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Biomedical subjects

M D Grant

Publications and source records attributed to M D Grant.

At least 19 recordsLinked to original sources
PubMed2005

Cross-reactive cytotoxic T lymphocytes against human immunodeficiency virus type 1 protease and gamma interferon-inducible protein 30.

The gamma interferon (IFN-gamma)-inducible protein 30 (IP-30) signal peptide -11 to -3 (LLDVPTAAV) is a prominent self peptide expressed with the class I human histocompatibility leukocyte antigen A2 (HLA-A2). Stimulation of peripheral blood mononuclear cells (PBMC) from HLA-A2 human immunodeficiency virus type 1 (HIV-1)-infected individuals with an HLA-A2-restricted HIV protease (PR) peptide 76-84 (LVGPTPVNI) activated cytotoxic T lymphocytes (CTL) against the IP-30 signal peptide. Since HIV-1 PR 76-84 stimulated CD8+ T cells from these individuals to secrete IFN-gamma, we tested whether the activation of IP-30-specific CTL in vitro resulted from T-cell cross-reactivity or from up-regulation of IP-30 by IFN-gamma. Neither high levels of exogenous IFN-gamma nor incubation of PBMC with other HIV peptides triggering substantial IFN-gamma release activated IP-30-specific CTL. Although the IP-30 signal peptide did not stimulate IFN-gamma release from freshly isolated PBMC, it activated CTL in vitro against itself and HIV PR 76-84. Peptide-stimulated IFN-gamma release, cold target inhibition, and HLA-A2/immunoglobulin dimer-mediated binding and depletion of effector cells all indicated that in vitro stimulation with HIV PR 76-84 or the IP-30 signal peptide activated a comparable population of cross-reactive effector cells. Neither IP-30 nor HIV PR 76-84 activated CTL against themselves following in vitro stimulation of PBMC from non-HIV-infected HLA-A2 individuals. Peptide titrations indicated higher-avidity T-cell interactions with HIV PR 76-84 than with the IP-30 signal peptide. These data indicate that HIV PR 76-84 is a heteroclitic variant of the IP-30 signal peptide -11 to -3, which has implications for immune memory and autoimmunity.

Cells, Cultured↗
PubMed2001

Fas/FasL-independent activation-induced cell death of T lymphocytes from HIV-infected individuals occurs without DNA fragmentation.

We assessed the effects of activation with phorbol myrystic acetate (PMA) and ionomycin on peripheral blood mononuclear cells (PBMC) from HIV-infected individuals by (51)Cr release, propidium iodide (PI) uptake, electron microscopy, and DNA analysis. Up to 70% (51)Cr release was induced from PBMC of HIV-infected individuals, versus up to 26% (51)Cr release from PBMC of non-HIV-infected volunteers. Flow cytometry identified mostly T cells undergoing activation-induced cell death (AICD). The kinetics of (51)Cr release and the effects of cold target inhibitors were consistent with cell-mediated cytotoxicity. Certain anti-CD3 antibodies or extracellular Ca(2+) chelation prevented AICD, but antagonistic anti-Fas antibodies, caspase inhibitors, and cycloheximide had no effect. The antioxidants thiourea and N-acetylcysteine reduced AICD, indicating a role for oxidative stress. Electron microscopy revealed plasma membrane disruption with nuclear integrity, while DNA analysis showed intact chromosomal DNA. This form of T cell AICD triggered by PMA and ionomycin differs from classical apoptosis in the absence of either caspase involvement or DNA fragmentation.

Acetylcysteine↗
PubMed2001

Age-associated diseases and conditions: implications for decreasing late life morbidity.

