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Biomedical subjects

G W Nietgen

Publications and source records attributed to G W Nietgen.

12 recordsLinked to original sources
PubMed2001

[Therapy of radiation resistant malignant uveal melanoma with endoresection by pars plana vitrectomy in two patients].

BACKGROUND: Since introduction of brachytherapy using (106)ruthenium plaque therapy for treating malignant choroidal melanomas a number of comparative studies have shown that survival rates are equal between patients who underwent radiation or enucleation. When radiation treatment fails, the patient might be determined to choose removal of the tumor by pars plana vitrectomy. PATIENTS AND METHODS: Between 1995 and 1998 a total number of 48 patients underwent (106)ruthenium plaque irradiation. In 9 patients tumor regression was not sufficient. Two of these nine patients decided explicitly against enucleation and choose to have the tumor removed from within the eye employing pars plana vitrectomy. RESULTS: Intraoperatively, the previously radiated melanoma was easily removed with the vitrectomy cutter without significant bleeding. Postoperative recovery was without complications. Silicone oil removal was carried out in one patient after one year. Vision 9 months and 2.5 years after surgery was 0.2 and 0.02, respectively. The cosmetic results with parallel axis of the globes were very good and one patient gained binocular vision. No recurrent tumor growth was seen so far. Histologically, no mitotic figures were found. CONCLUSION: Malignant choroidal melanomas can be safely removed by pars plana vitrectomy with stable intraocular pressure. Previous radiation therapy alters the tumor, inducing fibrous tissue growth and necrosis of tumor cells. These tissue types are not prone to bleed when they are resected by the vitrectomy cutter. Long time studies have to elucidate the difference in survival rates between patients undergoing enucleation of the eye and patients who chose endoresection of the melanoma by pars plana vitrectomy.

Adult↗
PubMed1999

[Self-sealing, sutureless sclerotomy in pars plana vitrectomy].

BACKGROUND: If sutures are used in the regular closure of sclerotomies a trauma to the bulbus can be inflicted and intraocular bleeding might result. Phases of intraocular hypotony accompany the intraoperative exchange of instruments. Like in no-stitch cataract surgery we employed this type of self-sealing wound closure in pars-plana vitrectomies. A less traumatizing technique yielding a tight and effective closure is an alternative to the conventional approach and results of our experiences are presented. MATERIALS AND METHODS: A modified approach for sutureless sclerotomy closure was applied in 50 eyes (150 sclerotomies). A sclera-covered sclerotomy is performed after preparation of adequate scleral pouches in conventional positions. A minimal conjunctival peritomy allows at the end of surgery an electric cauterization, thus using no suture material in the whole course of vitrectomy. RESULTS: Sutureless vitrectomies can only be installed in the primary operation. However, re-operations on 3 eyes were possible in the same manner using the old sclerotomy sites up to 6 weeks after initial surgery. In 12 eyes the sclerotomy had to be covered with a single suture to obtain adequate wound closure. A repetitive change of instruments during the surgical procedure is possible with this technique and all types of intraocular instruments can be employed. CONCLUSIONS: Self-sealing sclerotomies are a simple and atraumatic approach for wound closure in pars-plana vitrectomies and allow a control of intraocular pressure during surgery.

Follow-Up Studies↗
PubMed1998

Influence of anesthetics on endogenous and recombinantly expressed G protein-coupled receptors in the Xenopus oocyte.

1. The oocyte of the African clawed toad (Xenopus laevis) offers a reliable, sensitive and disease resistant system to investigate recombinantly and endogenously expressed Ca2+ signaling G protein-coupled receptors and their intracellular signaling pathways. 2. To study receptor induced Ca2+ release, two-electrode voltage clamping can quantify a Ca2+-activated transmembrane Cl- current. Intracellular steps of the signaling pathway can be inhibited by injections of EDTA or heparin into the oocyte. Components of the intracellular pathway can be activated directly by GTPgammaS or IP3 injection. 3. We have investigated the effects of volatile, local and i.v. anesthetics on the signaling properties of the endogenous lysophosphatidate receptor and on mammalian receptors expressed recombinantly by intracellular injection of the encoding mRNA or cDNA. A number of receptors are sensitive to these anesthetics. Anesthetics interact with muscarinic, thromboxane A2 and lysophosphatidate signaling. 4. Investigations of the intracellular pathways revealed that the receptor or the receptor-G protein coupling is affected primarily and that mechanisms further downstream are not influenced by the various types of anesthetics.

Anesthetics↗
PubMed1998

Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function.

