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Biomedical subjects

R M Grant

Publications and source records attributed to R M Grant.

At least 37 records · Page 2Linked to original sources
PubMed1999

Simian immunodeficiency virus disease course is predicted by the extent of virus replication during primary infection.

To elucidate the relationship between early viral infection events and immunodeficiency virus disease progression, quantitative-competitive and branched-DNA methods of simian immunodeficiency virus (SIV) RNA quantitation were cross-validated and used to measure viremia following infection of rhesus macaques with the pathogenic SIVmac251 virus isolate. Excellent correlation between the methods suggests that both accurately approximate SIV copy number. Plasma viremia was evident 4 days postinfection, and rapid viral expansion led to peak viremia levels of 10(7) to 10(9) SIV RNA copies/ml by days 8 to 17. Limited resolution of primary viremia was accompanied by relatively short, though variable, times to the development of AIDS (81 to 630 days). The persistent high-level viremia observed following intravenous inoculation of SIVmac251 explains the aggressive disease course in this model. Survival analyses demonstrated that the disease course is established 8 to 17 days postinfection, when peak viremia is observed. The most significant predictor of disease progression was the extent of viral decline following peak viremia; larger decrements in viremia were associated with both lower steady-state viremia (P = 0.0005) and a reduced hazard of AIDS (P = 0.004). The data also unexpectedly suggested that following SIVmac251 infection, animals with the highest peak viremia were better able to control virus replication rather than more rapidly developing disease. Analysis of early viral replication dynamics should help define host responses that protect from disease progression and should provide quantitative measures to assess the extent to which protective responses may be induced by prophylactic vaccination.

Animals↗
PubMed1999

Sustained CD4 responses after virological failure of protease inhibitor-containing therapy.

This article explores current controversies related to 'discordant' responses to antiviral therapy, that is to say, patients with a sustained CD4 cell response despite virological failure. Observational clinical data of patients receiving protease inhibitor-based therapy who had a sustained CD4 cell count even with incomplete viral suppression will be presented, as well as possible mechanisms and clinical implications.

Antiretroviral Therapy, Highly Active↗
PubMed1998

Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure.

OBJECTIVE: To evaluate the virologic activity of a ritonavir plus saquinavir-containing regimen in patients who have failed an indinavir or ritonavir-containing regimen. DESIGN: Patients were identified through a retrospective study evaluating the incidence of indinavir or ritonavir failure in our clinic. PATIENTS: Eighteen patients failing indinavir or ritonavir therapy and who switched to a ritonavir-saquinavir-containing regimen were evaluated. Indinavir or ritonavir failure was defined as a plasma viral load > 1500 copies/ml (branched DNA) after 16 weeks of continuous therapy. INTERVENTIONS: All patients switched to ritonavir (400 mg twice daily) plus saquinavir (400 mg twice daily) and received concurrent therapy with two nucleoside reverse transcriptase inhibitors (NRTI). Twelve of the 18 patients modified their NRTI regimen at the time ritonavir-saquinavir was initiated. OUTCOME MEASURES: Plasma viral load was monitored using a branched DNA assay. Genotypic analysis was performed using a point mutation differential hybridization technique, and was confirmed with direct sequencing. RESULTS: Fourteen out of 18 patients completed at least 24 weeks of therapy; the remaining four patients discontinued therapy after week 12 due to a lack of virologic response or intolerance. Plasma viral load decreased a median 1.4 log10 after 4 weeks of treatment with ritonavir-saquinavir. Only four patients had a greater than 0.5 log10 decrease in viral load after 24 weeks of therapy. In eight out of 10 patients evaluated, the V82A mutation was present at the time of the switch to ritonavir-saquinavir. Viral rebound on ritonavir-saquinavir was associated with the emergence of mutations at amino acids 46, 48, 54 and 90. CONCLUSION: The combination of ritonavir, saquinavir and two NRTI resulted in a moderate but transient suppression of viral replication in patients who have failed indinavir or ritonavir therapy. Failure of ritonavir-saquinavir may be associated with the emergence of mutations associated with resistance to ritonavir/saquinavir monotherapy, particularly the L90M mutation.

Anti-HIV Agents↗
PubMed1998

High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection.

