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Biomedical subjects

P Hertzog

Publications and source records attributed to P Hertzog.

At least 19 recordsLinked to original sources
PubMed2001

Ets-2 is induced by oxidative stress and sensitizes cells to H(2)O(2)-induced apoptosis: implications for Down's syndrome.

An elevated production of hydrogen peroxide mediates the increased rate of apoptosis of cells derived from individuals with Down's syndrome. The mechanism via which this occurs is unknown. Here we show that Ets-2, a transcription factor located on human chromosome 21 and already overexpressed in multiple tissues in Down syndrome (DS, trisomy 21), is induced by low concentrations of hydrogen peroxide. Moreover, cells with an imbalance in the antioxidant enzymes SOD-1/GPX-1, such as occurs in DS through the overexpression of the chromosome 21 gene SOD-1, also results in increased Ets-2 expression. The increase in Ets-2 expression is dependent on mRNA transcription. Importantly, we further demonstrate that 3T3 fibroblasts that overexpress Ets-2 are sensitized to hydrogen peroxide-induced apoptosis. These data implicate Ets-2 in the regulation of oxidant-induced apoptosis and provide a possible rationale for both the (5- to 7-) fold increase in Ets-2 protein level in DS tissues, above the expected gene dosage of 1.5-fold, and the elevated rate of apoptosis in DS cells.

Animals↗
PubMed2001

Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets.

Dendritic cells (DC) not only stimulate T cells effectively but are also producers of cytokines that have important immune regulatory functions. In this study we have extended information on the functional differences between DC subpopulations to include differences in the production of the major immune-directing cytokines IL-12, IFN-alpha, and IFN-gamma. Splenic CD4(-)8(+) DC were identified as the major IL-12 producers in response to microbiological or T cell stimuli when compared with splenic CD4(-)8(-) or CD4(+)8(-) DC; however, all three subsets of DC showed similar IL-12 regulation and responded with increased IL-12 p70 production if IL-4 was present during stimulation. High level CD8 expression also correlated with extent of IL-12 production for DC isolated from thymus and lymph nodes. By using gene knockout mice we ruled out any role for CD8alpha itself, or of priming by T cells, on the superior IL-12-producing capacity of the CD8(+) DC. Additionally, CD8(+) DC were identified as the major producers of IFN-alpha compared with the two CD8(-) DC subsets, a finding that suggests similarity to the human plasmacytoid DC lineage. In contrast, the CD4(-)8(-) DC produced much more IFN-gamma than the CD4(-)8(+) or the CD4(+)8(-) DC under all conditions tested.

Animals↗
PubMed2001

Desrt, an AT-rich interaction domain family transcription factor gene, is an early marker for nephrogenic mesoderm and is expressed dynamically during mouse limb development.

Desrt is a mouse gene of the AT-rich interaction domain family of transcription factors. Here we describe the temporal and spatial pattern of expression of Desrt during mouse organogenesis. Desrt expression is first detected in the intermediate plate mesoderm, providing an early embryonic marker for this tissue, and subsequently in the nephrogenic cords of the urogenital ridges. A highly dynamic expression pattern is observed in the developing limb, implicating Desrt in limb patterning. Desrt is also detected in the myotome of the somites, the oro-naso-pharyngeal ectoderm and underlying mesenchyme, otic vesicles, the gut and its derivatives, and transiently in the liver.

Animals↗
PubMed2001

Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury.

Glutathione peroxidase is an antioxidant enzyme that is involved in the control of cellular oxidative state. Recently, unregulated oxidative state has been implicated as detrimental to neural cell viability and involved in both acute and chronic neurodegeneration. In this study we have addressed the importance of a functional glutathione peroxidase in a mouse ischemia/reperfusion model. Two hours of focal cerebral ischemia followed by 24 h of reperfusion was induced via the intraluminal suture method. Infarct volume was increased three-fold in the glutathione peroxidase-1 (Gpx-1) -/- mouse compared with the wild-type mouse; this was mirrored by an increase in the level of apoptosis found at 24 h in the Gpx-1 -/- mouse compared with the wild-type mouse. Neuronal deficit scores correlated to the histologic data. We also found that activated caspase-3 expression is present at an earlier time point in the Gpx-1 -/- mice when compared with the wild-type mice, which suggests an enhanced susceptibility to apoptosis in the Gpx-1 -/- mouse. This is the first known report of such a dramatic increase, both temporally and in level of apoptosis in a mouse stroke model. Our results suggest that Gpx-1 plays an important regulatory role in the protection of neural cells in response to the extreme oxidative stress that is released during ischemia/reperfusion injury.

Animals↗
PubMed2001

Identification and characterization of alternatively spliced murine Rgs11 isoforms: genomic structure and gene analysis.

