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Biomedical subjects

C Blum

Publications and source records attributed to C Blum.

At least 19 recordsLinked to original sources
PubMed2001

Thymus medulla consisting of epithelial islets each derived from a single progenitor.

The thymus is organized into medullary and cortical zones that support distinct stages of T-cell development. The formation of medulla and cortex compartments is thought to occur through invagination of an endodermal epithelial sheet into an ectodermal one at the third pharyngeal pouch and cleft, respectively. Epithelial stem/progenitor cells have been proposed to be involved in thymus development, but evidence for their existence has been elusive. We have constructed chimaeric mice by injecting embryonic stem (ES) cells into blastocysts using ES cells and blastocysts differing in their major histocompatibility complex (MHC) type. Here we show that the MHC class-II-positive medullary epithelium in these chimaeras is composed of cell clusters, most of which derive from either embryonic stem cell or blastocyst, but not mixed, origin. Thus, the medulla comprises individual epithelial 'islets' each arising from a single progenitor. One thymic lobe has about 300 medullary areas that originate from as few as 900 progenitors. Islet formation can be recapitulated after implantation of 'reaggregated fetal thymic organs' into mice, which shows that medullary 'stem' cells retain their potential until at least day 16.5 in fetal development. Thus, medulla-cortex compartmentalization is established by formation of medullary islets from single progenitors.

Animals↗
PubMed2001

Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent.

Although transgenic mice expressing murine B7-1 (mCD80) on their pancreatic beta cells under the rat insulin-1 promoter (RIP-mCD80(+) mice) rarely develop spontaneous beta cell destruction and diabetes, we have previously reported the transgene-dependent induction of profound insulitis and lethal diabetes following multiple low dose injections of the beta cell toxin streptozotocin (MLDS) in RIP-mCD80(+) mice. Here, we have further characterized this MLDS-induced diabetes model using the RIP-mCD80(+) mice and now demonstrate that disease is critically dependent on T cell signaling via CD28. Thus, although naive RIP-mCD80(+) and nontransgenic littermates have comparable gross beta cell mass, and immediately following MLDS induction the mice display similar degrees of insulitis and decrements in the beta cell mass, only transgenic mice continued to destroy their beta cells and develop insulin-dependent diabetes mellitus. Strikingly, MLDS-induced diabetes was completely prevented in CD28-deficient mice (RIP-mCD80(+)CD28(-/-)) due to abrogation of leukocytes infiltrating their pancreatic islets. We further characterized MLDS-induced diabetes in the RIP-mCD80(+) mice by demonstrating that the MLDS-induced lymphocytic islet infiltrate contained a substantial frequency of autoantigen-specific, IFN-gamma-secreting, CD8(+) T cells. We conclude that MLDS-induced beta cell destruction and subsequent insulin-dependent diabetes mellitus in RIP-mCD80(+) mice is T cell-mediated as it involves both Ag-specific recognition of self-target molecules in the inflamed pancreatic islet (signal 1) and is CD28 costimulation dependent (signal 2).

Animals↗
PubMed2001

Combining decision support and image processing: a PROforma model.

This paper addresses two important problems in medical image interpretation:(1) integration of numeric and symbolic information, (2) access to external sources of medical knowledge. We have developed a prototype in which image processing algorithms are combined with symbolic representations for reasoning, decision making and task management in an integrated, platform-independent system for the differential diagnosis of abnormalities in mammograms. The prototype is based on PROforma, a generic technology for building decision support systems based on clinical guidelines. The PROforma language defines a set of tasks, one of which, the enquiry, is used as means of interaction with the outside world. However, the current enquiry model has proved to be too limited for our purposes. In this paper we outline a more general model, which can be used as an interface between symbolic functions and image or other signal data.

Algorithms↗
PubMed2000

Toddler drowning in domestic swimming pools.

