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Biomedical subjects

B M Davis

Publications and source records attributed to B M Davis.

At least 55 records · Page 3Linked to original sources
PubMed1997

Overexpression of nerve growth factor in skin increases sensory neuron size and modulates Trk receptor expression.

Sensory neuron development and differentiation is dependent on a family of growth factors known as neurotrophins. Neurotrophins modulate neuron development via trk tyrosine kinase receptor proteins trkA, trkB and trkC. To determine how elevated levels of a target-derived neurotrophin might affect neuronal differentiation, we analysed trk expression in the trigeminal ganglion of transgenic mice that overexpressed nerve growth factor (NGF) in the skin. Increased levels of NGF caused a five-fold increase in neurons expressing trkA mRNA and a two-fold increase in neurons expressing trkC. In control mice, cell size distributions of neuronal subpopulations expressing each trk mRNA showed the three subpopulations distributed over a narrow, overlapping range. In contrast, cell size distribution in NGF-transgenic mice was significantly divergent due in large part to hypertrophy of trkA neurons and, to a lesser extent, trkC neurons. In addition, we examined neurons that bound the isolectin B4 from Bandeiraea simplicifolia (BS-IB4) because most of these neurons do not express any trk receptor in the adult. There was a significant increase in the size of BS-IB4-positive neurons in transgenic mice; however, there was no increase in their number. These studies indicate that an increased level of target-derived NGF affects the development of sensory neurons that in the adult express trkA or trkC, as well as neurons that do not express trk receptors.

Animals↗
PubMed1997

Human alkyltransferase-transduced murine myeloid progenitors are enriched in vivo by BCNU treatment of transplanted mice.

Retroviral gene transfer into murine hematopoietic progenitors of the human O6alkylguanine-DNA alkyltransferase cDNA, methylguanine methyltransferase (MGMT) has been shown to result in MGMT expression, increased alkyltransferase (AGT) activity, and resistance to 1,3-bis-(2-chloroethyl) nitrosourea (BCNU) both in vitro and in vivo. In the present study we show that MGMT expressing bone marrow (BM) progenitors can be selected for in vivo by BCNU administration. MGMT+ mice treated with multiple doses of BCNU and examined 13 to 17 weeks after transplantation displayed a 2.4-fold increase in the percentage of progenitors with evidence of proviral integration (p < 0.0001). Likewise, percentage of the BCNU IC50 in these progenitors was 1.8-fold higher than that observed in progenitors of MGMT+ mice not treated with BCNU (p = 0.0027) and 3.6-fold higher than in mock-transduced progenitors (p < 0.001). AGT expression in myeloid cells was 3.8-fold higher in mice treated with BCNU than in untreated mice (p = 0.0378) and 64-fold higher than endogenous AGT levels. These findings demonstrate that after transplantation with MGMT-transduced BM cells, BCNU treatment enriches for MGMT+ cells, resulting in an increase in MGMT expression and AGT activity in vivo. This approach may be used to enrich for transduced hematopoietic cells in patients after clinical transplantation, to decrease myelosuppression after repeated nitrosourea exposure, and to increase the proportion of genetically altered hematopoietic cells.

Animals↗
PubMed1996

Excess nerve growth factor in the periphery does not obscure development of whisker-related patterns in the rodent brain.

We have addressed the issue of whether or not peripherally expressed nerve growth factor (NGF) influences the formation of whisker-specific patterns in the brain by regulating the survival of sensory neurons. Transgenic mice that overexpress an NGF cDNA in the skin were examined. In these animals, excess NGF expression is controlled by promoter and enhancer sequences of a keratin gene, thus restricting the higher levels of NGF expression to basal keratinocytes of the epidermis. Twice the number of trigeminal sensory neurons survive in transgenic mice as in normal animals, and a corresponding hyperinnervation of the whisker pad is noted, both around the vibrissa follicles and along the intervibrissal epidermis. However, the increased survival of sensory neurons and the enhanced peripheral projections do not interfere with the development of whisker-specific patterns in the trigeminal brainstem, in the ventrobasal thalamic complex or in the face-representation region of the primary somatosensory (SI) cortex. These results demonstrate that vibrissa-related central patterns are able to form in the virtual absence of trigeminal ganglion cell death and suggest that mechanisms other than a selective elimination of sensory neurons control the development of whisker-specific neural patterns in the brain.

