Tumor rejection by gene transfer of the MHC class II transactivator in murine mammary adenocarcinoma cells

The murine mammary adenocarcinoma cell line TS/A is a highly malignant MHC class II-negative tumor. We show that transfection of TS/A cells with the MHC class II transactivator CIITA renders them MHC class II-positive and highly immunogenic in vivo. These cells were fully rejected by 51% of syngeneic recipients and had a significantly lower growth rate in the remaining 49% of animals. This directly correlated to the amount of MHC class II molecules expressed in the transfected tumor. Tumor rejecting animals were protected against rechallenge with the parental TS/A tumor. The rejection required CD4(+) and CD8(+) T cells. CD4(+) T cells were fundamental in the priming phase of the antitumor response. CTL-specific for a peptide of the envelope gp70 of an endogenous ecotropic retrovirus were identified and explained the specificity of the effector mechanism of rejection against the TS/A and the antigenically related C26 carcinoma cells but not against the unrelated gp70-negative syngeneic fibrosarcoma F1F cells. This is the first example of successful tumor vaccination by genetic transfer of CIITA. These results open the way to a possible use of CIITA for increasing both the inducing and the effector phase of the antitumor immune response.     

Obstetric and nonmalignant gynecologic bleeding: treatment with angiographic embolization

Eight patients (seven post partum, one post abortion) with massive pelvic hemorrhage related to pregnancy and one patient with uncontrollable bleeding following a cervical biopsy underwent angiography to facilitate the identification and treatment of bleeding sites. In all nine patients pelvic hemorrhage was successfully controlled with embolization under angiographic guidance. Angiographic embolization allowed preservation of the uterus in six patients referred prior to hysterectomy, and one patient subsequently became pregnant. When conservative measures and minor surgical repairs have failed, embolization should be the next step in the treatment of postpartum hemorrhage to avoid major surgery in an unstable patient and to maintain reproductive function.     

The aging process and potential interventions to extend life expectancy

Aging is commonly defined as the accumulation of diverse deleterious changes occurring in cells and tissues with advancing age that are responsible for the increased risk of disease and death. The major theories of aging are all specific of a particular cause of aging, providing useful and important insights for the understanding of age-related physiological changes. However, a global view of them is needed when debating of a process which is still obscure in some of its aspects. In this context, the search for a single cause of aging has recently been replaced by the view of aging as an extremely complex, multifactorial process. Therefore, the different theories of aging should not be considered as mutually exclusive, but complementary of others in the explanation of some or all the features of the normal aging process. To date, no convincing evidence showing the administration of existing “anti-aging” remedies can slow aging or increase longevity in humans is available. Nevertheless, several studies on animal models have shown that aging rates and life expectancy can be modified. The present review provides an overlook of the most commonly accepted theories of aging, providing current evidence of those interventions aimed at modifying the aging process.     

Pulmonary lymphangitic spread of carcinoma: appearance on CT scans

Chest computed tomography (CT), including high-resolution CT with thin (1.5-mm) sections was used to evaluate proved (pathologically or clinically) lymphangitic spread (LS) of tumor in 12 patients. These appearances were compared with thin-section scans obtained in 11 healthy subjects. Thin-section CT demonstrated findings consistent with thickening of the normal lung interstitium. In all patients, thin sections showed an increase in the number of peripheral lines (1-2 cm in length) that were diffuse in generalized disease and localized in focal disease. Normal peripheral arcades were not increased in number, but the limbs forming the arcades were thickened in all patients. A diffuse increase in linear and curvilinear structures (reticular pattern) was seen toward the center of the lung. Polygonal structures 1-2 cm in diameter were seen in seven patients with LS but not in healthy subjects. Fissures were thickened in nine patients. Selected 1.5-mm-thick CT sections are recommended through abnormal areas (seen at CT or on chest radiographs) or if these are normal at three levels (midapex, hilus, and 3 cm above the diaphragm) when scanning patients with tumors known to cause LS.     

A case of infant botulism associated with honey feeding in Italy

A case of infant botulism in a 9 week-old female is described. A strain of C. botulinum type B was isolated from the feces of the baby. The epidemiologic study detected in a sample of home canned honey Clostridium botulinum spores of the same serotype that was isolated from the patient. The honey had been used only to sweeten the pacifier of the baby. This is the first case of infant botulism in Europe linked conclusively to honey.Corresponding author.     

