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M Blum

Publications and source records attributed to M Blum.

At least 73 records · Page 4Linked to original sources
PubMed1999

Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat.

Neuregulins have been shown to play an important role in the development of the central nervous system, but their function in adult tissues is still unclear. We investigated the expression of the neuregulin receptors erbB3 and erbB4 in the adult rat brain by in situ hybridization histochemistry. Areas with considerable expression of erbB4 receptor mRNA include cortex, amygdala, hippocampus, medial habenula, reticular thalamic nucleus, several hypothalamic nuclei, subthalamic nucleus, substantia nigra pars compacta, and ventral tegmental area. Immunostaining for tyrosine hydroxylase and dopamine depletion by 6-hydroxydopamine indicate that erbB4 is expressed in dopamine neurons in the latter two nuclei. Substantial erbB4 expression is also present in clusters of cells along the ventral and medial border of the striatum/nucleus accumbens and in the subependymal zone along the lateral and olfactory ventricles (rostral migratory stream), suggesting a role for neuregulins in adult cell proliferation. In contrast, erbB3 mRNA is mostly expressed in white matter throughout the brain and in the ependyma of the ventral half of the third ventricle (tanycytes). These results demonstrate that expression of erbB3 and erbB4 receptors is widespread in the adult rat brain and suggest a function for neuregulins into adulthood.

Animals↗
PubMed1999

The weaver GIRK2 mutation leads to decreased levels of serum thyroid hormone: characterization of the effect on midbrain dopaminergic neuron survival.

The selective neurodegenerative changes occurring in the weaver mutant cerebellum and midbrain are linked to a point mutation in an inward rectifying potassium channel (GIRK2). However, given that GIRK2 is widely expressed in the CNS, it is not understood why this mutation only leads to neuroanatomically selective and developmentally specific neuronal cell death. Here we show that the phenotype of the weaver mutant mouse includes hypothyroidism, which is associated with delays in somatic development and decreased expression of striatal transforming growth factor alpha (TGF-alpha). Since thyroid hormone has major effects on brain development, further studies were performed to address whether some of pathological changes detected the weaver mutant mouse are due to the reduced thyroid hormone levels. We observed that daily thyroid hormone replacement was able to stimulate somatic growth and restore TGF-alpha expression to wild-type levels, indicating that while these mice are responsive to thyroid hormone they possibly have a defect in the ability to regulate its release at the level of the hypothalamic pituitary axis. However, when we assessed whether thyroid hormone replacement could rescue midbrain dopaminergic neurons we found that this treatment accelerated rather than attenuated neurodegeneration. We did not observe that thyroid hormone was able to directly regulate expression of GIRK2 mRNA levels in the midbrain and therefore, speculate that the mechanism by which thyroid hormone accelerates midbrain dopaminergic neurodegeneration is by enhancing the maturation of the striatonigral inputs. In summary, we detected reduced levels of serum thyroid hormone in the weaver mutant mouse, which appears to be responsible for delays in somatic growth and the onset of neurodegenerative changes in the midbrain.

Animals↗
PubMed1999

Noninvasive measurement of the Bayliss effect in retinal autoregulation.

PURPOSE: The Bayliss effect describes the reaction of smooth muscle cells in the arterial wall to changes in blood pressure. A rise in mean arterial blood pressure (MAP) causes an autoregulatory myogenic vessel constriction by smooth muscle cells in the arterial wall. The responsiveness of retinal vessels to changes in MAP were analyzed using the Retinal Vessel Analyzer (RVA). METHODS: Continuous measurement of retinal arterial vessels was performed in 40 healthy volunteers (age 18-56 years.) over a 9-min period. After a 3-min baseline measurement (phase I), isometric exercise caused a rise in MAP over the next 3 min (phase II). During the last 3 min (phase III) recovery was observed. Blood pressure and ECG were documented simultaneously throughout the experiment. RESULTS: Exercise caused a significant rise of 22.8 (+/-6.0) mm Hg in MAP (phase II vs. phase I: P<0.001). Retinal arterioles showed 5.5% (+/-2.8%) vasoconstriction (P<0.001). During phase III vessel diameters returned to normal, with no difference from phase I (P = 0.179). CONCLUSION: Noninvasive measurement and quantitative analysis of the Bayliss effect in human retinal vessels by means of the RVA is possible. Analysis of retinal arterial autoregulation may provide valuable insight into pathologic conditions such as diabetic or hypertensive retinopathy.

