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Biomedical subjects

A Cavalli

Publications and source records attributed to A Cavalli.

At least 55 records · Page 3Linked to original sources
PubMed1999

Four new DP alleles identified in a study of 500 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 500 donor recipient pairs in a retrospective analysis sponsored by the National Marrow Donor Program (NMDP) identified four new DP alleles, two DPB1 and two DPA1. DNA sequencing confirmed that DPB1*8001 and *8101, each found in a single individual, are novel combinations of previously described sequence motifs in the six variable regions of DPB1. DPA1*02014, found in two individuals, is identical to DPA1*02011 except for a novel silent substitution, a G to A transition at the third position of codon 14. DPA1*01032, found in one individual, is identical to DPB1*01031 except for a silent G to A transition at the third position of codon 20. The identification of these novel alleles brings the total number of reported DPB1 alleles to 85 and DPA1 alleles to 15.

Alleles↗
PubMed1998

Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives.

Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.

Acetylcholinesterase↗
PubMed1998

Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection.

Adult↗
PubMed1998

Incidence and prognosis of early primary ventricular fibrillation in acute myocardial infarction--results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) database.

Primary ventricular fibrillation (VF) complicating acute myocardial infarction (MI) predicts short-term mortality. The broad category of patients with primary VF might include subgroups with different outcomes. It is still not certain whether early-onset (< or =4 hours) primary VF is a risk predictor, and information on correlates of these early fibrillations is scarce. This study sought to prospectively analyze the incidence and prognosis of early, as opposed to late (time window >4 to 48 hours) primary VF and retrospectively identify predisposing factors for early-onset primary VF. We analyzed the incidence and recurrence rate of early and late primary VF in 9,720 patients with a first acute MI, treated with thrombolytics, enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-2 trial. The independent prognostic significance of early and late primary VF was assessed by logistic regression analysis. The incidence rates of early and late primary VF were 3.1% and 0.6%, respectively; recurrence rates were 11% and 15%, respectively. The 2 variables most closely related to early primary VF were hypokalemia and systolic blood pressure < 120 mm Hg on admission. Patients with early primary VF had a more complicated in-hospital course than matched controls. Both early (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.48 to 4.13) and late primary VF (OR 3.97, 95% CI 1.51 to 10.48) were independent predictors of in-hospital mortality. Postdischarge to 6-month death rates were similar for both primary VF subgroups and controls. Primary VF, irrespective of its timing, was an independent predictor of in-hospital mortality. Postdischarge to 6-month prognosis was unaffected by the occurrence of either early or late primary VF.

Anti-Arrhythmia Agents↗
PubMed1998

mu Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality.

The mu opioid receptor gene (MOR) was mutated in mice by a gene targeting procedure. In these MOR-knockout mice, the analgesic effects of morphine, its major metabolites, morphine-6-glucuronide (M-6-G) and morphine-6-ethereal sulfate (M-6-S), and endomorphin-2, as well as morphine-induced lethality, were drastically reduced, whereas the effects of DPDPE and U50488 remained unchanged. It is concluded that analgesic effects of mu-specific opioid ligands and acute morphine lethality are mediated by the mu receptor.

Analgesics, Opioid↗
PubMed1998

Antiviral cell-mediated immune responses during hepatitis B and hepatitis C virus infections.

