Biomedical subjects

L Granger

Publications and source records attributed to L Granger.

At least 19 recordsLinked to original sources

PubMed2001

The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation.

The expression of DCC (deleted in colorectal cancer) is often markedly reduced in colorectal and other cancers. However, the rarity of point mutations identified in DCC coding sequences and the lack of a tumor predisposition phenotype in DCC hemizygous mice have raised questions about its role as a tumor suppressor. DCC also mediates axon guidance and functions as a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. We now show that DCC drives cell death independently of both the mitochondria-dependent pathway and the death receptor/caspase-8 pathway. Moreover, we demonstrate that DCC interacts with both caspase-3 and caspase-9 and drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c or Apaf-1. Hence, DCC defines an additional pathway for the apoptosome-independent caspase activation.

Apoptosis↗

PubMed2000

The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.

The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro-apoptotic effect of RET is inhibited in the presence of its ligand glial cell line-derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro-apoptotic domain of RET. In addition, we report that Hirschsprung-associated RET mutations impair GDNF control of RET pro-apoptotic activity. These results indicate that HSCR may result from apoptosis of RET-expressing enteric neuroblasts.

Apoptosis↗

PubMed2000

Programming for cytotoxic effector function occurs concomitantly with CD4 extinction during CD8(+) T cell differentiation in the thymus.

CD4(+) T cells are generally specialized to function as helper cells and CD8(+) T cells are generally specialized to function as cytotoxic effector cells. To explain how such concordance is achieved between co-receptor expression and immune function, we considered two possibilities. In one case, immature CD4(+)CD8(+) thymocyte precursors might first down-regulate expression of one co-receptor molecule, with the remaining co-receptor molecule subsequently activating the appropriate helper or cytotoxic functional program. Alternatively, we considered that the same intrathymic signals that selectively extinguished expression of one or the other co-receptor molecule might simultaneously initiate the appropriate helper or cytotoxic functional program. In the present study, we attempted to distinguish between these alternatives by examining thymocyte precursors of CD8(+) T cells for expression of Cathepsin C and Cathepsin W, molecules important for cytotoxic effector function. We report in developing thymocytes that Cathepsin C and Cathepsin W are expressed coordinately with extinction of CD4 co-receptor expression. We conclude that CD4 extinction and initiation of the cytotoxic functional program occurs simultaneously during differentiation of CD8(+) T cells in the thymus.

Animals↗

PubMed1999

Positive selection as a developmental progression initiated by alpha beta TCR signals that fix TCR specificity prior to lineage commitment.

During positive selection, immature thymocytes commit to either the CD4+ or CD8+ T cell lineage ("commitment") and convert from short-lived thymocytes into long-lived T cells ("rescue"). By formal precursor-progeny analysis, we now identify what is likely to be the initial positive selection step signaled by alpha beta TCR, which we have termed "induction". During induction, RAG mRNA expression is downregulated, but lineage commitment does not occur. Rather, lineage commitment (which depends upon the MHC class specificity of the alpha beta TCR) only occurs after downregulation of RAG expression and the consequent fixation of alpha beta TCR specificity. We propose that positive selection can be viewed as a sequence of increasingly selective developmental steps (induction-->commitment-->rescue) that are signaled by alpha beta TCR engagements of intrathymic ligands.

Animals↗

PubMed1999

Small stress protein Hsp27 accumulation during dopamine-mediated differentiation of rat olfactory neurons counteracts apoptosis.

The small stress protein Hsp27 is expressed during mammalian neural development. We have analyzed the role of this protein in immortalized rat olfactory neuroblasts. In the presence of dopamine a fraction of these cells differentiate into neurons while the remaining cells undergo apoptosis. We report here that the dopamine induced differentiation and apoptosis are associated with a transient and specific accumulation of Hsp27. Moreover, transfection experiments have shown that Hsp27 overexpression drastically decreases the fraction of cells undergoing apoptosis. In contrast, reduction of the endogenous level of Hsp27 led to abortion of differentiation and, therefore, drastically increased the number of apoptotic cells. Furthermore, in the normal cell population we show that Hsp27 accumulation takes place only in differentiating cells that were not undergoing apoptosis. We therefore conclude that Hsp27 may represent a key protein that controls the decision of olfactory precursor cells to undergo either differentiation or cell death.

Animals↗

PubMed1997

Telomere lengthening and telomerase activation during human B cell differentiation.