We discuss two types of age-associated diseases; aging-dependent such as Alzheimer's disease and congestive heart failure which increase logarithmically with age, versus age-dependent such as multiple sclerosis and amyotrophic lateral sclerosis which occur at proscribed ages, and then occurrence of new cases ceases or diminishes with further aging. Prevention strategies with both types emphasize postponement or delay of onset. The non-fatal aging-dependent diseases and conditions are an accumulating burden as we age, and increase overall morbidity in late years. These include Alzheimer's disease and other dementias, Parkinson's disease, loss of vision and hearing, incontinence, osteoporosis and hip fracture, osteoarthritis and depression. With mortality postponed, we will be living for many years at old and vulnerable ages. Life's quality will be reasonable for most. Still, increasing the chance that all will experience this desirable outcome requires pursuing the means to delay the onset of the physical and social events which we categorize as the non-fatal aging-dependent diseases and conditions. We must recognize that each added year occurs at the tip of an exponential curve where risk is maximal.

Age of Onset↗
PubMed2001

HIV-1 DNA burden in peripheral blood CD4+ cells influences disease progression, antiretroviral efficacy, and CD4+ T-cell restoration.

Integration of human immunodeficiency virus type-1 (HIV-1) proviral DNA into host cell genomic DNA ensures viral persistence despite suppression of active replication. Because HIV RNA originates from integrated HIV DNA, HIV RNA and DNA loads should interrelate when suppression of viral replication is incomplete. In addition, the link between proviral DNA formation and generation of HIV-1 genetic diversity suggests that the ease with which HIV escapes immune or drug-based suppression should vary with proviral load. Thus, HIV proviral load should have unique prognostic significance independent of the highly labile plasma HIV RNA levels commonly used to monitor patient status. To test this possibility, we developed a simple standardized research assay estimating the proportion of CD4+ peripheral blood mononuclear cells (PBMC) carrying HIV-1 DNA and investigated associations between this parameter, plasma virus load, long-term efficacy of antiretroviral therapy and restoration of CD4+ T cells. Lower proportions of CD4+ PBMC carrying HIV-1 DNA were associated with lower peak plasma HIV RNA levels and with more favorable long-term responses to antiretroviral therapy. These results suggest that HIV proviral load affects both disease progression and responsiveness to antiretroviral therapy. Therefore, new anti-HIV therapies addressing the stable pool of HIV proviral DNA should be developed to improve long-term prospects for suppression of HIV replication.

Anti-HIV Agents↗
PubMed2001

Male inflammatory breast cancer.

A case of a 48-year-old male with an inflammatory breast cancer is used to illustrate this uncommon malignancy. The physical examination of thickening and erythema made the clinical diagnosis. Mammographic findings of increased density in the right breast with coarsened stroma and an underlying mass confirmed the clinical findings. The sonographic evaluation revealed a 2-cm ill-defined hypoechoic mass. The pathologic examination of the mastectomy specimen showed an infiltrating duct cell carcinoma with lobular features. Male breast cancer afflicts 1500 men each year. Clinically it must be differentiated from gynecomastia, a much more common and benign condition.

Breast Neoplasms, Male↗
PubMed2000

Galactography in patients with nipple discharge.

Nipple discharge is a common presenting symptom of underlying breast pathology. This study examined the impact of galactography on the evaluation of abnormal nipple discharge. Thirty-five women with spontaneous, unilateral nipple discharge who underwent galactography from 1995 to 1997 were retrospectively studied. Their presenting signs as well as mammographic, galactographic, and pathology findings were evaluated. Nipple discharge was bloody (n = 24), clear (n = 7), or serous (n = 4). A palpable mass was found in 5 patients, and discharge was spontaneous in 29 patients (83%). Mammography was normal in 25 patients (71%). Thirty patients (86%) had an abnormal ductogram that was characterized as a filling defect (n = 20), cutoff sign (n = 5), or ductal dilatation (n = 5). The ductogram demonstrated the location and depth of the lesion in 29 patients (97%). Excision was performed in 27 of 30 patients with an abnormal ductogram: 14 received complete subareolar duct excisions; 12, focused excisions; and 1, excision with a vacuum-assisted biopsy device. Pathology included intraductal papilloma (n = 20) and ductal ectasia (n = 7). Follow-up was completed in 24 patients, including 2 postoperative patients who had persistent discharge on manipulation. In conclusion, galactography is accurate in identifying the location of the ductal abnormality. It allows a focused surgical approach to the pathologic lesion in these patients.