Adolescent↗
PubMed1999

Time course of lipopolysaccharide-induced nitric oxide synthase mRNA expression in rat glomeruli.

The decrease in glomerular filtration rate that is characteristic of sepsis has been shown to result from the local glomerular inhibition of endothelial nitric oxide synthase (NOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). iNOS activation depends on de novo synthesis of both RNA and protein. Therefore it is assumed that several hours are required for its full activation. Yet the renal hemodynamic response in sepsis has been documented as early as 60 minutes after lipopolysaccharide (LPS) administration. Experiments were designed to determine the time course of LPS-induced glomerular iNOS mRNA expression and activity in rats. Rats were treated with LPS (2 mg/kg body weight IP). Kidneys were removed after 1,2, 4, 6, and 16 hours. Glomeruli were isolated and incubated. Nitric oxide generation was measured with a Griess assay, and iNOS mRNA was studied by reverse transcriptase-polymerase chain reaction. Similar time course experiments were repeated in glomeruli isolated from normal rats and exposed to LPS in vitro. A significant increase in iNOS mRNA expression was evident as early as 60 minutes after both in vivo and in vitro administration of LPS. The quantity of iNOS mRNA reached its peak between 2 to 4 hours after administration and declined to baseline levels after 16 hours. Immunohistochemical studies were remarkable for a significant increase in the staining for iNOS in glomeruli 2 hours after the in vivo administration of LPS. Plasma nitric oxide concentration after the in vivo administration of LPS increased from a baseline level of 11.25 +/- 0.8 micromol/L to a peak level of 62.9 +/- 3.8 micromol/L (P < .05 vs baseline) at 4 hours and then decreased to 17.5 +/-1.9 micromol/L at 16 hours. Similar results were obtained when the glomerular generation of nitric oxide after in vivo administration of LPS was measured (2.6 +/- 0.8 pmol/h/microg tissue, 17.2 +/- 2.1 pmol/h/microg tissue (P < .05 vs baseline), and 0.4 +/- 0.65 pmol/h/microg tissue, respectively). These results provide evidence of the rapid activation of glomerular iNOS after in vivo and ex vivo administration of LPS and thus support the role of nitric oxide in the early renal hemodynamic response to LPS.

Animals↗
PubMed1999

Regulation of the heparan sulfate proteoglycan, perlecan, by injury and interleukin-1alpha.

Perlecan is a specific proteoglycan that binds to amyloid precursor protein and beta-amyloid peptide, is present within amyloid deposits, and has been implicated in plaque formation. Because plaque formation is associated with local inflammation, we hypothesized that the mechanisms involved in brain inflammatory responses could influence perlecan biosynthesis. To test this hypothesis, we first studied perlecan regulation in mice after inflammation induced by a brain stab wound. Perlecan mRNA and immunoreactivity were both increased 3 days after injury. Interleukin-1alpha (IL-1alpha) is a cytokine induced after injury and plays an important role in inflammation. As such, IL-1alpha may be one of the factors participating in regulating perlecan synthesis. We thus studied perlecan regulation by IL-1alpha, in vivo. Regulation of perlecan mRNA by this cytokine was area-specific, showing up-regulation in hippocampus, whereas in striatum, perlecan mRNA was unchanged. To support this differential regulation of perlecan mRNA by IL-1alpha, basic fibroblast growth factor (bFGF), a growth factor also present in plaques, was studied in parallel. bFGF mRNA did not show any regional difference, being up-regulated in both hippocampus and striatum in vivo. In vitro, both astrocyte and microglia were immunoreactive for perlecan. Moreover, perlecan mRNA was increased in hippocampal glial cultures after IL-1alpha but not in striatal glia. These results show an increase in perlecan biosynthesis after injury and suggest a specific regulation of perlecan mRNA by IL-1alpha, which depends on brain area. Such regulation may have important implications in the understanding of regional brain variations in amyloid plaque formation.