The function of the immune system is highly dependent on cellular differentiation and clonal expansion of antigen-specific lymphocytes. However, little is known about mechanisms that may have evolved to protect replicative potential in actively dividing lymphocytes during immune differentiation and response. Here we report an analysis of telomere length and telomerase expression, factors implicated in the regulation of cellular replicative lifespan, in human B cell subsets. In contrast to previous observations, in which telomere shortening and concomitant loss of replicative potential occur in the process of somatic cell differentiation and cell division, it was found that germinal center (GC) B cells, a compartment characterized by extensive clonal expansion and selection, had significantly longer telomeric restriction fragments than those of precursor naive B cells. Furthermore, it was found that telomerase, a telomere-synthesizing enzyme, is expressed at high levels in GC B cells (at least 128-fold higher than those of naive and memory B cells), correlating with the long telomeres in this subset of B cells. Finally, both naive and memory B cells were capable of up-regulating telomerase activity in vitro in response to activation signals through the B cell antigen receptor in the presence of CD40 engagement and/or interleukin 4. These observations suggest that a novel process of telomere lengthening, possibly mediated by telomerase, functions in actively dividing GC B lymphocytes and may play a critical role in humoral immune response by maintaining the replicative potential of GC and descendant memory B cells.

B-Lymphocyte Subsets↗

PubMed1997

Developmentally regulated expression of peanut agglutinin (PNA)-specific glycans on murine thymocytes.

Intrathymic maturation of T lymphocytes is characterized by variable expression of O-linked Gal beta 1,3GalNAc glycans reactive with peanut agglutinin (PNA) lectin. Recent studies on human thymocytes show that conversion from PNA+ to PNA- phenotype is correlated with increased expression of alpha 2,3 O-linked sialyltransferase (ST), which sialylates Gal beta 1,3GalNAc glycans, masking their binding sites for PNA. Interestingly, alpha 2,3 O-linked ST expression is highest within the regions of the thymus containing the most immature and most mature thymocyte subsets, suggesting that PNA-specific glycans are intermittently masked by sialylation during thymic selection processes. Here, we studied expression of PNA receptors on developing thymocytes in the murine system using thymocytes from both normal mice and transgenic mice that are genetically arrested at the early phases of T cell development. Our results confirm and extend recent findings in the human system by showing that murine T cells sequentially progress from PNAlo-->PNAhi-->PNAlo stages during their differentiation within the thymus. In addition, our data demonstrate that a similar set of polypeptides is variably masked by sialylation throughout T cell development.

Animals↗

PubMed1994

[Evaluation of long-term effectiveness of a social reintegration program].

This study evaluates the impact of a rehabilitation program developed by a specific unit (304) of Louis H. Lafontaine Hospital to prepare severely disabled long-term psychiatric inpatients for discharge. Patients who participated in the program were evaluated three years after their discharge and compared to control patients paired to them by age, sex and years of hospitalization and discharged from other units of the hospital. The results suggest that the rehabilitation program, if coupled with an adequately staffed residential environment giving patients continuous care, offers a better outcome, at least in the case of the severely disabled long-term psychiatric inpatients.

Adult↗

PubMed1994

Dysfunctional uterine bleeding in adolescents.

This retrospective, multicenter analysis was conducted on all adolescents admitted to three pediatric hospitals in Montreal, Quebec, Canada, over a 10-year period (1981-1991) with a primary diagnosis of dysfunctional uterine bleeding. The purpose was to assess the frequency of underlying medical disorders and their response to medical therapy. Sixty-one patient charts were identified. Newly diagnosed hematologic abnormalities were found in two patients (one with immune thrombocytopenic purpura and one with acute promyelocytic leukemia). Furthermore, all patients who were evaluated had normal factor VIII levels, partial thromboplastin times and prothrombin times. Twenty-nine percent of the patients had a past history of a significant medical problem. The mean age at presentation was 13.8 +/- 2.1 (SD) years. More than 50% of the patients had a history of irregular bleeding. Most patients (93.4%) responded to medical management. Only five (8.2%) required dilation and curettage. The history of irregular cycles, the early presentation after menarche, the infrequency of hematologic problems but high frequency of significant medical problems led us to conclude that the etiology of dysfunctional uterine bleeding in adolescence is often related to persistent immaturity of the hypothalamic-pituitary-ovarian axis. Medical therapy is highly effective in controlling such bleeding. Dilation and curettage is rarely required.

Administration, Oral↗

PubMed1994

[Update on menopause].

Explore the source record for details and available documents.

Estrogen Replacement Therapy↗

PubMed1993

T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny.

To study the source of regenerated T cells after bone marrow transplantation (BMT), lethally irradiated thymectomized and thymus-bearing C57BL/6 (Thy 1.2+) mice were injected with syngeneic T-cell depleted bone marrow (TCD BM) cells and graded numbers of congenic B6/Thy 1.1+ lymph node (LN) cells. LN cell expansion was the predominant source for T-cell regeneration in thymectomized hosts but was minimal in thymus-bearing hosts. Analysis of T-cell receptor (TCR) expression on LN progeny showed a diverse V beta repertoire. Therefore, peripheral T-cell progenitors exist within V beta families, but expansion of these progenitors after BMT is downregulated in the presence of a functional thymus. CD4+ cells derived from BM versus LN in thymus-bearing hosts displayed differential CD44 and CD45 isoform expression. BM-derived cells were primarily CD45RB+CD44lo and LN derived cells were nearly exclusively CD45RB- CD44hi. In thymectomized hosts, BM, host, and LN CD4+ progeny were CD45RB- CD44hi. We conclude that T-cell regeneration via peripheral T-cell progenitors predominates in hosts lacking thymic function and gives rise to T cells that display a "memory" phenotype. In contrast, the ability to generate sizable populations of "naive" type T cells after BMT appears limited to the prethymic progenitor pool and could serve as a marker for thymic regenerative capacity.

