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Biomedical subjects

G Gross

Publications and source records attributed to G Gross.

At least 55 records · Page 3Linked to original sources
PubMed2001

Activation of c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) is critical for hypoxia-induced apoptosis of human malignant melanoma.

Mitogen-activated protein kinase (MAPK) signaling was examined in malignant melanoma cells exposed to hypoxia. Here we demonstrate that hypoxia induced a strong activation of the c-Jun NH2-terminal kinase (JNK), also termed stress-activated protein kinase (SAPK), in the melanoma cell line 530 in vitro. Other members of the MAPK family, e.g., extracellular signal-regulated kinase and p38, remained unaffected by the hypoxic stimulus. Activated JNK/SAPK could also be observed in the vicinity of hypoxic tumor areas in melanoma metastases as detected by immunohistochemistry. Functional analysis of JNK/SAPK activation in the melanoma cell line 530 revealed that activation of JNK/SAPK is involved in hypoxia-mediated tumor cell apoptosis. Both a dominant negative mutant of JNK/SAPK (SAPKbeta K-->R) and a dominant negative mutant of the immediate upstream activator of JNK/SAPK, SEK1 (SEK1 K-->R), inhibited hypoxia-induced apoptosis in transient transfection studies. In contrast, overexpression of the wild-type kinases had a slight proapoptotic effect. Inhibition of extracellular signal-regulated kinase and p38 pathways by the chemical inhibitors PD98058 and SB203580, respectively, had no effect on hypoxiainduced apoptosis. Under normoxic conditions, no influence on apoptosis regulation was observed after inhibition of all three MAPK pathways. In contrast to recent findings, JNK/SAPK activation did not correlate with Fas or Fas ligand (FasL) expression, suggesting that the Fas/FasL system is not involved in hypoxia-induced apoptosis in melanoma cells. Taken together, our data demonstrate that hypoxia-induced JNK/SAPK activation appears to play a critical role in apoptosis regulation of melanoma cells in vitro and in vivo, independent of the Fas/FasL system.

Apoptosis↗
PubMed2001

BMP signaling pathways in cartilage and bone formation.

This review focuses on the molecular aspects of osteogenesis and chondrogenesis as they relate to cellular and developmental levels. We discuss BMP (bone morphogenetic protein)-mediated signaling pathways for the patterning of skeletal elements and mechanisms for the induction of cartilage and bone formation. We emphasize BMP-mediated initiation of chondrogenesis and osteogenesis and consider BMP-dependent signaling cascades in mesenchymal progenitor cells during the development of the axial and appendicular skeleton and during growth plate and joint formation. In particular, we discuss BMP-signaling mediators of the Smad and TAK family and the modulation of these signals by cross-talk and integration with other signaling pathways.

Alkaline Phosphatase↗
PubMed2000

Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms.

BACKGROUND: Recently, homocysteine (HCY) levels have been suggested to be a risk factor in cardiac allograft vascular disease (CAVD). As plasma levels are partially under genetic control, we investigated the influence of the methylenetetrahydrofolate reductase (MTHFR) polymorphism on HCY levels and development of CAVD in heart transplant (HTX) recipients. METHODS: Genotyping and assessment of fasting HCY levels were performed in a cohort of 146 HTX recipients and correlated to the onset and progression of CAVD, assessed by serial angiography. RESULTS: Actuarial freedom from CAVD did not differ significantly between the genotypes. However, patients positive for CAVD presented with higher HCY levels than CAVD-negative individuals (21.0+/-9.4 vs. 18.2+/-6.6 micromol/L, P=0.046). CONCLUSIONS: There is some evidence that plasma HCY might be involved in development of CAVD. However, polymorphism of the MTHFR gene could not be shown to be related to severity of allograft vascular disease.