Animals↗
PubMed1996

Overexpression of nerve growth factor in epidermis of transgenic mice preserves excess sensory neurons but does not alter the somatotopic organization of cutaneous nerve projections.

To determine how target-derived nerve growth factor (NGF) affects sensory neuronal survival and the development of topographic nerve projections in the spinal cord, anatomical studies were performed on transgenic mice that overexpress NGF in skin and other keratinized epithelial structures. Transgenic animals showed a 100% increase in the number of sensory neurons in specific dorsal root ganglia and exhibited significantly more fibers immunoreactive for calcitonin gene-related peptide in the dorsal horn compared to control animals. This confirms earlier studies which suggested that naturally occurring sensory neuronal death is decreased, or eliminated, in the transgenic mice. Nerve labeling studies showed that the somatotopic organization of cutaneous nerve projections was not altered in the transgenic animals. These data suggest that neuronal death does not act to remove sensory neurons that project to inappropriate regions of the spinal cord.

Animals↗
PubMed1996

Effects of NGF overexpression on anatomical and physiological properties of sympathetic postganglionic neurons.

To examine the effects of increased target derived nerve growth factor (NGF) on the sympathetic nervous system, the superior cervical ganglion was characterized in transgenic mice overexpressing NGF in keratinized epithelium (e.g. skin, tongue and oral cavity). In these mice NGF overexpression was achieved via expression of an NGF transgene driven by the K14 keratin promoter. This promoter is expressed at approximately embryonic day 11 and thereafter expressed constitutively in the adult. This expression results in supranormal levels of NGF in targets of sympathetic postganglionic neurons prior to the period of programmed cell death. Examination of postnatal day 6 (PN6) and adult transgenic mice shows ca. 2.5-fold increase in neuron number in the superior cervical ganglion (SCG). Analysis of SCG neuronal size revealed a dramatic hypertrophy in the transgenic mice that is present by PN6 and is maintained in the adult. Intracellular physiological measurements of control superior cervical ganglia identified two distinct types of neurons identified on the basis of their response to depolarizing current; 'phasic' neurons fire a single action potential while 'tonic' neurons fire continuously. In adult transgenic mice the phasic neurons were 102% larger than control phasic neurons while the tonic neurons only increased 44% relative to controls. The hypertrophy of sympathetic ganglia in the transgenic mice was correlated with an increased innervation of skin and dorsal root ganglia, structures that either express the transgene or concentrate NGF produced by the skin.

Animals↗
PubMed1996

Cellular localization of Pan-trk immunoreactivity and trkC mRNA in the enteric nervous system.

The members of the trk family of tyrosine receptor kinases, trkA, trkB, and trkC, are the functional receptors for neurotrophins, a family of related neurotrophic factors. In this study, we investigated 1) the distribution of neurotrophin receptors in the developing and adult rat digestive tract with a pan-trk antibody that recognizes all known trks and 2) the cellular localization of trk-encoding mRNAs in the adult gut with single-stranded RNA probes specific for trkA, trkB, and trkC. In the developing myenteric plexus, trk immunoreactivity was present at embryonic day (ED) 14. Cells and fibers immunoreactive for trk could be visualized in the myenteric plexus at ED 16. At this age, dense staining was found in thick bundles of fibers in proximity to the myenteric plexus in the longitudinal muscle and in association with blood vessels in the mesentery. At ED 18, trk immunoreactivity was also seen in thin processes running from the myenteric plexus into the circular muscle, and in fibers and cells in intrapancreatic ganglia. By ED 20, immunoreactive staining was quite dense in both the myenteric and submucosal plexuses. At birth, virtually all enteric ganglia displayed strong trk immunoreactivity; the intensity of the staining at this age made it difficult to discern individual cells. During postnatal development, there was a decrease in cell body staining and an increase in the density of trk-containing fibers that became widely distributed to the gut wall and pancreas. The adult pattern of trk immunoreactivity was established between postnatal days 5 and 10. In adults, trk immunoreactivity was found in numerous enteric and intrapancreatic ganglion cells and in dense networks of fibers innervating all the layers of the gut, the pancreas, and vasculature. The trkC mRNA was expressed in adult enteric ganglion cells of both the myenteric and submucous plexus. By contrast, the trkA and trkB mRNAs could not be detected in enteric ganglia. All three trk mRNAs were expressed in dorsal root ganglia, which were used as positive controls. The density and wide distribution of trk immunoreactivity together with its persistence in adulthood support the concept that neurotrophins play a broad role in the digestive system from development through adult life, perhaps being involved in differentiation, phenotypic expression, and tissue maintenance. The presence of trkC mRNA in enteric neurons along with recent evidence that neurotrophin-3 plays a role in the development of the enteric nervous system suggest that trkC and neurotrophin-3 are a major neurotrophin system in the gastrointestinal tract.