Alzheimer Disease↗
PubMed1999

Intravenous iron for the treatment of predialysis anemia.

This article, based on our own studies and those of others, presents evidence to show that the anemia of chronic renal failure in the predialysis period is, to a significant extent, caused by iron deficiency and can be improved in most cases by the administration of intravenous (i.v.) but not oral iron. We estimate that in approximately 30% of all predialysis patients with anemia, a target hematocrit (Hct) of 35% can be reached and maintained by giving i.v. iron alone without exceeding currently acceptable limits of serum ferritin (500 microg/liter) or the percentage of iron saturation (40%). If, in addition, subcutaneous erythropoietin (EPO-usually in only low doses-is added, the combination has an additive effect on the Hct response, and almost all anemic predialysis patients can reach and maintain the target Hct of 35% over a one-year period. Therefore, the advantage of maintaining adequate iron stores with i.v. iron is that if EPO is needed, lower doses will be required to achieve the target Hct than if EPO were used alone. This not only avoids the high cost of EPO therapy but also its associated side-effects, especially hypertension. Using Venofer, a ferric hydroxide sucrose complex, as our i.v. iron supplement, we have seen no anaphylactic reactions in over 20,000 infusions over a four-year period in 360 hemodialysis, 123 predialysis, and 58 peritoneal dialysis patients.

Administration, Oral↗
PubMed1999

The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping.

Left-right asymmetry in vertebrates is controlled by activities emanating from the left lateral plate. How these signals get transmitted to the forming organs is not known. A candidate mediator in mouse, frog and zebrafish embryos is the homeobox gene Pitx2. It is asymmetrically expressed in the left lateral plate mesoderm, tubular heart and early gut tube. Localized Pitx2 expression continues when these organs undergo asymmetric looping morphogenesis. Ectopic expression of Xnr1 in the right lateral plate induces Pitx2 transcription in Xenopus. Misexpression of Pitx2 affects situs and morphology of organs. These experiments suggest a role for Pitx2 in promoting looping of the linear heart and gut.

Abnormalities, Multiple↗
PubMed1999

Pregnancy decreases immunoreactive parathyroid hormone level in rats with chronic renal failure.

Normal pregnancy is associated with an increase in serum parathyroid hormone and 1,25-dihydroxyvitamin D3 (calcitriol). The effect of pregnancy on these hormones in chronic renal failure (CRF) is unknown. The present work was undertaken to study the changes of serum immunoreactive parathyroid hormone (iPTH) and calcitriol in pregnant rats with CRF. The following experimental groups were studied: CRF1 (5/6 nephrectomized virgin female rats), CRF2 (5/6 nephrectomized pregnant rats at day 20-21 of pregnancy), CRF3 (5/6 nephrectomized rats 2 weeks after delivery) and their respective sham-operated control groups: N1, N2 and N3. The 5/6 nephrectomy (CRF1) resulted in renal failure with very high serum iPTH (100+/-18 pg/ml) and low calcitriol levels (10.6+/-4.3 pg/ml) compared with normal rats [N1: 14+/-2.5 pg/ml (P<0.001) and 18.2+/-4.2 pg/ml (P<0.01) respectively]. The pregnancy in CRF rats (CRF2) resulted in normalization of serum iPTH levels (18.2+/-5.41 pg/ml), which was associated with a parallel increase in serum calcitriol (29.4+/-8.0 pg/ml) similar to that in pregnancy of normal rats (N2). Two weeks after delivery the CRF rats (CRF3) once again had high serum iPTH (87+/-17 pg/ml) and low calcitriol levels (9.3+/-1.2 pg/ml), similar to those observed in non-pregnant uraemic rats (CRF1). It is concluded that pregnancy decreases serum iPTH in 5/6 nephrectomized CRF rats most probably by the increased level of calcitriol synthesized by the feto-placental unit.

