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Biomedical subjects

R A Lang

Publications and source records attributed to R A Lang.

At least 37 records · Page 2Linked to original sources
PubMed1997

Lens induction by Pax-6 in Xenopus laevis.

Despite extensive study following the pioneering work of Spemann on lens development (Spemann, H. (1901) Verh. Anat. Ges. 15, 61-79) and the subsequent establishment of the concept of embryonic induction, the molecular mechanism of vertebrate lens induction remains largely unknown. Here we report that in Xenopus expression of Pax-6 results in lens formation in a cell autonomous manner. In animal cap experiments, Pax-6 induced expression of the lens-specific marker beta B1-crystallin without inducing the general neural marker NCAM. Ectopic Pax-6 expression also resulted in the formation of ectopic lenses in whole embryos as well as in animal cap explants indicating that in vertebrates, as well as Drosophila (Halder, G., Callaerts, P., and Gehring, W.J. (1995) Science 267, 1788-1792), Pax-6 can direct the development of major components of the eye. Interestingly, ectopic lenses formed in whole embryos without association with neural tissue. Treatments giving rise to anterior neural tissue in animal cap explants resulted in the expression of both beta B1-crystallin and Pax-6. Given the ability of Pax-6 to direct lens formation, we propose that the establishment of Pax-6 expression in the presumptive lens ectoderm during normal development is likely to be a critical response of lens-competent ectoderm to early lens inducers.

Animals↗
PubMed1997

Apoptosis in mammalian eye development: lens morphogenesis, vascular regression and immune privilege.

Formation of the mammalian eye requires a complex series of tissue interactions that result in an organ of exquisite sensory capability. The early steps in eye development involve extensive cell death associated with morphogenesis. Later, suppression of programmed cell death is essential for tissue differentiation and in the adult, the immune privileged status of the eye is maintained in part through factors that induce inflammatory cell apoptosis. Experimental evidence suggests that suppression of apoptosis in cells of the lens lineage by fibroblast growth factors is one component of their action during lens morphogenesis. Fibroblast growth factors are also required for normal lens fiber-cell differentiation. This includes a degenerative step for organelles that is presumably an adaptation for the clearance of light scattering elements from the optic axis. The process of organelle degeneration may be related to apoptosis in a few of its features. Actively-induced apoptosis becomes important for eye development as the temporary ocular vasculatures regress. This too, is presumably an adaptation for the disposal of cells that would disturb the passage of light to the retina. Ocular macrophages appear to be essential for the induction of apoptosis in the endothelial cells comprising the ocular vasculatures. In the adult, inflammatory cells entering the eye are exposed to the pro-apoptotic agents transforming growth factor-beta2 and Fas ligand. The expression of these molecules in the eye, and their action in killing inflammatory cells, has evolved as a means of preventing inflammation and subsequent loss of vision. Thus, the eye offers a unique and versatile system for studying the role of programmed cell death in lens development, vascular regression and immune privilege.

Journal Article↗
PubMed1997

Macrophages induce apoptosis in normal cells in vivo.

It is well established that macrophages have a function in scavenging apoptotic bodies from cells undergoing programmed cell death. Here we show that macrophages can also induce apoptosis of normal cells. Using injected toxic liposomes to eliminate macrophages in the anterior chamber of the rat eye, we provide direct evidence that, in vivo, macrophages induce apoptosis in normal vascular endothelial cells during programmed capillary regression. Macrophage elimination resulted in the survival of endothelial cells that normally would die and the persistence of functional capillaries. Furthermore, replacement of eliminated macrophages with bone-marrow-derived macrophages 'rescued' lack of capillary regression. Viability of the persistent target cells was demonstrated through their lack of apoptotic morphology, expression of intracellular esterases and synthesis of DNA. These results uncover a new function for macrophages in the remodeling of tissues through the induction of programmed cell death and provide direct evidence of a key role for macrophages in capillary regression.

Animals↗
PubMed1996

Do macrophages kill through apoptosis?

