The structure of the age pigment, lipofuscin, and its accumulation site in the human eye.
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Humans↗
Biomedical subjects
G Wolf
Publications and source records attributed to G Wolf.
TGF-beta stimulates rat mesangial cell proliferation in culture: role of PDGF beta-receptor expression.
Transforming growth factor (TGF)-beta is known to increase mesangial cell (MC) matrix; however, its possible role on MC proliferation is controversial. We therefore studied the influence of TGF-beta on MC proliferation in culture and evaluated its effect on the platelet-derived growth factor (PDGF) B-chain as well as the expression of the PDGF beta-receptor. TGF-beta (1 ng/ml) increases MC DNA synthesis by approximately threefold after 48 h of incubation. TGF-beta-induced MC proliferation was also confirmed by cell counts. A neutralizing anti-TGF-beta antibody completely blocked this growth promoting activity. The levels of PDGF beta-receptor steady-state mRNA were increased by TGF-beta at 48 h. This was associated with an increase in receptor density per cell as measured by receptor kinetic studies. PDGF B-chain mRNA was also increased by TGF-beta at 48 h. A neutralizing anti-PDGF B-antibody causes no reduction of TGF-beta-induced DNA synthesis; however, suramin completely inhibited the mitogenic effect of TGF-beta. We conclude that TGF-beta stimulates MC growth in long-term culture, a process in which upregulation of the PDGF beta-receptor and enhanced synthesis of PDGF B-chain might be involved.
Animals↗
[The clinically occult breast cancer. Screening and preoperative marking].
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Adult↗
Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta.
Previous studies by our group have demonstrated that angiotensin II (ANG II), as a single factor in serum-free medium, induces cellular hypertrophy of a cultured murine proximal tubular cell line (MCT). The present study was performed to test the hypothesis that this growth effect was mediated by activation of endogenous transforming growth factor-beta (TGF-beta). Exogenous TGF-beta 1 (1 ng/ml) mimicked the growth effects observed with 10(-8) M ANG II (inhibition of DNA synthesis and induction of cellular hypertrophy). A neutralizing anti-TGF-beta antibody attenuated the ANG II-induced increase in de novo protein and total RNA synthesis as well as total protein content. This antibody also abolished the ANG II-mediated inhibition of [3H]thymidine incorporation into quiescent MCT cells. Control IgG or an unrelated antibody had no effect. A bioassay for TGF-beta using mink lung epithelial cells revealed that MCT cells treated with ANG II released active TGF-beta into the cell culture supernatant. Northern blot analysis and semi-quantitative cDNA amplification demonstrated increases in steady-state levels for TGF-beta 1 mRNA after ANG II stimulation of MCT cells, but not in a syngeneic murine mesangial cell line. Our data indicate that the ANG II-induced hypertrophy in MCT cells is mediated by synthesis and activation of endogenous TGF-beta. It is intriguing to speculate that TGF-beta may play a role in the early tubular cell hypertrophy and the subsequent interstitial scarring observed in several models of chronic renal injury that are characterized by increased activity of intrarenal ANG II.
Angiotensin II↗
Development of the paranasal sinuses in children: implications for paranasal sinus surgery.
The pediatric nasal cavity and paranasal sinuses, when compared to those in adults, differ not only in size but also in proportion. Knowledge of the unique anatomy and pneumatization of children's sinuses is an important prerequisite to understanding the pathogenesis of sinusitis and its complications. It is also important in evaluation of radiographs and in planning surgical interventions. In order to study the development of the paranasal sinuses in children and relate clinical anatomy to sinus surgery, the sinuses in 102 pediatric skulls and cadaver heads were measured. The results were classified by stage of development into 4 different age groups: newborn and 1 to 4, 4 to 8, and 8 to 12 years. The characteristics of each group and their clinical importance for paranasal sinus surgery are described.
Child↗
Angiotensin II as a renal growth factor.
Angiotensin II (ANG II) can have multiple effects on the kidney, including influences on the regulation of glomerular hemodynamics and tubular transport as well as consequences for the glomerular processing of macromolecules. The recognized suppressive effects of angiotensin-converting enzyme inhibitors on compensatory renal growth, even in the absence of hemodynamic effects, and the well-documented proliferative effect of ANG II on vascular smooth muscle cells have provided the background for the recent intensive interest in this peptide as a renal cytokine. Diverse cell types along the nephron express a variety of ANG II receptors. These receptors and their putative signal transduction pathways have been best characterized in mesangial and proximal tubular cells. Culture experiments provide convincing evidence that ANG II can be a phenotypic influence on these cell types. The growth responses and the associated signal transduction pathways, however, are different in mesangial and proximal tubular cells. These ANG II-mediated responses are also associated with an increase in the synthesis of distinct collagen subtypes, potentially linking the growth stimulatory effects of ANG II to the irreversible changes of glomerulosclerosis and tubulointerstitial fibrosis observed in chronic renal failure. Preventing the intrarenal actions of ANG II with angiotensin-converting enzyme inhibitors or with the new, orally active, selective ANG II receptor antagonists may provide a rational therapeutic approach to attenuate the progression of a variety of kidney diseases.