Adult↗
PubMed2000

Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control. OBJECTIVE: Our purpose was to compare the efficacy and safety of salmeterol 50 microg combined with fluticasone 100 microg (in a combination dry powder product) with that of placebo, fluticasone, or salmeterol alone. METHODS: A 12-week randomized, double-blind, multicenter study was conducted in 356 patients aged 12 years or older with asthma. After a 14-day screening period, patients were randomized to treatment with salmeterol 50 microg combined with fluticasone 100 microg (combination product), salmeterol 50 microg, fluticasone 100 microg, or placebo administered in the Diskus dry powder inhaler (GlaxoWellcome, UK) twice daily. RESULTS: Mean change in FEV(1) at end point was significantly (P < or =.003) greater with the combination product (0.51 L) compared with placebo (0.01 L), salmeterol (0.11 L), and fluticasone (0.28 L). The combination product significantly increased (P < or =.013) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo, salmeterol, and fluticasone at week 1 and week 12. Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups (P < or =.020). The combination product significantly increased (P < or =.012) morning PEF (combination, 52.5 L/min; placebo, -23.7 L/min; salmeterol, -1.7 L/min; fluticasone, 17.3 L/min) and evening PEF at end point compared with the other groups. The combination product significantly (P < or =.025) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol. All treatments were equally well tolerated. CONCLUSION: Salmeterol 50 microg and fluticasone 100 microg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses.

Administration, Inhalation↗
PubMed2000

An assistive device for the treatment of positional plagiocephaly.

An assistive device (AD) was used to treat 122 infants with moderate-to-severe positional plagiocephaly. Clinical evaluations indicate that the AD provided the most benefit when applied to 2- to 8-month-old children. Our results suggest that the AD may join molding helmets and physical therapy as a treatment for moderate-to-severe positional plagiocephaly in infants under the age of 1 year.

Craniosynostoses↗
PubMed2000

European course on HPV associated pathology: guidelines for primary care physicians for the diagnosis and management of anogenital warts.

The European Course on HPV Associated Pathology (ECHPV) was founded in 1990 by a group of clinicians, pathologists, and virologists to teach important principles for the practice and management of human papillomavirus (HPV) disease to gynaecologists, dermatologists, and other medical disciplines. These guidelines are intended to assist the practice of primary care physicians for diagnosis and treatment of anogenital warts.

Adjuvants, Immunologic↗
PubMed2000

Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse.

Prostaglandins (PGs) have proven important during parturition, but inhibition of PG production treating preterm labor (PTL) results in significant maternal and fetal side effects. We hypothesize that specific inhibition of either cyclooxygenase (COX)-1 or -2 may result in separation of therapeutic and toxic effects. We demonstrate that COX-2, but not COX-1, is induced during inflammation-mediated PTL caused by lipopolysaccharide (LPS) administration. A two- to threefold increase in uterine and ovarian PG concentrations coincides with this induction of COX-2. The COX-2-selective inhibitor SC-236 proved effective in stopping preterm delivery and the increases in PGs. The COX-1-selective inhibitor SC-560 also attenuated uterine and ovarian PG production after LPS but did not inhibit PTL as efficiently as SC-236. COX-1-deficient mice, which show delay in the onset of term labor, exhibited no delay in onset of PTL after LPS. These findings suggest that the mechanisms for initiation of inflammation-mediated PTL and term labor differ and that selective COX-2 inhibition may provide a means of stopping inflammation-induced PTL in humans.

Animals↗
PubMed2000

Anal verrucous carcinoma and penile condylomata acuminata.

A 50-year-old man presented with recurrent tumorous lesions on the penis and the anal region. The anal lesion was histologically diagnosed as verrucous carcinoma (VC) and the penile lesions were in line with condylomata acuminata. Samples taken from tumors of both sites were human papillomavirus (HPV) DNA positive. Two of them taken from the penis and the perianal region scored HPV DNA 6 positive by using polymerase chain reaction and the Southern blot method. Treatment of both VC and condylomata acuminata consisted in surgery and adjuvant immune therapy. Neither tumor recurrence nor metastases occurred up until 6 months after therapy.

Anus Neoplasms↗
PubMed2000

The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchymal progenitors C3H10T1/2.

