Biomedical subjects
Publications and source records attributed to P Tolentino.
We report the electrochemical insertion of copper in polypyrrole films followed by XAS spectroscopy. Depending on the applied potential the copper remains as an ionic form like Cu(+n)-(OSO3-)n. For more reductive potentials metal particles are synthesized. Small particles with an estimated average diameter of 20 A were obtained.
Since a decreased interferon response has been linked with certain chronic viral infections, a preliminary study was undertaken to determine whether an altered interferon response may be involved in the pathogenesis of chronic hepatitis, a complication of type B hepatitis. The production of interferon by lymphocytes from patients with chronic hepatitis was compared with the production by lymphocytes from normal subjects. The amount of interferon produced by paramyxovirus-stimulated lymphocytes from 16 patients was substantially smaller than that produced by lymphocytes from 12 healthy donors. The results indicate that decreased production of interferon may be responsible for the chronicity of the disease. However, further studies are necessary to establish causality.
In naive mice the selective D2 agonist LY171555 dose-dependently (0.5-5 mg/kg) induces defensive responses toward non-aggressive conspecifics. In order to investigate possible anxiogenic properties of the D2 agonist, its behavioural effects were compared with those produced by the benzodiazepine receptor inverse agonist methyl-beta-carboline-3-carboxylate(beta-CCM) in the elevated plus maze and in social interactions with non-aggressive opponents. When tested in the elevated plus maze, mice injected with LY 171555 (0.005-1 mg/kg) showed no decrease either of the number of entries or of the time spent in the open arms. At 5 mg/kg an actual increase of these two measures was observed. By contrast, beta-CCM (1-3 mg/kg) dose-dependently decreased both the number of entries and the time spent in the open arms without altering locomotion. The effects of beta-CCM were antagonized by the benzodiazepine receptor antagonist RO 15-1788 (3 mg/kg) showing a selective involvement of benzodiazepine receptors in their modulation. On the other hand, beta-CCM, (1-3 mg/kg) did not produce significant effects on defensive behaviour of mice interacting with non-aggressive opponents and the defensive responses of mice treated with 1 mg/kg LY 171555 were not prevented by 5 mg/kg chlordiazepoxide. These results show that DA D2-mediated hyperdefensiveness and anxiety modulated by benzodiazepine receptors are unrelated phenomena and suggest that this behavioural response may represent a model of those forms of fear-related reaction that do not respond to benzodiazepine treatment.
Herpes simplex virus encodes a 175-kilodalton immediate-early transactivating protein referred to as ICP4. A mutant ICP4 molecule expressed from a stable transformed cell line lacks the sequences required for transactivation yet retains the ability to specifically associate with DNA and to form homodimers. Expression of the mutant ICP4 peptide from this cell line, designated X25, resulted in the inhibition of herpes simplex virus growth. Wild-type ICP4 homodimers were depleted in X25-infected cells by the formation of heterodimers containing the wild-type ICP4 molecule and the mutant peptide. While the ICP4 heterodimer retained DNA-binding activity, immunological studies suggest that the wild-type subunit of the heterodimer is conformationally altered in a region that serves as the antigenic epitope. Physical studies that determined the composition of the heterodimer and its native size and approximate shape support this observation. The structural change is in a region of ICP4 genetically implicated as important for transactivation and may result in an alteration in an interaction between ICP4 and a target protein essential to promote transcriptional activation. Sequestering wild-type monomers of a viral regulatory protein into heterodimers which are less proficient in transactivation may explain the dominant inhibitory activity of the X25 cells, resulting in attenuation of viral growth.
