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Biomedical subjects

R Ahmed

Publications and source records attributed to R Ahmed.

At least 163 records · Page 9Linked to original sources
PubMed1994

Class III antiarrhythmic drugs.

Pharmacological therapy of cardiac arrhythmias continues to evolve, with an increasing shift from class I to class III compounds and beta-blockers. This is engendered by increasing concern that class I antiarrhythmic drugs might adversely affect mortality in patients with significant structural heart disease. The focus now is on complex molecules such as amiodarone and sotalol, as well as D-sotalol and structurally diverse newer class III agents (such as dofetilide, MK-499, ibutilide, almokalant, and MS-551 among many others), which act only by increasing the time course of myocardial repolarization. In the development of newer drugs, the main endpoint in clinical trials is also beginning to shift to mortality from surrogate endpoints such as those determined by Holter monitoring and programmed electrical stimulation. The advent of implantable devices allows the performance of clinical trials with a mortality endpoint in patients with manifest ventricular tachycardia and fibrillation while providing an alternative mode of therapy for these arrhythmias. In the case of manifest ventricular tachycardia and fibrillation and aborted sudden death, adequately designed, controlled trials can now be undertaken by the use of implantable devices. In such trials, implantable cardioverter-defibrillators may serve in lieu of the placebo arm of a randomized trial. Trials involving a comparison of implantable cardioverter-defibrillators and best medical therapy (for the present, amiodarone and sotalol) are currently in progress. To what extent the newer class III agents will meet the requirements of an ideal antifibrillatory agent that reduces mortality in patients with structural heart disease remains a continuing investigative challenge.

Amiodarone↗
PubMed1994

Tissue-mediated selection of viral variants: correlation between glycoprotein mutation and growth in neuronal cells.

Viral variants with different biological properties predominate in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the Armstrong strain of lymphocytic choriomeningitis virus. The CNS isolates have the same phenotype as the parental strain and cause acute infections in adult mice, while the spleen-derived isolates cause chronic infections associated with suppressed T-cell responses and susceptibility to opportunistic infections. Our previous studies have identified a single amino acid change in the viral glycoprotein, a phenylalanine-to-leucine (F-->L) mutation at residue 260, that correlates with the tissue-specific selection and the persistent and immunosuppressive phenotype of the spleen isolates (R. Ahmed, C.S. Hahn, T. Somasundaram, L. Villarete, M. Matloubian, and J. H. Strauss, J. Virol. 65:4242-4247, 1991). In this study, we screened viral isolates obtained from the spleen, liver, kidney, and brain of carrier mice for the presence of this mutation and determined the temporal selection of variants as they appear in these organs. We found that this F-->L amino acid change is common to > 90% of the spleen and liver isolates and is selected for rapidly by day 32 postinfection (p.i.). Although the kinetics observed in the kidney are relatively slower than in the spleen and liver, this F-->L mutation predominates in the kidney-derived isolates by 250 days p.i. In contrast, the majority of the CNS isolates retain the parental sequence up to 250 days p.i. In addition, most of the brain isolates replicated efficiently in a neuronal cell line, and this enhanced growth phenotype in neurons correlated with the parental F genotype. This linkage with neurotropism, along with our earlier finding that the F-->L mutation is necessary for enhanced infection of macrophages (M. Matloubian, S. R. Kolhekar, T. Somasundaram, and R. Ahmed, J. Virol. 67:7340-7349, 1993), provides a cellular basis for the molecular changes associated with tissue-specific selection. Taken together, these results suggest that tropism for macrophages is a critical determinant in selection of variants with the F-->L mutation in tissues such as spleen and liver, and tropism for neurons is important in retention of the F genotype in the CNS.

Animals↗
PubMed1994

CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection.