The RGS proteins comprise a large family of proteins which were recently identified as negative Regulators of G-protein Signaling. They have been shown to act as GTPase Activating Proteins (GAPs) towards the G(alpha) subunits of heterotrimeric G-proteins. In addition to this GAP activity, which has been shown to occur through the RGS domain, RGS proteins are likely to possess other functions due to the existence of other domains in these molecules (De Vries and Farquhar, 1999; Hepler, 1999). Here, we report the molecular characterization of the murine Rgs11 gene. The gene encodes a protein with high homology to human RGS11 (79.9%), containing conserved DEP (Dishevelled/EGL-10/Pleckstrin) and GGL (G protein gamma-like) domains. The gene is comprised of at least 13 exons, spanning 8-9 kb. Spliced transcript variants were identified which are co-expressed with 5A3, a transcript that contains the largest ORF. Expression of mouse Rgs11 was found to be restricted to specific tissues with a unique pattern of expression observed in brain.

Alternative Splicing↗
PubMed2000

Role of type I interferons during macrophage activation by lipopolysaccharide.

Activation of macrophages by bacterial lipopolysaccharide (LPS) is accompanied by the secretion of type I interferons (IFNs) which can act in an autocrine manner. We examined the role of type I IFNs in macrophage responses to LPS using bone marrow-derived macrophages (BMM) from IFNAR1-/- mice, which lack a component of the type I IFN receptor and do not respond to type I IFNs. We found that, unlike wild-type (WT) BMM, LPS-treated IFNAR1-/- cells failed to produce nitric oxide (NO), or express inducible NO synthase (iNOS), indicating that type I IFNs are essential for all LPS-stimulated NO production in BMM. Exogenously added type II IFN (IFNgamma) rescued these responses in LPS-treated IFNAR1-/- BMM. In contrast to effects on NO, type I IFNs negatively regulated respiratory burst activity in LPS-primed BMM. We also found that while type I IFNs mediated the anti-proliferative effects of lower concentrations of LPS, at higher concentrations LPS acted in a type I IFNs-independent manner. Finally, we report that type I IFNs are a survival factor for BMM. Despite this, the ability of LPS to also prevent apoptosis in BMM was independent of type I IFNs. These findings highlight the diverse roles of type I IFNs in mediating LPS-stimulated macrophage responses.

Animals↗
PubMed1999

Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization.

Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.

Animals↗
PubMed1998

Type I IFNs enhance the terminal differentiation of dendritic cells.

This study identifies type I IFNs as activating cytokines in a serum-free system in which human dendritic cells (DC) were generated from CD34+ progenitor cells. After 14 days of culture in GM-CSF, TNF-alpha, and IL-4, CD34+ progenitors gave rise to a population of large, immature DC expressing CD1a and CD11b but lacking CD14, CD80, CD83, CD86, and CMRF44. During the next 2 wk, this population spontaneously matured into nonadherent, CD1a(low/-), CD11b(low/-), CD14-, CD80+, CD83+, CD86+, CMRF44+ DC with high allostimulatory activity in the MLR. To examine which factors influenced this maturation, 25 different cytokines or factors were added to the immature DC culture. Only type I IFNs (alpha or beta) accelerated this maturation in a dose-dependent manner, so that after only 3 days the majority of large cells acquired the morphology, phenotype, and function characteristics of mature DC. Furthermore, supernatants from cultures containing spontaneously maturing DC revealed low levels of endogenous IFN production. Because of the similarity of the activation of DC in our culture system with the phenotypic and functional changes observed during Langerhans cells activation and migration in vivo, we investigated the effect of IFN-alpha on human Langerhans cell migration. IFN-alpha also activated the migration of human split skin-derived DC, demonstrating that this effect was not limited to DC derived in vitro from hemopoietic progenitor cells. DC activation by type I IFNs represents a novel mechanism of immunomodulation by these cytokines, which could be important during antiviral responses and autoimmune reactions.

Adjuvants, Immunologic↗
PubMed1998

Recent advances in cytokines, cytokine receptors and signal transduction.

The Fifth Annual Conference of the International Cytokine Society was held on November 9-13, 1997 at Lake Tahoe, Nevada. This meeting kept up with the tradition of exciting talks and posters, presenting significant advances in our understanding of the cytokine world. As we advance our knowledge, a complex network of interacting cellular communication pathways is revealed. Targeted disruption of genes coding for cytokines, their receptors and their cytoplasmic signaling molecules, became the standard method for a proper assessment of the role of a given cytokine in vivo. Yet, fundamental questions remain unresolved. For instance, it is not yet known how signal specificity is maintained when different cytokine receptors use the same cytoplasmic signaling pathways. The following summary is not comprehensive, rather, it is a collection of representative communications. Many more top quality studies were presented at the meeting and we apologize for not being able to review all of them here.