AIMS: To identify how toddlers who drowned gained access to private swimming pools; to recommend preventive strategies to reduce the incidence of toddler drowning and near drowning. METHOD: The study reviewed critically all completed investigations into the drowning deaths of toddlers aged 1-4 years reported to the state coroner (n=33) as a result of unintentional submersion incidents in domestic swimming pools in Victoria, Australia, from 1 January 1992 to 31 December 1997. RESULTS: There was a predominance of 1 year olds, and boys. Forty six per cent of the children drowned in the three summer months. The majority of pools were in-ground; most were located on the child's home property. Over half the pools lacked fencing of any kind; of those that did have fences, only three appear to have met Australian standards. CONCLUSIONS: More than half of the children studied drowned in unfenced pools and spas. In not one case did a child gain unaided access to a pool fitted with a fully functional gate and fence that met the Australian standard. Where children gained access to fenced pools, the majority did so via faulty or inadequate gates, or through gates that were propped open. This finding highlights the need for pool owners to install Australian standard approved fences and gates, and to maintain existing fences and gates regularly. Door locks and supervision were inadequate primary prevention strategies.

Accident Prevention↗
PubMed1999

Cutting edge: anti-CD1 monoclonal antibody treatment reverses the production patterns of TGF-beta 2 and Th1 cytokines and ameliorates listeriosis in mice.

Protection against intracellular bacteria by T cells is regulated by Ag-presenting molecules, which comprise classical MHC class I molecules, MHC class II molecules, and nonclassical MHC class Ib molecules. The role of CD1 molecules, which are structurally similar to classical MHC class I gene products, but less polymorphic, is not understood so far. We show that CD1 surface expression increased on APC in Listeria-infected mice. The in vivo treatment with anti-CD1 mAb reduced TGF-beta 2 levels and concomitantly increased secretion of the proinflammatory cytokine TNF, the Th1 cell promoting cytokine IL-12, and the Th1 cell cytokine IFN-gamma at the onset of listerial infection. These findings point to a regulatory role of CD1-reactive cells in the immune response against listeriosis.

Animals↗
PubMed1999

Quantification of microglial late reaction to stereotactic irradiation of the rat brain using computer-aided image analysis.

The role of microglial cells in the late delayed reaction following radiotherapy of brain tumors has not been elucidated. To investigate the late delayed response of microglial cells to radiation, we stereotactically irradiated spherical treatment volumes in the right frontal lobe of rat brains. Doses of 20, 30, 40, and 50 Gy were used in combination with two different collimators. The response of microglial cells at 10 and 19 months after irradiation was determined with Anti-CD 11 b/c (Ox 42) as an immunohistochemical marker. For evaluation of immunostaining, we developed a method using computer-aided image analysis in which the ratio of the area of stained cells to that of nonstained brain tissue is calculated. In addition, quantification of Ox-42+ cells per microscopic field was performed. Animals treated with 30 Gy or more had significantly increased total areas of staining at both time points studied. In contrast, the number of stained cells at 10 months increased significantly only in animals treated with 30 or 40 Gy. Likewise, at 19 months, this number increased significantly only in animals treated with 40 Gy or more. These results indicate that computer-aided determination of the area of stained cells is more sensitive than the counting of stained cells. We have demonstrated that microglial cells respond to stereotactic irradiation in a dose-dependent fashion. The image analysis we employed for this purpose is a systematic method to evaluate immunohistochemical staining.

Animals↗
PubMed1999

Regional tumor oxygenation and measurement of dynamic changes.

We recently described a novel approach to measuring regional tumor oxygen tension using (19)F pulse burst saturation recovery (PBSR) nuclear magnetic resonance (NMR) echo planar imaging (EPI) relaxometry of hexafluorobenzene. We now compare oxygen tension measurements in a group of size-matched R3327-AT1 Dunning prostate rat tumors made using this new method with those using a traditional polarographic method: the Eppendorf histograph. Similar oxygen tension distributions were found using the two methods, and both techniques showed that tumors with volume greater than 3.5 cm(3) were significantly (P < 0.0001) less well oxygenated than smaller tumors (volume less than 2 cm(3)). Using the (19)F EPI approach, we also examined the response to respiratory challenge. Increasing the concentration of inspired oxygen from 33% to 100% O(2) produced a significant increase (P < 0.0001) in tumor oxygenation for a group of small tumors. In contrast, no change was observed in the mean pO(2) for a group of large tumors. Consideration of individual tumor regions irrespective of tumor size showed a strong correlation between the maximum pO(2) observed when breathing 100% O(2) compared with mean baseline pO(2). These results further demonstrate the usefulness of (19)F EPI to assess changes in regional tumor oxygenation.