In this study, we have examined the relative contributions of CD4+ and CD8+ T cells in controlling an acute or chronic lymphocytic choriomeningitis virus (LCMV) infection. To study acute infection, we used the LCMV Armstrong strain, which is cleared by adult mice in 8 to 10 days, and to analyze chronic infection, we used a panel of lymphocyte-tropic and macrophage-tropic variants of LCMV that persist in adult mice for several months. We show that CD4+ T cells are not necessary for resolving an acute LCMV infection. CD4+ T-cell-depleted mice were capable of generating an LCMV-specific CD8+ cytotoxic T-lymphocyte (CTL) response and eliminated virus with kinetics similar to those for control mice. The CD8+ CTL response was critical for resolving this infection, since beta 2-microglobulin knockout (CD8-deficient) mice were unable to control the LCMV Armstrong infection and became persistently infected. In striking contrast to the acute infection, even a transient depletion of CD4+ T cells profoundly affected the outcome of infection with the macrophage- and lymphocyte-tropic LCMV variants. Adult mice given a single injection of anti-CD4 monoclonal antibody (GK1.5) at the time of virus challenge became lifelong carriers with high levels of virus in most tissues. Unmanipulated adult mice infected with the different LCMV variants contained virus for prolonged periods (> 3 months) but eventually eliminated infection from most tissues, and all of these mice had LCMV-specific CD8+ CTL responses. Although the level of CTL activity was quite low, it was consistently present in all of the chronically infected mice that eventually resolved the infection. These results clearly show that even in the presence of an overwhelming viral infection of the immune system, CD8+ CTL can remain active for long periods and eventually resolve and/or keep the virus infection in check. In contrast, LCMV-specific CTL responses were completely lost in chronically infected CD4-depleted mice. Taken together, these results show that CD4+ T cells are dispensable for short-term acute infection in which CD8+ CTL activity does not need to be sustained for more than 2 weeks. However, under conditions of chronic infection, in which CD8+ CTLs take several months or longer to clear the infection, CD4+ T-cell function is critical. Thus, CD4+ T cells play an important role in sustaining virus-specific CD8+ CTL during chronic LCMV infection. These findings have implications for chronic viral infections in general and may provide a possible explanation for the loss of human immunodeficiency virus-specific CD8+ CTL activity that is seen during the late stages of AIDS, when CD4+ T cells become limiting.

Animals↗
PubMed1994

T-cell response to cottontail rabbit papillomavirus structural proteins in infected rabbits.

Cottontail rabbit papillomavirus (CRPV)-induced papillomas progress at a high frequency to carcinomas and thus can serve as a model for high-cancer-risk human papillomavirus infection. Previously, we have shown that antibodies to nonstructural and structural proteins are detected in only a fraction of papilloma-bearing animals. However, the antibody response to structural proteins drastically increases as papillomas progress to carcinoma (Y.-L. Lin, L. A. Borenstein, R. Selvakumar, R. Ahmed, and F. O. Wettstein, J. Virol. 67:382-389, 1993). Here we have monitored the cellular immune response to viral proteins during the course of infection and particularly during progression from papilloma to carcinoma. This was done by measuring the in vitro proliferation response of peripheral blood mononuclear cells (PBMCs) to CRPV structural proteins L1 and L2. The proliferating cells were identified as T cells by selective removal of B or T cells. In general, the T-cell response was low for rabbits at the papilloma stage and none responded to L2. Lymphocytes from animals with carcinomas more frequently and more strongly responded to L1, and more than half also responded to L2. In addition to stimulation of PBMCs, L1- and L2-specific proliferation could also be demonstrated with lymph node and spleen cells. Overall, our data show that progression of papilloma to carcinoma is associated with an increased T-cell response to CRPV structural proteins in addition to an increased humoral response. This greater immune reactivity, however, was not associated with a selectively increased expression of structural proteins, since RNA isolated from papillomas and carcinomas contained similar relative levels of late and early RNA as shown by dot blot analysis. Thus, the heightened immune reactivity seen in carcinoma-bearing rabbits most likely reflects greater stimulation of the immune system owing to dissemination of the tumor. These findings suggest that increased immune responses to papillomavirus proteins may be prognostic of progression to carcinoma and particularly of the development of metastases.