The role of the bone morphogenetic protein (BMP)-signaling mediator Smad1 in osteogenic or chondrogenic differentiation was investigated in murine parental mesenchymal progenitors C3H10T1/2 and its derivatives constitutively expressing BMP-2 (C3H10T1/2-BMP-2) and, therefore, undergo BMP-mediated osteogenic/ chondrogenic development. The functions of the three Smad1 domains, that is, the N-terminal (MH1) domain, the C-terminal (MH2) domain, and the midregional proline-rich linker domain, were documented and compared with full-length Smadl. We showed that expression of the MH2 domain in parental C3H10T1/2 cells was sufficient to initiate osteogenic differentiation. Interestingly, MH1 was sufficient to initiate transcription of osteogenic marker genes like the osteocalcin or parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor. However, MH1 interfered with the histologically distinct formation of osteoblast-like cells. A dominant-negative effect on MH2-mediated osteogenic development in C3H10T1/2 cells was observed by the dose-dependent trans-expression of the midregional linker domain. Importantly, in contrast to osteogenic differentiation, Smad1 and its domains do not mimic or interfere with BMP-2-dependent chondrogenic development as monitored by the inability of MH2 to give rise to histologically distinct chondrocytes in parental C3H10T1/2 cells and by the inefficiency of the MH1 or linker domain to interfere with BMP-2-mediated chondrogenic differentiation.

Alkaline Phosphatase↗
PubMed1999

Apolipoprotein E (ApoE), a Bmp-2 (bone morphogenetic protein) upregulated gene in mesenchymal progenitors (C3H10T1/2), is highly expressed in murine embryonic development.

Apolipoprotein E (ApoE) was identified as upregulated by Bmp-2 (bone morphogenetic protein-2) in the murine mesenchymal progenitor cell line C3H10T1/2 by a subtractive cloning strategy. Expression of recombinant Bmps in mesenchymal C3H10T1/2 progenitors results in the differentiation into the osteogenic, the chondrogenic, and the adipogenic lineage. In addition, ApoE is also expressed in primary osteoblasts isolated from murine calvariae late in the in vitro osteoblast developmental sequence. To infer possible roles of ApoE in organogenesis and tissue differentiation, ApoE expression during mouse embryonic development was analyzed in murine midgestation and late embryonic development by in situ hybridization. ApoE is highly expressed at many sites of organ development (liver, brain, heart, eye, lung), probably in a subset of neural crest cells and ectodermal derivatives suggestive for important functions of ApoE during embryonic differentiation and organ development.

Animals↗
PubMed1999

Developmental expression analysis of murine autotaxin (ATX).

The murine homologue of the human motility-stimulating protein autotaxin (ATX) was identified as a BMP2 upregulated gene by subtractive cloning from mesenchymal progenitors C3H10T1/2 (Bächner, D., Ahrens, M., Betat, N., Schröder, D., Hoffmann. A., Lauber, J., Steinert, P., Flohe, L., Gross, G., 1998. Bmp-2 downstream targets in mesenchymal development identified by subtractive cloning from recombinant mesenchymal progenitors (C3H10T1/2). Dev. Dyn. 213, 398-411). ATX mRNA transcription is induced during BMP2 mediated osteo-/chondrogenic differentiation in vitro several orders of magnitude. To delineate a potential role for ATX in osteo-/chondrogenic development, its expression pattern during murine embryogenesis was examined in comparison with Col1a1 and Col2a1, a marker either of osteoblast, odontoblast and tendon or of chondrocyte development, respectively. Localization of murine ATX was first observed in the floor plate of the neural tube at day 9.5 of mouse embryonic development. Later, enhanced ATX expression levels were observed in proliferating subepithelial mesenchyme, during osteo-/chondrogenic and tooth development, in choroid plexus epithelium, in late kidney development, and in smooth muscles of the ductus deferens and the bladder.

Animals↗
PubMed1999

Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma.

