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Biomedical subjects

D L Carter

Publications and source records attributed to D L Carter.

At least 19 recordsLinked to original sources
PubMed2001

Functional analyses of natural killer cells in macaques infected with neurovirulent simian immunodeficiency virus.

Clearance of HIV and SIV from the peripheral blood by the cellular immune system lessens the viral burden in infected individuals and may have an impact on virus infection of the CNS and the development of CNS lesions. However, the role of immune responses in preventing or limiting CNS infection has not been clearly defined. We investigated the role of natural killer cells in the outcome of SIV infection of macaques as a model for humans with AIDS and HIV encephalitis. In our study, six pig-tailed macaques were infected with the neurovirulent virus, SIV/17E-Fr, and the immunosuppressive virus, SIV/ DeltaB670, in a model system that causes rapid progression to AIDS and a high frequency of CNS lesions. NK lytic activity in each macaque was monitored longitudinally. In addition, we enumerated NK cells and tested macaque PBMC for the ability to lyse SIV-infected target cells. We found that there was a significant inverse correlation (P=0.02) between the robustness of NK response and the development of CNS lesions. Animals lacking strong NK cell responses developed more severe CNS lesions than those with robust NK responses did. Furthermore, pre-infection levels of NK activity were predictive of CNS lesion severity. The macaque with the most robust pre-infection NK activity developed no CNS lesions. In these infected macaques, NK activity was shown to be directed against SIV-infected cells. We extended these in vivo findings to delineate precisely which cell type was mediating this SIV-directed lysis. We used both macaque and human cells to demonstrate that the population that mediated anti-SIV and anti-HIV cytolytic effects was NK cells. Furthermore, we showed that this anti-SIV and anti-HIV cytolytic effect was directed at the envelope protein and not gag proteins. Thus, NK cells have the capacity to recognize and lyse cells expressing SIV and HIV antigens. These data support a role for NK cells in the modulation of CNS disease.

AIDS Dementia Complex↗
PubMed1999

CD56 identifies monocytes and not natural killer cells in rhesus macaques.

BACKGROUND: CD56 is a lineage-specific marker of human natural killer (NK) cells. There are conflicts in the literature regarding the role of CD56 as a marker of NK cells in non-human primates. In the present study, we examined the role of CD56 in identifying rhesus NK cells. METHODS: The immunophenotype of normal macaque and human NK cells was analyzed by two- and three-color flow cytometry. Flow cytometric cell sorting was subsequently used to deplete or purify NK cells; the resulting cell populations were then used in standard chromium release assays of NK lytic function. RESULTS: In peripheral blood mononuclear cells of the rhesus macaque, CD56 was expressed primarily on cells with the light scatter and immunophenotypic profile of monocytes. Flow cytometric depletion of rhesus CD56(+) monocytic cells did not diminish functional activity against K562 cells, whereas depletion of CD8(+) or CD16(+) lymphocytes completely abrogated functional activity. Three-color flow cytometric analysis of CD8(+), CD16(+) lymphocytes showed that they expressed other markers (CD2, CD7, TIA-1) associated with NK cells, but notably, not CD56. CONCLUSIONS: These studies demonstrate that CD56 is not suitable as a marker of NK cells in the rhesus macaque.

Animals↗
PubMed1999

Double blind randomized trial of sucralfate vs placebo during radical radiotherapy for head and neck cancers.