Animals↗

PubMed1993

T cell receptor V alpha-V beta combinatorial selection in the expressed T cell repertoire.

This study has evaluated whether preferential pairing occurs between TCR alpha- and beta-chains expressing specific V alpha and V beta gene products in the mature peripheral T cell population, as a result of either thymic selection or of structural constraints on chain pairing. The association of specific V alpha products with specific V beta products on individual T cells was found, in multiple instances, to be highly selective. Moreover, patterns of preferential V alpha-V beta association were highly strain-specific and were independently expressed in CD4+ and CD8+ T cell subsets. Although these findings do not exclude the possibility that structural constraints may limit V alpha-V beta pairing in other instances, they indicate that the observed instances of skewed expression are not caused by structural constraints in chain pairing. Rather, they suggest that strain-specific selective events alter the expressed V alpha V beta repertoire as a result of recognition of self or environmental Ag during T cell repertoire selection.

Animals↗

PubMed1993

Embryonic resistance to tumour necrosis factor-alpha mediated cytotoxicity: novel mechanism underlying maternal immunological tolerance to the fetal allograft.

The cytokine tumour necrosis factor-alpha (TNF alpha) has been postulated to play an essential role in the cytotoxic activity of cell-mediated immunity against allogenic or tumour cells invading the host. Several tumour cell lines, however, are resistant to TNF mediated cytotoxicity and respond paradoxically by cellular proliferation and by autocrine secretion of TNF alpha. In view of the metastatic character of the mammalian embryo, the aim of this study was to assess the potential of murine embryos to secrete TNF alpha in vitro, to express TNF receptors and to resist TNF alpha mediated cytotoxicity during their in-vitro development to the blastocyst stage. The potential of human embryos to secrete TNF alpha in vitro until the blastocyst stage was also investigated. From a total of 11 human embryos, which were allowed to proceed to blastocyst formation, seven secreted TNF alpha in the range of 2-117 pg/ml/24 h. A total of 123 C57BL/6J mouse embryos were studied of which 55% secreted TNF alpha in the range of 1.25-3.95 mg/ml/24 h. The presence of high levels of exogenous TNF alpha (10-300 IU) was not detrimental to the in-vitro development of murine embryos. Using immunohistochemical techniques, we were not able to detect the presence of type I or II TNF receptors on the surface of murine embryos. Our findings suggest that human and C57BL/6J murine embryos have the potential to secrete TNF alpha in vitro during the developmental stages leading to blastocyst formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Analysis of mRNA decay and rRNA processing in Escherichia coli multiple mutants carrying a deletion in RNase III.

RNase III is an endonuclease involved in processing both rRNA and certain mRNAs. To help determine whether RNase III (rnc) is required for general mRNA turnover in Escherichia coli, we have created a deletion-insertion mutation (delta rnc-38) in the structural gene. In addition, a series of multiple mutant strains containing deficiencies in RNase II (rnb-500), polynucleotide phosphorylase (pnp-7 or pnp-200), RNase E (rne-1 or rne-3071), and RNase III (delta rnc-38) were constructed. The delta rnc-38 single mutant was viable and led to the accumulation of 30S rRNA precursors, as has been previously observed with the rnc-105 allele (P. Gegenheimer, N. Watson, and D. Apirion, J. Biol. Chem. 252:3064-3073, 1977). In the multiple mutant strains, the presence of the delta rnc-38 allele resulted in the more rapid decay of pulse-labeled RNA but did not suppress conditional lethality, suggesting that the lethality associated with altered mRNA turnover may be due to the stabilization of specific mRNAs. In addition, these results indicate that RNase III is probably not required for general mRNA decay. Of particular interest was the observation that the delta rnc-38 rne-1 double mutant did not accumulate 30S rRNA precursors at 30 degrees C, while the delta rnc-38 rne-3071 double mutant did. Possible explanations of these results are discussed.

DNA Mutational Analysis↗

PubMed1992

Selenium toxicosis in feeder pigs.

