Search PubMed⌕ Search

Biomedical subjects

R E Hammer

Publications and source records attributed to R E Hammer.

At least 91 records · Page 5Linked to original sources
PubMed1995

Relationships among gender, cognitive style, academic major, and performance on the Piaget water-level task.

Many researchers have found that more college-age adults than would be expected fail Piaget's water-level task, with women failing more frequently than men. It has been hypothesized that differences in cognitive style may account for performance differences on the water-level task. In the present study, 27 male and 27 female architectural students and 27 male and 27 female liberal-arts students were assessed for their performance on both Piaget's Water-level Task and Witkin's Group Embedded Figures Test. No difference was found in performance of male and female architectural students on either task, but male liberal-arts students scored significantly higher than female liberal-arts students on both measures. A disembedding cognitive style predicted success on the water-level task for the architectural students but not for the liberal arts students.

Adolescent↗
PubMed1995

Characterization of psoriasiform and alopecic skin lesions in HLA-B27 transgenic rats.

We have previously reported a multisystem inflammatory disease in transgenic rat lines with high expression of HLA-B*2705 and human beta 2 microglobulin. Skin disease in these rats includes two predominant lesions: 1) marked psoriasiform dermatitis of the tail and digits; and 2) progressive alopecia of face, neck, trunk, and extremities. Here we present the results of a systematic survey of these lesions. Tail and digit skin showed psoriasiform hyperplasia of the epidermis associated with parakeratosis, with marked dermal and epidermal inflammation. The alopecic skin showed perifollicular and follicular mononuclear infiltration and increased numbers of atrophic follicles. Immunohistochemical analysis revealed that B27 expression was prominent on keratinocytes in hyperplastic epidermis where lymphocytic infiltrates were prominent, but was absent in the absence of inflammation. In alopecic lesions, B27 was strongly expressed on follicular epithelium and dermal hair papillae associated with mononuclear infiltrates. T cells, both CD8 and CD4, were most prominent in inflammatory lesions and rat MHC-II expression on keratinocytes, and follicular epithelium was dramatically increased. This study suggests that T cell-mediated immune mechanisms participate in development of cutaneous lesions in HLA-B27 transgenic rats.

Alopecia↗
PubMed1995

High prevalence of colorectal cancer in HLA-B27 transgenic F344 rats with chronic inflammatory bowel disease.

BACKGROUND/AIMS: Transgenic rats expressing the human major histocompatibility class I molecule HLA-B27 develop a spontaneous multisystem disease that includes a chronic colitis resembling ulcerative colitis. The availability of this phenotype in B27 transgenic rats of 2 different inbred strains provided the opportunity to inquire whether colorectal neoplasia, which occurs with increased frequency in humans with inflammatory bowel disease (IBD), would develop in either or both rat genetic backgrounds. METHODS: Clinical and histologic evaluation of B27 transgenic rats with chronic inflammatory bowel disease (IBD) on the F344 and LEW inbred backgrounds. RESULTS: In B27 transgenic rats on an inbred F344 background, hyperplastic lesions evolved in the setting of chronic colitis, with a high frequency of colorectal polyp formation and frequent histologic progression from adenoma to adenocarcinoma. In contrast, no neoplasia occurred in B27 transgenic rats on an inbred LEW background, despite similar colitis. CONCLUSION: A high incidence of spontaneous colorectal neoplasia occurs in a line of B27 F344 rats that shares some features of both sporadic and inflammatory bowel disease-associated human colorectal cancer. This represents a novel example of spontaneous colorectal neoplasia in rodents that is not based on germline modification of one or more already-identified cancer-related genes.

Animals↗
PubMed1995

Kainic acid-induced neuronal death is associated with DNA damage and a unique immediate-early gene response in c-fos-lacZ transgenic rats.

Previously, we established that persistent upregulation of c-fos expression preceded kainic acid (KA)-induced neuronal death in mice. To discriminate between events that are products of the seizures elicited by KA and those that are specifically associated with its neurotoxic actions, we have examined the expression of cellular immediate-early genes (cIEGs) following KA or pentylenetetrazol (PTZ) treatment in c-fos-lacZ transgenic rats. While both chemoconvulsants elicit seizures, only KA causes selective neuronal death. Following treatment of transgenic rats with KA there was a protracted expression of Fos-lacZ that lasted for 2-3 d. In contrast, PTZ elicited a transient increase in the transgene product that lasted about 6 hr. Normally, Fos and Fos-lacZ were detected only in neuronal nuclei. However, 6 hr following kainic acid (but not PTZ) administration, beta-galactosidase activity appeared in the cytoplasm of neurons within vulnerable regions (as determined by the terminal transferase biotinylated-UTP nick end labeling (TUNEL) procedure). Like c-fos, transcripts for other cIEGs were elevated for longer periods in the KA-treated rat hippocampus. In addition, fra-1 and fra-2 were only induced in the KA-treated rat. These changes in mRNA levels were paralleled by a sustained increase in AP-1 DNA binding activity. Thus, quantitative and qualitative changes in AP-1 DNA binding complexes accompany neurotoxic cell death that are not observed following seizures.