BACKGROUND: This study sought to determine whether sucralfate prophylaxis during a course of high dose radiation therapy (RT) for head and neck cancer decreases acute side effects. METHODS: Patients receiving curative intent RT for advanced head and neck cancers participated in a single institution double-blind randomized trial comparing sucralfate to placebo. Patients were stratified according to fractionation, use of concurrent chemotherapy, Karnofsky performance status (KPS), age, and pretreatment presence of a feeding gastrostomy. Patients were prospectively evaluated during weekly treatment checks, and analyzed with regard to time (measured in terms of dose) until development of the following: weight loss, mucositis, pain, nutritional intake, and need for a treatment break. After completion of RT, time until healing was similarly compared. RESULTS: Fifty-two patients received sucralfate and 50 received placebo. The mean (+/-SD) prescribed dose was 69 +/- 7 Gy. Sixty-nine patients received BID fractionation and 27 received concurrent chemotherapy. No difference was detected in any outcome measure in the direct comparison between the two groups. On multivariate analysis, weight loss >5% or >10% occurred more frequently in patients receiving chemotherapy (p < 0.01 and p = 0.05, respectively). Grade 3 mucositis was more common in patients receiving chemotherapy (p = 0.05) or BID fractionation (p = 0.04) or having a poor KPS (p = 0.02). Interval to healing was not associated with any of the pretreatment- or treatment-related factors. Sucralfate did not result in any additional toxicity. CONCLUSIONS: Prophylactic treatment with sucralfate during high-dose head and neck RT did not decrease acute treatment side effects. Other modalities should be investigated.

Carcinoma, Squamous Cell↗
PubMed1999

High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis.

AIDS dementia and encephalitis are complications of AIDS occurring most frequently in patients who are immunosuppressed. The simian immunodeficiency virus (SIV) model used in this study was designed to reproducibly induce AIDS in macaques in order to examine the effects of a neurovirulent virus in this context. Pigtailed macaques (Macaca nemestrina) were coinoculated with an immunosuppressive virus (SIV/DeltaB670) and a neurovirulent molecularly cloned virus (SIV/17E-Fr), and more than 90% of the animals developed moderate to severe encephalitis within 6 months of inoculation. Viral load in plasma and cerebrospinal fluid (CSF) was examined longitudinally to onset of AIDS, and viral load was measured in brain tissue at necropsy to examine the relationship of systemic and central nervous system (CNS) viral replication to the development of encephalitis. In all animals, plasma viral load peaked at 10 to 14 days postinfection and remained high throughout infection with no correlation found between plasma viremia and SIV encephalitis. In contrast, persistent high levels of CSF viral RNA after the acute phase of infection correlated with the development of encephalitis. Although high levels of viral RNA were found in the CSF of all macaques (six of six) during the acute phase, this high level was maintained only in macaques developing SIV encephalitis (five of six). Furthermore, the level of both viral RNA and antigen in the brain correlated with the severity of the CNS lesions. The single animal in this group that did not have CNS lesions had no detectable viral RNA in any of the regions of the brain. The results substantiate the use of CSF viral load measurements in the postacute phase of SIV infection as a marker for encephalitis and CNS viral replication.

Animals↗
PubMed1999

Impact of consolidation radiotherapy in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow rescue.

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994,425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT-). The assignment of RT was not randomized. The RT+ and RT- groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT- patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT-groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT- groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.

Adult↗
PubMed1998

Magnetic resonance thermometry during hyperthermia for human high-grade sarcoma.

PURPOSE: To determine the feasibility of measuring temperature noninvasively with magnetic resonance imaging during hyperthermia treatment of human tumors. METHODS: The proton chemical shift detected using phase-difference magnetic resonance imaging (MRI) was used to measure temperature in phantoms and human tumors during treatment with hyperthermia. Four adult patients having high-grade primary sarcoma tumors of the lower leg received 5 hyperthermia treatments in the MR scanner using an MRI-compatible radiofrequency heating applicator. Prior to each treatment, an average of 3 fiberoptic temperature probes were invasively placed into the tumor (or phantom). Hyperthermia was applied concurrent with MR thermometry. Following completion of the treatment, regions of interest (ROI) were defined on MR phase images at each temperature probe location, in bone marrow, and in gel standards placed outside the heated region. The median phase difference (compared to pretreatment baseline images) was calculated for each ROI. This phase difference was corrected for phase drift observed in standards and bone marrow. The observed phase difference, with and without corrections, was correlated with the fiberoptic temperature measurements. RESULTS: The phase difference observed with MRI was found to correlate with temperature. Phantom measurements demonstrated a linear regression coefficient of 4.70 degrees phase difference per degree Celsius, with an R2 = 0.998. After human images with artifact were excluded, the linear regression demonstrated a correlation coefficient of 5.5 degrees phase difference per degree Celsius, with an R2 = 0.84. In both phantom and human treatments, temperature measured via corrected phase difference closely tracked measurements obtained with fiberoptic probes during the hyperthermia treatments. CONCLUSIONS: Proton chemical shift imaging with current MRI and hyperthermia technology can be used to monitor and control temperature during treatment of large tumors in the distal lower extremity.

