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Biomedical subjects

C S Carter

Publications and source records attributed to C S Carter.

At least 73 records · Page 4Linked to original sources
PubMed1998

Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults.

The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.

Adult↗
PubMed1998

T cell-depleted granulocyte colony-stimulating factor (G-CSF) modified allogenic bone marrow transplantation for hematological malignancy improves graft CD34+ cell content but is associated with delayed pancytopenia.

To increase the stem cell content of T cell-depleted bone marrow transplants (BMT), we treated 12 patients with hematological malignancies with BMT from HLA-identical sibling donors given G-CSF 10 microg/kg/day for 5 days before marrow harvest. After CD34+ cell selection, patients received a median of 1.7 (range, 0.82-3.1) x 10(6) CD34+ cells/kg and 2.3 (range, 0.25-4.0) x 10(5) CD3+ cells/kg. All patients had initial engraftment but four developed pancytopenia between days 55-130 post-BMT. In two patients, this required a second infusion of G-CSF-mobilized donor peripheral blood progenitor cells. We observed no delayed pancytopenia in a matched historical group of 24 patients receiving T cell-depleted BMT without prior G-CSF stimulation. Compared to this control group, G-CSF-stimulated marrow recipients showed a significant decline in neutrophil and monocyte counts after 8 weeks. However, outcome after BMT was otherwise comparable, with a similar incidence of acute graft-versus-host disease and transplant-related mortality. Disease-free survival was 63 vs 67% for controls matched for CD34+ cell dose (P = NS). These results indicate that G-CSF stimulation can increase the CD34+ cell content of T cell-depleted marrow but carries a risk of late graft failure.

Adolescent↗
PubMed1998

Functional hypofrontality and working memory dysfunction in schizophrenia.

OBJECTIVE: Hypofrontality is a common but not invariable finding in schizophrenia. Inconsistencies in the literature may reflect, in part, the fact that abnormal physiological responses in the prefrontal cortex are best identified under conditions that place well-specified functional demands on this region. METHOD: The authors studied eight patients with schizophrenia and eight matched comparison subjects using [(15)O]H2O positron emission tomography and the "N-back" task, which activates the prefrontal cortex as a function of working memory load in normal subjects. RESULTS: Under low-working-memory-load conditions, the accuracy of both groups in the N-back task was equal, but when the memory load increased, the patients' performance deteriorated more than did that of the comparison subjects. The regional cerebral blood flow response to increased working memory load was significantly reduced in the patients' right dorsolateral prefrontal cortex. CONCLUSIONS: These results confirm the importance of using tasks that tap specific cognitive functions, linked to specific neural systems, in studies of brain-behavior relationships in schizophrenia. Hypofrontality is reliably demonstrated in schizophrenia during tasks that engage working memory functions of the prefrontal cortex.

Functional Laterality↗
PubMed1997

Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease.

Little is known about the potential for engraftment of autologous hematopoietic stem cells in human adults not subjected to myeloablative conditioning regimens. Five adult patients with the p47(phox) deficiency form of chronic granulomatous disease received intravenous infusions of autologous CD34(+) peripheral blood stem cells (PBSCs) that had been transduced ex vivo with a recombinant retrovirus encoding normal p47(phox). Although marrow conditioning was not given, functionally corrected granulocytes were detectable in peripheral blood of all five patients. Peak correction occurred 3-6 weeks after infusion and ranged from 0.004 to 0.05% of total peripheral blood granulocytes. Corrected cells were detectable for as long as 6 months after infusion in some individuals. Thus, prolonged engraftment of autologous PBSCs and continued expression of the transduced gene can occur in adults without conditioning. This trial also piloted the use of animal protein-free medium and a blood-bank-compatible closed system of gas-permeable plastic containers for culture and transduction of the PBSCs. These features enhance the safety of PBSCs directed gene therapy.

