Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized... more Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized that show excellent in vitro efficacy in protecting acetylcholinesterase (AChE) from inhibition by a broad variety of organophosphorus compounds (OPCs). However, oximes themselves are also AChE inhibitors, albeit at higher concentrations, which is a major cause of their toxicity and may be a dose-limiting factor in oxime therapy. To assess the efficacy of the experimental K-oximes in vivo, the extent of oxime-conferred protection from mortality induced by paraoxon was quantified. Rats received paraoxon in a dosage of 1, 5, or 10 mumol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD(01). The relative risk of death (RR) over time was estimated by Cox survival analysis for treatment with experimental K-oximes (K-53, K-74, K-75, K-107, K-108, and K-113), with the clinically available oximes pralidoxime (2-PAM) and obidoxime, and with the well-characterized K-oximes K-27 and K-48, comparing results with the no-treatment group. Best protection was conferred by K-27, reducing the RR to 20% of controls (P </= 0.05), which was significantly (P <or= 0.05) better than all other tested oximes. Marked reduction in mortality was also achieved by K-48 and the three new bispyridinium oximes containing two aldoxime groups, but no xylene linker: K-48 (RR = 0.32), K-53 (RR = 0.36), K-74 (RR = 0.42), K-75 (RR = 0.35). This effect was significantly (P <or= 0.05) superior to that of all other oximes, except K-27. The remaining oximes, i.e., obidoxime (RR = 0.64), 2-PAM (RR = 0.78), K-107 (RR = 0.70), K-108 (RR = 0.77), and K-113 (RR = 0.87) reduced paraoxon-induced mortality only poorly, but significantly (P <or= 0.05). Our data show that K-27, K-48, K-53, K-74, and K-75, due to their far superior in vivo efficacy, are the most promising candidates to eventually replace the established oximes 2-PAM and obidoxime. Further studies in other species exposed to a broader spectrum of OPCs are, however, necessary before considering their use in humans.
Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect agai... more Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of organophosphorus compounds (OPCs). The usefulness of pyridostigmine, the only compound approved by the Food and Drug Administration (FDA) for such pretreatment, has been questioned. In search for more efficacious alternatives, we have examined in vivo the efficacy of a group of ten compounds with known anti-AChE activity (pyridostigmine, metoclopramide, tiapride, ranitidine, physostigmine, tacrine, amiloride, methylene blue, 7- methoxytacrine and K-27) to reduce mortality induced by the OPC methyl-paraoxon. AChE inhibitors were given intraperitoneally in equitoxic dosage (25% of LD₀₁) 30 min before OPC exposure. Protection was quantified in rats by determining the relative risk of death (RR) by Cox analysis, with RR=1 for animals given only methyl-paraoxon, but no pretreatment. Only physostigmine (RR=0.39), K-27 (RR=0.40) and tacrine (RR=0.48) significantly (p≤ 0.05) reduced methylparaoxon- induced mortality, when given prophylactically. Pretreatment with pyridostigmine, ranitidine, tiapride, amiloride, metoclopramide and methylene blue did not significantly protect against the lethal effects of methyl-paraoxon. 7-methoxytacrine (7-MEOTA) significantly (p≤ 0.05) increased the relative risk of methyl-paraoxon-induced death (RR=1.31). These results indicate that pretreatment with pyridostigmine cannot be considered a broad-spectrum approach against OPC exposure. K-27 may be a suitable alternative if passage into the brain is contraindicated.
Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mo... more Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01 ) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p ≤ 0.05) as compared with the non-treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option.
ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects... more ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects in the treatment of Alzheimer disease. However, its exact mechanisms of action have not been fully elucidated. The modulation of nicotinic acetylcholine receptors (nAChRs) has been suggested to play a role in the pathogenesis of various neurodegenerative diseases. Therefore, in the present study, the effect of MB on the function of the cloned α7 subunit of the human nAChR expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. MB reversibly inhibited ACh (100 μM)-induced currents in a concentration-dependent manner with an IC50 value of 3.4 ± 0.3 µM. The effect of MB was not dependent on the membrane potential. MB did not affect the activity of endogenous Ca2+-dependent Cl- channels, since the inhibition by MB was unaltered in oocytes injected with the Ca2+ chelator 1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid and perfused with Ca2+-free bathing solution containing 2 mM Ba2+. MB decreased the maximal ACh-induced responses without significantly affecting ACh potency. Furthermore, specific binding of [125I] α-bungarotoxin, a radioligand selective for the α7 nAChR, was not altered by MB (10 µM), indicating that MB acts as a noncompetitive antagonist on α7 nAChRs. In hippocampal slices, whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the γ-aminobutyric acid-mediated spontaneous postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for α7 nAChRs, were abolished after 10 min application of 3 μM MB. These results demonstrate that MB inhibits the function of human α7 nAChRs expressed in Xenopus oocytes and of α7 nAChR-mediated responses in rat hippocampal neurons.
Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridiniu... more Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) propane dibromide] and K-48 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], show good in vitro efficacy in protecting acetylcholinesterase from inhibition by different organophosphorus compounds (OPCs), including nerve agents. To assess their efficacy in vivo, the extent of oxime-conferred protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified and compared with that of five established oximes. Materials and Methods. Rats received DFP intraperitoneally in a dosage of 6, 8, or 10 micromol/rat and immediately thereafter intraperitoneal injections of K-27, K-48, pralidoxime, obidoxime, trimedoxime, methoxime, or HI-6. The relative risk (RR) of death over time (48 h) was estimated by Cox survival analysis, comparing results with the no-treatment group. Results. Best protection was observed when K-27 was used, reducing the RR of death to 19% of control RR (p < or = 0.005), whereas obidoxime (RR = 26%, p < or = 0.01), K-48 (RR = 29%, p < or = 0.005) and methoxime (RR = 26%, p < or = 0.005) were comparable. The RR of death was reduced only to about 35% of control by HI-6, to 45% by trimedoxime, and to 59% by 2-PAM (p < or = 0.005). Whereas the differences between the best oximes (K-27, obidoxime, methoxime, and K-48) were not statistically significant; these four oximes were significantly more effective than 2-PAM (p < or = 0.05). The efficacy of K-27 was also significantly higher than that of HI-6, trimedoxime, and 2-PAM (p < or = 0.05). Conclusion. Our data provide further evidence that K-27 is a very promising candidate for the treatment of intoxication with a broad spectrum of OPCs.
ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects... more ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects in the treatment of Alzheimer disease. However, its exact mechanisms of action have not been fully elucidated. The modulation of nicotinic acetylcholine receptors (nAChRs) has been suggested to play a role in the pathogenesis of various neurodegenerative diseases. Therefore, in the present study, the effect of MB on the function of the cloned α7 subunit of the human nAChR expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. MB reversibly inhibited ACh (100 μM)-induced currents in a concentration-dependent manner with an IC50 value of 3.4 ± 0.3 µM. The effect of MB was not dependent on the membrane potential. MB did not affect the activity of endogenous Ca2+-dependent Cl- channels, since the inhibition by MB was unaltered in oocytes injected with the Ca2+ chelator 1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid and perfused with Ca2+-free bathing solution containing 2 mM Ba2+. MB decreased the maximal ACh-induced responses without significantly affecting ACh potency. Furthermore, specific binding of [125I] α-bungarotoxin, a radioligand selective for the α7 nAChR, was not altered by MB (10 µM), indicating that MB acts as a noncompetitive antagonist on α7 nAChRs. In hippocampal slices, whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the γ-aminobutyric acid-mediated spontaneous postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for α7 nAChRs, were abolished after 10 min application of 3 μM MB. These results demonstrate that MB inhibits the function of human α7 nAChRs expressed in Xenopus oocytes and of α7 nAChR-mediated responses in rat hippocampal neurons.
The effects of three types of behavior on c-fos activation in different brain regions of the muds... more The effects of three types of behavior on c-fos activation in different brain regions of the mudskipper, Periophthalmus cantonensis, were studied by immunocytochemistry. Animals were divided into four groups: The control group did not undergo any specific treatment. The second group consisted of animals that were agitated for an hour with a glass rod at an irregular speed. The third group contained animals showing aggressive behavior during an hour of monitoring, i.e. documented territorial hostility by raising of dorsal fins and pursuit of intruders. In contrast to these three groups, which had last been fed 24h earlier, the fourth group included animals that had been nourished 1h prior to sacrifice. Results showed that, in most brain regions of control animals, there were relatively few c-fos positive cells. After fish had been agitated, however, very prominent c-fos label was seen in the lateral and medial parts of the telencephalon, the thalamus, hypothalamus, pituitary and medulla. In aggressive fish, a significant increase in the number of c-fos positive sites, as compared to control fish, was observed in the diencephalons, pons and medulla, but not in the telencephalon. After feeding, there was a less substantial increase in c-fos protein expression in the diencephalon, but an even more prominent c-fos activation in the pons and medulla. Our present results support the hypothesis that, in fish, the medial telencephalon is involved in avoidance reaction and the lateral telencephalon in spatial memory, whereas rhombencephalic activation may reflect activity of cranial nerve nuclei.