Muscarinic acetylcholine signalling plays major roles in regulation of consciousness, cognitive functioning, pain perception and circulatory homeostasis. Halothane has been shown to inhibit m1 muscarinic signalling. However, no comparative data are available for desflurane, sevoflurane or isoflurane, nor have the anaesthetic effects on the m3 subtype (which is also prominent in the brain) been studied. Therefore, we have investigated the effects of these compounds on isolated m1 and m3 muscarinic receptor function. Defolliculated Xenopus oocytes expressing recombinant m1 or m3 muscarinic or (for comparison) AT1A angiotensin II receptors were voltage clamped, and Ca(2+)-activated Cl- currents (ICl(Ca)) induced by acetyl-beta-methylcholine (Mch) or angiotensin II were measured in the presence of clinically relevant concentrations of halothane, sevoflurane, desflurane or isoflurane. To determine the site of action of the volatile anaesthetics we compared anaesthetic effects on m1, m3 and AT1A receptor function and studied the effects of volatile anaesthetics on signalling induced by intracellular injection of the second messenger IP3. Desflurane had a biphasic effect on m1 signalling, enhancing at a concentration of 0.46 mmol litre-1 but depressing at 0.92 mmol litre-1. A similar, although not significant, trend was observed with m3 signalling. Isoflurane had no effect on m1 signalling, but profoundly inhibited m3 signalling. Sevoflurane depressed the function of m1 and m3 signalling in a dose-dependent manner. Halothane, similar to its known effect on m1 signalling, dose-dependently depressed m3 function. ICl(Ca) induced by intracellular injections of IP3 were unaffected by all four anaesthetics. Similarly, none of the anaesthetics tested affected AT1A signalling. Absence of interference with AT1A signalling and intracellular pathways suggest that the effects of anaesthetics on muscarinic signalling most likely result from interactions with the m1 or m3 receptor molecule. Multiple interaction sites with different affinities may explain the biphasic response to desflurane. Anaesthetic-specific effects on closely related receptor subtypes suggest defined sites of action for volatile anaesthetics on the receptor protein.

Anesthetics, Inhalation↗
PubMed1998

Influence of volatile anesthetics on thromboxane A2 signaling.

BACKGROUND: Thromboxane A2 (TXA2) is a member of the prostaglandin family; activation of its receptor induces several important effects, including platelet aggregation and smooth muscle contraction. Because volatile anesthetics interfere with aggregation and contraction, the authors investigated effects of halothane, isoflurane, and sevoflurane on TXA2 signaling in an isolated receptor model. METHODS: mRNA encoding TXA2 receptors was prepared in vitro and expressed in Xenopus oocytes. The effects of halothane, isoflurane, and sevoflurane on Ca2+-activated Cl- currents induced by the TXA2 agonist U-46619 and on those induced by intracellular injection of inositol 1-4-5 trisphosphate or guanosine 5'-O-(2-thiodiphosphate) were measured using the voltage-clamp technique. RESULTS: Expressed TXA2 receptors were functional (half maximal effect concentration [EC50], 3.2 x 10(-7) +/- 1.1 x 10(-7) M; Hill coefficient (h), 0.8 +/- 0.2). Halothane and isoflurane inhibition of TXA2 signaling was reversible and concentration dependent (halothane half maximal inhibitory concentration [IC50], 0.46 +/- 0.04 mM; h, 1.6 +/- 0.21; isoflurane IC50, 0.69 +/- 0.12 mM; h, 1.3 +/- 0.27). 0.56 mM halothane (1%) right-shifted the U-46619 concentration-response relationship by two orders of magnitude (EC50, 1 x 10[-5] M). That h and maximal effect (Emax) were unchanged indicates that halothane acts in a competitive manner. In contrast, isoflurane acted noncompetitively, decreasing Emax by 30% (h and EC50 were unchanged). Both halothane and isoflurane had no effect on intracellular signaling pathways. Sevoflurane (0-1.3 mM) did not affect TXA2 signaling. CONCLUSIONS: Both halothane and isoflurane inhibit TXA2 signaling at the membrane receptor, but by different mechanisms. This suggests that the effects of these anesthetics on TXA2 signaling are evoked at different locations of the receptor protein: halothane probably acts at the ligand binding site and isoflurane at an allosteric site.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Intercellular signaling by lysophosphatidate.

Lysophosphatidate (LPA) is an intercellular phospholipid messenger with a wide range of biologic effects. The first discovered source of LPA in the human body were activated platelets, but several other sites of LPA generation are now known. The number of cellular interactions is also growing steadily and responses to the compound range wide, from induction of mitogenesis to neurite retraction. LPA acts via a specific G protein-coupled receptor, of which one or more subtypes may exist. Intracellularly, this receptor activates several heterotrimeric G proteins. LPA induces cell proliferation via the small GTP-binding proteins ras, and triggers actin-based cytoskeletal events through rho. This review describes the most relevant recent developments in our understanding of LPA signaling.

Eukaryotic Cells↗
PubMed1997

Inhibition of lysophosphatidate signaling by lidocaine and bupivacaine.