Angiotensin II↗
Differential effects of ACE inhibitors and vasodilators on renal function curve in patients with primary hypertension.
OBJECTIVE: In experimental studies differential effects of antihypertensive agents on the renal function curve have been observed: in SHR captopril lowered the slope of the renal function curve, i.e. blood pressure (BP) became salt sensitive, whereas hydralazine shifted the curve without changing its slope. To evaluate whether ACE inhibitors and vasodilators have different effects on salt sensitivity of BP in humans, we compared the effect of the ACE inhibitor cilazapril and the vasodilator dihydralazine on the renal function curve in a randomized prospective single blind cross-over study. DESIGN: Nine patients (1 f, 8 m, mean age 41 +/- 4 y) with mild to moderate primary hypertension were put on low (20 mmol/d) and on high salt diet (200 mmol/d). Drugs were given in random low salt+cilazapril, high salt+cilazapril; low salt+dihydralazine, high salt+dihydralazine; or in reverse order. RESULTS: All antihypertensive interventions lowered BP, but the averaged posttreatment MAP was significantly (p < 0.02) lower with cilazapril on low salt intake (83.6 +/- 2.8 mmHg) than with all of the following: cilazapril on high salt intake (86.4 +/- 2.9 mmHg), dihydralazine on low (91.6 +/- 3.2 mmHg) and high salt (90.1 +/- 3.3 mmHg) intake. Probably as a result of sympathetic activation, average daily heart rate was higher after dihydralazine on low (72.9 +/- 2.9 b/min) and high salt intake (72.4 +/- 2.8 b/min) than after cilazapril on either salt intake (68.7 +/- 3.1 and 62.7 +/- 3.2 b/min). CONCLUSIONS: The results document that BP reduction after acute ACE inhibition is a function of salt intake, i.e. with ACE inhibitor therapy, BP is "salt sensitive". In contrast, vasodilators of the dihydralazine type have similar antihypertensive effects on low and high salt intake. To the extent that the findings of this short-term study can be extrapolated to long-term effects they suggest that intrarenal mechanisms, i.e. resetting of the pressure-natriuresis relationship, are involved in the long-term antihypertensive action of ACE inhibitors.
Adult↗
Oligomycin F, a new immunosuppressive homologue of oligomycin A.
Oligomycin F, a new homologue of oligomycin A (1), was isolated from a Streptomyces species and structure 2 was deduced by NMR methods. Compound 2 is highly active against plant pathogenic fungi and is an extremely potent suppressive agent for various immunological systems.
Animals↗
Angiotensin II stimulates cellular hypertrophy of LLC-PK1 cells through the AT1 receptor.
We have investigated possible growth-promoting effects of angiotensin II (ANG II) in the pig tubular epithelial cell line LLC-PK1. 10(-6)-10(-10) M ANG II inhibited proliferation as measured by [3H]thymidine incorporation. However, the same concentration of peptide induced tubular hypertrophy as assessed by increases in de novo protein synthesis, total protein, and RNA content. These effects were mediated through AT1 receptors. Furthermore, LLC-PK1 cells exhibited specific binding sites for ANG II and expressed mature mRNA for the vascular smooth muscle AT1 receptor. ANG II incubation of cells significantly lowered intracellular cAMP, and the hypertrophogenic action of ANG II was abolished by co-incubation with the relative stable analogue dibutyryl-cAMP, suggesting the involvement of intracellular nucleotides in the signal-transduction processes leading to hypertrophy. Our results collectively suggest that ANG II is a hypertrophogenic growth factor for LLC-PK1 cells. Considering the importance of tubular hypertrophy in the progression of renal failure in many models, strategies to block the action of ANG II on tubular cells may offer an attractive alternative way to control deterioration of renal function besides modulation of haemodynamics.
Angiotensin II↗
Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain.
