Biomedical subjects
Publications and source records attributed to S Martin.
Blood flow via an aberrant internal carotid artery within the tympanic cavity is a rare pathogenic embryonic variation causing pulsatile tintinus and a vascularized tympanum. CT-scan provides the diagnosis. MRI and 3D time-of-flight MRA appear ideal for exploring aberrant flow both for diagnostic purposes and to establish the vascular morphology.
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During the last years the intensified insulin therapy has proven to be more successful than standard insulin treatment in patients with type I diabetes mellitus. For this kind of insulin therapy, intermediate and short acting insulin is injected in an independent manner. The basic need for insulin of the organism is covered with the intermediate insulin while application of the short acting insulin depends on carbohydrate intake and blood glucose levels. The patients are learning the intensified insulin therapy by structured guidance that they are able to modify the insulin dosage by themselves. The patients have to take several parameters into account to calculate the actual insulin need such as physical activity, interval between meal and injection, infectious diseases, or the circadian rhythm. An intensified insulin therapy involves a great deal of time for the patient since he has to perform insulin injections and measurements of blood glucose levels up to four times a day. However, this kind of treatment increases the flexibility of the patient's food intake and metabolic control which reduces the onset of diabetic side effects.
Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder, predisposing to the development of various tumors (central nervous system and retinal hemangioblastomas, endolymphatic sac tumors, renal cell carcinoma and/or renal cysts, pheochromocytomas, pancreatic cysts and/or tumors). Incidence of the disease is 1/36,000. Central nervous system hemangioblastomas and renal cell carcinoma are the main causes of death. The VHL gene, located on chromosome 3p25-26, is a tumor-suppressor gene encoding for a 213 amino acid protein which plays a major role in regulation of VEGF expression. Germline mutations of the VHL gene are identified in about 75-80% of the patients. Somatic mutations of the VHL gene are found in both sporadic central nervous system hemangioblastomas and sporadic "clear" renal cell carcinomas. For neurosurgeons search for VHL disease should be imperative in presence of a patient with apparently "sporadic" central nervous system or endolymphatic sac tumor.
Leishmaniasis is a recurrent health problem for the U.S. and other militaries. Health care workers may be unfamiliar with the risk factors, transmission, clinical features, diagnosis, and treatment of this disease. A team of highly trained specialists is required to properly manage service members with leishmaniasis. Such care is available only in a few medical centers. Although there are no prophylactic drugs to prevent this disease, control of insect populations and use of personal protection measures can minimize arthropod-related casualties. The impact of leishmaniasis on military operations and research initiatives to better prevent, diagnose, and treat infection are discussed.
The dose-response relationship and time course of effect on motor activity after a single dose of methylphenidate given at different times of the light/dark cycle was investigated using a computerized infrared activity analysis system. After 5 to 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate at 08:00, 14:00, 20:00, or 02:00. Recording was then resumed for an additional 36 to 48 hours. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements. Saline and 0.6 mg/kg did not alter motor activity, but 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) motor activity. The time to the maximum effect and the duration of effect increased with dose. Ten mg/kg had the most robust effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. A single injection of methylphenidate had only transient effects. The locomotor stimulating effects of the lower doses were similar whether given during the light or dark phase, despite the large diurnal variations in baseline activity between the activity phases. The stereotypic effects of the highest dose of methylphenidate, however, varied between the light and dark phase, with a smaller stereotypic effect during the dark phase when compared to administration during the light phase.
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The local expression of CD44 splice variants in human breast cancer tissue has been previously shown to be associated with metastasis. We show here that elevated systemic serum levels of CD44 splice variants occur in breast cancer and may represent a new tool for staging and differential diagnosis. Sera of node-negative and node-positive breast cancer patients in comparison with healthy control subjects were analyzed for serum CD44 (sCD44) and 2 different splice variants (v5 and v6). Node-positive breast cancer patients showed significantly (p < 0.01) elevated levels of sCD44-v5 and -v6 splice variants in comparison to node-negative patients and healthy controls. None of the node-negative breast cancer patients or healthy controls showed elevated levels of both sCD44-v5 and -v6. Interestingly, no differences were seen for serum levels of non-spliced sCD44-standard between the 3 groups. Soluble forms of CD44 variants may promote migration of tumor cells. This may occur through interference with tumor cell adhesion or by modulation of immune defense mechanisms.
