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Biomedical subjects

M L Albert

Publications and source records attributed to M L Albert.

At least 19 recordsLinked to original sources
PubMed2001

Effect of socioeconomic status on aphasia severity and recovery.

Low levels of educational attainment and low socioeconomic status have been significantly linked to poor health and increased incidence of disease, including Alzheimer's disease and diseases of the cardiovascular, pulmonary, renal, and gastrointestinal systems. Our goal in the present study was to determine the degree to which educational level and socioeconomic status influence initial severity of aphasia and subsequent recovery. We evaluated the records of 39 persons with aphasia twice: at about 4 months and 103 months postonset. We found early severity of aphasia to be significantly greater for subjects in the lower educational and occupational groups. However, rate of recovery (the slope of the recovery curve) was the same regardless of educational or occupational status.

Aphasia↗
PubMed2001

Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells.

In vivo models have shown that tissue-restricted antigen may be captured by bone marrow-derived cells and cross-presented for the tolerization of CD8+ T cells. Although these studies have shown peripheral tolerization of CD8+ T cells, the mechanism of antigen transfer and the nature of the antigen-presenting cell (APC) remain undefined. We report here the establishment of an in vitro system for the study of cross-tolerance and show that dendritic cells (DCs) phagocytose apoptotic cells and tolerize antigen-specific CD8+ T cells when cognate CD4+ T helper cells are absent. Using this system, we directly tested the "two-signal" hypothesis for the regulation of priming versus tolerance. We found that the same CD83+ myeloid-derived DCs were required for both cross-priming and cross-tolerance. These data suggested that the current model for peripheral T cell tolerance, "signal 1 in the absence of signal 2", requires refinement: the critical checkpoint is not DC maturation, but instead the presence of a third signal, which is active at the DC-CD4+ T cell interface.

Abatacept↗
PubMed2000

Cdr2, a target antigen of naturally occuring human tumor immunity, is widely expressed in gynecological tumors.

The paraneoplastic neurological disorders provide perhaps the best known example of naturally occurring tumor immunity in humans. For example, patients with paraneoplastic cerebellar degeneration (PCD) appear to suppress the growth of occult breast or ovarian tumors that express a neuronal antigen termed cdr2. PCD patients harbor cdr2-specific CTLs in their peripheral blood, and these cells are likely mediators of the tumor suppression. Whereas cdr2 therefore appears to be the target of an effective immune response in patients with PCD, the general relevance to cancer patients has been unclear, due in part to reports indicating that cdr2 is not expressed in tumors obtained from neurologically normal patients. We have reexamined this question, and we find that cdr2 is widely expressed in such tumors, indicating that cdr2 is in fact an important tumor antigen in the general population of breast and ovarian cancer patients.

Antigens, Neoplasm↗
PubMed2000

Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells.

Cell death by necrosis is typically associated with inflammation, in contrast to apoptosis. We have identified additional distinctions between the two types of death that occur at the level of dendritic cells (DCs) and which influence the induction of immunity. DCs must undergo changes termed maturation to act as potent antigen-presenting cells. Here, we investigated whether exposure to apoptotic or necrotic cells affected DC maturation. We found that immature DCs efficiently phagocytose a variety of apoptotic and necrotic tumor cells. However, only exposure to the latter induces maturation. The mature DCs express high levels of the DC-restricted markers CD83 and lysosome-associated membrane glycoprotein (DC-LAMP) and the costimulatory molecules CD40 and CD86. Furthermore, they develop into powerful stimulators of both CD4(+) and CD8(+) T cells. Cross-presentation of antigens to CD8(+) T cells occurs after uptake of apoptotic cells. We demonstrate here that optimal cross-presentation of antigens from tumor cells requires two steps: phagocytosis of apoptotic cells by immature DCs, which provides antigenic peptides for major histocompatibility complex class I and class II presentation, and a maturation signal that is delivered by exposure to necrotic tumor cells, their supernatants, or standard maturation stimuli, e.g., monocyte-conditioned medium. Thus, DCs are able to distinguish two types of tumor cell death, with necrosis providing a control that is critical for the initiation of immunity.

Animals↗
PubMed2000

alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells.