Journal Article↗
PubMed2000

Reproductive longevity and increased life expectancy.

BACKGROUND: Female life expectancy in developed countries has increased by 30 years in the twentieth century. AIM: To determine if there has been an increase in reproductive longevity. METHODS: We analysed age-specific fertility data from birth statistics for the USA, Canada, Japan, France, Sweden, the UK and Australia. RESULTS: Since 1940, birth rates for women aged 35 and over have declined. Among women aged 50 years and older, there has been no increase in births. Fertility rates in 1990 were 0.0 to 0.044 per 1000 women, with total numbers ranging from 0 to 60 births. CONCLUSION: The fertile years have not been prolonged in the cohort of women whose life expectancy has increased so dramatically this century. This suggests that reproductive senescence is tightly controlled and not extended by factors that enhance female longevity. Other physiological mechanisms may also be fixed within narrow age limits.

Adult↗
PubMed1999

Functional and genetic integrity of the CD8 T-cell repertoire in advanced HIV infection.

BACKGROUND: HIV-specific cytotoxic T lymphocytes (CTL) can restrict HIV replication in acute and chronic infection, but disease progression occurs in parallel with declining CTL activity. An understanding of why CTL fail to control HIV replication might reveal important mechanisms of disease progression and enhance prospects for developing effective CTL-based immunotherapies. OBJECTIVES: To investigate the functional integrity, T-cell repertoire diversity, and HIV reactivity of CD8 T lymphocytes in individuals with advanced HIV infection. METHODS: Individuals were considered to have progressed to advanced HIV infection if their total T-cell count was < 500 x 10(6) cells/(l) on at least two successive clinic visits. CD8 T cells from these individuals were analyzed for CTL function, HIV reactivity and T-cell receptor (TCR) diversity by chromium release assays and reverse transcriptase polymerase chain reaction. RESULTS: CD8 T cells from all individuals with advanced HIV infection proliferated and differentiated into functional CTL in vitro. Despite extremely low T-cell counts and previous AIDS-defining illnesses, six individuals had inducible anti-HIV CTL responses. In two additional cases, HIV-specific CTL activity became detectable following significant treatment-associated remission of T-cell lymphopenia. Assessment of TCRbetaV gene family representation and betaV gene intrafamily diversity indicated CD8 T-cell repertoire diversity is maintained through advanced HIV infection. CONCLUSIONS: These data suggest that HIV-specific CTL activity can be selectively compromised while the functional and genetic integrity of the CD8 population as a whole remains intact. A substantial fraction of individuals retain inducible anti-HIV CTL activity through advanced HIV infection and, in at least some cases, effective treatment can restore HIV-specific CTL responses even at this late stage of disease.

Animals↗
PubMed1999

Differences in locomotor activity across the lifespan of Drosophila melanogaster.

The identification of differential patterns of change across the lifespan in quantitative traits is of abiding interest in the biological and gerontological research communities. These differential phenotypic patterns in complex systems illuminate developmental processes and form the foundation for the identification of putative biomarkers of aging. The goal of the present study was to explore changes in locomotor activity through the lifespan of Drosophila melanogaster. A replicated serial cross-sectional sampling design was used to test activity in five genetically independent inbred strains at 7, 14, 21, 28, 35, and 42 days of age. Differences were observed in activity level across ages and strains, suggesting that patterns of activity throughout the lifespan of D. melanogaster are influenced by genetic factors. Observed sex differences in change in activity level indicate that the aging processes may proceed differently in males and females.

Animals↗
PubMed1999

Perforin and Fas/Fas ligand-mediated cytotoxicity in acute and chronic woodchuck viral hepatitis.