Adult↗
PubMed1998

Pathogenesis of simian immunodeficiency virus pneumonia: an immunopathological response to virus.

Although many human immunodeficiency virus-infected individuals develop lymphocytic interstitial pneumonia, the roles of host and viral factors in the pathogenesis of pneumonia are not well defined. Human immunodeficiency virus-infected children with lymphocytic interstitial pneumonia have human immunodeficiency virus-specific cytotoxic T cells in pulmonary infiltrates, increased survival time, and a reduced incidence of opportunistic infections, suggesting that lymphocytic interstitial pneumonia may reflect an effective antiviral immune response. In this study, 20 macaques were inoculated with related macrophage-tropic simian immunodeficiency viruses and examined for pulmonary lesions and virus gene expression. Ten macaques developed moderate to severe pneumonia characterized by perivascular, peribronchial, and interstitial infiltrates of lymphocytes and macrophages. Large numbers of pulmonary cytotoxic lymphocytes were demonstrated in macaques with moderate to severe pneumonia (P < 0.05) by immunostaining for TIA-1. There was no difference in viral load between macaques with moderate to severe pneumonia and those with mild to no pulmonary lesions. In five macaques inoculated with the same virus swarm, there was a significant (P < 0.05) inverse correlation between the percentage decline in CD4+ T-cell counts and the severity of pulmonary lesions. Pulmonary infiltrates of cytotoxic lymphocytes, the lack of correlation between severity of pulmonary lesions and virus gene expression, and the inverse relationship between pneumonia and inmune status suggest that simian immunodeficiency virus pneumonia may represent an immunopathological response to macrophage-tropic virus.

Animals↗
PubMed1997

Impact of setup variability on incidental lung irradiation during tangential breast treatment.

PURPOSE: This study aimed to determine the variability in treatment setup during a 5-week course of tangential breast treatment for patients immobilized in a customized hemibody cradle, to assess the relationship between the height of the lung shadow on the tangential port film and the percentage of lung volume irradiated, and to estimate the impact of setup variabilities on irradiated lung volume. METHODS: One hundred seventy-two port films were reviewed from 20 patients who received tangential beam treatment for breast cancer. The height of the lung shadow at the central axis (CLD) on each port film was compared to the corresponding simulator film as an assessment of setup variability. A three-dimensional dose calculation was performed, and the percentage of total lung volume within the field was correlated with the CLD. The three-dimensional dose calculation was repeated for selected patients with the location of the treatment beams modified to reflect typical setup variations. RESULTS: The CLD measured on the port films was within 3 mm of that prescribed on the simulator film in 43% (74 of 172) of the port films. The variation was 3-5 mm in 26%, 5-10 mm in 25%, and >10 mm in 6%. The height of the lung shadow correlated with the percentage of lung volume included in the radiation field (r2 = 0.6). Typical variations in treatment setup resulted in < or = 5% fluctuation in the absolute volume of ipsilateral lung irradiated. CONCLUSION: The current immobilization system used in our clinic provides a clinically acceptable reproducibility of patient setup. The height of the lung shadow is reasonably well correlated with the percentage of irradiated lung volume. During a typical 5-week course of radiotherapy, the ipsilateral irradiated lung volume fluctuates <5%.

Breast Neoplasms↗
PubMed1997

Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV.