Analysis of Variance↗
PubMed1999

Vertebrate left-right asymmetry: old studies and new insights.

During vertebrate embryonic development, the organs of the chest and abdomen, heart, lung and gastrointestinal tract, acquire characteristic asymmetric positions with respect to the left-right body axis. In the beginning of the 20th century Hans Spemann and his co-workers described manipulations of amphibian embryos which resulted in inversion of organ laterality in a predictable manner. Hedwig Wilhelmi concluded from these experiments that determinants on the left side of the embryo specify laterality, and Meyer postulated that a mediator should transfer this positional information to the forming heart. In this review we discuss the classical experiments in the light of recent advances in the molecular understanding of left-right development, with a focus on the mediator role of the homeobox gene Pitx2.

Amphibians↗
PubMed1999

Middle ear defects associated with the double knock out mutation of murine goosecoid and Msx1 genes.

A number of developmental regulatory genes, including homeobox genes, are dynamically expressed in the mammalian cephalic ectomesenchyme during craniofacial morphogenesis. Owing to the vast amount of gene knock out experiments, functions of such genes are now being revealed in the mammalian skeletal patterning process. The murine goosecoid (Gsc) and Msx1 genes are expressed during craniofacial development and each mutant mouse displays intriguing facial abnormalities including those of middle ear ossicles, suggesting that both genes play roles in spatial programming of craniofacial regions. In order to examine whether these genes could function in concert to direct particular craniofacial morphogenesis, double knock out mice were analyzed. The phenotype of the double mutant mice was restricted to the first arch derivatives and was apparently additive of the single gene mutant mice, implying region specific genetic interactions of these homeobox genes expressed in overlapping regions of middle ear forming ectomesenchyme. Our results also suggested that the patterning of distal portions of the malleus depends on the tympanic membrane, for which normal expressions of both the genes are prerequisite.

Animals↗
PubMed1999

Retinoic acid teratogenicity: the role of goosecoid and BMP-4.

Retinoic acid (RA) plays a pivotal role during vertebrate development, both as morphogen and as potent teratogen. While RA function in axial development has been extensively studied, little is known about the genetic control of RA teratogenicity. The knockout of the homeobox gene goosecoid in the mouse revealed similarities to RA induced embryopathy. We show that RA treatment of mouse gastrula embryos in vitro and of E10.5 embryos in utero led to a rapid but transient down-regulation of goosecoid expression. Repression was dependent on retinoid X receptors (RXR). BMP-4 was repressed by RA-treatment as well, both in embryos and in F9 teratocarcinoma cells. Our data suggest that both goosecoid and BMP-4 function as mediators of RA teratogenicity in mouse embryos.

Animals↗
PubMed1998

Induction of interleukin-1 associated with compensatory dopaminergic sprouting in the denervated striatum of young mice: model of aging and neurodegenerative disease.