Animals↗
PubMed1994

Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.

Endothelins act on two subtypes of G protein-coupled receptors, termed endothelin-A and endothelin-B receptors. We report a targeted disruption of the mouse endothelin-B receptor (EDNRB) gene that results in aganglionic megacolon associated with coat color spotting, resembling a hereditary syndrome of mice, humans, and other mammalian species. Piebald-lethal (sl) mice exhibit a recessive phenotype identical to that of the EDNRB knockout mice. In crossbreeding studies, the two mutations show no complementation. Southern blotting revealed a deletion encompassing the entire EDNRB gene in the sl chromosome. A milder allele, piebald (s), which produces coat color spotting only, expresses low levels of structurally intact EDNRB mRNA and protein. These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes. We postulate that defects in the human EDNRB gene cause a hereditary form of Hirschsprung's disease that has recently been mapped to human chromosome 13, in which EDNRB is located.

Animals↗
PubMed1994

Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.

Defects in the gene encoding the endothelin-B receptor produce aganglionic megacolon and pigmentary disorders in mice and humans. We report that a targeted disruption of the mouse endothelin-3 ligand (EDN3) gene produces a similar recessive phenotype of megacolon and coat color spotting. A natural recessive mutation that results in the same developmental defects in mice, lethal spotting (ls), failed to complement the targeted EDN3 allele. The ls mice carry a point mutation of the EDN3 gene, which replaces the Arg residue at the C-terminus of the inactive intermediate big EDN3 with a Trp residue. This mutation prevents the proteolytic activation of big EDN3 by ECE-1. These findings indicate that interaction of EDN3 with the endothelin-B receptor is essential in the development of neural crest-derived cell lineages. We postulate that defects in the human EDN3 gene may cause Hirschsprung's disease.

Amino Acid Sequence↗
PubMed1994

The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats.

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.

Animals↗
PubMed1994

Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse.

Mice carrying a mutation in the synaptotagmin I gene were generated by homologous recombination. Mutant mice are phenotypically normal as heterozygotes, but die within 48 hr after birth as homozygotes. Studies of hippocampal neurons cultured from homozygous mutant mice reveal that synaptic transmission is severely impaired. The synchronous, fast component of Ca(2+)-dependent neurotransmitter release is decreased, whereas asynchronous release processes, including spontaneous synaptic activity (miniature excitatory postsynaptic current frequency) and release triggered by hypertonic solution or alpha-latrotoxin, are unaffected. Our findings demonstrate that synaptotagmin I function is required for Ca2+ triggering of synchronous neurotransmitter release, but is not essential for asynchronous or Ca(2+)-independent release. We propose that synaptotagmin I is the major low affinity Ca2+ sensor mediating Ca2+ regulation of synchronous neurotransmitter release in hippocampal neurons.

Animals↗
PubMed1994

Asialoglycoprotein receptor deficiency in mice lacking the minor receptor subunit.

The asialoglycoprotein receptor is an abundant heterooligomeric endocytic receptor that is predominantly expressed on the sinusoidal surface of the hepatocytes. Proposed physiological and pathophysiological functions ascribed to this hepatic lectin (HL) include the removal of desialylated serum glycoproteins and apoptotic cells, clearance of chylomicron remnants, and a role as a homing receptor for lymphatic and metastatic cells. The assembly of two homologous subunits, HL-1 and HL-2, is required to form functional, high affinity receptors on the cell surface. However, the importance of the individual subunits for receptor transport to the cell surface has been controversial. To explore the significance of the minor HL-2 subunit for receptor expression and function in vivo, we have disrupted the HL-2 gene in mice. Homozygous HL-2-deficient animals are superficially normal. However, HL-1 expression in the liver is greatly reduced, indicating that HL-2 may promote HL-1 stability. Although these mice are completely unable to clear asialoorosomucoid, a high affinity ligand for asialoglycoprotein receptor, they do not accumulate desialylated glycoproteins or lipoproteins in their circulation.