Integrin receptors are important for the phagocytosis of apoptotic cells. However, little is known about their function in mediating internalization, as previous studies used blocking antibodies for the inhibition of binding. Here we show that the alphavbeta5 receptor mediates both binding and internalization of apoptotic cells. Internalization is dependent upon signalling through the beta5 cytoplasmic tail, and engagement of the alphavbeta5 heterodimer results in recruitment of the p130cas-CrkII-Dock180 molecular complex, which in turn triggers Rac1 activation and phagosome formation. In addition to defining integrin-receptor signalling as critical for the internalization of apoptotic material, our results also constitute the first evidence in human cells that the CED-2-CED-5-CED-10 complex defined in Caenorhabditis elegans is functionally analagous to the CrkII-Dock180-Rac1 molecular complex in mammalian cells. By linking the alphavbeta 5 receptor to this molecular switch, we reveal an evolutionarily conserved signalling pathway that is responsible for the recognition and internalization of apoptotic cells by both professional and non-professional phagocytes.

Apoptosis↗
PubMed2000

Forced hyperphasia and environmental dependency syndrome.

A distinctive, language related fragment of the environmental dependency syndrome is described: compulsive, involuntary, environmentally dependent speaking. Because this syndrome represents the observe of aphasia, it is named forced hyperphasia. An 84 year old woman with acute left frontal infarction was admitted to hospital with gait disturbance, forced grasp reflex, and striking imitation behaviour. After 2 weeks her imitation behaviour disappeared, but an equally striking new behaviour emerged. In the presence of others she would call out the names of objects in the room, and also call out the actions and gestures of people in the room, even though she was not asked to do so, and even though she was asked to stop. For example, if the doctor scratched his nose, she said, "The doctor is scratching his nose." Brain CT, MRI, and SPECT showed cerebral atrophy and a left superior frontal subcortical infarct. It is suggested that "forced hyperphasia" is a clinical fragment of the environmental dependency syndrome and that her compulsive, impulsive, involuntary release of spoken language resulted from the release of frontal inhibition of the complex reflex linking environmental cues to the set of motor, limbic, spatial, and linguistic associations underlying spoken language.

Aged↗
PubMed2000

Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration.

Patients with paraneoplastic cerebellar degeneration (PCD) offer the opportunity to explore the mechanisms underlying tumor immunity and immune-mediated neuronal degeneration. Cytotoxic T lymphocytes (CTLs) specific for the PCD onconeural antigen cdr2 found in the blood of patients with PCD are likely to be effectors of PCD tumor immunity. Here, we suggest a role for CTLs in the autoimmune destruction of Purkinje neurons. More than 75% of the cells obtained from the cerebrospinal fluid (CSF) of PCD patients were CD3+ alphabeta T cells. In patients with active/progressive disease, 20% to 40% of CSF cells were activated T cells, and the CD4+ helper cells were Th1-type cells. Three PCD patients were given tacrolimus, a specific inhibitor of activated T cells, which markedly reduced these cells in the CSF. Tacrolimus also reduced the number of activated cdr2-specific CTLs in the peripheral blood, but did not lead to tumor recurrence. We suggest that activated cdr2-specific CTLs in the CSF contribute to Purkinje degeneration in PCD, and that tacrolimus therapy may benefit patients with paraneoplastic neurological disease and other T cell-mediated autoimmune neurological disorders.

Female↗
PubMed1999

Incorporating standardized patients into a psychosocial nurse practitioner program.

Interactions with standardized patients (SPs) provide customized, immediate clinical learning for graduate nursing students. SPs are lay persons trained to portray a role in a faculty-designed health care scenario for a series of students. Student learning results from the experience of the encounter, performance feedback from the SP, subsequent classroom discussion with peers, faculty critique, and review of the videotaped interaction. Design and implementation of an SP experience involves clarification of goals for the encounter, development of the clinical scenario, recruitment and training of SPs, preparation of students, and management of the logistics of the exercise. Although the process is labor-intensive, we have found SP experiences versatile, valuable, and popular with students.

Curriculum↗
PubMed1999

Verb naming in normal aging.

Few studies have examined verb naming in normal aging, although decline in the ability to name nouns has been well documented. In this study, we examined longitudinal performance on the Action Naming Test (ANT), a confrontation naming test for verbs. The purpose of this study was to confirm the verb naming deficit associated with aging, which was previously seen only in cross-sectional studies, and to provide additional normative data on verb naming ability that may prove useful to studies on verb naming in populations with brain dysfunction. Sixty-six healthy men and women aged 30 to 79 were each tested with the ANT 3 times over a 7-year span. ANT performance showed a significant decline over time for all participants except the youngest group. Longitudinal methodology supports the conclusion that this finding of a decline in verb naming ability arises from true age-related changes and not from cohort differences.