Young mice challenged with the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which selectively destroys the substantia nigra dopaminergic neurons in the midbrain, exhibit spontaneous recovery of dopaminergic nerve terminals. However, such recovery becomes attenuated with age. Here we report that newly sprouted fibers originate from spared dopaminergic neurons in the ventral tegmental area. We found that interleukin-1 (IL-1), an immune response-generated cytokine that can enhance dopaminergic sprouting when exogenously applied, increased dramatically in the denervated striatum of young mice (2 months) compared with middle-aged mice (8 months) after MPTP treatment. Young mice displayed a maximal 500% induction of IL-1alpha synthesis that remained elevated for several weeks in the dorsal and ventral striatum, whereas middle-aged mice exhibited a modest 135% induction exclusively in the dorsal striatum for a week. IL-1alpha immunoreactivity was localized in GFAP-immunoreactive hypertrophied astrocytes and neurons within the denervated striatum of young mice. However, no induction of IL-1alpha mRNA was seen in the midbrain in either age group despite glial activation. Because we have reported that IL-1 can regulate astroglia-derived dopaminergic neurotrophic factors, it was surprising that no changes were observed in acidic and basic fibroblast growth factor or glial cell line-derived neurotrophic factor mRNA levels associated with MPTP-induced plasticity of dopaminergic neurons in the striatum of young mice. Interestingly, we found that dopaminergic neurons express IL-1 receptors, thus suggesting that IL-1alpha could directly act as a target-derived dopaminergic neurotrophic factor to initiate or enhance the sprouting of dopaminergic axonal terminals. These findings strongly suggest that IL-1alpha could play an important role in MPTP-induced plasticity of dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Negative autoregulation of the organizer-specific homeobox gene goosecoid.

The homeobox gene goosecoid has been implicated to play a central role in the Spemann organizer tissue of the vertebrate embryo. Misexpression of goosecoid on the ventral side of a Xenopus laevis gastrula embryo was shown to result in a partial duplication of the primary body axis, reminiscent of the Spemann organizer graft. Normal embryonic development thus requires tight temporal and spatial control of genes instrumental for organizer function. In the present study we investigated the transcriptional control of goosecoid gene expression. Sequence analysis of the mouse and human promoter region revealed the presence of two palindromic binding elements for homeobox genes of the prd type to which goosecoid belongs. We show that Goosecoid protein can bind to these sites in vitro. By using reporter gene constructs of the human and mouse promoter, we demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site. Our results suggest a role for goosecoid in restricting organizer activity in the vertebrate gastrula embryo.

Amino Acid Sequence↗
PubMed1998

Malformation of trachea and pelvic region in goosecoid mutant mice.

The homeobox gene goosecoid is expressed in the Spemann organizer tissue of gastrulating vertebrate embryos, and in the craniofacial region and appendicular skeleton during organogenesis. The goosecoid knockout mutant mouse revealed defects related to the second phase of expression. Here we describe new expression sites in the developing trachea and external genitalia, and in the developing shoulder and hip joint with their associated ligaments and muscles. We show that mutant mice display abnormalities in the forming trachea and appendicular skeleton related to these sites of gene expression. In addition, we discuss evidence for the existence of at least three goosecoid genes in vertebrates, which may account for the lack of a defect of axial patterning in goosecoid mutant mice.

Animals↗
PubMed1998

Acute intermittent nicotine treatment produces regional increases of basic fibroblast growth factor messenger RNA and protein in the tel- and diencephalon of the rat.

Several findings show a neuroprotective effect of nicotine treatment in different experimental models, and a negative correlation has been observed between cigarette smoking and the incidence of Parkinson's disease. It seems possible that nicotine may in part exert its neuroprotective actions by favouring the synthesis of neurotrophic factors. The aim of this study was to determine whether the nicotine treatment could be associated with the induction of a neurotrophic factor in brain regions with nicotinic receptors. Thus, we analysed by in situ hybridization and RNAse protection assay the effects of (-)nicotine on basic fibroblast growth factor messenger RNA and by immunocytochemistry fibroblast growth factor-2 protein in the tel- and diencephalon of rats following single or acute intermittent (-)nicotine treatment. The present results showed that acute intermittent (-)nicotine treatment (four i.p. injections at intervals of 30 min), but not single injections, lead to a substantial and dose-related (0.1-2 mg/kg) up-regulation of fibroblast growth factor-2 messenger RNA levels in the cerebral cortex, in the hippocampus, in the striatum and ventral midbrain. This induction of fibroblast growth factor-2 expression peaked 4 h after the first injection and returned to normal levels within 24 h. The change of fibroblast growth factor-2 messenger RNA levels was associated with increased fibroblast growth factor-2 immunoreactivity mainly localized to nerve cells. The treatment was effective also when repeated in the same animals three or five days after the first injection. The pre-treatment with the non-competitive (-)nicotine receptor antagonist mecamylamine blocked the (-)nicotine effects on fibroblast growth factor-2 messenger RNA levels. In the above areas, no changes were observed in the fibroblast growth factor-1, 2 and 3 receptor messenger RNA levels nor in brain-derived neurotrophic factor messenger RNA levels. The present data indicate an ability of intermittent (-)nicotine to increase fibroblast growth factor-2 in many tel- and diencephalic areas. In view of the trophic function of fibroblast growth factor-2, the previously observed neuroprotective effects of (-)nicotine may at least in part involve an activation of the neuronal fibroblast growth factor-2 signalling, and open up new avenues for treatment of Parkinson's disease and Alzheimer's disease based on the existence of nicotinic receptor subtypes enhancing fibroblast growth factor-2 signalling in many regions of the tel- and diencephalon.