Animals↗
PubMed1998

Administration of imiquimod, an interferon inducer, in asymptomatic human immunodeficiency virus-infected persons to determine safety and biologic response modification.

A phase I study to determine safety, maximum tolerated dose, and biologic response during multiple once-a-week administration of oral imiquimod, an immune response modifier, was conducted in 12 adults with early human immunodeficiency virus (HIV) infection. All completed the dose-escalation phase of weekly dosing at 100-mg increments and received at least one maintenance dose, 100 mg below the patient's toxic dose, for 12 weeks. Dose-limiting toxicity occurred in 3 patients at 200-mg, 5 at 300-mg, and 3 at 400-mg dose levels. One tolerated the 500-mg dose without dose-limiting toxicity. Dose-limiting toxicities included fatigue, fever, malaise, increased transaminases, hypotension, vomiting, and depression. Seven of 12 completed 12 weeks of maintenance. At > or = 200 mg of imiquimod, all patients had biologic responses, measured by elevations in serum interferon, beta2-microglobulin, and neopterin levels. Imiquimod induced pronounced levels of circulating interferon in asymptomatic HIV-infected persons, with variable effect on virus load.

Administration, Oral↗
PubMed1982

[Diaphragmatic eventration in adults. Apropos of 20 cases].

Twenty adults with a mean age of 49 were operated on between 1972 and 1980 for eventration of the diaphragm. The etiology was probably traumatic in 11 cases; it was congenital in 2 and degenerative in 7. The functional signs were usually respiratory (55%) or digestive (10%). In all cases, the diagnosis was based on standard fluoroscopy showing superelevation of the hemidiaphragm, which was visualized fluoroscopically as immobile while a pneumoperitoneum showed a absense of any tear. Spirography confirmed a restrictive deficit which was sited broncho-spirometrically on the eventration side. Surgical repair was achieved in most cases by thoracotomy (19 cases) and consisted in plication (17 cases) or incision followed by suturing of the overlapping edges of the muscle (3 cases). Postoperative complications included the death of the patient with multiple trauma, on the eight postoperative day, as a result of the cerebrovascular accident, and in another case rutpure of the repair on the second day, requiring a second operation. Apart from one patient who died as a result of a fatal accident two years postoperatively, all the surgically treated cases are alive, and, with one exception, symptom free. After an average follow up period of 2 years and 2 months, the control respiratory function tests show a 21% improvement in vital capacity and a 20% increase in FEV1. On the basis of these results, the authors conclude that this functional surgery is justified in the case of patients presenting with typical clinical symptoms, and worth considering in cases where respiratory function tests show a restrictive deficit, but also in patients who do not complain of breathlessness.

Adult↗
PubMed1981

The apparent inhibition of urothelial DNA synthesis in neonatal rats by dietary saccharin.

[3H]Thymidine ([3H]TdR) incorporation into urothelial DNA of male neonatal rats was measured autoradiographically at birth and during the first 3 weeks of life. The rats were derived from control parents and those fed saccharin (1, 3, 5 and 7.5%) in the diet from before pregnancy. [3H]TdR incorporation was inhibited and there were more lightly labeled cells (compared with controls), in all the saccharin-exposed rats in a rough dose-dependent manner. The results, in comparison with controls, suggest that saccharin exposure in utero causes DNA damage in the neonatal urothelium manifesting as reduced thymidine incorporation and a greater proportion of lightly labeled cells.

Animals↗
PubMed1981

Differential effect of several inducers on hepatic and mammary benzo(A)pyrene metabolism in rat and hamster.

Rat and hamster mammary gland, in comparison with the liver, were examined for their in vitro ability to metabolize polycyclic aromatic hydrocarbons, and for the effects of pretreatment with various mixed function oxidase inducers on this metabolism. Hamster mammary microsomal benzo(a)pyrene (BP) hydroxylase activity was 4-fold greater than that in the rat, and this activity was induced 3- to 5-fold in the hamster, and 7- to 13-fold in the rat, by pretreatment with 7,12-dimethylbenz(a)anthracene, beta-naphthoflavone, Aroclor 1254 or 3-methylcholanthrene. Hamster hepatic microsomal BP-hydroxylase activity was 80-fold greater than in the rat. Whereas pretreatment with these enzyme inducers enhanced rat hepatic activity by 20- to 30-fold, little effect of "inducers" was observed on the hamster hepatic enzyme, even when the formation of the various BP metabolites was determined by high pressure liquid chromatography.

Animals↗