Macrophages can kill target cells independent of conventional immune specificity. Based on a re-examination of literature three decades old and recent experiments, Antonios Aliprantis and colleagues propose that macrophages kill target cells by inducing apoptosis. For this purpose, macrophages employ a selection of pro-apoptotic mediators including reactive oxygen and nitrogen species and tumour necrosis factor alpha.

Animals↗
PubMed1995

FGF suppresses apoptosis and induces differentiation of fibre cells in the mouse lens.

To determine whether fibroblast growth factor (FGF) has a role in lens development, we have generated transgenic mice expressing a dominant-negative form of the murine FGF receptor-1 (FGFRDN) in the lens. Using the fibre cell-specific alpha A-crystallin promoter to express the FGFRDN, we have asked whether FGF is required for fibre cell differentiation. The transgenic mice display diminished differentiation of fibre cells as indicated by their reduced elongation. In addition, transgenic lenses have an unusual refractile anomaly that morphological and biochemical data show results from the apoptosis of fibre cells in the central region of the lens. These results show that lens fibre cells are dependent on FGF for their survival and differentiation, and demonstrate that growth factor deprivation in vivo can lead to apoptosis.

Animals↗
PubMed1993

Macrophages are required for cell death and tissue remodeling in the developing mouse eye.

To identify and characterize tissue remodeling processes mediated by macrophages, we have generated transgenic mice in which diphtheria toxin is expressed from a macrophage-specific transgene. Expression of the transgene disrupts subsets of mature macrophages in both the eye and the peritoneal cavity and results in the persistence of two normally transient ocular tissues, the hyaloid vasculature and the pupillary membrane. Furthermore, the cells comprising the pupillary membrane appear alive up to 14 days after the structure is normally remodeled, suggesting that the macrophage actively elicits target cell death. Thus, these transgenic mice provide direct evidence for the active involvement of macrophages in developmentally programmed tissue remodeling and identify the hyaloid vessels and the pupillary membrane in the eye as targets of macrophage-mediated remodeling.

Aging↗
PubMed1992

TNF alpha, IL-1 alpha and bFGF are implicated in the complex disease of GM-CSF transgenic mice.

Transgenic mice aberrantly expressing the granulocyte-macrophage colony stimulating factor (GM-CSF) gene develop an unusual syndrome of blindness, tissue damage and wasting which is associated with accumulations of hemopoietic cells. In order to further characterize this disease state, we have used messenger RNA detection techniques to show that the genes for tumor necrosis factor (TNF alpha), interleukin-1 alpha (IL-1 alpha) and basic fibroblast growth factor (bFGF) are expressed at abnormally high levels in both macrophages and granulocytes in transgenic mice. Furthermore, since these cell types also express the GM-CSF transgene, it is likely that they are autocrine stimulated by GM-CSF. These observations raise the possibilities that, first, the expression of tumor necrosis factor alpha, interleukin-1 alpha and basic fibroblast growth factor in hemopoietic cells is a direct consequence of their autostimulation by GM-CSF, and second, that these cytokines may be responsible for some aspects of the transgenic mouse disease.

Animals↗
PubMed1991

Quantitative EEG studies of pedophilia.

Ninety six pedophiles, whose sexual orientation was confirmed by phallometric response to sexual stimuli, were investigated with quantitative EEG and compared to age- and sex-matched healthy controls. The EEG analysis showed a pattern of increased frontal delta, theta and alpha power (especially during verbal processing) and a pattern of reduced interhemispheric and increased intrahemispheric-interhemispheric coherence, right and left (only during verbal processing), an effect that was restricted to those who showed maximal erotic arousal for sexual partners aged 6-12 years. These findings will be discussed in the context of recent studies which suggest that sexual deviations in the male relate to altered dominant hemispheric functions with disruption of frontal interhemispheric relationships.

Brain↗
PubMed1990

Macrophage products IL-1 alpha, TNF alpha and bFGF may mediate multiple cytopathic effects in the developing eyes of GM-CSF transgenic mice.