The thymus in adults infected with the HIV-1 is generally thought to be inactive, both because of age-related involution and viral destruction. We have revisited the question of thymic function in adults, using chest-computed tomography (CT) to measure thymic tissue in HIV-1-seropositive (n = 99) or HIV-1-seronegative (n = 32) subjects, and correlating these results with the level of circulating CD4(+) and CD8(+) T cells that are phenotypically described as naive thymic emigrants. Abundant thymic tissue was detectable in many (47/99) HIV-1-seropositive adults, aged 20-59. Independent of age, radiographic demonstration of thymic tissue was significantly associated with both a higher CD4(+) T cell count (P = 0.02) and a higher percentage and absolute number of circulating naive (CD45RA+CD62L+) CD4(+) T cells (P < 0.04). The prevalence of an abundant thymus was especially high in younger HIV-1-seropositive adults (</= 39 yr) with CD4 counts in the range 300-500 cells/microl and in older subjects (> 40 yr) regardless of CD4 count (P = 0.03). These studies suggest that the thymus is functional in some but not all adults with HIV-1 disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

MRI findings in macrocephaly-cutis marmorata telangiectatica congenita.

We describe a child with macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC), cherry red macules, megalencephaly with hemifacial and segmental overgrowth, macrosomia, and cutis marmorata telangiectasia congenita of the trunk, and visceral and subcutaneous cavernous hemangiomas. The megalencephaly is accompanied by MRI findings of CNS dysgenesis with protrusion of the cerebellar tonsils through the foramen magnum (Chiari I), lumbar syrinx, and hydrops of the optic nerves. The report of this additional patient further confirms the newly described macrocephaly-cutis marmorata telangiectatica congenita as a distinct clinical phenotype.

Abnormalities, Multiple↗
PubMed1998

Different approaches to the tasks of educating and training information systems professionals, within the National Health Service (UK).

In 1994, La Sainte Union College of Higher Education (LSU) developed an MSc in Health Informatics course, in conjunction with Southampton University NHS Trust (SUHT). The original part-time, 1 day per week mode of delivery has since been broadened to include a distance leaning route and recently a block release mode, by which students combine usage of the distance learning materials with attendance in College for an intensive 2-day taught element. Because the course was designed in close co-operation with a major teaching hospital, it has always been 'market led' to meet the needs both of the individual students and of the organisations that they work for. At the same time, students acquire a quality-assured qualification from a premier UK university, a qualification that holds credence outside the National Health Service (NHS). At the same time as LSU and SUHT were developing the MSc in Health Informatics, the UK NHS Training Division (NHSTD) started to promote a professional qualification for health service professionals. the so-called 'Statement of Recognition' (SoR). In contrast to the academic format of an MSc, the SoR was not a formal course, but a combination of modules designed to help candidates demonstrate their competence and achievement at work by portfolio evidence. This approach has national standing throughout the UK in a set of qualifications known as NVQs (National Vocational Qualifications). The NHSTD, through its successor, the Institute of Health Care Development (IHCD), has further refined this competency based model, culminating in the launch in 1996 of the Diploma and Advanced Diploma in Information and Technology (Health). Professionals within the area of Information Management and Technology (IM&T) in the NHS now have the alternatives of an academic or a competency route to achieve their goals. This paper traces the development of and the relationship between, these two approaches to the educational and training of healthcare professionals. It will illustrate the shift from Information Technology (IT) to Information Management skills, which is a pre-requisite to satisfy the changing needs of information users. It will also consider how a single Master's course can lead to a range of courses which meet the needs of professionals at various levels. Finally, it makes some recommendations for future developments of the programmes, suggestions which may have some relevance outside of the UK.

Education, Graduate↗
PubMed1998

Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques.

Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) do not develop immunodeficiency despite the presence of viral loads of 10(5) to 10(7) RNA copies/ml. To investigate the basis of apathogenic SIV infection in sooty mangabeys, three sooty mangabeys and three rhesus macaques were inoculated intravenously with SIVmac239 and evaluated longitudinally for 1 year. SIVmac239 infection of sooty mangabeys resulted in 2- to 4-log-lower viral loads than in macaques and did not reproduce the high viral loads observed in natural SIVsmm infection. During acute SIV infection, polyclonal cytotoxic T-lymphocyte (CTL) activity coincident with decline in peak plasma viremia was observed in both macaques and mangabeys; 8 to 20 weeks later, CTL activity declined in the macaques but was sustained and broadly directed in the mangabeys. Neutralizing antibodies to SIVmac239 were detected in the macaques but not the mangabeys. Differences in expression of CD38 on CD8(+) T lymphocytes or in the percentage of naive phenotype T cells expressing CD45RA and CD62L-selection did not correlate with development of AIDS in rhesus macaques. In macaques, the proportion of CD4(+) T lymphocytes expressing CD25 declined during SIV infection, while in mangabeys, CD25-expressing CD4(+) T lymphocytes increased. Longitudinal evaluation of cytokine secretion by flow cytometric analysis of unstimulated lymphocytes revealed elevation of interleukin-2 and gamma interferon in a macaque and only interleukin-10 in a concurrently infected mangabey during acute SIV infection. Differences in host responses following experimental SIVmac239 infection may be associated with the divergent outcome in sooty mangabeys and rhesus macaques.

Animals↗
PubMed1998

Multiple sclerosis in Fife.

Patients in Fife with multiple sclerosis were identified from three sources: a postal questionnaire to all general practices in Fife, hospital discharge data, rehabilitation service database. A total of 508 patients were identified in a population of 354,273 giving a crude prevalence rate of 143/100,000. The Standardised Prevalence Rate was 178/100,000. The sex ratio was 2.43 females to males. The prevalence was higher than identified in southern parts of the United Kingdom and similar to northern Scotland. A total of 200 (40%) cases were identified as having relapsing-remitting disease and of these 151 were ambulant, making them eligible for treatment with interferon beta-lb under current licensing criteria. Only 90 (60%) of the 151 currently eligible for the drug were under the care of a specialist and almost half the practices felt that they would change their referring habits. These factors may have implications for the workload of specialist clinics.

Adolescent↗
PubMed1996

Frequent presence of a novel herpesvirus genome in lesions of human immunodeficiency virus-negative Kaposi's sarcoma.

While Kaposi's sarcoma (KS) is extremely common in homosexual men infected with human immunodeficiency virus (HIV), it is also found in several clinical settings in which HIV infection is absent. Recently, sequences from the genome of a novel member of the herpesvirus family have been identified within KS biopsies in the AIDS-associated form of the disease. The presence of these sequences was sought in 6 cases of HIV-negative KS, including 4 cases of endemic KS from Africa, and was found in 5 of the 6. These findings strengthen the association between infection with this virus and the development of KS and argue against the notion that this association is simply the result of opportunistic superinfection of profoundly immunodeficient hosts.

Adult↗
PubMed1996

Comparison of saliva and serum for human immunodeficiency virus type 1 antibody testing in Uganda using a rapid recombinant assay.

The accuracy and acceptability of saliva human immunodeficiency virus type 1 (HIV-1) antibody testing were compared with serum testing in a study of paired specimens from HIV-1-seropositive and HIV-1-seronegative Ugandan adults attending a clinic for sexually transmitted diseases. Saliva collection was performed with the Omni-sal device (Saliva Diagnostic Systems, Vancouver, Wash.), and antibody testing was performed by a rapid filter paper assay (Test-Pack; Abbott Laboratories, Abbott Park, Ill.). Relative to serum testing, the sensitivity of saliva testing was 95% (195 of 205) and the specificity was 99% (295 of 297). The sensitivity of saliva testing was higher for patients with elevated levels of beta-2 microglobulin in sera and greater numbers of HIV-1-related symptoms. Pre- and poststudy interviews indicated that saliva testing did not foster inordinate fears of saliva exposure. The development of saliva tests that are inexpensive and do not require electricity is needed.

Adult↗
PubMed1995

Activation of virus replication after vaccination of HIV-1-infected individuals.