To investigate the viral and host factors that contribute to neurological disease, nine macaques were intravenously co-inoculated with SIV/DeltaB670, a primary isolate of SIV consisting of at least 21 different genotypes, and SIV/17E-Fr, a neurovirulent recombinant clone. CD4+ cell counts and antigenemia were measured throughout infection. The SIV env V1 region was amplified from brain and peripheral blood mononuclear cell DNA to compare the genotypes present in brain and blood. Seven of the 9 macaques (78%) developed typical SIV-associated neurological lesions classified as severe (4 macaques), moderate (2 macaques), or mild (1 macaque) with a mean time to euthanasia of 7 months. Macaques with severe neurological lesions progressed more rapidly, with a mean time to euthanasia of 3-6 months. SIV/17E-Fr was detected in brain homogenates from all four macaques with severe encephalitis, and in three of the four, SIV/17E-Fr was the only genotype identified in the central nervous system. Macaques with less severe or no neurological lesions usually had one of various genotypes of SIV/DeltaB670 in brain. A variety of genotypes of SIV/DeltaB670 and SIV/17E-Fr were detected in peripheral blood mononuclear cells throughout infection. Macaques with severe neurological lesions had the most precipitous declines in CD4+ cell counts, the highest levels of antigenemia, and the greatest expression of viral RNA and protein in the central nervous system. Macaca nemestrina were more likely to develop severe neurological lesions than M. mulatta or M. fascicularis (P = 0.048). This study demonstrated that neurovirulent strains within the virus swarm can selectively enter and become established in the central nervous system and that the neurological lesions that develop are correlated with the development of host immunosuppression. The species differences in severity of neurological lesions seen in this study suggest that host factors are also important in determining the outcome of lentiviral infection.

Animals↗
PubMed1994

Mammographically detected breast cancer. Nonpalpable is not a synonym for inconsequential.

BACKGROUND: Needle-guided breast biopsy has become a regularly recommended procedure to excise nonpalpable, questionable breast lesions detected by mammography. Whether cancers detected in this manner have a more favorable outcome than those detected by clinical examination is not clearly documented. METHODS: To address questions about the biology of mammographically detected cancer and likelihood of axillary node metastasis, as well as the accuracy of screening mammography, data from 3752 needle-guided breast biopsies and 1175 nonpalpable breast cancers were reviewed. RESULTS: Between 1974 and 1992, 3752 needle-guided biopsies were performed in 3441 women for nonpalpable breast lesions. Benign disease was disclosed in 2575 (68.7%) biopsies and malignancy in 1175 (31.3%). Of 1130 malignancies, 61.8% were invasive carcinomas; 4.8% were microinvasive ductal carcinomas; 28.5% were ductal carcinomas in situ; and 4.8% were lobular carcinomas in situ. Axillary dissection in 558 patients with invasive carcinoma revealed that 27.1% had at least one positive axillary node. Of patients with invasive cancers presenting as nonpalpable calcifications alone, 27.5% had at least one positive axillary node. CONCLUSIONS: More than one fourth of patients with nonpalpable, invasive cancer in this series had axillary node metastasis. Therefore, axillary dissection is an important treatment consideration for all patients with invasive carcinoma, despite technique of detection. Ductal carcinomas in situ detected as limited calcifications do not require axillary dissection. In this study, 31% of biopsies proved the presence of malignancy, an acceptable and appropriate benign-to-malignant ratio.

Biopsy, Needle↗
PubMed1994

Neurovirulent simian immunodeficiency virus replicates productively in endothelial cells of the central nervous system in vivo and in vitro.