Selenium toxicosis was diagnosed in feeder pigs on a central Michigan farm. Use of a commercial supplement, found to contain approximately 20 times the intended Se concentration, resulted in a Se concentration of 8.1 mg/kg of the complete feed. This was fed for 34 days during which daily feed consumption decreased approximately 35%, several pigs developed weakness and forelimb paresis, and 1 pig died. The highest serum Se concentration measured was 1,550 ng/ml (normal range, 140 to 190 ng/ml). Normal feed consumption returned when an alternative feed was provided. Mean serum Se concentrations of representative pigs, monitored over the subsequent 26 days, decreased from 905 to 258 ng/ml. Histologic examination of a recovering pig revealed skeletal and cardiac myopathy and bilaterally symmetric malacia of the gray matter of the ventral horns of the spinal cord. During the developing toxicosis, the pigs consumed an estimated 11.4 mg of Se/pig/d.

Animal Feed↗

PubMed1992

Human embryos produce transforming growth factors alpha activity and insulin-like growth factors II.

OBJECTIVE: To assess whether growth factors are produced by early human embryos in culture. DESIGN: We studied various growth factors in the culture media of human embryos (n = 6) cultured from days 3 to 8 after fertilization. MAIN OUTCOME MEASURES: Four growth factors were measured: Insulin growth factors I and II (IGF-I and IGF-II), epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) activity. RESULTS: Nonconditioned INRA Menezo B2 (Biomerieux, S.A., Paris, France) culture medium contained significant levels of TGF alpha activity (5.2 ng/mL) and low levels of IGF-I (1.02 ng/mL) and IGF-II (2.8 ng/mL), whereas EGF was below detection of our assay. With human embryo, the culture media contained lower TGF alpha activity on days 3 and 4 after fertilization (2.5 ng/mL and 2.8 ng/mL, P less than 0.05). From days 5 to 8 after fertilization, a significant increase in TGF alpha activity and IGF-II was detected (TGF alpha activity: day 5: 3.7 ng/mL; day 6: 4.4 ng/mL; day 7: 6.4 ng/mL; day 8: 8.4 ng/mL) (IGF-II: day 5: 3.4 ng/mL; day 6: 3.1 ng/mL; day 7: 4.1 ng/mL; day 8: 4.2 ng/mL). Epidermal growth factor was undetectable, and IGF-I did not vary significantly. CONCLUSION: Transforming growth factor alpha activity and IGF-II are produced by human embryos in culture at a time when they could play a role in morula to blastocyst transformation.

Analysis of Variance↗

PubMed1988

Identification of sterol acceptors that stimulate cholesterol efflux from human spermatozoa during in vitro capacitation.

The nature of cholesterol-binding proteins acting upon human spermatozoa during in vitro capacitation was determined by measuring the efflux of [3H]cholesterol and of [3H]cholesteryl sulfate from labeled spermatozoa. Efflux of [3H]sterols was stimulated when the labeled gametes were incubated in Ham's F-10 medium supplemented with female serum or follicular fluid. Upon centrifugation of capacitated spermatozoa and application of the supernatant to density-gradient ultracentrifugation for lipoprotein analysis, both [3H]cholesterol and [3H]cholesteryl sulfate were found to be carried by very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), high-density lipoproteins (HDL), as well as the albumin fraction (d greater than 1.21) in serum. When the capacitation medium was supplemented with follicular fluid, the [3H]sterols were bound to HDL's and to the albumin fraction; when the latter fraction was analysed by molecular sieve chromatography, 60-70% of the radioactivity eluted in fractions with a mean molecular weight corresponding to that of human serum albumin. Sperm cholesterol efflux was also stimulated when serum or follicular fluid was added to a simplified medium (50 mM Tris-HCl, 0.56% NaCl, pH 7.8); efflux of [3H]cholesterol from labeled gametes progressed in a time-dependent manner, but was low in the absence of serum components. The [3H]cholesterol/cholesterol ratios were higher in the albumin and HDL fractions, indicating some degree of specificity of these sterol acceptors. It was observed that follicular fluid albumin has a [3H]sterol binding capacity that is 2-3-fold higher than that of serum albumin. Commercial human serum albumin also promoted sperm cholesterol efflux. These results provide new information concerning those components of follicular fluid which may play a role in human sperm capacitation and provide further support for the concept that loss of cholesterol from the sperm plasma membrane is an important component of the capacitation process.

Acrosome↗

PubMed1986

Jumping Frenchmen of Maine.

The "Jumping Frenchmen of Maine" were described by George Beard in 1878. They had an excessive startle response, sometimes with echolalia, echopraxia, or forced obedience. In 1885, Gilles de la Tourette concluded that "jumping" was similar to the syndrome that now bears his name. Direct observations of jumpers have been scarce. We studied eight jumpers from the Because region of Quebec. In our opinion, this phenomenon is not a neurologic disease, but can be explained in psychological terms as operant conditioned behavior. Our cases were related to specific conditions in lumber camps in the 19th and the beginning of the 20th century.

Culture↗