Adenocarcinoma↗
PubMed1998

Bioavailability of soilborne lead in adults, by stable isotope dilution.

Using stable isotope dilution, we determined the bioavailability of soilborne lead (Pb) in human adult volunteers. Soil from a residential yard at a mining-impacted federal Superfund site that had negligible amounts of other priority pollutants was dried and screened through a 25-micron mesh sieve. The < 250-micron fraction, which likely represents that ingested via hand-to-mouth activity, was then sterilized by exposure to radiation. Ten replicate samples yielded a mean (SD) soil Pb concentration of 2924 +/- 36 ppm, and a mean 206Pb/207Pb ratio of 1.1083 +/- 0.0002, indicating remarkable soil homogeneity. Six adults with 206Pb/207Pb ratios of > 1.190 were admitted to the clinical research center and fasted overnight prior to dosing with 250 micrograms Pb/70 kg bw (i.e., 85.5 mg soil/70 kg) in a gelatin capsule. Blood for Pb and 206Pb/207Pb ratios was obtained at 14 time points through 30 hr. Results of the isotopic analyses from these subjects indicate that on average 26.2% +/- 8.1 of the administered dose was absorbed. Six additional subjects were subsequently studied but ingested soil immediately after a standardized breakfast. Bioavailability in this group was only 2.52% +/- 1.7. Collectively, this study provides the first experimental estimates of soil Pb absorption in humans, and should allow for more precise estimates of health risks due to Pb-contaminated soil.

Adult↗
PubMed1997

Lethal tuberculosis in interleukin-6-deficient mutant mice.

Tuberculosis is a chronic infectious disease which causes major health problems globally. Acquired resistance is mediated by T lymphocytes and executed by activated macrophages. In vitro studies have emphasized the importance of macrophage activation for mycobacterial growth inhibition. In vivo, the protective host response is focused on granulomatous lesions in which Mycobacterium tuberculosis is contained. A cellular immune response of the T helper 1 (Th1) type is considered central for control of tuberculosis. Using interleukin-6 (IL-6)-deficient mice, we here demonstrate a crucial role of this pluripotent cytokine in protection against M. tuberculosis but not against Mycobacterium bovis BCG. Infection with M. tuberculosis was lethal for the IL-6-deficient mice at inocula that were still controlled by IL-6-competent mice. Spleen cells from M. tuberculosis-infected IL-6-/- mouse mutants produced elevated levels of IL-4 and reduced levels of gamma interferon compared to the control levels. Cytofluorometric analyses of spleen cells from M. tuberculosis-infected mice revealed more-profound alterations in T-cell ratios in IL-6-/- mice than in control mice. We assume that IL-6 contributes to host resistance by its proinflammatory activity and by its influence on cytokine secretion.

Animals↗
PubMed1996

IL-4 neutralization or TNF-alpha treatment ameliorate disease by an intracellular pathogen in IFN-gamma receptor-deficient mice.

Successful control of infectious disease depends on aquisition of an appropriate protective immune response. IFN-gamma, first produced by NK cells and then by Th1 cells, is central to acquired resistance against intracellular bacteria, including Listeria monocytogenes. In contrast, IL-4 is not generated to a measurable degree. Here we show that IL-4 is produced during listeriosis by IFN-gamma receptor gene disruption (IFN-gammaR(-/-)) mutant mice. Production of TNF was diminished, whereas IL-12 production was virtually unchanged in these mutants. Neutralization of IL-4 with anti-IL-4 mAb, as well as TNF-alpha reconstitution with rTNF-alpha, ameliorated listeriosis. These findings demonstrate the detrimental effects of IL-4 in listeriosis independent of IFN-gamma down-regulation and document the far-reaching consequences of a single cytokine deficiency on other cytokines. In cases where the primary gene defect cannot be restored, precise identification of secondary effects will promote rational immunotherapy based on neutralization or reconstitution of secondary immune deviations.