Animals↗
PubMed1998

Expression of androgen receptor mRNA during mouse embryogenesis.

Androgen receptor (AR) is a member of the nuclear receptor superfamily which acts as a ligand-dependent transcription factor (Beato, M., Herrlich, P., Schütz, 1989. Steroid hormone receptors: many actors in search of a plot. Cell 83, 851-857). It plays a pivotal role in sexual development and reproduction (Wilson, J.D., Griffin, J.E., George, F.W., Leshin, M., 1981. The role of gonadal steroids in sexual differentiation. Rec. Prog. Horm. Res. 37, 1-39; Jost, A., 1990. Hormonal control of the masculinization of the body. In: Baulieu, E.E., Kelly, D.A., (Eds.), Hormones, from Molecules to Disease. Chapman and Hall, New York and London, pp. 439-442.). Mutations in the AR sequence cause a number of physiological disorders, such as partial and complete androgen insensitivity syndromes, that lead to abnormal sexual development (Patterson, M.N., McPhaul, M.J., Hughes, I.A., 1994. Androgen insensitivity syndrome. Ballière's Clin. Endocrinol. Metab. 8, 379-404.). There are indications that AR may also have other functions. For example, structural alterations of the AR sequence have been implicated in prostate cancer (Visakorpi, T., Huytinen, E., Koivisto, P., Tanner, M., Keinänen, R., Palmberg, C., Palotie, A., Tammela, T., Isola, J., Kallioniemi, O.-P., 1995. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet. 9, 401-406.) and in the development of spinal and bulbar muscular atrophy, a neurodegenerative disease (Kennedy, W.R., Alter, M., Sung, J.H., 1968. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 18, 671-680.). Here, we have investigated the spatial and temporal expression of AR during mouse organogenesis by in situ hybridisation. We demonstrate that AR transcripts occur in the developing external genitalia, pituitary, adrenals, kidneys and musculus levator ani, in addition to the known expression sites in the Wolffian ducts and its derivatives and during development of the mammary glands.

Animals↗
PubMed1998

A null mutation in TGF-alpha leads to a reduction in midbrain dopaminergic neurons in the substantia nigra.

Transforming growth factor (TGF)-alpha is neurotrophic for midbrain dopaminergic neurons in vitro. Here I investigated whether a null mutation in the TGF-alpha gene affects the normal development or survival of dopaminergic neurons in either the substantial nigra (SN) or the ventral tegmental area (VTA). The SN of TGF-alpha knockout mice contained 50% fewer dopaminergic neurons than the control SN, but VTA neuron number was unchanged. In addition, the overall volume of the dorsal striatum was reduced by 20%. Newborn mice showed a similar decrease in the number of SN dopaminergic neurons, suggesting that TGF-alpha is unlikely to regulate developmental neuron death. These studies indicate that TGF-alpha is required for the normal proliferation or differentiation of a select population of dopaminergic neurons within the SN.

Animals↗