BACKGROUND: Lidocaine and bupivacaine impair wound healing, but the mechanism of this side effect has not been determined. The phospholipid messenger lysophosphatidate is released from activated platelets and induces fibroblast and smooth muscle proliferation. Because it may play a role in wound healing, the authors studied the effects of local anesthetics on lysophosphatidate signaling in Xenopus oocytes. METHODS: Defolliculated Xenopus oocytes expressing endogenous G protein-coupled lysophosphatidate receptors were voltage clamped and studied in the presence or absence of lidocaine or bupivacaine. Lysophosphatidate-induced Ca(2+)-activated Cl- currents (IC1(Ca)) were measured. To determine the site of action of the local anesthetics on the signaling pathway, the authors studied 1) the effects of local anesthetics on signaling induced by intracellular injection of the second messenger inositoltrisphosphate, and 2) the effects of local anesthetics on functioning of recombinantly expressed angiotensin II receptor signaling through the same pathways as the lysophosphatidate receptor. RESULTS: Lysophosphatidate signaling was inhibited in the presence of local anesthetics. The half maximal inhibitory concentration (IC50S) for lidocaine and bupivacaine were 29.6 mM and 4.7 mM, respectively. Neither responses induced by inositoltrisphosphate injection nor angiotensin signaling were influenced by local anesthetics. CONCLUSIONS: Lysophosphatidate signaling is inhibited by the extracellular application of lidocaine or bupivacaine. In contrast, inositoltrisphosphate or angiotensin signaling was not affected by local anesthetics. Therefore local anesthetics have a specific, extracellular effect on lysophosphatidate receptor functioning. As the local anesthetic concentrations used were similar to those observed after injection around surgical wounds, LP inhibition may play a role in the observed detrimental effects of local anesthetics on wound healing.

Anesthetics, Local↗
PubMed1997

Synergistic inhibition of muscarinic signaling by ketamine stereoisomers and the preservative benzethonium chloride.

BACKGROUND: Ketamine (Ketalar; Parke-Davis, Morris Plains, NJ) has been shown to inhibit muscarinic signaling with a median inhibitory concentration (IC50) of 5.7 microM. Whereas Ketalar is a racemic mixture, recent interest has focused on clinical use of the S(+) ketamine isomer, which is three times as potent an analgesic as the R(-) isomer yet seems to be associated with fewer psychoactive side effects. Therefore, the authors studied the effects of S(+) and R(-) ketamine and the preservative benzethonium chloride on muscarinic signaling. METHODS: Rat ml muscarinic acetylcholine receptors were expressed recombinantly in Xenopus laevis oocytes. Ca2(+)-activated Cl- currents in response to 10(-7) M acetyl-beta-methylcholine were determined by two-electrode voltage clamping in the presence of various concentrations of ketamine and benzethonium. Concentration-inhibition curves were constructed and used for algebraic and isobolographic analysis. RESULTS: The IC50. was 125 +/- 33 microM for S(+) ketamine, and 91 +/- 19 microM for R(-) ketamine. This difference was not statistically significant, indicating that muscarinic inhibition by ketamine is not stereoselective. The R(-)/S(+) mixture had an IC50 of 48 +/- 1 microM, and thus the stereoisomers interact synergistically. When appropriate concentrations of benzethonium were added, an IC50 of 15 +/- 2 microM resulted. CONCLUSIONS: The muscarinic inhibitory action of ketamine isomers is not stereoselective. Because S(+) ketamine is a significantly more potent analgesic, it should have less muscarinic inhibitory action than R(-) ketamine when used in clinically equivalent doses. A significant fraction of the muscarinic inhibitory action of Ketalar is due to the preservative benzethonium. If reconstituted with a different preservative, Ketalar might be a less potent muscarinic antagonist.

Animals↗
PubMed1992

Intrahepatic bile duct loss in biliary atresia despite portoenterostomy: a consequence of ongoing obstruction?

The histological and immunohistochemical characteristics of the liver in 44 children (28 boys, 16 girls) with extrahepatic biliary atresia at different stages of the clinical course were studied. Thirty-four wedge liver biopsy specimens taken during Kasai operations (25 specimens) and relaparotomy (9 specimens) and 20 hepatectomy explants taken at the time of transplantation were examined. Routine histological stains and monoclonal antibodies against different molecular weight cytokeratins and HLA-DR were used. The histopathological changes and the pattern of cytokeratin expression observed during the course of the disease were suggestive of persistent or recurrent extrahepatic biliary obstruction that occurred despite the Kasai operation and eventually led to cirrhosis and liver failure. Quantitative studies showed a progressive loss of intrahepatic bile ducts over the time course of the disease. This destruction of bile ducts had a geographic anatomical distribution in hepatectomy specimens, and in two livers it occurred predominantly in only one lobe. This geographic distribution of the vanishing bile ducts probably indicates an unpredictable and uneven obliteration of bile ducts in the porta hepatis during portoenterostomy wound healing and scarring.

Bile Ducts, Intrahepatic↗