Cell-mediated immune responses to hepatitis B (HBV) and hepatitis C virus (HCV) antigens are vigorous and multispecific in acute, self-limited infections. Moreover, the prevalent cytokine pattern of circulating virus-specific T cells from patients who recover spontaneously from acute hepatitis is Th1-like. Longitudinal analysis of the T cell response to HCV antigens from the early stages of HCV infection in patients who recover from hepatitis and those who do not indicates that weaker responses and a prevalent Th2 pattern of cytokine production is associated with viral persistence and chronic evolution of disease. Although similar sequential studies are missing in hepatitis B, the observation that HBV-specific T cell responses are very weak or totally undetectable in the peripheral blood of patients with long-lasting chronic hepatitis B suggests that strength and quality of virus-specific T cell responses at the early stages of infection may influence the final outcome of both hepatitis B and C. While T cell hyporesponsiveness seems to be an important determinant for HBV persistence once chronic hepatitis has developed, this mechanism appears to be less critical in chronic HCV infection, because the vigor and quality of HCV-specific T cell responses seem to improve as a function of the duration of infection. This is shown by the finding that HCV-specific CD4- and CD8-mediated responses are easily detectable in the peripheral blood of patients with long-lasting chronic hepatitis C and that production of Th1 cytokines predominates within their livers. HCV therefore seems to be able to persist even in the face of an active T cell response and to acquire the capacity to survive within a host environment apparently unfavorable to its persistence. The high variability of HCV may explain its efficiency in escaping immune surveillance.

Hepatitis B↗
PubMed1998

Comparative molecular field analysis of non-steroidal aromatase inhibitors: an extended model for two different structural classes.

Aromatase is a cytochrome P450 isozyme, whose inhibition is known to be therapeutically relevant in the treatment of the breast cancer. A comparative molecular field analysis (CoMFA) has been carried out on a series of non-steroidal aromatase inhibitors belonging to two different structural classes. One subset of compounds consists of fadrozole analogues and was studied in a previous work, from which a 'local' 3-D quantitative structure-activity relationship (QSAR) model for the inhibition of aromatase was obtained. In the present paper, that model is extended to include a second subset of compounds bearing a tetralone nucleus and acting at the same enzyme site with the same mechanism as the azoles. The critical alignment step has been solved by using two different steroidal inhibitors of aromatase as rigid templates, on which the non-steroidal compounds have been superimposed. The final 3-D QSAR models are discussed in terms of predictivity and some implications regarding the steric and electronic requirements of steroidal and non-steroidal inhibitors are pointed out.

Aromatase Inhibitors↗
PubMed1998

Three new DP alleles identified in sub-Saharan Africa: DPB1*7401, DPA1*02013, and DPA1*0302.

HLA-DP genotyping of over 400 individuals from sub-Saharan Africa identified three new DP alleles: DPB1*7401, DPA1*02013, and DPA1*0302. DNA sequencing confirmed that DPB1*7401, found in one individual, is a novel combination of previously described sequence motifs in the six variable regions of DPB1. DPA1*02013, found in one individual, is identical to DPA1*02012 except for two silent substitutions, a T to C transition in codon 37, and an A to G transition in codon 38. DPA1*0302, identified in seven individuals, is identical to DPA1*0301 except for a C to T transition at the second position of codon 66. The identification of these novel alleles brings the total number of reported DPB1 alleles to 77 and DPA1 alleles to 11.

Africa South of the Sahara↗
PubMed1997

Decreased blood pressure response in mice deficient of the alpha1b-adrenergic receptor.

To investigate the functional role of different alpha1-adrenergic receptor (alpha1-AR) subtypes in vivo, we have applied a gene targeting approach to create a mouse model lacking the alpha1b-AR (alpha1b-/-). Reverse transcription-PCR and ligand binding studies were combined to elucidate the expression of the alpha1-AR subtypes in various tissues of alpha1b +/+ and -/- mice. Total alpha1-AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex of the alpha1b -/- as compared with +/+ mice. Because of the large decrease of alpha1-AR in the heart and the loss of the alpha1b-AR mRNA in the aorta of the alpha1b-/- mice, the in vivo blood pressure and in vitro aorta contractile responses to alpha1-agonists were investigated in alpha1b +/+ and -/- mice. Our findings provide strong evidence that the alpha1b-AR is a mediator of the blood pressure and the aorta contractile responses induced by alpha1 agonists. This was demonstrated by the finding that the mean arterial blood pressure response to phenylephrine was decreased by 45% in alpha1b -/- as compared with +/+ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in alpha1b-/- mice. The alpha1b-AR knockout mouse model provides a potentially useful tool to elucidate the functional specificity of different alpha1-AR subtypes, to better understand the effects of adrenergic drugs, and to investigate the multiple mechanisms involved in the control of blood pressure.