The insulin-responsive glucose transporter GLUT-4 is found in muscle and fat cells in the trans-Golgi reticulum (TGR) and in an intracellular tubulovesicular compartment, from where it undergoes insulin-dependent movement to the cell surface. To examine the relationship between these GLUT-4-containing compartments and the regulated secretory pathway we have localized GLUT-4 in atrial cardiomyocytes. This cell type secretes an antihypertensive hormone, referred to as the atrial natriuretic factor (ANF), in response to elevated blood pressure. We show that GLUT-4 is targeted in the atrial cell to the TGR and a tubulo-vesicular compartment, which is morphologically and functionally indistinguishable from the intracellular GLUT-4 compartment found in other types of myocytes and in fat cells, and in addition to the ANF secretory granules. Forming ANF granules are present throughout all Golgi cisternae but only become GLUT4 positive in the TGR. The inability of cyclohexamide treatment to effect the TGR localization of GLUT-4 indicates that GLUT-4 enters the ANF secretory granules at the TGR via the recycling pathway and not via the biosynthetic pathway. These data suggest that a large proportion of GLUT-4 must recycle via the TGR in insulin-sensitive cells. It will be important to determine if this is the pathway by which the insulin-regulatable tubulo-vesicular compartment is formed.
Low molecular chemicals (haptens) frequently cause T cell-mediated adverse immune reactions. Our previous work provided evidence that hapten-specific T cells, in analogy to those specific for nominal peptide antigens, direct their TCR towards hapten-modified, MHC-associated peptides. We now demonstrate that trinitrophenyl (TNP)-specific, class I MHC-restricted CTL from mice may exhibit exquisite specificity for subtle structural details of these hapten determinants, surpassing even the specificity of immunoglobulins. More importantly, these CTL could be antagonized by ligands altered either in their peptide sequence or in their hapten structure. The system was employed to examine the molecular basis of T cell antagonism. Whereas agonists resulted in a dose-dependent downregulation of TCR in different mouse T cell clones, antagonistic peptides totally failed to do so despite engaging the specific TCR. Moreover, simultaneous presentation of antagonist and agonist on the same antigen presenting cell prevented TCR internalization. No signs of anergy or functional receptor inactivation were observed in CTL treated with antagonist-loaded target cells. Based on a serial triggering model of T cell activation, our data favor a model in which antagonists block T cell functions by competitively engaging the specific TCR in unproductive interactions.
Dendritic cells (DC) are potent inducers of CD8+ T cells and can stimulate protective antitumor immunity when pulsed with an antigenic peptide or protein. We used a replication-deficient adenovirus containing a Kb-restricted antigenic peptide of chicken OVA to study CTL induction in vitro and in vivo after adenovirus-mediated gene transfer into DC. The efficiency of adenovirus-infected DC in eliciting a specific CTL response was compared with immunizations with a recombinant vaccinia virus and DC pulsed with peptide or protein. An immortalized DC line derived from a C57BL/6 mouse and freshly isolated splenic DC from C57BL/6 mice were used in CTL induction. Virus-infected DC elicited the strongest Ag-specific CTL response in vitro and in vivo and induced protective antitumor immunity to a challenge with EG.7 tumors (EL-4 cell line expressing OVA). Direct immunization of mice with recombinant adenovirus resulted in the induction of high titers of neutralizing Abs, which precluded a boost of a CTL response after repeated inoculations. However, repeated injections of virus-infected DC induced only low titers of neutralizing Abs. Furthermore, the presence of neutralizing Abs specific for the virus did not affect the usefulness of infected DC as repeated applications of virus-infected DC boosted the CTL response even in mice previously infected with the recombinant vector. The use of DC infected with a recombinant virus has advantages over other forms of immunization and could provide an alternative approach for designing vaccination therapies.