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Serological evidence of infection with the hepatitis B virus associated delta agent (delta) was found in 34 of 270 Italian children with HBsAg-positive liver disease. In different histological forms of chronic HBsAg hepatitis the prevalence of delta infection increased in parallel with the activity of the disease and was maximal in children with cirrhosis. During two to seven years of follow up the hepatitis deteriorated in 38% of the 34 patients with delta infection and ameliorated only in 9%. By contrast the disease usually ran a mild course in the 236 delta-negative carriers of HBsAg, with remission in 55% of these children and deterioration in only 7%. The outcome of chronic hepatitis associated with delta infection was not influenced by treatment with steroids and azathioprine. Chronic delta infection in children is usually accompanied by serious liver disease, that has a tendency to progress and is unresponsive to conventional immunosuppressive treatment.
In 21 subjects HBsAg positive affected by different forms of chronic hepatitis and in one carrier we compared the presence in the liver of HBsAg, HBcAg and delta studied by means of I.F. and the presence of serological markers of hepatitis B virus infection. By the I.F. test, HBsAg was present in all cases, HBcAg in 15 cases (71%), delta in 8 cases (38%). These percentages are almost the same as those of other researches in chronic hepatitis in immunodepressive treatment. About the serological markers, HBsAg and HBcAb were present in 100% of cases, while, regarding the e-anti e system, HBeAg was present in 12 cases (57%) and HBeAb in 7 (33%). In the work effected there is no relation between delta and HBeAg because in 50% of the positive delta subjects there was HBeAb. On the contrary HBcAg and HBeAg are strictly correlated. Therefore the antigens core and delta are not interdependent. We wanted to verify the existence of relation between HBcAg and HBeAg and came to the conclusion that this relation exists in 17 out of 21 subjects (81%). In our researches is clear the long persistence of the hepatic antigens without any connection with the time of treatment and the course of the various chronic hepatitis. The change in the serum from HBeAg to HBeAb occurred in many improved cases but not in all of them. We presume that the long immunodepressive treatment (about 4 years) has influenced our results.
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13 children with chronic HBsAg negative hepatitis were examined in this work with the I.F. method. Comparison can be made with a previous work on chronic HBsAg positive hepatitis. 8 of these patients were cases of ECP, 1 was a ECA-A and 4 were ECA-B. Research has been done to point out immunoglobulins and immunocomplexes in the liver and serum. On the whole, fluorescence was less both in liver and serum than fluorescence in chronic HBsAg positive hepatitis. Reasons of it can be: the absence of anti-virus B antibodies (HBcAb, delta-Ab, HBsAb), the relative lightness of our cases and, probably, a better answer of HBsAg negative hepatitis than of HBsAg positive one to immunodepressive treatment.
The results obtained in a study of liver biopsies from children affected by different forms of chronic hepatitis during an immunodepressive treatment, accomplished by means of immunofluorescence are summarized. The different antigens correlated to B virus, localized in the nuclei (core and delta), the immunological phenomena observed in the tissue (immunoglobulins and immunocomplexes) and in serum (autoantibodies) have been investigated. The presence of HBcAg, looking finely granular, has been found in 77% of cases of CAH, similar to that found in adults. Delta Ag has been found only in 29% of cases, in the nuclei, like core Ag, but nuclei were more large and not homogeneous. The 2 antigens could be found also in the same patient, differently from adults. The absence of the two antigens has a good prognostic significance; the presence of delta antigen has on the contrary a bad prognostic meaning; the persistence of core antigen under immunodepressive treatment may correspond to a tolerance against antigen. Immunoglobulins and/or immunocomplexes, binding complement, were found in 69% of cases. The fluorescence can be found in different patterns: nuclear, due to immunocomplexes of HBV and antibodies penetrated through impaired membranes; of hepatocyte membranes, linear, probably against auto-antigens (lipoproteins liver-specific) or neo-antigens induced by the virus; in inflammatory cells (K-cells or phagocytic monocytes); or scattered granular, may be from non-eliminated immunocomplexes. Autoantibodies in serum, tested on autologous substrates, were present in 97% of cases, in prevalence antinuclear or against hepatocytary membranes, but also against cytoplasmatic components. Important variations exist between the different forms, both as for what concerns the morphological patterns and the intensity of the reactions. A statement about the severity and the evolution of the disease, with prognostic implication could be hypothetically made in the future, after further studies.