BACKGROUND: The current stepwise approach to pharmacotherapy in the treatment of asthma includes the initiation of an inhaled corticosteroid with the addition of a long-acting inhaled bronchodilator if low dose inhaled corticosteroid fails to control asthma symptoms. OBJECTIVE: To determine whether initiation of salmeterol and fluticasone propionate treatment together improves asthma control greater than initiation of monotherapy with the individual agents alone with no additional safety risk in patients with asthma who had not previously been treated with inhaled corticosteroids. METHODS: A total of 136 male and female patients at least 12 years of age with asthma [forced expiratory volume in 1 second (FEV) between 50% and 80% of predicted] were randomized to twice daily salmeterol 42 microg, fluticasone propionate 88 microg, fluticasone propionate 220 microg, salmeterol 42 microg plus fluticasone propionate 88 microg, salmeterol 42 microg plus fluticasone propionate 220 microg, or placebo for 4 weeks. RESULTS: Patients treated with salmeterol combined with fluticasone propionate had improvements over baseline in FEV at endpoint that were at least twice as great (0.6 to 0.7 L) as improvements in patients treated with salmeterol (0.3 L) or fluticasone propionate alone (0.3 L) (P < .05). Patient-rated data (peak expiratory flow, asthma symptom scores, percent of days with no asthma symptoms) confirmed greater (P < .05) mean change from baseline improvements after combined treatment compared with fluticasone propionate alone. No clinically significant differences were noted between treatment groups in any safety measurement. CONCLUSION: Initiation of maintenance therapy with salmeterol and fluticasone propionate in patients with asthma treated with short-acting beta2-agonists alone provides greater improvements in pulmonary function and symptom control than initiation of maintenance therapy with fluticasone propionate alone.

Adolescent↗
PubMed1999

Diskus and diskhaler: efficacy and safety of fluticasone propionate via two dry powder inhalers in subjects with mild-to-moderate persistent asthma.

BACKGROUND: Fluticasone propionate is a topically active glucocorticoid with potent antiinflammatory activity in the treatment of asthma. OBJECTIVE: This study evaluated the safety and efficacy of fluticasone propionate administered via the Diskus and Diskhaler powder delivery devices in subjects with mild-to-moderate asthma. METHODS: Fluticasone propionate (500 microg twice daily) or placebo was administered via the Diskus and Diskhaler to 213 adolescent and adult asthma subjects in a randomized, double-blind, double-dummy, parallel-group study for 12 weeks. Subjects were stratified according to baseline therapy of inhaled corticosteroids or beta2-agonists alone. Subjects were dropped from the study if they met predefined criteria for lack of efficacy. RESULTS: Fluticasone propionate improved pulmonary function both in subjects previously treated with inhaled corticosteroids or beta2-agonists alone. At endpoint, fluticasone propionate significantly improved forced expiratory volume in 1 second (P < .001), morning and evening peak expiratory flow (P < .001), and asthma symptom scores (P < or = .016), and significantly reduced nighttime awakenings (P = .016; Diskhaler group only) and rescue albuterol use (P < .001). Overall, efficacy measurements for the Diskus and Diskhaler were similar. More placebo-treated subjects (34%) withdrew from the study due to lack of efficacy than subjects in the Diskus (5%) or Diskhaler (5%) groups. The incidence and severity of adverse events were similar across groups. Measurement of plasma fluticasone propionate and cortisol concentrations showed no apparent influence of device on systemic exposure. CONCLUSION: Fluticasone propionate powder, administered via the Diskus or Diskhaler inhalation devices, was well tolerated and effective in the treatment of mild-to-moderate persistent asthma.

Administration, Inhalation↗
PubMed1999

A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy.

Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA receptor-selective LU 112313 was the least selective compound in this model, indicating that non-NMDA antagonists acting at both AMPA and kainate receptors are more effective in this model than AMPA receptor-selective drugs. Three of the novel compounds, i.e. LU 97175, LU 115455 and LU 136541, exerted potent anticonvulsant effects without inducing motor impairment in the rotarod test. This combination of actions is thought to be a prerequisite for selective anticonvulsant drug action.

Amygdala↗