Animals↗
PubMed1994

Paucibacillary leprosy patients treated with multidrug therapy four years experience (1988 to 1991) in Bangladesh.

Two hundred and fifty paucibacillary (PB) leprosy patients were treated with WHO recommended multidrug therapy (MDT) and followed up them for four years. The paucibacillary MDT regimen (PBR) was well accepted and tolerated by the patients. Clinical regression was attained in 60% patients after 6 doses of PBR. Reversal reaction occurred in 14% cases and relapse were found in 1.6% cases 18-24 months after completing the treatment. The incidence of reversal reaction was high in patients with more than 2 thickened nerve trunks associated with more than 5 patches.

Adolescent↗
PubMed1994

Intramuscular diclofenac sodium for postoperative analgesia after laparoscopic cholecystectomy: a randomised, controlled trial.

Laparoscopic cholecystectomy is the surgical treatment of choice for symptomatic gallstones. Nonsteroidal antiinflammatory drugs offer effective analgesia, avoiding the central side effects of opiate drugs. To assess intramuscular diclofenac sodium (Voltarol; Ciba-Geigy) after laparoscopic cholecystectomy, 55 consecutive patients (41 female; 14 male; mean age: 50 years) were randomised to receive either diclofenac or placebo in double-blind fashion. Six patients were withdrawn from study (three conversions to open cholecystectomy; three incomplete documentation). Pain scores were assessed at 4, 24, and 48 h using a linear analogue scale; opiate consumption and time to first oral fluid and food were recorded. In 26 patients receiving diclofenac, median scores at 4 h were 1.6 (range 0-7.6) as compared with 4.1 (range 0-7.6) in 23 control patients (p = 0.05, 95% confidence limits 3.2, 0; Mann-Whitney U test). Nausea scores, return to diet, and time to discharge did not differ significantly between the groups. Intramuscular diclofenac significantly reduces early postoperative pain after laparoscopic cholecystectomy and is worthy of consideration if the procedure were ever undertaken as day case surgery.

Adolescent↗
PubMed1994

Amoebic appendicitis--a rare entity.

Appendectomy is the most common surgical procedure performed in routine general surgical practice. However, not all the appendices removed, are submitted for histopathological examination in this part of the world. We reviewed 1400 appendices received by our department from within our hospital and from outside the hospital. Of these 13 cases were reported as amoebic appendicitis. These patients did not have any different clinical presentation from the patients who were reported as acute appendicitis without amoebae. Microscopically these appendices had minimal neutrophil polymorph infiltration accompanied by tissue necrosis and amoebic trophozoites within the appendiceal wall. After histological diagnosis, different tests (IHA and stool examination) were done to exclude a possibility of secondary involvement of the appendix, on 8 patients from our hospital which were negative, thus confirming that these patients had primary appendiceal involvement. Hence we recommend that all the appendices removed should be subjected for histological examination, since ths may help in subsequent management of these patients.

Adolescent↗
PubMed1993

Progression from papilloma to carcinoma is accompanied by changes in antibody response to papillomavirus proteins.

Cottontail rabbit papillomavirus induces benign tumors, papillomas, in rabbits which progress at a high frequency to malignant tumors, carcinomas. Cottontail rabbit papillomavirus therefore provides an experimental model for oncogenic human papillomaviruses. The nature of the antigens recognized by the host has not been identified at any stage of tumor development. Here, we characterized the humoral immune response to viral antigens in cottontail and domestic rabbits at the papilloma stage, in domestic rabbits at the carcinoma stage, and in animals in which papillomas had regressed. Antibodies to linear epitopes were identified by Western blotting (immunoblotting) with bacterial fusion proteins, and evidence for recognition of conformational epitopes was obtained by immunoprecipitation. An immune response to the early proteins E1, E2, E6, and E7 was detected only in a fraction of the animals, and all animals were negative for E4 and E5. The response to E6 and E7 peaked around 7 months and then decreased, while that to E1 and E2 remained level after an initial raise. The antibody response to structural proteins was low at the papilloma stage, and antibodies to L1 recognized predominantly conformational epitopes. As papillomas progressed to carcinomas, there was a drastic increase in the response to L1 and L2, suggesting a change in interaction between virus-infected host cells and the host's immune system.