On liver biopsies of 20 children with different forms of chronic HBsAg-positive hepatitis, submitted to immunodepressive treatment, the presence and the distribution of core and delta antigens and their correlation with the different clinical forms have been studied with the direct immunofluorescence technique. Core antigen was present in 11 patients, delta antigen in 4 patients: both antigens in 3 cases. The percent rate of positive nuclei varied from 5 to 80%. All subjects negative for both antigens showed a favourable course. Delta antigen seems to be associated to forms with unsatisfactory course notwithstanding therapy, particularly to relapses and recurrences of chronic hepatitis in such a way as to hypothesize the possible responsibility either of another hepatitic virus (non A, non B virus) or of a different virus. Core morphological expression frequent in chronic hepatitis submitted to immunodepressive treatment, corresponded approximately to the finding thus far reported for the adults. The interpretation of these results, though difficult, shows remarkable interest for the pathogenetic and therapeutic considerations which follow.
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Chromosome aberrations of short and long-term cultured lymphocytes have been studied in 12 subjects with chronic hepatitis B. Short-term cultures show "stickiness", aneuploidy, and fragmentations. Long-term cultures show minor damages, made up almost totally of "lacunae" and sporadic fragmentations. Major size chromosomes appear to be more affected, among the latter those containing sites for the interferon. This latter findings would suggest that the interferon decrease in patients might be bound, even only partially to the virus-linked chromosome alterations.
Liver failure is a complication of viral hepatitis, as well as a consequence of acute mushroom or drug poisoning. The different therapies to be employed in a "pre emergency" state, or in case of "emergency" (resistant to medical treatment or starting as "fulminant" hepatic failure) are summarized. The percentage of survival, even by means of sophisticated treatment, does not overcome 30%.
Liver biopsies from patients (mostly children) affected by chronic hepatitis (persistent or active, HBsAg positive or negative forms), part of them treated by immunosuppressive therapy, have been studied by means of immunofluorescence techniques. A cytoplasmic localization of HBsAg and a nuclear localization of HBcAg have been demonstrated. Moreover, a nuclear localization of immunocomplexes was demonstrated, as well as the presence of immunoglobulins. Persistent forms showed a lesser fluorescence than active forms, and so did the treated patients, if compared with recent, not yet treated subjects.
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Stool specimens, collected from 8 children with viral hepatitis [5 of type A, presumably, and 3 of type B (HBsAg-positive)] during the acute phase, were examined in the electron microscope. The presence of 27-nm virus-like particles, aggregated by the convalescent serum of a chimpanzee infected with MS-1 and not by the serum of the same animal drawn before infection, was detected by immune electron microscopy (IEM) in the stools of 3 out of the 5 children with suspected hepatitis A. The virus-like particles (HA-Ag) present in the stools were aggregated by the serum drawn from the corresponding subject during convalescence and not by that obtained in the acute phase of the disease. Employing as antigen a stool particle preparation purified by isopycnic banding in cesium cloride, it was pointed out that, in all 5 children with suspected hepatitis A, antibodies capable to cause the aggregation of HA-Ag particles, appeared. Anti-HA antibodies turned out to be present also in three lots of commercial immunoglobulins. In the three subjects with type B hepatitis (HBsAg-positive) neither virus-like particles with a 27-nm diameter were observed, nor anti-HA antibodies appeared in the convalescent serum.
A 5-year-old boy was admitted with an acute febrile illness and painful and enlarged cervical lymph nodes. A chest X-ray showed right tracheobronchial lymph nodes. A lymph node biopsy demonstrated a tuberculoid appearance, with epitheloid cells, giant cells, and also necrotic zones. Cryptococcus neoformans was isolated both in culture and after animal inoculation. While amphotericin B was not tolerated by the patient, the oral administration of 5-fluorocytosine resulted in a rapid recovery.