The perivascular location of human immunodeficiency virus-infected cells suggests that the virus enters the central nervous system (CNS) by traversing the blood-brain barrier (BBB). In this study, the simian immunodeficiency virus (SIV) macaque model was used to determine whether SIV infects CNS endothelial cells. SIV RNA was detected in capillary endothelial cells in brain sections from animals parenterally inoculated with a neurovirulent strain of SIV by double immunohistochemistry and in situ hybridization and by reverse transcriptase-in situ PCR. These in vivo observations were extended by examining whether SIV replicated productively in cultured macaque brain endothelial cells (MBEC). A neurovirulent strain, SIVmac239/17E-Br, replicated productively in MBEC as determined by the presence of viral cytopathic effect (syncytia), viral DNA by PCR, viral RNA by in situ hybridization, and viral antigen by immunohistochemistry and by the production of high titers of cell-free virus. Virus replication was confirmed by electron microscopy. In contrast, a nonneurovirulent strain, SIVmac239, did not infect MBEC. Infection of the endothelial cells was not blocked by soluble CD4. Thus, endothelial cells may provide a CD4-independent pathway of virus entry to the CNS. In addition, damage to the BBB as a result of endothelial cell infection may provide a mechanism for amplification of viral load in the CNS and may contribute to the CNS dysfunction that characterizes AIDS dementia and SIV encephalitis. These data suggest that MBEC may serve a selective role in determining virus entry to the CNS.

Animals↗
PubMed1993

Influence of orally administered epidermal growth factor on normal and damaged intestinal mucosa in rats.

The effect of orally administered epidermal growth factor (EGF) on the mucosal growth and hydrolase activity of normal and damaged small intestine was examined in rats. Adult rats fed EGF daily at 10 times the estimated daily intake of EGF from human milk showed increases in specific activity but not total activity of various brush-border hydrolases with unaffected mucosal protein content and villus-to-crypt ratios through day 9. Ingestion of EGF for 13 days resulted in significant decreases in mucosal protein content without changes in villus height or hydrolase activity. The effect of oral EGF on recovery of damaged intestine was studied in rats fed a liquid diet supplemented with EGF at 0, 1, 10, or 20 times the estimated daily intake from human milk after treatment with methotrexate (MTX) to induce acute intestinal injury. Animals treated with MTX showed significant reductions in body weight and small intestinal villus height, mucosal protein content, and hydrolase activities through day 6 posttreatment. Daily ingestion of EGF did not affect the MTX-induced reductions in mucosal protein content and hydrolase activity by day 3 but caused significant increases in mucosal disaccharidase and leucine aminopeptidase activity by day 6 at the 1- or 10-times human milk EGF levels. Similar changes were not observed in MTX-treated rats fed the 20-times human milk level of EGF. These studies suggest that oral EGF is capable of modulating mucosal protein levels and stimulating enterocyte hydrolase expression during repair of the intestinal mucosa.

Administration, Oral↗
PubMed1993

Smoking prevalence among perinatal women: the role of socioeconomic status, race, and ethnicity.

Baseline data were collected as part of an intervention project designed to reduce substance abuse among pregnant and postpartum women in Waterbury. Personal interviews, including questions on smoking behavior were conducted with a sample of 503 perinatal women. African American and Hispanic women represented respectively 11.8% and 10.2% of the population. Twenty-six percent of respondents reported they smoked cigarettes during pregnancy which exceeds the nationally comparable rate of 19.1%. Socioeconomic status was a stronger predictor of smoking status than other sociodemographic variables. Logistic regression analysis showed that lower socioeconomic status women were 3.7 times (P < .001) more likely to smoke during pregnancy than their higher status counterparts. Hispanics were 70% (P < .01) less likely to smoke than Whites and there were no significant differences between respondents based on race, marital status, age, or source of prenatal care. The authors conclude that smoking during pregnancy continues to be a major problem requiring multifaceted interventions and attention to underlying structural factors.

Adolescent↗
PubMed1993

Cause and current management of reoperative hyperparathyroidism.