Adolescent↗
PubMed1997

Retroviral gene transduction of adult peripheral blood or marrow-derived CD34+ cells for six hours without growth factors or on autologous stroma does not improve marking efficiency assessed in vivo.

Our previous work in patients undergoing autologous transplant for multiple myeloma (MM) or breast cancer (BC) has shown that retroviral transduction of adult CD34+ cells for 72 hours in the presence of interleukin-3 (IL-3), IL-6, and stem cell factor (SCF) resulted in .01% to 1% long-term marking of peripheral blood and marrow cells (Blood 85:3948, 1995). In this study we compare these previous studies to transduction with no added growth factors, previously shown to result in higher levels of marking in children (Lancet 342:1134, 1993) or transduction in the presence of an autologous stromal layer. Peripheral blood (PB) mononuclear cells were collected via apheresis after high-dose cyclophosphamide and granulocyte colony-stimulating factor. Bone marrow (BM) was also harvested in all patients. One third of both BM and PB collections were enriched for CD34+ cells and transduced with one of two marking vectors containing the neomycin-resistance gene to distinguish cells originating from BM and PB posttransplantation. Cells from 3 MM and 2 BC patients were transduced without growth factors for 6 hours and cells from 2 MM and 2 BC patients were transduced in the presence of autologous marrow stroma. Immediately posttransduction, the percentage of Neo-resistant PB and BM progenitors (colony-forming units) were: 0% to 19% in the 6-hour no growth factor group and 0% to 36% in the autologous stroma group. After conditioning therapy, both transduced and untransduced PB and BM fractions were infused into the patients. Semi-quantitative nested DNA polymerase chain reaction was performed on total, mononuclear, and granulocyte fractions of PB and BM at 1, 3, 6, 9, 12, and 18 months. Poor marking has been observed in both groups, with no consistently positive patients. These results compare unfavorably with our prior experience using growth factors during transduction. Further optimization of transduction conditions and vectors needs to be developed to improve transduction efficiency of adult human repopulating hematopoietic cells.

Adult↗
PubMed1997

The integrative neurobiology of affiliation. Introduction.

The research presented at this conference, including a series of excellent posters from junior investigators, documents the pervasive importance of affiliation and other social behaviors. Affiliative behaviors interact with, but are distinct from reproductive and aggressive behaviors. Patterns of social behaviors tend to be more species-typical than the behaviors associated with reproduction or aggression. However, neural circuits necessary for approach or avoidance also are necessary for the expression of various types of affiliative behavior such as maternal behavior or pair-bond formation. Furthermore, candidate neurochemical systems have been identified that contribute to various types of affiliative behavior. For example, studies revealing new behavioral functions for steroid hormones of the adrenal axis, such as corticosterone, and neuropeptides, including the endorphins, oxytocin and vasopressin, extend our general knowledge of neurobiology; they may also lead to studies that expand our understanding of social behavior and the connections to systems that regulate emotions. The work represented in this volume also has important implications for the study of serious neuropsychiatric disorders. For example, episodes of certain of these disorders can be induced by social stressors; in other disorders, a marked decrease in affiliative behaviors is a prominent feature of the patients' difficulties. Furthermore, abnormalities in animal systems implicated in the neurobiology of affiliation (oxytocin, vasopressin, and the hypothalamic-pituitary-adrenal system) have also been documented for major depression in humans. Animal models, such as those described at this conference, offer evolutionary perspectives, from which it is possible to extract general principles. At the same time, our understanding of the mechanistic and neurobiological substrates of both constructive and destructive social behaviors is increasing. At the conference, the evolutionary and mechanistic perspectives converged on the theme that studies of affiliative behaviors cannot be fully interpreted in isolation from other social behaviors; neither can they effectively be isolated from the biological and social contexts that shape their expression. Advances in this research area seem dependent on integrating experimental research across levels of analysis. Although this task is challenging, we are confident that an awareness of integrative principles can lead to new and important research opportunities.