Animals↗
PubMed1993

Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus.

This study documents that the immunosuppressive lymphocytic choriomeningitis virus (LCMV) variant, clone 13, shows a specific predilection for enhanced infection of macrophages both in vitro and in vivo and that single amino acid changes in the viral polymerase and glycoprotein are responsible for macrophage tropism. The growth difference seen between variant clone 13 and the parental Armstrong strain was specific for macrophages, since both clone 13 and Armstrong grew equally well in fibroblasts and neither isolate infected lymphocytes efficiently. Complete sequencing of the clone 13 genome, along with genetic analysis, showed that a single amino acid change in the polymerase (K-->Q at position 1079) was the major determinant of virus yield in macrophages. This was proven unequivocally by comparing the sequences of parental and reassortant viruses, which were identical at all loci except for the single mutation in the polymerase gene. This finding was further strengthened by showing that reversion at this site back to lysine (Q-->K) resulted in loss of macrophage tropism. In addition, an independently derived macrophage-tropic variant of LCMV, clone 28b, had a K-->N mutation at the same position. Thus, these results show that substitution of the positively charged amino acid K with a neutral amino acid (either Q or N) at residue 1079 of the polymerase resulted in enhanced viral replication in macrophages. In addition to the polymerase change, a mutation in the glycoprotein was also associated with macrophage tropism. This single amino acid change in the glycoprotein (F-->L at position 260) did not affect virus yield per macrophage but was critical in determining the number of macrophages infected. Our previous studies have shown that the same two mutations in the polymerase and glycoprotein are essential for establishing a chronic infection in adult mice. Since the same mutations confer macrophage tropism and ability to persist in vivo, these studies provide compelling evidence that infection of macrophages is a critical determinant of viral persistence and immune suppression.

Animals↗
PubMed1993

Cottontail rabbit papillomavirus L1 protein-based vaccines: protection is achieved only with a full-length, nondenatured product.

Papillomas induced by the cottontail rabbit papillomavirus (CRPV) progress at a high frequency to carcinomas. In this regard, CRPV and its tumors can serve as an animal model for highly oncogenic human papillomaviruses. We have previously shown that immunization with major structural protein L1 elicits neutralizing antibodies and protects rabbits from papilloma development (Y.-L. Lin, L.A. Borenstein, R. Selvakumar, R. Ahmed, and F.O. Wettstein, Virology 187:612-619, 1992). In this study, we demonstrated that vaccination with the TrpE-L1 fusion protein not only protected rabbits from papilloma development but also prevented latent infection. This was indicated by the failure to amplify CRPV sequences by polymerase chain reaction in biopsies from infection sites of immunized animals. Furthermore, we showed that TrpE-L1 immunization protected rabbits from papilloma formation induced by virus but not from that induced by viral DNA. To explore the possibility of developing vaccines based on L1 subfragments, we mapped the linear L1 epitopes recognized by TrpE-L1-immunized rabbits and by virus-infected rabbits resistant to superinfection. Sera from papilloma-bearing rabbits reacted with one major epitope located at the carboxy-terminal end of L1, between amino acids (aa) 480 and 505. A second epitope, and in some animals a third one, was located in the amino-terminal region, between aa 78 and 101, as well as between aa 37 and 62. Sera from TrpE-L1-immunized animals recognized only one major epitope, located between aa 6 and 37. Immunization of rabbits with L1 subfragment fusion proteins led to seroconversion, but no neutralizing antibodies were produced and the animals were not protected against papilloma formation. The data indicate that a successful papillomavirus vaccine must be based on immunization with full-length native L1 and that further simplification to smaller peptides containing major linear epitopes is not feasible.