1. Serosally added synthetic endothelin-1 (ET-1) increased short-circuit current (Isc) across isolated muscle-stripped human colonic mucosa in vitro. Bumetanide inhibited Isc responses, indicating that ET-1 stimulates electrogenic Cl- secretion. 2. In isolated human jejunal mucosa, ET-1 exhibited a concentration-dependent dual action. At low concentrations it induced rapid increases in Isc and these were inhibited by bumetanide. At a higher concentration (0.1 microM), ET-1 provoked a drastic and progressive decrease in Isc below the baseline value. 3. Pretreatment with phlorizin or omission of glucose from the Krebs-Ringer solution at the apical (luminal) side of the jejunal mucosa prevented the decreases in Isc evoked by ET-1, suggesting that the peptide inhibits the glucose-coupled electrogenic Na+ absorption. Indeed, flux experiments with D-[14C]glucose demonstrated that ET-1 decreases jejunal glucose absorption by approximately 80% within 30 min. 4. Electron microprobe analyses of cryosections of human jejunum showed that ET-1 (0.1 microM) evokes a significant decrease in intracellular Na+ concentrations of villus (not crypt) epithelial cells, suggesting that the peptide attenuates apical Na(+)-glucose entry by reducing the activity of the Na(+)-glucose cotransporter, SGLT1. 5. In the presence of tetrodotoxin (TTX), ET-1-induced Cl- secretion was significantly reduced, in both human jejunal and colonic mucosa. However, the inhibitory effect on jejunal Na(+)-glucose absorption was not affected by TTX. 6. ET-1 increases electrogenic Cl- secretion across human intestinal mucosa in vitro. This effect is mediated in part via the activation of enteric nerves. Responses of the human jejunal mucosa to high ET-1 concentrations exhibit a second component, namely the rapid inhibition of electrogenic Na(+)-glucose absorption, which might be mediated by an inhibition of the transport activity of SGLT1. This effect is independent from neuronal mediators. Our results suggest different cellular action sites for ET-1 in human small and large intestine.
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Analysis of antigen-induced negative selection of thymocytes in T cell receptor (TCR)-transgenic mice is complicated by the presence of an antigen-responsive peripheral T cell compartment. Our experiments address the question of whether and how peripheral T cell activation can affect immature thymocytes. Following three daily injections of peptide antigen into mice expressing a peptide-specific transgenic TCR and deficient for TAP1, we and others have found profound deletion of the CD4+CD8+ (DP) thymocyte subset. However, our work shows that even though mature CD8+ T cells are inefficiently selected in TAP1-deficient mice, there was a striking degree of peripheral expansion and activation of CD8+ peripheral T cells. Furthermore, when cells from TCR-transgenic mice were adoptively transferred, we found that deletion of nontransgenic DP thymocytes occurred in Thy-1-congenic and even more efficiently in TAP1-deficient recipients after repeated peptide injection resulting in peripheral T cell activation. In the adoptive transfer experiments the degree of deletion of immature bystander thymocytes was decreased upon blocking of TNF. These data show that deletion of DP thymocytes can result from excessive peripheral T cell activation and identify TNF as an important effector molecule for this process. When steps are taken to avoid peripheral T cell activation, peptide antigen can induce TCR-mediated thymocyte deletion, presumably in the thymus cortex, since injection of TAP1-deficient TCR-transgenic mice resulted in deletion of immature DP thymocytes prior to detectable peripheral T cell expansion and activation. This effect was not blocked by inhibiting tumor necrosis factor activity. In addition, DP depletion was seen in the absence of peripheral T cell activation when antibody-mediated depletion of CD8+ T cells was performed. Our work clearly shows that two mechanisms for deletion of DP thymocytes exist: deletion induced by antigen presentation in the thymus and deletion as a consequence of repeated stimulation of mature peripheral T cells.