Aggression↗
PubMed1997

Integrative functions of lactational hormones in social behavior and stress management.

For mammalian reproduction to succeed, self-defense and asociality must be subjugated to positive social behaviors, at least during birth, lactation, and sexual behavior. Perhaps the important task of regulating the interaction between social and agonistic behaviors is managed, in part, by interactions between two related neurochemical systems that incorporate oxytocin and vasopressin in their functions. The neuropeptides oxytocin and vasopressin participate in important reproductive functions, such as parturition and lactation, and homeostatic responses, including modulation of the adrenal axis. Recent evidence also implicates these hormones in social aspects of reproductive behaviors. For example, oxytocin is important for a variety of positive social behaviors, including the regulation of maternal-infant interactions. In adult animals, oxytocin may facilitate both social contact and selective social interactions associated with social attachment and pair bonding, and it participates in the regulation of parasympathetic functions. Vasopressin, in contrast, is associated with behaviors that might be broadly classified as "defensive" including enhanced arousal, attention, or vigilance, increased aggressive behavior, and a general increase in sympathetic functions. On the basis of the literature on the functions of these hormones and our own recent findings, we propose that dynamic interactions between oxytocin and vasopressin are components of a larger system which integrates the neuroendocrine and autonomic changes associated with mammalian social behaviors and the concurrent regulation of the stress axis. In addition, studies of lactating females provide a valuable model for understanding the more general neuroendocrinology of the stress axis. Peptide hormones, including oxytocin and vasopressin, do not readily cross the blood-brain barrier and must be administered centrally (i.c.v.) to reach the brain. Nasal sprays have been used to promote milk let down and have been used in some behavioral studies, but the extent to which such compounds reach the brain is not known. Therefore, virtually nothing is known regarding the effects in humans of centrally administered oxytocin. The study of human lactation, in conjunction with animal research, provides an opportunity to begin to develop viable hypotheses regarding the behavioral effects of oxytocin.

Adrenal Glands↗
PubMed1997

Perinatal hormone exposure alters the expression of selective affiliative preferences in prairie voles.

In the present study, perinatal administration of corticosterone and testosterone significantly influenced affiliative preferences only in females. Despite the very high levels of steroids given, no significant differences were noted among treated and untreated groups of males. Prairie voles apparently are uniquely adapted to tolerate high levels of endogenous steroids. However, females of this species may be capable of exploiting variations in corticosterone levels to regulate sexually dimorphic traits, including social behaviors, in adulthood. Perinatal responsivity to adrenal hormones could allow animals to adapt their social behaviors, including traits that have been used to characterize monogamy and/or communal breeding, to environmental demands.

Animals↗
PubMed1997

The hypothalamic-pituitary-adrenal axis of prairie voles (Microtus ochrogaster): evidence for target tissue glucocorticoid resistance.

Basal plasma corticosterone levels in prairie voles (Microtus ochrogaster) are extremely high, in the absence of any apparent negative consequences of glucocorticoid excess. We tested the hypothesis that prairie voles are a novel rodent model of target tissue resistance to glucocorticoids. Prairie voles had a significantly higher adrenal-to-body weight ratio, 5- to 10-fold greater basal plasma corticosterone, and 2- to 3-fold greater basal plasma ACTH concentrations than montane voles (Microtus montanus) and rats. While plasma corticosterone binding globulin (CBG) was 2-fold higher in prairie voles than in rats, both estimated and directly measured plasma free corticosterone were significantly higher in prairie voles than in rats. Plasma corticosterone levels in prairie voles were responsive to both circadian cues and a stressor, but were resistant to suppression by the synthetic glucocorticoid, dexamethasone (DEX). Western blots of brain and liver protein extracts, using a glucocorticoid receptor (GR) antibody, revealed the presence of a approximately 97 kDa immunoreactive band, the expected size for GR. Binding assays revealed significantly lower DEX affinity of corticosteroid receptors (CR) in cytosol of prairie vole brain and liver than that in the same tissues in rats. We conclude that prairie voles are a novel rodent model of glucocorticoid resistance, and that decreased affinity of CR for ligand might be partially responsible for this phenomenon.