GM-CSF transgenic mice develop eye disease during ontogeny that is mediated by autostimulated macrophages. The ocular pathology is characterized in part by corneal and vitreous neovascularization, pronounced GFAP expression by retinal Müller cells and degeneration of the retinal photoreceptor layer. The invading intraocular macrophages express the genes for the cytokines interleukin-1 alpha, tumor necrosis factor alpha and basic fibroblast growth factor, which may contribute to the multifaceted developmental ocular disorder. These cytokines, suspected to be angiogenic, may be responsible for neovascularization of the cornea in our transgenic animals. GFAP is normally made by astrocytes in the superficial retina and is induced in Müller cells in models of retinal degeneration. This protein is abnormally and copiously produced by Müller cells in the transgenic mice, which we suggest may be due to the release of cytokines from the invading macrophages. We suggest a mechanism by which autostimulated macrophages, through a perturbation of their normal developmental role, may be responsible for photoreceptor cell death in these transgenic animals.

Animals↗
PubMed1990

Autocrine growth factors and tumourigenic transformation.

The development of tumours requires the simultaneous presence of a number of molecular perturbations. It is becoming increasingly clear that autocrine growth factor production, the topic of this review, is one such perturbation. Richard Lang and Antony Burgess summarize recent findings from a variety of in vitro and in vivo animal studies, and speculate on the possibilities for anti-growth factor therapy.

Animals↗
PubMed1990

Marital relations in incest offenders.

The study compared 92 incest perpetrators to 40 (noncriminal) married males on two marital inventories, the Clarke Martial Relations Questionnaire (CMRQ), and the Sexual Behavior and Marital Satisfaction Questionnaire (SBMSQ). Results showed that marital disharmony, in the form of mistrustfullness, lack of mutual friends and time together, emotional instability (in both partners), but not sexual relations, were predominant factors in incest perpetrators' profiles. A discriminant function analysis correctly classified 91.3% of incest offenders, but only 30.0% of controls, into their a priori group. Incest perpetrators reported less mutual give-and-take in disagreements with their spouses, a trend to confide less in their wives, and being more lonely in their marriage. Incest offenders reported they knew their spouses less well prior to marriage, despite the lack of any between-group differences in length of marriage or number of prior marriages. No differences emerged with respect to the range of sexual behaviors experienced or the degree of satisfaction with them. There were no group differences in the frequency of coitus nor in sexual dysfunction. In general, the lack of a satisfying emotional relationship between the incest offenders and their wives appeared as the most prominent factor in their marital relationships. The prominent aspects of their marital disharmony and sexual relations identified in the study reflect, in part, the inherent treatment goals needed for the incest perpetrator.

Adult↗
PubMed1989

Nonneoplastic hematopoietic myeloproliferative syndrome induced by dysregulated multi-CSF (IL-3) expression.

Post 5-fluorouracil-treated murine marrow cells were infected with a retroviral vector (MPZen) bearing a multi-potential colony stimulating factor (Multi-CSF) cDNA insert and then transplanted into lethally irradiated syngeneic recipients to study the effects of autocrine production of Multi-CSF in normal hematopoietic cells. Extremely high levels (14,000 U/mL) of Multi-CSF were detected in the sera and in media conditioned by various hematopoietic tissues of the transplanted animals. While spleen, peritoneal, and peripheral blood cellularity increased approximately 10-fold, 10-fold, and 50-fold, respectively, bone marrow cellularity decreased twofold. Progenitor numbers were depressed twofold in the bone marrow but elevated more than 100-fold in the spleen and peritoneum. The majority (80%) of transplanted mice died within 5 weeks of transplantation and showed extensive neutrophilic infiltration of the spleen, lung, liver, and muscle, often with mast cell foci; a phenomenon also seen in the skin and intestine. Neither the infected cells from hematopoietic tissues of the primary mice, nor autonomous mast cell-lines that grew from these cells in liquid culture produced any overt disease when transplanted into normal or sublethally irradiated secondary recipients. In contrast, injection into mice of autonomous FDC-P1 cells transformed by the same retroviral construct led to tumor formation in vivo within 4 weeks. Thus, dysregulated Multi-CSF expression by normal hematopoietic cells produces a fatal but nonneoplastic myeloproliferative syndrome.