Using a polymerase chain reaction-mediated approach we have characterized cDNAs from human and mouse origin representing a novel type of receptor protein tyrosine kinase (RTK). The deduced amino acid sequence (855 amino acids) of the longest open reading frame has a unique extracellular region encompassing a factor VIII-like domain, not previously described for RTKs. The most closely related RTKs are members of the neurotrophin receptors (TRK), which showed 47-49% homology with the kinase domain of the new RTK. Therefore, the new gene has been called TKT (Tyrosine-Kinase related to TRK). TKT orthologs from man and mouse were 98% similar. In both species a major transcript of 10 kb was found to be expressed at high levels in heart and lung. Low levels of this mRNA-species were detected in human brain, placenta, liver, skeletal muscle, kidney and in mouse brain and testis. Analysing human/mouse somatic cell hybrids we demonstrated that TKT segregates with human chromosome 1.
Amino Acid Sequence↗
PCR mediated detection of a new human receptor-tyrosine-kinase, HEK 2.
We have previously amplified cDNA subfragments of protein-tyrosine-kinases (PTKs) by using the polymerase chain reaction (PCR) and specific sets of oligonucleotide primers derived from nucleotide sequences of their kinase domain. In this study we have used a more directed approach to identify new members of the EPH/elk-family by PCR of human embryonic cDNA: we utilized oligonucleotide primers specifically designed to a highly conserved N-terminal motif and the kinase region of EPH/elk-PTKs in RNA-PCRs. The 5' and 3' elongation of the primary PCR product was achieved by the RACE (rapid amplification of cDNA ends)-technique. Sequence analysis of 3.8 kb of overlapping PCR products allowed to identify a novel receptor-PTK, HEK 2 (human embryo kinase 2), as an additional member of this family, without the need to screen a cDNA library. This approach should be useful for the rapid isolation of other PTK-genes as well. Analysis of genomic DNA placed HEK 2 on chromosome 3. Northern blot analysis demonstrated the expression of a 4.6 kb HEK 2-mRNA in lung, brain, pancreas, liver, placenta, kidney, skeletal muscle, heart and several human cells. In a protein kinase assay with HEK 2-specific immunoprecipitates from the human epidermoid carcinoma cell line A431, a protein of 130 kDa was found phosphorylated.
Amino Acid Sequence↗
[Long-term follow-up of Mobin-Uddin umbrella filter implantation for prevention of pulmonary embolism].
A follow-up of 40 cases of Mobin-Uddin-umbrella implants for prophylaxis of secondary pulmonary embolism is presented. The all-over lethality was 35% (14 patients) including one embolic recurrence. 25 patients could be re-examined 0.2-11.1 years after the implantation, using the patient's history, clinical examination, native X-ray of the umbrella, B-scan of the inferior vena cava, phlebodynamometry of the legs, spirometry, ergometry, manometry of the pulmonary artery pressure. Possible or probable recurrences of embolism were recorded in 15% (5 patients). The umbrella was totally occluded in 48% and partially occluded in 23%. Umbrella-related complications due to faulty insertion were not observed. Patients without additional cardiopulmonary diseases did not show pulmonary hypertension or ventilatory disorders at rest. 86% of the patients suffered from a symptomatical chronic venous insufficiency of one or both legs. Today the Mobin-Uddin-umbrella has been replaced by other percutaneously applicable cava filters. However, their application may also be followed by complications. Therefore the decision to use cava filters of any type should be based on severe selection criteria.
Adolescent↗
Angiotensin II as a hypertrophogenic cytokine for proximal tubular cells.
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Angiotensin II↗
[Localization of non-palpable lesions by mammography for preoperative marking and tissue removal].
Mammography screening can increase survival by 15-50%. Minute nonpalpable breast carcinomas can be detected and surgically removed using precise localization techniques. Various techniques are shown, including localization by means of grid mammography and conventional localization with several needles. Stereotactic localization is recommended if the focus cannot be detected by sonography--a procedure now almost always possible if mammography units have the necessary additional equipment. In future it will often become necessary, following a good response to pre-operative chemotherapy, for the tumor, which as a result has become nonpalpable, to be marked prior to surgery (e.g. remaining microcalcifications). This is essential if a representative area of tissue is to be made available for histological examination.
Breast Neoplasms↗
Nitric oxide synthase in rat brain is predominantly located at neuronal endoplasmic reticulum: an electron microscopic demonstration of NADPH-diaphorase activity.
Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) of the rat brain, apparently identical with nitric oxide (NO) synthase, was demonstrated at the electron microscopic level by means of the tetrazolium salt 2-(2'-benzothiazolyl)-5-styryl-3-(4'-phthalhydrazidyl)tetrazolium chloride (BSPT). BSPT is a non-osmiophilic compound that yields an insoluble, osmiophilic, and lipophobic formazan on reduction. The reaction product was deposited sharply on membranes of the endoplasmic reticulum including the nuclear envelope. Other membrane structures were, as a rule, free of reaction product, likewise mitochondria. Occasionally, however, the outer membrane of mitochondria was labeled, and their contents displayed a homogeneous, medium electron density. The findings suggest that NADPH-d, i.e. neuronal NO synthase, is a predominantly membrane-bound enzyme, which is ubiquitously distributed in cells of brain tissue, but highly concentrated in nerve cells described as 'NADPH-d-positive' at the light microscopic level.
Amino Acid Oxidoreductases↗
Memantine prevents quinolinic acid-induced hippocampal damage.
Memantine, used as a drug for treatment of spasticity and other extrapyramidal disorders as well as dementia, was shown to prevent brain damage caused by the glutamate (N-methyl-D-aspartate, NMDA) receptor agonist, quinolinic acid. Studies were focused on the hippocampal formation which is known to be highly vulnerable to quinolinate. Pretreatment of animals with memantine added to the food led to a reliable protection of hippocampal neurons when the drug was administered chronically for a period of 10 days prior to quinolinate exposure (i.c.v. injected). Additional i.p. administration of memantine (simultaneously with quinolinic acid or up to 24 h later) did not substantially add to the protective potency of the memantine diet. Our findings indicate that memantine may have beneficial effects in the treatment of brain disorders which are mediated by excitotoxic effects of glutamate.
Animals↗
The effect of sphingosine and phorbol ester on the signal transduction enzymes and fibronectin release in cell culture.
In testing the hypothesis that the stimulation of the release of fibronectin (FN) by 12-O-tetradecanoylphorbol 13-acetate (TPA) from human lung fibroblasts in culture is the result of activation of protein kinase C (PKC), we found that the PKC inhibitor sphingosine strongly inhibited FN release in presence and even in absence of TPA. However, a different PKC inhibitor, calphostin C, despite almost complete inhibition of PKC, had no effect on FN release. We concluded that sphingosine is a potent inhibitor of FN release from the cell surface, independent of its inhibition of PKC; and that TPA stimulates release of FN by a pathway other than activation of PKC. We found that the activation of PKC by TPA was accompanied by inhibition of the cAMP-dependent protein kinase (PKA). When PKA was inhibited by an antagonist (H8, a cAMP analogue) at a concentration specific for PKA inhibition, the release of FN was stimulated similar to the stimulation with TPA. Activation of PKA with forskolin resulted in decreased FN release. In conclusion, we have shown that: (1) sphingosine had a robust effect inhibiting the release of FN from fibroblasts, independent of its action on PKC; (2) TPA treatment of these cells resulted in inhibition of PKA; (3) inhibition of PKA stimulated FN release whereas its activation decreased this release. It is possible that PKA, by phosphorylating a protein, may function, directly or indirectly, in keeping FN attached to the cell surface of fibroblasts.
Cell Line↗
Unexpected, late cardiovascular effects of surgery for peripheral artery disease. Veterans Affairs Cooperative Study 199.
In reviewing late morbidity of a multicenter clinical trial comparing balloon angioplasty (percutaneous transluminal angioplasty) with bypass surgery for lower-extremity ischemia, an unexpectedly high incidence of adverse systemic events in surgical patients was uncovered. The study was prospective and randomized, and included a total of 263 patients, with follow-up from 2 to 6 years. When end points of related deaths, amputations, and intervention failures were summed, surgery was favored over percutaneous transluminal angioplasty at 4 years. Progression of cardiac and renal dysfunction and mortality differed between groups. A total of 42 deaths were in the group who underwent surgery and 27 in those who underwent percutaneous transluminal angioplasty. The percentage difference in death rate between the two groups increased each year to reach 10% at 5 years. A significant difference in renal function was noted in nine patients who underwent surgery and zero who underwent percutaneous transluminal angioplasty. Myocardial infarctions were greater on follow-up of surgical patients. After 6 years, congestive heart failure had occurred in 19 patients who underwent surgery and eight who underwent percutaneous transluminal angioplasty. The trends in this study of patients with only moderately severe peripheral arterial disease suggest an increased rate of deterioration of cardiac and renal function in patients who have arterial operations. In surgical patients, mortality was 13.1% per year, whereas it was 8.4% for patients treated with percutaneous transluminal angioplasty. Future intervention studies should include long-term follow-up of such cardiovascular events.
Amputation, Surgical↗