Adrenocorticotropic Hormone↗
PubMed1997

Sexual differentiation in prairie voles: the effects of corticosterone and testosterone.

Prairie voles (Microtus ochrogaster) exhibit low levels of physical sexual dimorphism and have endogenous basal corticosterone levels that are 5-10 times higher than those measured in rats; prairie voles also do not show a postnatal period of adrenal hyporesponsivity. On the basis of studies in rats suggesting that adrenal hyperactivity during the perinatal period could reduce masculinization or feminize sexual behavior, we hypothesized that adrenal hormones might influence sexual differentiation in prairie voles. We also examined the hypothesis that the effects of testosterone in prairie voles might differ from those reported in other rodents. Treatments with either corticosterone or testosterone propionate (TP) were given prenatally (gestational Days 12-20), via maternal injection, or postnatally (Days 1-6), by directly injecting the pups. Additional groups of males were castrated or sham-operated on postnatal Day 1, and a subgroup of castrated males received postnatal TP. Male and female sexual behavior was observed in adulthood following gonadectomy and hormone treatments. Corticosterone treatment was associated with high levels of mounting in both sexes and did not inhibit lordosis behavior in females. Postnatal TP treatment inhibited lordosis in females but did not facilitate mounting in either sex. Males that were castrated at birth showed unexpectedly high levels of mounting in response to adult androgens. The results of this study suggest that in prairie voles corticosterone is capable of masculinizing without defeminizing sexual behavior, whereas postnatal testicular secretions are not essential for, and may actually inhibit, masculinization in this species.

Animals↗
PubMed1997

Enumeration of CD34+ hematopoietic progenitor cells in peripheral blood and leukapheresis products by microvolume fluorimetry: a comparison with flow cytometry.

There is increasing interest in both standardization and simplification of methods for enumeration of CD34+ hematopoietic progenitor cells (HPC) to facilitate cellular therapies and to improve interinstitutional comparison of clinical and laboratory results. We evaluated a novel method for CD34+ cell enumeration based on microvolume fluorimetry (MVF) compared with our laboratory's routine flow cytometric method on samples of peripheral blood and leukapheresis products. The MVF method is semiautomated and uses a 633-nm light from a helium-neon laser to scan fluorochrome-labeled cells held in stasis in a capillary known volume. The performance of the MVF assay for enumeration of CD34+ cells was found to be comparable to our routine flow cytometric assay in linearity and accuracy in the range of 5-1500 cells per microliter. Precision of MVF for replicate assays on the same instrument was demonstrated by coefficient of variation (CV) values of 8.4% at a CD34+ cell concentration of 284/microliters for a sample volume of 0.8 microliters, and 15.7% at 12/microliters for a sample volume of 3.2 microliter. Precision among three different instruments was demonstrated, using sample volumes of 1.6 microliters, by CV values of 44% at 6 cells/microliters and 4.6% at 733 cells/microliters. In a field sample evaluation, precision of the entire assay system for paired measurements on 0.8-microliter sample volumes was demonstrated by CV values of 50%, 31%, and 15% for peripheral blood samples with concentrations of 0-10, 10-20, and 20-100 CD34+ cells/microliters, respectively, and 6.3%, 8.1% and 6.5% for leukapheresis samples with concentrations of 0-100, 100-1,000, and 1,000-2,500 CD34+ cells/microliters, respectively. The MVF assay was easy to perform, required minimal technical training time, and had a turnaround time of 40 min, of which less than 10 min was actual technical time. These observations suggest that the MVF method for CD34+ cell enumeration may prove useful to clinical laboratories providing support for HPC collection, processing, and transplantation services that require relatively simple, rapid assays for product quality control or to guide real-time clinical decisions.