Animals↗
PubMed1989

Developmental ocular disease in GM-CSF transgenic mice is mediated by autostimulated macrophages.

The eyes of transgenic mice aberrantly expressing the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene contain an additional population of phagocytic cells which perturb ocular development. Immunohistochemical analysis shows that these phagocytic cells bear macrophage-specific surface antigens, while hybridization histochemical and transcription analyses indicate that they also express the GM-CSF transgene. Macrophages play a physiological role in the developing mammalian eye, in the removal of both the temporary hyaloid vasculature in the vitreous and redundant neurons from the retina. The onset of ocular disease in transgenic mice coincides with this period of remodeling and the onset of transgene expression. In GM-CSF transgenic mice we observed an amplification of the phagocytic response, loss of its tissue-specific and temporal regulation, and resultant damage to normal ocular tissues. We propose that this disease is a consequence of autostimulation of resident intraocular macrophages at a crucial time in ocular development.

Animals↗
PubMed1987

Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage.

Transgenic mice carrying the murine granulocyte-macrophage colony stimulating factor (GM-CSF) gene expressed from a retroviral promoter exhibit elevated levels of GM-CSF in the serum, urine, peritoneal cavity, and eye. The eyes of transgenic mice are opaque, contain accumulations of macrophages, and develop retinal damage. Similarly, lesions containing macrophages develop in striated muscle. The mice also display an accumulation of large, often multinucleate, activated macrophages in the peritoneal and pleural cavities. The transgene is transcribed in peritoneal cells, as well as in eyes and infiltrated striated muscle. A high proportion of transgenic mice die with muscle wasting when aged 2-4 months, possibly because of macrophage activation resulting from the high levels of GM-CSF.

Animals↗
PubMed1985

Expression of a hemopoietic growth factor cDNA in a factor-dependent cell line results in autonomous growth and tumorigenicity.

Production of a growth factor by a cell that responds to this factor has been termed "autocrine" stimulation of proliferation. Considerable experimental data have suggested that tumor cells often exhibit autocrine growth stimulation and that this may contribute to the process of malignant transformation. To experimentally approach the relationship of autocrine growth stimulation to the malignant transformation of hemopoietic cells, we have used a retroviral vector to express sequences encoding a hemopoietic growth factor, granulocyte-macrophage colony stimulating factor (GM-CSF) in a factor-dependent murine cell line (FDC-P1). Virally infected cells synthesized and secreted GM-CSF, grew independently of exogenous CSF, and--unlike the parental FDC-P1 cells--produced tumors in syngeneic mice. We have thus experimentally induced autocrine growth regulation in a factor-dependent hemopoietic cell line and have shown that this results in tumorigenicity.

Animals↗
PubMed1985

Goal attainment scaling with hospitalized sexual offenders.

Forty-six hospitalized sex offenders participated in a 6-month evaluation of treatment outcome. This study used the concept of goal attainment scaling, an individualized, scaled description of personal goals, for measuring therapeutic outcome. Conjoint therapist and patient goal setting resulted in 180 treatment goals being set. At follow-up, 38 patients exceeded the "expected" success level on a total of 159 treatment goals, whereas eight patients only made minimal progress on 21 of their 40 selected goals. Despite the benign clinical improvement shown by most patients, few patients actually achieved the best anticipated level of attainment on all of their personal goals (usually three to six goals). Retrospective review of all goal attainment scaling protocols indicated that four major content dimensions account for nearly all of the goals devised: sexual deviation, 30 goals; anger and emotional expression, 64 goals; self concept, 31 goals; and poor interpersonal relations, 51 goals. These goal-oriented profiles may have important ramifications for the future assessment, program planning, and rehabilitation of convicted sex offenders.

Adolescent↗