Animals↗
PubMed1997

A comparative QSAR analysis of acetylcholinesterase inhibitors currently studied for the treatment of Alzheimer's disease.

Considering the relevance of acetylcholinesterase inhibitors as potential agents for the treatment of the Alzheimer's disease, we have undertaken a comparative QSAR analysis aimed at individuating the physico-chemical properties governing the inhibitory activity of such compounds. The QSAR equations for 13 series of derivatives have been calculated and discussed. The series studied are all those we found in the literature suitable for a QSAR analysis and represent the three main classes of acetylcholinesterase inhibitors currently investigated, namely, physostigmine analogues, 1,2,3,4-tetrahydroacridines and benzylamines. The equations we obtained show that, within each class, the main physico-chemical properties affecting the inhibitory activity are almost the same for all the series and can be individuated by the use of proper parameters. The conclusions of this study can be summarized as follows: (a) hydrophobicity plays a critical role in both the physostigmine- and the benzylamine-derived classes; (b) electronic effects are important for the interactions carried out by the variable portion of benzylamine derivatives; and (c) steric factors are also significant, but, as in other cases, the collinearity between steric and hydrophobic parameters does not allow one to draw any final conclusion.

Acetylcholinesterase↗
PubMed1997

Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B.

The cytokine pattern secreted by T cells on viral antigen recognition is believed to exert a profound influence on both the type of disease caused by the infecting agent and the final outcome of the viral infection. To characterize the cytokine pattern associated with spontaneous resolution of acute hepatitis B, we analyzed interferon gamma (IFN-gamma), interleukin (IL)-4, and IL-5 production by a wide series of hepatitis B virus (HBV) nucleocapsid-specific T-cell lines (34 lines) and T-cell clones (71 clones) derived from the peripheral blood of 13 patients during the acute or recovery phase of hepatitis B (2 and 7 of them were studied only in the recovery or the acute phase, respectively, and 4 during both). Most T-cell lines (67%) and clones (77%) isolated during the acute phase of infection expressed a T-helper (Th) 1 cytokine profile dominated by the production of IFN-gamma. A larger proportion (74%) of T-cell lines produced several years after resolution of hepatitis was able to secrete not only IFN-gamma, but also IL-4 and IL-5 (Th0-like cells). Results indicate that the antigen-specific fraction of peripheral blood T cells in acute self-limited hepatitis B selectively secrete Th1-type eytokines, suggesting that Th1-mediated effects may contribute not only to liver cell injury, but probably also to recovery from disease and successful control of infection.

Acute Disease↗
PubMed1996

Amino acids of the alpha1B-adrenergic receptor involved in agonist binding: differences in docking catecholamines to receptor subtypes.

Site-directed mutagenesis and molecular dynamics analysis of the 3-D model of the alpha1B-adrenergic receptor (AR) were combined to identify the molecular determinants of the receptor involved in catecholamine binding. Our results indicate that the three conserved serines in the fifth transmembrane domain (TMD) of the alpha1B-AR play a distinct role in catecholamine binding versus receptor activation. In addition to the amino acids D125 in TMDIII and S207 in TMDV directly involved in ligand binding, our findings identify a large number of polar residues playing an important role in the activation process of the alpha1B-AR thus providing new insights into the structure/function relationship of G protein-coupled receptors.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1996

Long-lasting memory T cell responses following self-limited acute hepatitis B.

The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO+T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects. to conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control.

Acute Disease↗
PubMed1996

Reactivation of caprine herpesvirus 1 in latently infected goats.

The authors report CapHV.1 reactivation in two latently infected adult goats treated with dexamethasone (DMS) (4.40 mg/kg BW) for 6 days. Virus was reisolated from vaginal swabs from the 3rd to the 12th day post-treatment with DMS and from nasal swabs for 2 days (6th and 7th day post-treatment). The animals also showed an increase of neutralizing antibody (SN) titer to CapHV.1 3 weeks after the end of treatment with DMS.

Animals↗