-specific T helper repertoire. These findings demonstrate that limited tissue distribution of an autoantigen may result in "split" tolerance to that autoantigen.     

Association between carotid lesions evaluated by Doppler color echocardiography and cardiovascular risk factors in the elderly. Preliminary results

BACKGROUND: The valuation of the extracranial carotid by echo color-Doppler takes on an extraordinary importance for the prevention of cerebral ictus at geriatric age. In this "naturalistic" study a population of old people (> 65 yrs) of Cagliari's province was considered in order to: 1) discriminate the lesions of the carotid that are imputed to atherosclerotic disease by anatomic changes of the arterial wall caused by aging; 2) study relations between lesions of the carotid and cardiovascular risk factors. METHODS: The carotids of 50 old subjects were studied by echo color-Doppler and the lesion classified in different classes of severity, according to the hemodynamic standard, comparing them with the presence of the most important cardiovascular risk factors. Hypercholesterolemia was the most frequent risk factor (76%), followed by hypertension (62%), over-weight (54%) and smoking (42%). Moreover a diffused intima-media thickening (IMT) was constant in all the subjects with values > 0.75 mm; athero-sclerotic plaques were even present in 39 subjects which only in 4 cases could be considered at risk of cerebral ischemia. RESULTS: A significant correlation between the severity of the lesions and levels of total cholesterol and LDL cholesterol for the male sex emerged, while for smoking only a trend of correlation has been obtained. CONCLUSIONS: Considering this experience it is suggested that in old subjects the presence of a diffused IMT with values > 0.75 mm must be considered as a marker of aging of the arterial wall of the carotid and not as a cardiovascular risk factor as reported in the literature for the middleaged.     

Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Str?ussler-Scheinker disease

The clinicopathological phenotype of the Gerstmann-Str?ussler-Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of approximately 21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt-Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and "synaptic" pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion diseases largely depends on the type of PrP-res fragment that forms in vivo. Because the formation of PrP-res fragments of 7-8 kDa with ragged N and C termini is not a feature of Creutzfeldt-Jakob disease or fatal familial insomnia but appears to be shared by most GSS subtypes, it may represent a molecular marker for this disorder.     

Mechanism-based inactivation of cytochrome P-450-3A4 by mifepristone (RU486)

Mifepristone (RU486), an 11beta-substituted nor-steroid containing a 17alpha-1-propynyl group used clinically as an antiprogestin agent for medical abortions, was demonstrated to be a selective mechanism-based inactivator of human cytochrome P-450-3A4 (CYP-3A4). The loss of testosterone 6beta-hydroxylation activity was time- and concentration-dependent as well as requiring metabolism of mifepristone in a purified CYP-3A4 reconstituted system. The inactivation exhibited pseudofirst-order kinetics. The values for KI and kinactivation were 4.7 microM and 0.089 min-1, respectively. The reduced-CO spectrum of CYP-3A4 was decreased by 76%, whereas approximately 81% of the activity was lost following incubation with mifepristone in the reconstituted system in the presence of NADPH. However, the Soret peak of the inactivated CYP-3A4 was slightly increased. High-performance liquid chromatography analysis of the incubation mixture showed that the peak containing the heme dissociated from the inactivated CYP3A4 was almost identical with that seen for the -NADPH control. Covalent binding of [3H]mifepristone to apoCYP3A4 was demonstrated by SDS-PAGE and high-pressure liquid chromatography analyses of the reconstituted system containing CYP-3A4, NADPH-CYP reductase, cytochrome b5 and lipids in the presence of NADPH. The stoichiometry was determined to be approximately 1 mol of mifepristone bound per 1 mol of CYP-3A4 inactivated. Therefore, the mechanism of inactivation of CYP-3A4 by mifepristone involves irreversible modification of the apoprotein at the enzyme active site instead of being the result of heme adduct formation or heme fragmentation. Mifepristone exhibits selectivity for CYP-3A4 as evidenced by the fact that it did not show mechanism-based inactivation of CYPs 1A, 2B, 2D6, and 2E1, although a competitive inhibition of CYP 2B1 and 2D6 was observed.     

Hot Bands of Water up to 6nu2-5nu2 in the 933-2500 cm-1 Region

Emission spectra have been recorded for hot water at temperatures up to 1550 degreesC. Separate spectra have been recorded in the 800-1900 and 1800-2500 cm-1 range. Assignments are made using a linelist generated from high accuracy, variational nuclear motion calculations, and energy differences. The spectra contain many hot bending transitions of the form (0n0)-(0n-10), where states up to n = 6 have been assigned. Detailed analysis shows that the spectra contain lines from 34 separate vibrational bands including other hot bending transitions and the difference bands (030)-(100), (110)-(020), (011)-(020), (100)-(010), (040)-(110), (040)-(011), (120)-(030), (012)-(030), (011)-(100), (110)-(001), and (101)-(110), all of which have not been observed previously. From a total of 8959 lines recorded, 6810 have been assigned; 4556 of these lines are new. These spectra represent the first detection of the (060) vibrational band, for which a band origin of 8870.54 +/- 0.05 cm-1 is determined. The (050) band origin is confirmed as 7542.40 +/- 0.03 cm-1. The assignments extend the range of J and Ka values observed for the bending states, particularly for (050) and (060), where 63 and 27 different rotational levels, respectively, have now been observed; 53 frequencies given in HITRAN are corrected. Copyright 1999 Academic Press.