Animals↗
PubMed1996

Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy.

Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3' untranslated region of a putative protein kinase (DMPK). To elucidate the role of DMPK in DM pathogenesis we have developed Dmpk deficient (Dmpk-/-) mice. Dmpk-/-mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM. Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis. Adult Dmpk-/-mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice. Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology.

Animals↗
PubMed1996

Cutaneous overexpression of NT-3 increases sensory and sympathetic neuron number and enhances touch dome and hair follicle innervation.

Target-derived influences of nerve growth factor on neuronal survival and differentiation are well documented, though effects of other neurotrophins are less clear. To examine the influence of NT-3 neurotrophin overexpression in a target tissue of sensory and sympathetic neurons, transgenic mice were isolated that overexpress NT-3 in the epidermis. Overexpression of NT-3 led to a 42% increase in the number of dorsal root ganglia sensory neurons, a 70% increase in the number of trigeminal sensory neurons, and a 32% increase in sympathetic neurons. Elevated NT-3 also caused enlargement of touch dome mechanoreceptor units, sensory end organs innervated by slowly adapting type 1 (SA1) neurons. The enlarged touch dome units of the transgenics had an increased number of associated Merkel cells, cells at which SA1s terminate. An additional alteration of skin innervation in NT-3 transgenics was an increased density of myelinated circular endings associated with the piloneural complex. The enhancement of innervation to the skin was accompanied by a doubling in the number of sensory neurons expressing trkC. In addition, measures of nerve fibers in cross-sectional profiles of cutaneous saphenous nerves of transgenics showed a 60% increase in myelinated fibers. These results indicate that in vivo overexpression of NT-3 by the epidermis enhances the number of sensory and sympathetic neurons and the development of selected sensory endings of the skin.

Animals↗
PubMed1996

Current progress in the gene therapy of cancer.

Gene transfer for the treatment of cancer is a rapidly expanding field. Recent studies can be divided into four main areas: 1) transfer of suicide genes that convert inactive prodrugs into cytotoxic compounds, 2) transfer of genes encoding cytokines and stimulatory markers to enhance immunogenicity against tumors, 3) transfer of tumor-suppressor genes to block tumor cell proliferation, and 4) transfer of drug resistance genes into hematopoietic stem cells to increase their resistance to myelo-suppressive chemotherapeutic agents. This review discusses recent advances in technique and knowledge and their application to the gene therapy of cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Transfer of drug resistance genes into hematopoietic progenitors to improve chemotherapy tolerance.

A number of drug resistance genes have been identified that may be useful in gene therapy approaches to ameliorate chemotherapy toxicity. Hematopoietic tissue is the most suitable target for drug resistance gene therapy because myelosuppression is the dose-limiting toxicity of the many chemotherapeutic agents. Recent studies have shown that murine and human hematopoietic progenitors can be transduced ex vivo using retroviral vectors to overexpress P-glycoprotein, dihydrofolate reductase, and O6-alkylguanine DNA alkyltransferase. In all instances, gene transfer results in significant drug resistance in hematopoietic progenitors both in vitro and in vivo. Clinical trials are underway to evaluate the role of MDR-1 gene therapy in amelioration of chemotherapy induced myelosuppression. Other genes being examined for their potential to transfer drug resistance to hematopoietic cells include genes encoding aldehyde dehydrogenase, nucleotide excision repair proteins, multidrug resistant protein, and superoxide dismutase. As a group these proteins could confer significant levels of chemotherapy drug resistance to bone marrow cells. When compared with other somatic gene therapy approaches, drug resistance gene therapy has the aim of protecting normal cells and preventing toxicity. In addition many of these genes could be used to select for cells carrying the drug resistance gene as well as cotransduced therapeutic gene. Thus, gene transfer of drug resistance genes will have broad applications in the field of gene therapy as well as in protecting hematopoietic cells from chemotherapy toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Retroviral-mediated gene transduction of human alkyltransferase complementary DNA confers nitrosourea resistance to human hematopoietic progenitors.