The Fas ligand (FasL)/Fas and the perforin-granzyme cytotoxic pathways presumably play a central role in the development of hepatocellular injury in viral hepatitis. To recognize the potential contribution of FasL and perforin-based cell killing in hepadnaviral infection, we adopted a cytotoxic assay using murine Fas+ P815 and human Fas- K562 cells as targets. Freshly isolated peripheral blood mononuclear cells (PBMC) from woodchucks with newly acquired woodchuck hepatitis virus (WHV) infection (n = 6), with chronic WHV hepatitis (n = 9), and from healthy animals (n = 11) were used as effector cells. We have found that woodchuck lymphoid cells kill cell targets via both the FasL/Fas and the perforin death pathways. The contribution of Fas-dependent cytolysis was ascertained in blocking experiments with anti-Fas antibody and by incubation of PBMC with cyclohexamide to prevent de novo synthesis of FasL. The involvement of the perforin pathway was confirmed by treatment of K562 cells with colchicine to inhibit the microtubule-dependent perforin release. Comparative analysis showed that peripheral lymphoid cells from acute WHV hepatitis, but not those from chronic WHV infection, are more cytotoxic and that this increase seems to be entirely due to activation of perforin-mediated killing. The data indicate that acute infection in woodchucks is associated with the augmented capacity of lymphoid cells to elicit perforin-dependent killing, but in chronic infection, independent of the severity of liver disease and duration of chronicity, these cells have the same or lower cytotoxic potential as PBMC from healthy controls. These findings suggest a role for non-specific cellular immunity, presumably natural killer (NK) cells, in the control of early WHV infection and in the progression of chronic hepatitis.

Acute Disease↗
PubMed1998

Gastrostomy placement and mortality among hospitalized Medicare beneficiaries.

CONTEXT: Although the use of feeding tubes among older individuals stirs considerable controversy, population-based descriptive data regarding patient outcomes are scarce. OBJECTIVE: To describe hospitalized Medicare beneficiaries having gastrostomies placed and their associated mortality rates. DESIGN: Retrospective cohort study. SETTING AND PATIENTS: Hospitalized Medicare beneficiaries aged 65 years or older discharged in 1991 following gastrostomy placement (excluding individuals in health maintenance organizations). MAIN OUTCOME MEASURES: Mortality at 30 days, 1 year, and 3 years following gastrostomy and characteristics of individuals undergoing gastrostomy placement. RESULTS: In 1991, claims reflecting gastrostomy insertion were submitted for 81105 older Medicare beneficiaries following hospital discharge. The in-hospital mortality rate was 15.3%. Cerebrovascular disease, neoplasms, fluid and electrolyte disorders, and aspiration pneumonia were the most common primary diagnoses. The overall mortality rate at 30 days was 23.9% (95% confidence interval [CI], 23.65%-24.2%), reaching 63.0% (95% CI, 62.7%-63.4%) at 1 year and 81.3% (95% CI, 81.0%-81.5%) by 3 years. One in 131 white and 1 in 58 black Medicare beneficiaries aged 85 years or older was discharged alive or deceased from a hospital in 1991 following gastrostomy placement. CONCLUSIONS: Gastrostomies are frequently placed in older individuals and more often in blacks; mortality rates following placement are substantial.

Black or African American↗
PubMed1996

Evaluation of neoadjuvant chemotherapeutic response of locally advanced breast cancer by magnetic resonance imaging.

BACKGROUND: The implementation of new treatment protocols for locally advanced breast cancer is currently limited by inaccurate evaluation of response to neoadjuvant chemotherapy. A recently developed dedicated breast magnetic resonance imaging (MRI) method (RODEO MRI) was evaluated as a tool for determining tumor response and extent of residual disease after neoadjuvant chemotherapy. METHODS: Thirty-nine patients with Stage II, III, or IV breast carcinoma were prospectively evaluated prior to and following neoadjuvant chemotherapy by MRI, physical examination, and mammography. Assessment of response determined by the three methods was compared. In addition, detailed pathologic correlation of residual disease was determined by serial sectioning of 31 mastectomy specimens from 30 patients. Nine patients had breast conservation, and were included in the response evaluation only. Estimates of tumor response were made by both surgical and medical oncologists. Independent interpretations of MRI studies without knowledge of clinical response were made by three radiologists. RESULTS: The surgical oncologists assessed complete response (CR), partial response (PR), and no response (NR) in 11, 22, and 7 cases, respectively. The medical oncologists assessed CR, PR, and NR in 12, 21, and 7 cases, respectively. The surgical and medical oncologists' clinical assessment of response agreed with the results of MRI in 52% and 55% of cases, respectively, and with each other in 30 of 40 cases (75%). Mammography correlated with MRI response in only 52% of cases. However, MRI accurately predicted the pathologic determination of residual disease in 30 of 31 cases (97%). There was no disagreement in the assessments of residual disease or response among the three radiologists. CONCLUSIONS: RODEO breast MRI accurately estimates residual disease after induction chemotherapy. It assesses response to neoadjuvant chemotherapy better than traditional methods of physical examination or mammography. The information obtained from this MRI technique may be used as an objective tool during clinical trials, and to select patients better for breast conservation after neoadjuvant chemotherapy for locally advanced disease.