Adult↗
PubMed1998

Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes.

Dendritic cells, but not macrophages, efficiently phagocytose apoptotic cells and cross-present viral, tumor, and self-antigens to CD8(+) T cells. This in vitro pathway corresponds to the in vivo phenomena of cross-priming and cross-tolerance. Here, we demonstrate that phagocytosis of apoptotic cells is restricted to the immature stage of dendritic cell (DC) development, and that this process is accompanied by the expression of a unique profile of receptors, in particular the alphavbeta5 integrin and CD36. Upon maturation, these receptors and, in turn, the phagocytic capacity of DCs, are downmodulated. Macrophages engulf apoptotic cells more efficiently than DCs, and although they express many receptors that mediate this uptake, they lack the alphavbeta5 integrin. Furthermore, in contrast to DCs, macrophages fail to cross-present antigenic material contained within the engulfed apoptotic cells. Thus, DCs use unique pathways for the phagocytosis, processing, and presentation of antigen derived from apoptotic cells on class I major histocompatibility complex. We suggest that the alphavbeta5 integrin plays a critical role in the trafficking of exogenous antigen by immature DCs in this cross-priming pathway.

Antigen Presentation↗
PubMed1998

Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs.

CD8+ cytotoxic T lymphocytes (CTLs) mediate resistance to infectious agents and tumours. Classically, CTLs recognize antigens that are localized in the cytoplasm of target cells, processed and presented as peptide complexes with class I molecules of the major histocompatibility complex (MHC). However, there is evidence for an exogenous pathway whereby antigens that are not expected to gain access to the cytoplasm are presented on MHC class I molecules. The most dramatic example is the in vivo phenomenon of cross-priming: antigens from donor cells are acquired by bone-marrow-derived host antigen-presenting cells (APCs) and presented on MHC class I molecules. Two unanswered questions concern the identity of this bone-marrow-derived cell and how such antigens are acquired. Here we show that human dendritic cells, but not macrophages, efficiently present antigen derived from apoptotic cells, stimulating class I-restricted CD8+ CTLs. Our findings suggest a mechanism by which potent APCs acquire antigens from tumours, transplants, infected cells, or even self-tissue, for stimulation or tolerization of CTLs.

Antigen Presentation↗
PubMed1998

Treatment of aphasia.

Approximately 1 million people have aphasia in the United States today, yet with properly targeted therapy in selected patients effective communication can be restored. Current approaches to treatment of aphasia include psycholinguistic theory-driven therapy, cognitive neurorehabilitation, computer-aided techniques, psychosocial management, and (still on an experimental basis) pharmacotherapy.

Aphasia↗
PubMed1998

Visible changes in lesion borders on CT scan after five years poststroke, and long-term recovery in aphasia.

This study examined 12 aphasia patients at approximately 1 year poststroke (Time 1) and again at 5-12 years poststroke (Time 2) with language testing and CT scan. Significant increases in naming scores, and phrase length in nonfluent speech were observed after 5 years poststroke. Significant expansion in visible lesion borders (lesion size) was observed after 5 years poststroke; an increase in lesion size of > 1% was present in 9/12 cases (75%). Not one case had a second stroke. Thus, it appears that even though lesion expansion may occur after 5 years poststroke, as long as this expansion is unilateral and gradual, it has no adverse effect on language, and in fact, continued recovery in naming and nonfluent speech may also occur. Long-term recovery patterns in aphasia which may be associated with brain reorganization deserve further study, especially with functional brain imaging techniques.

Aged↗
PubMed1998

Tumor-specific killer cells in paraneoplastic cerebellar degeneration.

Models for immune-mediated tumor regression in mice have defined an essential role for cytotoxic T lymphocytes (CTLs); however, naturally occurring tumor immunity in humans is poorly understood. Patients with paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovarian cancer. Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2, this humoral response has not been shown to be pathogenic. Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA-A2.1+ PCD patients, providing the first description, to our knowledge, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby immature dendritic cells that engulf apoptotic tumor cells can mature and migrate to draining lymph organs where they could induce a CTL response to tissue-restricted antigens. In PCD, peripheral activation of cdr2-specific CTLs is likely to contribute to the subsequent development of the autoimmune neuronal degeneration.

Animals↗