Animals↗
PubMed1996

Control of natural killer cell-mediated innate resistance against the intracellular pathogen Listeria monocytogenes by gamma/delta T lymphocytes.

Listeria monocytogenes is an intracellular bacterium which causes an acute infectious disease in mice. Initial host resistance depends on innate immunity mediated primarily by natural killer (NK) cells followed by specific alpha/beta T cells, which are central to acquired specific immunity. Gamma/delta T lymphocytes seem to provide a link between the innate and the specific immune response. All these lymphocyte populations produce gamma interferon (IFN-gamma), which, because of its macrophage-activating potential, is central to antibacterial protection. IFN-gamma from NK cells not only contributes to early host resistance but also promotes development of protective T-cell responses of helper T type 1 (Th1) type. Here, we show that innate resistance and early IFN-gamma production in listeriosis are markedly impaired in T-cell receptor (TCR)-delta-/- but not TCR-beta-/- gene disruption mutant mice. By two-color cytofluorimetry, we demonstrate that NK cells rather than gamma/delta T lymphocytes are the major cellular source of IFN-gamma in immunocompetent mice and that IFN-gamma production by NK cells is impaired in the TCR-delta-/- mutants. Probably, reduced tumor necrosis factor production in listeria-infected TCR-delta-/- mutants contributed to impaired NK cell activation. Our data reveal a novel function of gamma/delta T cells as regulators of innate resistance against sublethal infection with an intracellular pathogen.

Animals↗
PubMed1995

Control of thymus-independent intestinal intraepithelial lymphocytes by beta 2-microglobulin.

Murine intestinal intraepithelial lymphocytes (i-IEL) comprise thymus-dependent cells such as T cell receptor (TcR) alpha/beta CD8 alpha/beta+ i-IEL, as well as thymus-independent ones such as TcR alpha/beta CD8 alpha/alpha+ and TcR gamma/delta CD8 alpha/alpha+ i-IEL. Whilst the development of the CD8 alpha/beta expressing i-IEL is strictly contingent on major histocompatibility complex (MHC) class I surface expression, that of CD8 alpha/alpha i-IEL appears largely MHC class I independent. We have used beta 2-microglobulin (beta 2m)-/- mutant mice lacking surface-expressed MHC class I and TcR alpha/beta CD8 alpha/beta+ i-IEL to analyze the potential impact of MHC class I on regional activation of thymus-independent i-IEL. To analyze the role of TcR gamma/delta i-IEL in regional cell interactions, these mice were treated with the anti-TcR gamma/delta mAb, GL3. Whilst numbers of TcR alpha/beta CD8 alpha/alpha i-IEL were markedly reduced in beta 2m-/- mice, those of TcR gamma/delta i-IEL were elevated. Administration of GL3 in vivo caused TcR down-modulation and functional inactivation of TcR gamma/delta i-IEL in beta 2m+/- mice. In contrast, TcR expression and functional activities of TcR gamma/delta i-IEL from beta 2m-/- mice were not impaired by GL3 treatment. The TcR alpha/beta CD8 beta- i-IEL from beta 2m-/- mice were expanded and functionally activated as a consequence of TcR gamma/delta engagement. The TcR gamma/delta i-IEL and TcR alpha/beta CD8 alpha/alpha+ i-IEL from athymic nu/nu mice which express MHC class I, but lack TcR alpha/beta CD8 alpha/beta+ i-IEL, responded to TcR gamma/delta engagement as those from the beta 2m+/- controls. In addition, the TcR gamma/delta i-IEL from TcR beta-/- and TCR beta+/- mutants were equally affected by GL3. We conclude that the absence of beta 2m renders TcR gamma/delta i-IEL resistant to TcR-mediated inactivation and promotes activation of TcR alpha/beta CD8 beta- i-IEL. The activation of TcR gamma/delta i-IEL seems to be directly controlled by beta 2m/MHC class I expression and independent from TcR alpha/beta CD8 beta+ i-IEL. Regulation of self-reactive thymus-independent i-IEL through beta 2m/ MHC class I may contribute to control of autoreactive immune responses in the intestine.