Adult↗
PubMed1996

Similar abnormalities of idiotype and immunoglobulin light chain expression and of cell-mediated cytotoxicity in HIV-infected humans and simian immunodeficiency virus (SIV)-infected rhesus macaques.

The pathogenesis of AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques models the pathogenesis of human AIDS. We investigated whether certain immunological abnormalities associated with HIV infection and implicated in disease progression also occur in SIV infection. We observed striking parallels between the rhesus macaque humoral immune response to SIV and unusual features of the human humoral immune response to HIV infection. Anti-SIV envelope antibodies from SIV-infected macaques exhibited skewed kappa/lambda L chain usage relative to the ratio of kappa/lambda L chain usage detected on total plasma Ig. In addition, the same idiotope conserved on human anti-HIV gag, pol and env antibodies was detected with a similar distribution pattern on macaque anti-SIV env, gag and pol antibodies. Skewed Ig L chain representation and selection of a highly conserved possible dominant regulatory idiotope on antibodies against key neutralizing antigens raise the possibility that the progressive failure of the humoral immune response to SIV and HIV involves skewed oligoclonal humoral immunity. We also found that SIV-infected macaques, like HIV-infected humans, have elevated levels of CD8+ lymphocyte-mediated cytotoxicity. Cytotoxicity against human B cells was higher in CD8+ effector lymphocytes from SIV-infected macaques than in those from uninfected macaques (P < 0.05). Cell-mediated cytotoxicity against human NK cell targets was not elevated in effector lymphocytes from the SIV-infected macaques, suggesting that CTL activity was selectively elevated. Two out of seven SIV-infected macaques tested had CD8+ cytotoxic lymphocytes that selectively killed activated uninfected CD4+ macaque lymphocytes. Oligoclonal B cell responses and persistently elevated CD8+ lymphocyte-mediated cytotoxicity are consistent features of primate retroviral infections leading to AIDS. Understanding immune predispositions to these features triggered by HIV and SIV may advance new prophylactic and therapeutic strategies.

Animals↗
PubMed1996

Declining cholesterol and mortality in a sample of older nursing home residents.

OBJECTIVE: To examine the association between declining serum cholesterol and mortality in a sample of older nursing home residents. DESIGN: A retrospective cohort study. SETTING: A 203-bed nursing home. PARTICIPANTS: Persons aged 65 and older, resident in the nursing home on January 1, 1988, or admitted through December 31, 1989, were eligible (n = 185) for the study. Follow-up for mortality was conducted until June 30, 1991. Fifty-five survivors with two or more cholesterol levels recorded before January 1, 1990, and the 76 decedents with two or more recorded cholesterol levels constituted the analytic sample (71% of eligible subjects). OUTCOME MEASURE: Mortality of the nursing home residents. RESULTS: Cholesterol declined 31.1 mg/dL/yr (95% confidence interval [CI], 19.7 to 42.6) among decedents, versus 4.2 mg/dL/yr (95% CI, -4.9 to 13.2) among survivors. The association between cholesterol decline (absolute or relative rates) and mortality was examined using logistic regression controlling for age, sex, and tube feeding. Compared with a referrent group with no change or increase, declining cholesterol greater than 45 mg/dL/yr was accompanied by an adjusted relative odds for death of 6.2 (95% CI, 2.1 to 18.4); declining cholesterol greater than 20% per year was accompanied by an adjusted relative odds for death of 7.3 (95% CI; 2.4 to 22.2). Extreme declines greater than 20% per year occurred in 47% of decedents but in only 15% of survivors. CONCLUSION: Precipitously declining cholesterol appeared to be a marker for mortality in the sample and may help explain the low cholesterol-mortality association in older nursing home residents.