Alleles↗
PubMed1994

Synaptic targeting domains of synapsin I revealed by transgenic expression in photoreceptor cells.

Synapsins are abundant nerve terminal proteins present at all synapses except for ribbon synapses, e.g. photoreceptor cell synapses. Multiple functions have been proposed for synapsins, including clustering of synaptic vesicles and regulation of synaptic vesicle exocytosis. To investigate the physiological functions of synapsin and to ascertain which domains of synapsin are involved in synaptic targeting in vivo, we expressed synapsin Ib and its N- and C-terminal domains in the photoreceptor cells of transgenic mice. In these cells synapsin Ib is targeted efficiently to synaptic vesicles but has no significant effect on the development, structure or physiology of the synapses. This suggests that synapsin I does not have dominant physiological or morphoregulatory functions at these synapses. Full-length synapsin Ib and the N-terminal domains of synapsin Ib but not its C-terminal domains are transported to synapses, revealing that the molecular apparatus for synaptic targeting of synapsins is also present in cells which form ribbon synapses that normally lack synapsins. This apparatus appears to utilize the conserved N-terminal domains that are shared between all synapsins.

Animals↗
PubMed1994

The role of Rab3A in neurotransmitter release.

The small GTP-binding protein Rab3A is a Rab family member that is abundant in brain synaptic vesicles. Here we show that mice in which the rab3A gene has been mutated by homologous recombination do not express Rab3A but are viable and fertile. Electrophysiological recordings in hippocampal CA1 pyramidal cells indicate that most of their synaptic parameters are also normal, although synaptic depression after short trains of repetitive stimuli (15-30 stimuli at 14 Hz) is significantly increased. Levels of the Rab3A-binding protein rabphilin are decreased by 70%, but expression of more than 20 other synaptic proteins is unchanged. No compensatory changes were detected in other GTP-binding proteins or in proteins that interact with Rab3. Rab3A thus appears not to be essential for synaptic vesicle exocytosis but to play a role in the recruitment of synaptic vesicles for exocytosis during repetitive stimulation.

Adaptor Proteins, Signal Transducing↗
PubMed1994

A single element of the elastase I enhancer is sufficient to direct transcription selectively to the pancreas and gut.

The elastase I (EI) gene is expressed at high levels in the exocrine pancreas and at lower levels in other regions of the gut. The transcriptional enhancer of the EI gene, from nucleotides -205 to -72, recapitulates the expression of the endogenous gene in transgenic mice; it directs not only pancreatic acinar cell expression of a human growth hormone (hGH) transgene but also expression to the stomach, duodenum, and colon. This pattern of selective expression limited to the gastroenteropancreatic organ system is specified by the A element, one of three functional elements in the EI enhancer. When multimerized, the A element directed expression of a hGH reporter gene selectively to the pancreas, stomach, and intestine in transgenic mice. Immunofluorescent localization of hGH indicated that the A element multimer transgenes were expressed in the acinar cells of the pancreas as well as in Brunner's gland cells of the duodenum. The A element binds a pancreatic acinar cell-specific factor, PTF1. Our results show that while the A element is responsible for directing tissue and cell type specificity, other elements of the enhancer must be involved in the regulation of the level of gene expression.

Animals↗
PubMed1994

A new transgenic mouse model of chronic hyperglycemia.

Expression under the control of the mouse transferrin promoter of a transgene encoding a soluble secreted derivative of the ectodomain of the human insulin receptor in transgenic mice results in the accumulation of this high-affinity insulin-binding protein in the plasma. Alterations of glucose homeostasis are observed including postabsorptive hyperglycemia concomitant with increased hepatic glucose production and hyperinsulinemia. Thus, this is the first transgenic animal model of chronic hyperglycemia with alterations in glucose homeostasis that are produced without a targeted alteration of pancreatic function. These mice provide a new experimental model to follow the progression and long-term consequences of chronic hyperglycemia.

Animals↗
PubMed1993

Short-term synaptic plasticity is altered in mice lacking synapsin I.

Synapsin I, the major phosphoprotein of synaptic vesicles, is thought to play a central role in neurotransmitter release. Here we introduce a null mutation into the murine synapsin I gene by homologous recombination. Mice with no detectable synapsin I manifest no apparent changes in well-being or gross nervous system function. Thus, synapsin I is not essential for neurotransmitter release. Electrophysiology reveals that mice lacking synapsin I exhibit a selective increase in paired pulse facilitation, with no major alterations in other synaptic parameters such as long-term potentiation. In addition to potential redundant functions shared with other proteins, synapsin I in normal mice may function to limit increases in neurotransmitter release elicited by residual Ca2+ after an initial stimulus.