Myelosuppression is the dose-limiting toxicity for nitrosourea chemotherapy due to low levels of the DNA repair protein O6-alkylguanine-DNA alkyltransferase in myeloid precursors. We have shown that high-efficiency myeloproliferative sarcoma virus (vM5MGMT)-mediated transduction of the human MGMT cDNA into murine bone marrow (BM) cells leads to high MGMT expression and increased progenitor resistance to 1,3-bis-(2-chloroethyl) nitrosourea (BCNU) in vitro immediately after infection and after BM transplantation. These experiments were designed to increase MGMT expression in human hematopoietic progenitors. CD34(+) BM cells were isolated over an immunoaffinity column (CEPRATE, CellPro, Inc.), resulting in a mean 66-fold enrichment in clonogenic progenitors (colony-forming unit granulocyte-macrophage + burst-forming unit erythroid + colony-forming unit granulocyte erythroid macrophage = megakaryocyte), with an average progenitor yield of 58 +/- 11.5% and a final population that was 54% CD34(+). Seventy % of progenitors derived from CD34(+) cells were transduced after coculture with AM12-vM5MGMT retroviral producers. vM5MGMT-transduced progenitors were over 2-fold more resistant to concentrations of BCNU between 30 and 50 micrometer than were concurrently LacZ-transduced progenitors (P < 0.003). In vitro selection of transduced, cytokine-stimulated CD34(+) cells with 20 micrometer BCNU resulted in survival of 4.7% of MGMT+ clonogenic progenitors compared to 0.05% of LacZ+ progenitors. These studies indicate that MGMT-transduced human hematopoietic progenitors have increased resistance to nitrosoureas, and in a clinical transplant setting, this strategy may reduce alkylating agent myelosuppression.

Antigens, CD34↗
PubMed1995

Posthatching development of preproenkephalin mRNA-expressing cell populations in the pigeon telencephalon.

Enkephalin peptides are highly expressed in the vertebrate telencephalon. Our previous investigations in the pigeon and in the chicken [26] suggested that the cellular distribution of these peptides is conserved in phylogenetically 'old' telencephalic regions (e.g. the basal ganglia), while it has species-specific organizations in areas (e.g. dorsomedial forebrain and bulbus olfactorius) that are likely to play important roles in species-specific behaviors. In the present study, we investigated the posthatching development of preproenkephalin (PPE) mRNA-containing cells in the pigeon forebrain using in situ hybridization histochemistry. These cells are densely distributed in the paleostriatal complex (corresponding to the mammalian caudate-putamen) at hatching, and their density progressively decreases during the first 9 days posthatching, when it is similar to that of adult pigeons. In the dorsomedial forebrain (corresponding to the mammalian hippocampus), PPE mRNA-expressing cells are present at hatching, and their density reaches a peak around the 6th day posthatching. In the bulbus olfactorius, the first PPE mRNA-containing cells are observed after 9 days posthatching. The developmental profile of PPE mRNA expression in these areas of the pigeon telencephalon shows remarkable similarities with the development of enkephalinergic cells in corresponding brain areas of mammals. As in the mammalian caudate-putamen, the developmental expression of enkephalin peptides in the paleostriatal complex is likely to be related to neuronal withdrawal from the mitotic cycle. The developmental pattern of expression of PPE mRNA in the dorsomedial forebrain suggests that enkephalin peptides contribute to the maturation of the behavioral functions of this area.

Animals↗
PubMed1995

Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain.