We reviewed 137 cases of hyperparathyroidism followed for 6-72 months to determine the reasons for failure and to outline the successful management of reoperative hyperparathyroidism. Of 127 patients treated initially at Thomas Jefferson University Hospital, three required reoperation (2.4%) and 10 were referred with recurrent or persistent hyperparathyroidism. Reasons for failure were a missed gland in eight cases (62%), an ectopic gland in two cases (15%), supernumerary glands in two cases (15%), and malignant degeneration of an autotransplant in one case (8%). One patient had shortterm hypoparathyroidism requiring vitamin D supplementation (5.6%), but there were no injuries to the recurrent laryngeal nerves. We conclude that adequate knowledge of the location of normal and ectopic glands with meticulous search will reduce most reoperations, and, with identification of all four glands and routine cervical thymectomy in multigland disease, the rate should be less than 5 per cent. Patients requiring reoperation should undergo noninvasive localization studies and, if equivocal, selective venous sampling for parathyroid hormone. The major complication rate should be less than 10 per cent.

Adult↗
PubMed1992

Inhibition by 1,25 dihydroxyvitamin D3 of c-myc down-regulation and DNA fragmentation in cytosine arabinoside-induced erythroid differentiation of K562 cells.

The effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on DNA fragmentation, altered expression of the heat shock protein (hsp) 70 gene, and protooncogenes c-myc and c-myb was studied during chemical induction of erythroid differentiation in K562 cells. Preincubation of K562 cells with 1,25(OH)2D3 did not alter the concentration of hemoglobin in cells which did differentiate, but led to a reduction in the accumulation of low molecular weight DNA generated by Ara-C administration. The extent of this reduction was similar to the degree of inhibition of hemoglobin formation in the culture as the whole. Preincubation with 1,25(OH)2D3 had no effect on the increase of hsp 70 gene expression induced by a 48-hr treatment with Ara-C, but prevented the Ara-C-induced down-regulation of the protooncogene c-myc. The protooncogene c-myb was down-regulated after 15 min of treatment with Ara-C, and exposure to 1,25(OH)2D3 prior to Ara-C caused a further down-regulation of its expression. The data suggest that the events associated with erythroid differentiation may be separable into at least two groups; one of these may have an influence on the kinetics of the cell cycle traverse, and the other may be related to the expression of the erythroid phenotype.

Blotting, Northern↗
PubMed1991

Inhibition by 1,25 dihydroxyvitamin D3 of chemically induced erythroid differentiation of K562 leukemia cells.

The physiologically active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], was found to inhibit erythroid differentiation of human leukemic K562 cells. Differentiation was induced by 1 mumol/L arabinocytosine (Ara-C), 40 mumol/L tiazofurin, 1 mumol/L aphidicolin, or 1 mumol/L hydroxyurea, and was monitored daily by the appearance of hemoglobin in an increasing proportion of cells. Pretreatment for 48 hours with 2.4 x 10(-8) mol/L 1,25(OH)2D3, a concentration that is also optimal for induction of monocytic differentiation of HL-60 cells, reproducibly inhibited subsequent induction of erythroid differentiation by all of the above inducers, and modified the morphologic changes that Ara-C produced in these cells. The inhibition of hemoglobinization was approximately 50% irrespective of the degree of differentiation produced by the various inducers, but growth inhibition associated with exposure to the inducers was not affected by 1,25(OH)2D3. Similar inhibition of differentiation by 1,25(OH)2D3 was observed in mouse erythroleukemia cells MEL-D1B treated with 5 mmol/L hexamethylenebisacetamide. The inhibitory effect of 1,25(OH)2D3 on erythroid differentiation of K562 cells was abrogated by cyclohexamide (20 micrograms/mL), an inhibitor of protein synthesis. The mRNA for 1,25(OH)2D3 receptor (VDR) was detected in K562 cells, and was downregulated by a 96-hour exposure to 1,25(OH)2D3 or a 48-hour exposure to Ara-C. The presence of VDR mRNA suggests a physiologic role for 1,25(OH)2D3 in K562 cells that are precursors of erythroid cells. This role is perhaps to shift the pathways of differentiation from the erythroid to the monocytic lineage.

Animals↗