Induction of apoptosis by monosaccharide butyrate stable derivatives in chronic lymphocytic leukemia cells.

BACKGROUND AND OBJECTIVE: Different therapeutic approaches are needed to restore apoptotic mechanisms in CLL cells, as present ones are not successful. We assessed the apoptotic effects of stable butyrate derivatives on CLL lymphocytes: in these molecules a mannose molecule is bound as ester to one-five butyrate moieties, conferring pharmacological stability to the pro-drugs which are able to induce apoptosis in primary AML blasts. DESIGN AND METHODS: Peripheral blood samples obtained from 17 patients with typical B-CLL were cultured in the presence of 0.5-1mM D1 (O-n-butanoyl-2, 3-O-isopropylidene-a-D-mannofuranoside), F1 (1-O-n-butanoyl-2, 3-O-isopropylidene-D,L-xylitol) and G1 (1-O-n-butanoyl-D,L-xylitol) derivatives for 4 days and equimolar sodium butyrate as comparison. After culture, apoptosis was evaluated by cell morphology, cellular DNA content, pattern of DNA fragmentation, annexin V exposure on cell membrane, and cell cycle parameters. Bcl2, bax, and fas oncogene expression were also evaluated by the APAAP method. RESULTS: The addition to cell cultures of D1 or F1 or G1 butyrate monosaccharides as well as sodium butyrate 0.5 and 1 mM determined to different extents an increase in the percentage of apoptotic cells in all CLL samples, relatively to the method and butyrate molecule added in culture. Heterogeneity in CLL cell sensitivity to the three butyrates was observed. Up to 60-68% apoptotic bodies were present in treated cultures after exposure to D1 0.5-1 mM, 60-72% after F1 0.5-1 mM and 48-60% after G1 0.5-1 mM. Comparison of untreated versus treated cultures yielded important significance (p< 0.001). At DNA content analysis, analyzed by flow cytometry, apoptotic events were accounting for up to 70-77% of D1-treated and 68-74% of F1-treated CLL cells at 0.5 and 1 mM concentrations (p= 0. 0001, vs controls 0-39%), and for 72-81% of G1 (0.5-1 mM) treated cells (overall, p=0.005). Cell cycle parameters were not altered by addition of butyrates, but expression of Annexin V was greatly enhanced. In a limited number of CLL cases fas, bcl2/bax ratio was analyzed and found unmodified. INTERPRETATION AND CONCLUSIONS: Monosaccharide butyrate stable derivatives are potent inducers of primary CLL cell apoptosis, both in untreated and alkylating agent pre-treated cases. Our results suggest that the apoptotic pathways elicited by butyrate in CLL lymphocytes are direct, specific and most probably do not involve bcl2/bax. Pro-apoptotic agents like the stable monosaccharide butyrate derivatives here studied could bring more insights into CLL biology and resistance to apoptosis, and possibly originate alternative treatments for CLL.     

Clinical pharmacokinetics of factor VIII in patients with classic haemophilia

Studies of Factor VIII pharmacokinetics in haemophiliacs can be classified into 2 groups depending on whether single-dose or multiple-dose Factor VIII curves are used. This review analyses information published so far in both these areas, with particular emphasis on the choice of appropriate models for pharmacokinetic analysis. Single-dose studies of Factor VIII kinetics have previously used a wide variety of methods for pharmacokinetic analysis (empirical methods of Factor VIII level prediction, graphical techniques for semilog analysis, 1-compartment and 2-compartment models). However, Factor VIII poses unique problems to the pharmacokineticist because decay curves can be either monophasic (monoexponential) or biphasic (biexponential) for unknown reasons, and because Factor VIII concentrations are generally subject to significant assay error. Problems of compartmental analysis that occurred in previous studies are highlighted, and a model-independent non-compartmental approach for analysing Factor VIII curves is proposed. To date, fewer data have been published on multiple-dose kinetics of Factor VIII. From a clinical point of view, repeated-dose regimens are most commonly required in patients undergoing surgery and in patients with severe bleeding. A fairly well defined 'therapeutic window' of optimal Factor VIII plasma concentrations has been identified, particularly in surgical patients. This fact has spurred research aimed at applying to haemophilia patients the pharmacokinetic dosing methods commonly used for therapeutic monitoring of drugs (e.g. Bayesian method for dosage individualization). A few papers have already been published in this field, and this review summarises problems encountered by previous investigators, and evaluates comparatively the pharmacokinetic methods used.     