Antigens, CD34↗
PubMed1997

Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance.

OBJECTIVE: Attentional deficits are a prominent aspect of cognitive dysfunction in schizophrenia. The anterior cingulate gyrus is proposed to be an important component of frontal attentional control systems. Structural and functional abnormalities have been reported in this region in schizophrenia, but their relationship to attentional deficits is unknown. The authors investigated the function of the anterior cingulate gyrus and the related neural systems that are associated with selective attention in patients with schizophrenia. METHOD: While subjects performed multiple blocks of a single-trial Stroop task, [15O]H2O positron emission tomography scans were obtained. Fourteen patients with schizophrenia were compared with 15 normal subjects matched for age, gender, and parental education. RESULTS: The patients with schizophrenia responded at the same rate but made more errors in color naming during the color-incongruent condition. Consistent with the authors' hypothesis, patients with schizophrenia showed significantly less anterior cingulate gyrus activation while naming the color of color-incongruent stimuli. CONCLUSIONS: Patients with schizophrenia fail to activate the anterior cingulate gyrus during selective attention performance. This finding adds to the understanding of the functional significance of the structural and metabolic abnormalities in schizophrenia that have been previously reported in this region of the brain.

Adult↗
PubMed1997

Anxiety disorders and the syndrome of chest pain with normal coronary arteries: prevalence and pathophysiology.

Recurrent chest pain in the presence of normal coronary arteries is a common and perplexing problem in primary care medicine and cardiology and is associated with significant morbidity and health care utilization. A series of carefully controlled prospective studies conducted over the past decade have suggested a strong association between this syndrome and the presence of anxiety disorders. Thirty percent to 50% of patients with recurrent chest pain and normal coronary arteries meet criteria for panic disorder. Generalized anxiety disorder may also be associated with this syndrome. In contrast, major depression seems strongly associated with the syndrome only when it presents as a comorbidity with panic disorder. Reluctance of nonpsychiatric physicians to diagnose and treat anxiety disorders in this population may reflect a lack of knowledge of the well-established pathophysiologic mechanisms that can mediate the association of anxiety disorders and cardiac symptoms. We propose a conceptual framework, derived from the neurologic literature and from recent studies using positron emission tomography and intravenous procaine challenge, which links anxiety and subjective cardiovascular symptoms to abnormal activity in neural circuits involving the anterior limbic system of the brain. This neuropsychiatric model of the role of anxiety disorders in the pathophysiology of chest pain in patients with normal coronary arteries is proposed to strengthen the rationale for the identification and treatment of anxiety disorders in this population by nonpsychiatric physicians.

Anxiety Disorders↗
PubMed1996

The effects of stress on social preferences are sexually dimorphic in prairie voles.

Prairie voles (Microtus ochrogaster) are monogamous rodents that form pair bonds characterized by a preference for a familiar social partner. In male prairie voles, exposure to either the stress of swimming or exogenous injections of corticosterone facilitate the development of a social preference for a female with which the male was paired after injection or swimming. Conversely, adrenalectomy inhibits partner preference formation in males and the behavioral effects of adrenalectomy are reversed by corticosterone replacement. In female prairie voles, swim stress interferes with the development of social preferences and corticosterone treatments inhibit the formation of partner preferences, while adrenalectomized females form preferences more quickly than adrenally intact controls. Because sex differences in both behavior and physiology are typically reduced in monogamous species, we initially predicted that male and female prairie voles would exhibit similar behavioral responses to corticosterone. However, our findings suggest an unanticipated sexual dimorphism in the physiological processes modulating social preferences. This dimorphic involvement of stress hormones in pair bonding provides a proximate mechanism for regulating social organization, while permitting males and females to adapt their reproductive strategies in response to environmental challenges.

Adrenalectomy↗