Animals↗
PubMed1995

Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis.

Tuberculosis is a chronic infectious disease which causes major health problems globally. Although acquired resistance crucially depends on alpha/beta lymphocytes, circumstantial evidence suggests that, in addition, gamma/delta T lymphocytes contribute to protection against tuberculosis. We have studied Mycobacterium tuberculosis infection in TcR-delta-/- or TcR-beta-/- gene deletion mutants which completely lack gamma/delta T cells or alpha/beta T cells, respectively. Low inocula of M. tuberculosis led to death of TcR-beta-/- mice and transient disease exacerbation in TcR-delta-/- mutants. Infection with higher inocula caused rapid death of TcR-delta-/- mice. The development of and bacterial containment in granulomatous lesions was markedly impaired in TcR-beta-/-, and less severely affected in TcR-delta-/- mutants. Mycobacteria-induced IFN-gamma production by spleen cells in vitro was almost abolished in TcR-beta-/- and virtually unaffected in TcR-delta-/- mice. Our data confirm the crucial role of alpha/beta T cells in protection against established tuberculosis and formally prove a protective role of gamma/delta T cells in early tuberculosis.

Animals↗
PubMed1994

The role of caregiver social networks in Alzheimer's disease.

Although the theoretical importance of social networks in alleviating caregivers' mental distress when a family member has Alzheimer's disease is well-established, empirical support has been less definitive. For 58 patient-spouse caregiver dyads, we used an array of network variables within a causal model of stress. We found that: caregiver networks are associated with severity of illness but not duration; increased illness severity was associated with network members assuming new roles; social networks had indirect effects but no direct or buffering effects on caregiver psychological distress; religious attendance had direct and indirect effects on caregiver psychological distress. These findings point to the important, but complex, role that social networks play in affecting caregivers. However, because of its cross-sectional nature and the relatively small sample size, this study will require replication on larger samples using longitudinal analyses.

Adaptation, Psychological↗
PubMed1994

Baseline silent cerebral infarction in the Asymptomatic Carotid Atherosclerosis Study.

BACKGROUND AND PURPOSE: In a group of patients with high-grade asymptomatic carotid artery stenosis, we prospectively determined the prevalence and radiological characteristics of clinically asymptomatic brain infarction evident on computed tomography. Risk factors and extent of carotid disease were also determined. METHODS: Patients randomized into the Asymptomatic Carotid Atherosclerosis Study (ACAS) underwent a neurological history, a detailed stroke/transient ischemic attack questionnaire, and a detailed neurological examination. Computed tomography scans were examined by standardized criteria developed as part of a quality-control program supervised by a neuroradiologist. The presence, location, and size of all cerebral infarctions evident by computed tomography were determined. RESULTS: Among 1132 patients, 848 had no history of stroke or transient ischemic attack. One hundred twenty-six patients (15%) had a silent infarct; 95 (11%) had one, 24 (3%) had two, and 7 (1%) had three or more infarcts. The infarct size was small and deep for 117 patients (72%), less than one-half lobe for 45 (28%), and one-half to less than one lobe for 1 (0.5%). The silent infarcts were evenly distributed ipsilaterally and contralaterally to the study artery but were significantly more frequent in the right hemisphere (P < .05). Factors associated with silent infarction were abnormal gait (P < .001), abnormal deep tendon reflexes or plantar responses (P = .038), but not degree of carotid stenosis. Silent infarction was less frequent among this totally asymptomatic cohort (15%) compared with those with transient ischemic attacks (34/139, 25%; P < .001). CONCLUSIONS: Silent infarction in the setting of asymptomatic carotid stenosis is not uncommon, but silent infarctions are rarely sizable. The clinical significance of silent cerebral infarction in patients with asymptomatic carotid artery stenosis has yet to be established.

Adult↗