Animals↗
PubMed1993

Coarctation of the aorta life and health 20-44 years after surgical repair.

OBJECTIVE: To examine the health and lifestyle of a group of patients who had repair of coarctation of the aorta 20-44 years ago (these were the first such operations in the United Kingdom) and to see how the results would influence current management strategies. DESIGN: Attempts were made to contact all patients by questionnaire. They were then requested to attend for a clinical examination. SETTING: Patients had their initial surgery at the Westminster Hospital (by Charles Drew) and the follow up examination at the same hospital. PATIENTS: 149 operations were performed. 70 of the 106 patients presumed to be alive were traced and 62 replied. 42 attended for examination. Only patients with the diagnosis of simple coarctation were included. Some patients had had coincidental ligation of a patent ductus arteriosus but none had any other cardiac abnormality requiring surgical or medical treatment. Those who died during the follow up period were described in paper by Bobby et al (Br Heart J 1991;65:271-6). MAIN OUTCOME MEASURES: Current symptoms and life situations, evidence of cardiac disease, further cardiac surgery, current and retrospective blood pressures, and Doppler echocardiographic examination. RESULTS: 29 (69%) had cardiovascular disorder. Doppler echocardiography did not show previously unrecognised major recoarctation. 19 (46%) had hypertension at follow up and there was evidence of enlargement of the aortic root or arch in seven (16%) patients, who tended to have had surgery at a later age. No evidence of cerebrovascular accident was found. CONCLUSIONS: In this group of patients with surgically repaired simple coarctation, late morbidity (particularly aortic aneurysm, aortic valve disease, and ischaemic heart disease) was common. The incidence of intracranial haemorrhage seemed to have been reduced by surgical repair. The integrity of the surgery remained good. Many patients did not have any regular cardiovascular review. Long-term anxiety related to early surgical experiences was evident. Even after apparently successful surgical repair of aortic coarctation. It would be prudent for all patients to have long-term review.

Adult↗
PubMed1992

Effective vaccination against papilloma development by immunization with L1 or L2 structural protein of cottontail rabbit papillomavirus.

Immunization of rabbits with either L1, the major structural protein, or L2, a minor structural protein of cottontail rabbit papillomavirus (CRPV), protected against challenge with the virus. Neutralizing antibodies were elicited by both the L1 and L2 trpE fusion proteins. Neutralization with anti-L1 serum, however, was more efficient than with anti-L2 serum. In contrast, when tested on Western blots the immune response to L2 was stronger than to L1. Rabbits were also protected against CRPV infection by immunization with L1 expressing recombinant vaccinia virus. Sera from two of three rabbits immunized with recombinant vaccinia virus were negative on Western blots but all three were positive in ELISA's with nondenatured fusion protein or in immunoprecipitations. The results suggest that both the viral structural proteins, L1 and L2, merit consideration in the development of a vaccine against papillomavirus.

Animals↗
PubMed1992

Multiple typing techniques applied to a Clostridium perfringens food poisoning outbreak.

Twenty-one stool specimens obtained from persons implicated in two food poisoning outbreaks at the same institution in Smith Falls, Ontario, were examined for Clostridium perfringens. Ninety-two colonies of Cl. perfringens (3-5 per stool specimen) were typed with antisera, bacteriocins and by plasmid analysis. They were also tested for the in vitro production of bacteriocin and enterotoxin. Sixteen of the 21 stool specimens were tested directly for enterotoxin. This was detected in 13, five of which were from individuals listed as 'asymptomatic' food handlers. The predominant strain isolated from 15 of the 21 stool samples produced bacteriocin and enterotoxin in vitro, contained no plasmids, and was of a common bacteriocin type and serotype.

Bacterial Typing Techniques↗
PubMed1992

Viral infection of the thymus.