Serotonin (5-HT) mediates its effects on neurons in the central nervous system through a number of different receptor types. To gain better insight as to the localization of 5-HT responsive cells, the distribution of cells expressing mRNAs encoding the three 5-HT receptor subtypes 1A, 1C, and 2 was examined in rat brain with in situ hybridization using cRNA probes. 5-HT1A receptor mRNA labeling was most pronounced in the olfactory bulb, anterior hippocampal rudiment, septum, hippocampus (dentate gyrus and layers CA1-3), entorhinal cortex, interpeduncular nucleus, and medullary raphe nuclei. 5-HT1C receptor mRNA labeling was the most abundant and widespread of the three 5-HT receptor subtypes examined. Hybridization signal was densest in the choroid plexus, anterior olfactory nucleus, olfactory tubercle, piriform cortex, septum, subiculum, entorhinal cortex, claustrum, accumbens nucleus, striatum, lateral amygdala, paratenial and paracentral thalamic nuclei, subthalamic nucleus, substantia nigra, and reticular cell groups. 5-HT2 receptor mRNA was localized to the olfactory bulb, anterior hippocampal rudiment, frontal cortex, piriform cortex, entorhinal cortex, claustrum, pontine nuclei, and cranial nerve motor nuclei including the oculomotor, trigeminal motor, facial, dorsal motor nucleus of the vagus, and hypoglossal nuclei. The distributions of mRNAs for the three different 5-HT receptor subtypes overlap with regions that bind various 5-HT receptor-selective ligands and are present in nearly all areas known to receive serotonergic innervation. The results of this study demonstrate that neurons which express these 5-HT receptor subtypes are very widespread in the central nervous system, yet possess unique distributions within the rat brain. Moreover, previously unreported regions of 5-HT receptor subtype expression were observed, particularly with the 5-HT2 receptor riboprobe in the brainstem. Finally, several brain areas contain multiple 5-HT receptor subtype mRNAs, which leads to the possibility that individual cells may express more than one 5-HT receptor subtype.

Animals↗
PubMed1995

Lichen sclerosus.

Lichen sclerosus, usually appearing in the dermatologic literature under the names of lichen sclerosus et atrophicus, balanitis xerotica obliterans, and kraurosis vulvae, is an inflammatory disease with a multifactorial origin. A past association of lichen sclerosus and genital squamous cell carcinoma is not as close as once thought. Once considered primarily a surgical problem, especially when the genitals were involved, lichen sclerosus will respond to a variety of systemic and topical therapies.

Autoimmune Diseases↗
PubMed1995

NGF modulates sympathetic innervation of lymphoid tissues.

Immune tissues are known to be innervated by the sympathetic nervous system, but little is known of what directs the innervation to specific tissue compartments. This report examines the sympathetic innervation of immune tissues in transgenic mice that overexpress nerve growth factor (NGF) in skin and other epithelial structures. NGF transgenic mice exhibited dramatic hyperinnervation in the splenic marginal zone, and the medulla and capsule of peripheral lymph nodes. In contrast, the transgenic mesenteric lymph nodes showed no hyperinnervation. This difference correlated with the location of these nodes; peripheral lymph nodes drain skin where the transgene was expressed while mesenteric lymph nodes drain non-transgene-expressing structures. In addition, the level of innervation correlated with the level of NGF peptide content as assayed by ELISA (3- and 13-fold increase in transgenic spleen and axillary lymph nodes, respectively; no increase in mesenteric nodes) and immunocytochemistry. RT-PCR showed that the NGF transgene was not being expressed in the immune tissues, suggesting that immune tissues can concentrate transgene-produced NGF. It was also demonstrated that the change in innervation had functional consequences. The mitogen response to concanavalin A (ConA) by spleen cells was decreased in the transgenics suggesting that elevated catecholamines or NGF can modulate the proliferative response of these cells. These mice demonstrate that NGF can modulate the sympathetic innervation and function of the immune system.

Animals↗
PubMed1995

Bullous drug eruption to griseofulvin in a man with Hailey-Hailey disease.

Hailey-Hailey disease (chronic benign familial pemphigus) is a blistering disease characterized by episodic maceration and erosions in areas subject to friction and trauma such as the neck, axilla, and other intertriginous areas. We report a case in which a griseofulvin-induced drug eruption led to a generalized vesiculobullous eruption requiring treatment in a burn treatment center. This emphasizes that Hailey-Hailey disease, usually confined to relatively small areas, has the potential to cause blistering throughout the epidermis under certain conditions.

Administration, Cutaneous↗