Animals↗
PubMed1993

Transfer of the inflammatory disease of HLA-B27 transgenic rats by bone marrow engraftment.

We have previously produced lines of rats transgenic for HLA-B27 and human beta 2-microglobulin (h beta 2m) that develop a progressive inflammatory disease sharing many clinical and histologic features with the B27-associated human spondyloarthropathies, including gut and male genital inflammation, arthritis, and psoriasiform skin lesions. Other transgenic lines that express lower levels of B27 and h beta 2m remain healthy. To investigate the cellular basis for the multisystem inflammatory disease in these rats, we transferred lymphoid cell populations from disease-prone transgenic lines to irradiated disease-resistant transgenic and nontransgenic recipients. In recipients of cells from two different disease-prone lines, successful transfer required engraftment of bone marrow cells. Transfer of disease with fetal liver cells suggested that neither mature effector cells nor active disease in the donors was necessary for induction of disease in the recipients. Remission of the spontaneous disease in irradiated transgenic rats was induced by engraftment of nontransgenic bone marrow. These results suggest that the expression of HLA-B27 in bone marrow-derived cells alone is sufficient for the development of B27-associated disease, and that disease transfer requires engraftment of a bone marrow precursor cell for which mature cells in spleen or in lymph node cannot substitute.

Animals↗
PubMed1993

Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression.

To investigate the role of the class I MHC molecule HLA-B27 in the spondyloarthropathies, we produced rats transgenic for HLA-B27 and human beta 2-microglobulin. Of five lines bearing > 1 copy of each transgene and showing hemizygous expression of both transgenes, two (lines 21-4H and 33-3) developed spontaneous inflammatory disease that closely resembled B27-associated human disease. Two lines, 21-4L and 25-6, remained healthy even when homozygous for the transgene locus, whereas the 21-3 line, bearing the third highest transgene copy number, developed disease similar to that of the 21-4H and 33-3 lines only when homozygous for the transgene locus. The disease-prone lines showed higher expression of B27--thymic mRNA in utero, splenic mRNA by 5 days of age, and splenic cell surface protein by the time of disease onset--than the disease-resistant lines. Disease susceptibility thus appeared to correlate with gene copy number and the quantity of B27 in lymphoid cells. The increase in the amount of B27 protein did not appear to be simply a consequence of the inflammatory disease because 1) there was no similar change in endogenous RT1 class I expression; 2) no alteration of B27 expression occurred in 21-4H rats with adjuvant-induced arthritis; 3) in rats with inflammatory disease transgenic for HLA-A2 and the 21-4H transgene locus, A2 expression was the same as in healthy rats transgenic for A2 but not B27; and 4) the transgenes in disease-prone and disease-resistant lines were equally susceptible to induction by IFN-gamma. Immunocytochemistry of the distal colon, an early site of inflammation, showed that the B27 Ag is expressed at high levels in cells of the lamina propria, but not at all in colonic epithelial cells. Taken together, the data suggest that the B27 transgene is expressed in a copy number dependent, position-independent manner in lymphoid tissue and that disease results from the expression of B27 above a critical threshold level.

Animals↗
PubMed1993

Sharing of an HLA-B27-restricted H-Y antigen between rat and mouse.

The purpose of this work was twofold: 1) to learn whether rats transgenic for HLA-B27 and the human beta 2-microglobulin gene HB2M can mount B27-restricted cytolytic T lymphocyte (CTL) responses to the male H-Y antigen, and 2) to learn whether such CTLs would recognize both rat and mouse H-Y in the context of HLA-B27. Female rats of the B27/HB2M transgenic line 21-4L were primed in vivo with cells from males of the same line. CTL effectors were generated from lymph node cells of these females following culture with irradiated antigen-presenting cells from either male 21-4L rats or male mice of the B27/HB2M transgenic 56-3 line. The CTLs showed male-specific, B27-specific lysis of both rat and mouse targets. Lysis of B27 targets was inhibitable by monoclonal antibodies specific for B27 or rat CD8. Specific lysis of male B27 rat and mouse targets was inhibitable equally by either rat or mouse male B27 cold targets, but not significantly by female or nontransgenic cold targets. The B27-restricted CTLs neither recognized nor were inhibited by B27+ or B27- male or female human targets. These results demonstrate that CD8+, B27-restricted, anti-H-Y CTLs recognize an evolutionarily conserved H-Y peptide antigen in both rats and mice. In addition, they establish the transgenic rat as a model system for examining the T-cell response to antigen presented by class I HLA molecules.

Animals↗