Quantitative platelet imaging and comparison of four mathematical models for the evaluation of platelet mean life span in patients with chronic immune thrombocytopenia

BACKGROUND AND METHODS. Twenty-five thrombocytopenic patients underwent quantitative in vivo platelet kinetic studies using a scintillation camera and a computer-assisted imaging system. They fulfilled the criteria for chronic immune thrombocytopenia, and the object of the study was to evaluate platelet sequestration and destruction in the spleen. In this sense, the differences in the distribution of the radiolabelled platelets in the spleen and the liver, as well as the differences in the platelet mean life span (MLS) as computed by different methods were assessed. Serial images of the spleen pool, liver and heart were taken after reinjection of In-111-oxine labelled autologous platelets. RESULTS AND CONCLUSIONS. The spleen/liver ratio proved to be a more reliable index in indicating the splenectomy outcome that the Z index (see text). Platelet survival curves were analyzed using four mathematical models, and it was found that MLS estimation is model dependent. Thus, it seem advisable to apply at least two different methods when analyzing experimental data.     

Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicentre double-blind placebo-controlled study

This multicentre, double-blind, randomized, placebo-controlled, parallel study was designed to evaluate the efficacy of combined oral lysine acetylsalicylate and metoclopramide (LAS-MCP) in the acute treatment of migraine attacks. A total of 266 patients, 18–65 years old, with two to six attacks of migraine with or without aura (IHS criteria) per month were included. The patients had to treat two migraine attacks with LAS-MCP (1620 mg lysine acetylsalicylate-the equivalent of 900 mg aspirin- combined with 10 mg metoclopramide) or placebo. The main outcome measure was headache relief (reduction in headache severity from grade 3 or 2-severe or moderate-to grade 1 or 0-mild or none) 2 h after treatment. LAS-MCP was superior to placebo for headache relief (56% vs 28%) and for the following secondary outcome measures: complete headache relief (18% vs 7%; p < 0.001), nausea (28% vs 44%; p < 0.001), vomiting (3% vs 11%; p = 0.001), use of rescue medication (47% vs 68%; p < 0.001), global efficacy judged as good or excellent (32% vs 14%; p < 0.001). The tolerability was considered as good in 94% of treated attacks in both groups. Combined oral lysine acetylsalicylate and metoclopramide is an effective and well-tolerated acute treatment of migraine attacks.     

The effectiveness and tolerability of epoetin alfa in patients with multiple myeloma refractory to chemotherapy

Anemia is a frequent complication of multiple myeloma, becoming chronic in patients who are resistant to chemotherapy. This randomized, parallel, controlled multicenter study (71 patients receiving concomitant chemotherapy) evaluated the efficacy and safety of epoetin alfa in improving anemia and eliminating the need for transfusions in multiple myeloma patients refractory to conventional first- or second-line chemotherapy. Forty patients were treated with subcutaneous epoetin alfa (150 IU/kg per dose, increasing to 300 IU/kg per dose, every 3 weeks) for 6 months, and 31 entered a control group. The epoetin alfa group had a significantly (P≤0.001) greater percentage of patients (75% vs. 21%) with increases in hemoglobin levels and/or reduced transfusion requirements. In 44 non pre-transfused patients (20 controls, 24 in the epoetin alfa group), the mean increase in hemoglobin was significantly (P≤0.0001) greater in the epoetin alfa group (+2.1 vs. −0.2 g/dl). Increases in hematocrit and red blood cells were also significantly (P≤0.0001) greater in epoetin alfa-treated patients, with corresponding reductions in transfusion requirement. In the 27 pre-transfused patients (11 controls, 16 in the epoetin alfa group), there was a trend towards reduced transfusional need in epoetin alfa-treated patients. Thus, in patients with multiple myeloma refractory to chemotherapy epoetin alfa is a well-tolerated treatment which improves anemia in non pre-transfused patients and appears to reduce transfusion need in those previously transfused.