Aged↗
PubMed1995

Self-reported health and survival in the Longitudinal Study of Aging, 1984-1986.

Changing and often declining health among elderly individuals makes interpreting the long-standing association between self-reported health (SRH) and mortality potentially problematic. This analysis of the Longitudinal Study of Aging from 1984 through 1986 explores changes over time in the association between a single self-report of health and survival among 4380 noninstitutionalized individuals aged 70 and older. Health was reported as excellent or very good (excellent/very good), good, fair or poor. The association between SRH and survival was modeled controlling for age, race, education, marital status, body mass index, difficulty performing activities of daily living, social contacts, self-reported stroke, heart disease, cancer, diabetes and recent hospitalization. Among women, SRH and survival were associated in a nonproportional model, with relative hazard declining over time. Women with poor vs excellent/very good SRH had adjusted relative hazards at 5, 14, 23 and 32 months of 3.8 [95% confidence interval (CI) 2.0-7.1], 2.7 (95% CI: 1.8-4.1), 2.0 (95% CI: 1.3-3.0), and 1.4 (95% CI: 0.7-2.7). The declining relative hazard was due to an increasing mortality rate over time among women initially reporting excellent/very good health. SRH was associated with survival among men in a proportional model (constant relative hazard over time). Men with poor vs excellent/very good SRH had an adjusted relative hazard of 1.7 (95% CI: 1.1-2.6) over the entire follow-up. The relative hazard of lesser magnitude among men reflects the weaker SRH-survival association, possibly too weak for any interaction with time to be detected. The constant relative hazard is also consistent with a rapid decline in health before death among men. The diminishing SRH-survival association among women is consistent with their longer period of declining health before death.

Activities of Daily Living↗
PubMed1994

Cytotoxic T-lymphocytes that kill autologous CD4+ lymphocytes are associated with CD4+ lymphocyte depletion in HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1)-infected individuals, but not HIV-seronegative controls, have non-HLA-restricted T-cell receptor alpha beta+ CD8+ cytotoxic T-lymphocytes (CTL) that kill activated uninfected CD4+ lymphocytes. In vitro stimulation of peripheral blood mononuclear cells from HIV-1-infected individuals with concanavalin A (Con A) or by coculture with phytohemagglutinin-activated autologous lymphoblasts induced CTL that killed autologous and heterologous CD4+ lymphocytes, but not Con A-activated CD8+ lymphocytes or Epstein-Barr virus (EBV)-transformed B lymphocytes. EBV did not stimulate such CTL in two subjects tested, although stimulation with Con A or autologous lymphoblasts induced CTL activity against CD4+ lymphocytes in both subjects. CTL activity against autologous CD4+ lymphocytes varied over time; killing of heterologous CD4+ lymphocytes was often higher than that of autologous CD4+ lymphocytes. HIV-infected individuals with Con A-inducible CTL against autologous CD4+ lymphocytes lost more CD4+ lymphocytes within 6 months of testing than HIV-infected individuals with no such CTL (p < .01). The mean (+/- SD) decrease in CD4+ lymphocyte counts in a group of HIV-infected individuals with CTL activity against autologous CD4+ lymphocytes was 121 +/- 84, or 36%, of total CD4+ lymphocytes over 6 months. In contrast, there was no significant change in mean CD4+ lymphocyte count over 6 months in a group of HIV-infected individuals without CTL activity against autologous CD4+ lymphocytes. In some HIV-infected individuals, CTL activity against autologous CD4+ lymphocytes fell coincident with a drop in CD4+ lymphocyte number in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

CD4-Positive T-Lymphocytes↗