We have examined infection of the thymus during congenitally acquired chronic lymphocytic choriomeningitis virus (LCMV) infection of mice, a classic model of antigen-specific T-cell tolerance. Our results show that (i) infection starts at the fetal stage and is maintained throughout adulthood, and (ii) this chronic infection of the thymus can be eliminated by transfer of virus-specific cytotoxic T lymphocytes (CTL) that infiltrate the thymus and clear all viral products from both medullary and cortical regions. Elimination of virus from the thymus results in abrogation of tolerance. During the fetal stage, the predominant cell type infected is the earliest precursor of T cells with a surface phenotype of Thy1+ CD4- CD8- J11d+. In the adult thymus, infection is confined primarily to the cortisone-resistant thymocytes present in the medullary region. The infected cells are CD4+ and J11d+. The presence of J11d, a marker usually associated with immature thymocytes, on infected single positive CD4+ "mature" thymocytes is intriguing and suggests that infection by this noncytolytic virus may affect development of T cells. There is minimal infection of the CD8+ medullary thymocytes or of the double positive (CD4+ CD8+) cells present in the cortex. Infection within the cortex is confined to the stromal cells. Interestingly, there is infection of the double negative (CD4- CD8-) thymocytes in the adult thymus, showing that even during adulthood the newly developing T cells are susceptible to infection by LCMV. Virus can be eliminated from the thymuses of these carrier mice by adoptive transfer of medullary region first and then from the thymic cortex. This result clearly shows the need to reevaluate the widely held notion that mature T cells are unable to reenter the thymus. In fact, in our experiments the donor T cells made up to 20 to 30% of the total cells in the thymus at 5 to 7 days after the transfer. The number of donor T cells declined as virus was eliminated from the thymus, and at 1 month posttransfer, the donor T cells were hardly detectable. The results of this study examining the dynamics of viral infection and clearance from the thymus, the primary site of T-cell development, have implications for understanding tolerance induction in chronic viral infections.

Aging↗
PubMed1992

Immunological memory against viruses.

Viral infections often result in long-term immunological memory. This article reviews the phenotypic changes seen in memory T cells and suggests a re-evaluation of the current dogma that T cell memory is maintained by persistence of antigen.

Animals↗
PubMed1991

Abrogation of tolerance to a chronic viral infection.

This study documents failure of peripheral tolerance mechanisms in a chronic viral infection and shows that T cell tolerance to a viral Ag seen as self from fetal life can be broken despite the presence of this Ag in extrathymic tissues. Congenital infection of mice with lymphocytic choriomeningitis virus (LCMV) results in T cell tolerance to the virus. Such mice become carriers for life harboring virus in many tissues including the thymus and exhibit no LCMV-specific CTL responses. Our previous studies have documented the curing of this congenitally acquired chronic infection after adoptive transfer of CD8+ T cells from LCMV-immune mice and the presence of host-derived, LCMV-specific CTL in these "cured" carriers. In this study we have examined the mechanism by which these carriers acquired T cell competence and show that these CTL differentiated from the bone marrow after elimination of viral Ag from the thymus. These results demonstrate that even when a chronic infection has been established in utero, the adult thymus retains the ability to restore immunocompetence to the host and to provide protection against reinfection. Surprisingly, these LCMV specific CTL were acquired at a time when infectious virus and intracellular viral Ag, although cleared from the thymus, were readily detectable in organs such as the kidney, testes, and brain. In fact, active viral replication in peripheral tissues was ongoing when these mice acquired new virus-specific T cells. These results show that clearance of virus form the thymus was sufficient to abrogate tolerance to a congenitally acquired chronic infection and that Ag in peripheral tissues did not tolerize newly developing T cells. These findings suggest that mechanisms that operate on immature cells within the thymus to silence self-reactive T cells are effective in induction of tolerance to viruses, but mechanisms of tolerizing mature T cells are likely to breakdown. This has implications for virus-induced autoimmunity and for treatment of chronic infections.

Animals↗