We report that the onset of Th1 insulitis is preceded by a rise of interferon-gamma inducing factor (IGIF) mRNA expression in the spleen. This systemic shift towards Th1 reactivities was underlined by a close correlation of IGIF and IL-12p40 mRNA levels in the spleen, as determined by semi-quantitative RT-PCR. Cyclophosphamide-induced IGIF expression was also observed in MHC congenic NOR mice, but not in MHC class II-incompatible NON mice. The systemic rise of IGIF was followed by the development of destructive Th1-associated intra-insulitis. Interestingly, immunohistochemistry showed IL-4-positive cells evenly dispersed throughout the infiltrate, while IFN-gamma-positive cells were restricted to the vicinity of beta-cells. We conclude that cyclophosphamide induces a systemic shift in antigen presenting cells towards favouring Th1 responses, in an MHC dependent manner. Despite this general bias in immune reactivity, activation of Th1 cells in insulitis occurs only close to beta-cells, indicating a crucial role of antigen presentation by beta-cells or in their immediate vicinity.
In order to study cytokine production profile (IFN-gamma, IL-4 and TNF-alpha) and TCRBV-gene usage of peripheral autoreactive T cells from IDDM patients, we have generated antigen-specific T cell lines with either tetanus toxoid, insulinoma membranes or a single beta-cell protein, recombinant ICA69, which has been shown to be a target of both autoantibodies and T cells in IDDM. By semi-quantitative polymerase chain reaction (PCR) analysis, we have determined the composition of the T cell receptor repertoire of these T cell lines and compared this with the general peripheral repertoire. T cell responses against beta-cell antigens and tetanus toxoid (TT) were shown to be associated with IFN-gamma and TNF-alpha production, suggestive of a Th1-like phenotype of the T-cell lines. The production of IFN-gamma was significantly higher in T-cell lines generated with ISG compared to those generated with TT. The cytokine production profiles of the T-cell lines generated with ICA69 did not provide an obvious explanation for the inverse relation between cellular and humoral responses to this protein observed earlier. Upon stimulation with beta-cell antigens, outgrowth of T cells using a restricted set of TCRBV elements was observed in newly diagnosed IDDM patients. However, this skewing in TCRBV-gene expression was patient-specific rather than antigen-associated, since the T-cell repertoire that is used for the recognition of these antigens was, overall, heterogeneous.
The macrophage product interleukin (IL)-12 is known to drive Th1 reactions in physiological and pathological immune responses. Here we report that treatment with the homodimeric IL-12p40 subunit, an antagonist of the bioactive IL-12p35/p40 heterodimer, suppresses diabetes development in cyclophosphamide-injected NOD mice. Female mice of 70 days old received cyclophosphamide (250 mg/kg) to accelerate and synchronize diabetes development, and daily injections of 1 microgram IL-12(p40)2. While there was no delay of the first diabetes cases, the incidence of overt diabetes was significantly decreased in treated mice (46 vs 23%, p < 0.05). Analysis of mRNA expression in the pancreas showed that administration of the IL-12 antagonist had dampened interferon-gamma gene expression, decreased the ratio of interferon-gamma/IL-10 mRNA levels and in parallel suppressed the expression of the inducible nitric oxide synthase. At the same time intra-islet infiltration was significantly decreased (p < 0.001). Interestingly, the administration of IL-12(p40)2 also affected IL-12 gene expression, by downregulation of p35 mRNA. We conclude that IL-12 p40 homodimer suppresses diabetes development in the NOD mouse by dampening islet inflammation via selective down-regulation of Th1 type responses. The naturally occurring IL-12 antagonist IL-12(p40)2 represents a new and specific Th1 directed approach to prevent autoimmune diabetes.
Investment in dietetics research has the potential to improve general health; increase work performance and learning capacity; extend disease-free life; reduce birth defects, infections, and chronic diseases; and decrease health care costs. Opportunities exist for research in the areas of solid waste management, global environment, health care reform, and foodservice systems management. Research efforts can focus on cost-effectiveness and medical efficacy of dietary services to improve third-party reimbursement. Educators have a stake in creating the future by conducting research, teaching research to dietetic students, and investigating the effectiveness of education.