Little is known about the factors that govern the level of HIV-1 replication in infected individuals. Recent studies (using potent antiviral drugs) of the kinetics of HIV-1 replication in vivo have demonstrated that steady-state levels of viremia are sustained by continuous rounds of de novo infection and the associated rapid turnover of CD4+ T lymphocytes. However, no information is available concerning the biologic variables that determine the size of the pool of T cells that are susceptible to virus infection or the amount of virus produced from infected cells. Furthermore, it is not known whether all CD4+ T lymphocytes are equally susceptible to HIV-1 infection at a given time or whether the infection is focused on cells of a particular state of activation or antigenic specificity. Although HIV-1 replication in culture is known to be greatly facilitated by T cell activation, the ability of specific antigenic stimulation to augment HIV-1 replication in vivo has not been studied. We sought to determine whether vaccination of HIV-1-infected adults leads to activation of virus replication and the targeting of vaccine antigen-responsive T cells for virus infection and destruction. Should T cell activation resulting from exposure to environmental antigens prove to be an important determinant of the steady-state levels of HIV-1 replication in vivo and lead to the preferential loss of specific populations of CD4+ T lymphocytes, it would have significant implications for our understanding of and therapeutic strategies for HIV-1 disease. To begin to address these issues, HIV-1-infected individuals and uninfected controls were studied by measurement of immune responses to influenza antigens and quantitation of virion-associated plasma HIV-1 RNA levels at baseline and at intervals after immunization with the trivalent influenza vaccine. Influenza vaccination resulted in readily demonstrable but transient increases in plasma HIV-1 RNA levels, indicative of activation of viral replication, in HIV-1-infected individuals with preserved ability to immunologically respond to vaccine antigens. Activation of HIV-1 replication by vaccination was more often seen and of greater magnitude in individuals who displayed a T cell proliferative response to vaccine antigens at baseline and in those who mounted a significant serologic response after vaccination. The fold increase in viremia, as well as the rates of increase of HIV-1 in plasma after vaccination and rates of viral decline after peak viremia, were higher in individuals with higher CD4+ T cell counts.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Hematological reference ranges among healthy Ugandans.

Reference values are essential for the interpretation of hematologic data in clinical practice and research studies. Symptom-free human immunodeficiency virus antibody-negative Ugandan adults (183 subjects, aged 15 to 74 years, 37.7% women and 62.3% men) were studied to establish hematological reference ranges. The central 95% areas under the distribution curves were 1,453 to 4,448 cells per microliters for the absolute lymphocyte count, 559 to 2,333 cells per microliters for the absolute CD4 count, 253 to 1,396 cells per microliters for the absolute CD8 count, and 0.68 to 4.4 for the CD4/CD8 ratio. Women had significantly higher mean absolute lymphocyte counts (2,826 versus 2,568/microliters), absolute CD4 counts (1,425 versus 1,154/microliters) and absolute CD4/CD8 ratios (2.58 versus 1.88) than did men. These reference ranges differ from those reported for populations outside Africa.

Adolescent↗
PubMed1995

beta-2 Microglobulin values among human immunodeficiency virus (HIV)-negative, HIV-positive asymptomatic, and HIV-positive symptomatic Ugandans.

Mean serum beta-2 microglobulin levels among healthy human immunodeficiency virus-seronegative and asymptomatic and symptomatic human immunodeficiency virus-seropositive Ugandans were found to be 2.35, 3.75, and 5.06 mg/liter, respectively (P < 0.001). The upper limit of the normal range (3.5 mg/liter) is higher in this African population than that reported elsewhere.

Adult↗
PubMed1991

Assessment of cisplatin-induced ototoxicity using derived-band ABRs.

Ototoxicity is an adverse side effect of numerous therapeutic agents (amino-glycoside antibiotics, blood chelating agents, diuretics and oncologic drugs) used in treatment of both adult and pediatric patients. Recently, there has been increasing interest in using the auditory brainstem response (ABR) to detect both short-term effects of ototoxicity in adults and long-term effects of drug administration on neonates and children. Since click ABRs have relatively poor frequency selectivity they best approximate the pure-tone hearing threshold in the 2000-4000 Hz frequency range. Hearing loss above or below that frequency range can be present without producing significant abnormalities in the ABR waveform parameters. Frequency-specific ABRs can be obtained using the derived response technique. The purpose of this study was to investigate early cisplatin ototoxicity using both the broadband click and derived ABR and to monitor progressive hearing loss with repeated drug trials in 18 patients studied over a 2-year period. ABRs were obtained serially prior to and following intravenous administration of cisplatin. Derived ABRs were found to be more sensitive than broadband click ABR in detecting early high-frequency hearing loss. For click ABRs, the cumulative dosage of cisplatin at age of ABR examination was correlated with hearing loss in only those patients under 3 years of age. No significant correlation was found between cumulative cisplatin dosage when tested and degree of hearing loss in those patients over 3 years of age.

Adolescent↗