Journal of Cancer Research and Clinical Oncology, 1985
In order to study structural changes in the lymph node architecture in the course of metastatic i... more In order to study structural changes in the lymph node architecture in the course of metastatic involvement by carcinoma, 70 axillary lymph nodes of 45 female patients affected by breast carcinoma were examined. The following growth pattern of the metastasis was observed: (1) Involvement of vasa afferentia and (marginal) sinuses; (2) lysis of sinus wall and infiltration, causing replacement and lysis of reticulin fibres; (3) appearance of fibrillary fibronectin (FN) as the first noticeable sign of tumor stroma; (4) immigration of fibroblasts along these fibres, appearance of argyrophilic fibres codistributed with fibrillary FN; (5) formation of the complete tumor stroma, neovessels included. The appearance of FN is thus the first step of stroma formation and is interpreted as an "in situ" precipitation of soluble plasma FN.
Trisomy 19 (ts19) of the mouse permits detailed studies on the influence of an extra autosome upo... more Trisomy 19 (ts19) of the mouse permits detailed studies on the influence of an extra autosome upon the postnatal development of the central nervous system. To examine gliogenesis and myelinogenesis, the optic nerves of 19 ts19 pugs aged 1-15 days have been examined by light and electron microscopy and compared to those of litter-mate controls. Differentiation of astrocytes and oligodendrocytes, myelinogenesis as well as the opening of the eyes are each delayed by about 2 days. Myelin sheaths are normally structured in ts19. There is a decrease in the percentage of myelinated fibres. The cross-sectional area of the ts19 optic nerve is reduced. The fibre density, which decreases with age both in ts19 and control mice, is higher in ts19 mice. Both with ts19 and control animals, the distribution of fibre diameters of myelinated axons overlaps with that of promyelinated and unmyelinated fibres, but myelinated axons cannot be observed below a diameter of 0.3 micron, and unmyelinated axons are always smaller than 1 micron. The mean diameter of promyelinated axons is identical in ts19 and control animals. Myelination is therefore not severely disturbed in the ts19 optic nerve. As retinal differentiation in ts19 is delayed by 2 days as well, reports on an asynchronous development of neurons and myelin sheaths cannot be confirmed for the visual system.
Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized... more Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized that show excellent in vitro efficacy in protecting acetylcholinesterase (AChE) from inhibition by a broad variety of organophosphorus compounds (OPCs). However, oximes themselves are also AChE inhibitors, albeit at higher concentrations, which is a major cause of their toxicity and may be a dose-limiting factor in oxime therapy. To assess the efficacy of the experimental K-oximes in vivo, the extent of oxime-conferred protection from mortality induced by paraoxon was quantified. Rats received paraoxon in a dosage of 1, 5, or 10 mumol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD(01). The relative risk of death (RR) over time was estimated by Cox survival analysis for treatment with experimental K-oximes (K-53, K-74, K-75, K-107, K-108, and K-113), with the clinically available oximes pralidoxime (2-PAM) and obidoxime, and with the well-characterized K-oximes K-27 and K-48, comparing results with the no-treatment group. Best protection was conferred by K-27, reducing the RR to 20% of controls (P </= 0.05), which was significantly (P <or= 0.05) better than all other tested oximes. Marked reduction in mortality was also achieved by K-48 and the three new bispyridinium oximes containing two aldoxime groups, but no xylene linker: K-48 (RR = 0.32), K-53 (RR = 0.36), K-74 (RR = 0.42), K-75 (RR = 0.35). This effect was significantly (P <or= 0.05) superior to that of all other oximes, except K-27. The remaining oximes, i.e., obidoxime (RR = 0.64), 2-PAM (RR = 0.78), K-107 (RR = 0.70), K-108 (RR = 0.77), and K-113 (RR = 0.87) reduced paraoxon-induced mortality only poorly, but significantly (P <or= 0.05). Our data show that K-27, K-48, K-53, K-74, and K-75, due to their far superior in vivo efficacy, are the most promising candidates to eventually replace the established oximes 2-PAM and obidoxime. Further studies in other species exposed to a broader spectrum of OPCs are, however, necessary before considering their use in humans.
Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect agai... more Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of organophosphorus compounds (OPCs). The usefulness of pyridostigmine, the only compound approved by the Food and Drug Administration (FDA) for such pretreatment, has been questioned. In search for more efficacious alternatives, we have examined in vivo the efficacy of a group of ten compounds with known anti-AChE activity (pyridostigmine, metoclopramide, tiapride, ranitidine, physostigmine, tacrine, amiloride, methylene blue, 7- methoxytacrine and K-27) to reduce mortality induced by the OPC methyl-paraoxon. AChE inhibitors were given intraperitoneally in equitoxic dosage (25% of LD₀₁) 30 min before OPC exposure. Protection was quantified in rats by determining the relative risk of death (RR) by Cox analysis, with RR=1 for animals given only methyl-paraoxon, but no pretreatment. Only physostigmine (RR=0.39), K-27 (RR=0.40) and tacrine (RR=0.48) significantly (p≤ 0.05) reduced methylparaoxon- induced mortality, when given prophylactically. Pretreatment with pyridostigmine, ranitidine, tiapride, amiloride, metoclopramide and methylene blue did not significantly protect against the lethal effects of methyl-paraoxon. 7-methoxytacrine (7-MEOTA) significantly (p≤ 0.05) increased the relative risk of methyl-paraoxon-induced death (RR=1.31). These results indicate that pretreatment with pyridostigmine cannot be considered a broad-spectrum approach against OPC exposure. K-27 may be a suitable alternative if passage into the brain is contraindicated.
Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mo... more Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01 ) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p ≤ 0.05) as compared with the non-treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option.
ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects... more ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects in the treatment of Alzheimer disease. However, its exact mechanisms of action have not been fully elucidated. The modulation of nicotinic acetylcholine receptors (nAChRs) has been suggested to play a role in the pathogenesis of various neurodegenerative diseases. Therefore, in the present study, the effect of MB on the function of the cloned α7 subunit of the human nAChR expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. MB reversibly inhibited ACh (100 μM)-induced currents in a concentration-dependent manner with an IC50 value of 3.4 ± 0.3 µM. The effect of MB was not dependent on the membrane potential. MB did not affect the activity of endogenous Ca2+-dependent Cl- channels, since the inhibition by MB was unaltered in oocytes injected with the Ca2+ chelator 1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid and perfused with Ca2+-free bathing solution containing 2 mM Ba2+. MB decreased the maximal ACh-induced responses without significantly affecting ACh potency. Furthermore, specific binding of [125I] α-bungarotoxin, a radioligand selective for the α7 nAChR, was not altered by MB (10 µM), indicating that MB acts as a noncompetitive antagonist on α7 nAChRs. In hippocampal slices, whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the γ-aminobutyric acid-mediated spontaneous postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for α7 nAChRs, were abolished after 10 min application of 3 μM MB. These results demonstrate that MB inhibits the function of human α7 nAChRs expressed in Xenopus oocytes and of α7 nAChR-mediated responses in rat hippocampal neurons.
Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridiniu... more Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) propane dibromide] and K-48 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], show good in vitro efficacy in protecting acetylcholinesterase from inhibition by different organophosphorus compounds (OPCs), including nerve agents. To assess their efficacy in vivo, the extent of oxime-conferred protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified and compared with that of five established oximes. Materials and Methods. Rats received DFP intraperitoneally in a dosage of 6, 8, or 10 micromol/rat and immediately thereafter intraperitoneal injections of K-27, K-48, pralidoxime, obidoxime, trimedoxime, methoxime, or HI-6. The relative risk (RR) of death over time (48 h) was estimated by Cox survival analysis, comparing results with the no-treatment group. Results. Best protection was observed when K-27 was used, reducing the RR of death to 19% of control RR (p < or = 0.005), whereas obidoxime (RR = 26%, p < or = 0.01), K-48 (RR = 29%, p < or = 0.005) and methoxime (RR = 26%, p < or = 0.005) were comparable. The RR of death was reduced only to about 35% of control by HI-6, to 45% by trimedoxime, and to 59% by 2-PAM (p < or = 0.005). Whereas the differences between the best oximes (K-27, obidoxime, methoxime, and K-48) were not statistically significant; these four oximes were significantly more effective than 2-PAM (p < or = 0.05). The efficacy of K-27 was also significantly higher than that of HI-6, trimedoxime, and 2-PAM (p < or = 0.05). Conclusion. Our data provide further evidence that K-27 is a very promising candidate for the treatment of intoxication with a broad spectrum of OPCs.
ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects... more ABSTRACT Methylene Blue (MB) is being investigated in clinical studies for its beneficial effects in the treatment of Alzheimer disease. However, its exact mechanisms of action have not been fully elucidated. The modulation of nicotinic acetylcholine receptors (nAChRs) has been suggested to play a role in the pathogenesis of various neurodegenerative diseases. Therefore, in the present study, the effect of MB on the function of the cloned α7 subunit of the human nAChR expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. MB reversibly inhibited ACh (100 μM)-induced currents in a concentration-dependent manner with an IC50 value of 3.4 ± 0.3 µM. The effect of MB was not dependent on the membrane potential. MB did not affect the activity of endogenous Ca2+-dependent Cl- channels, since the inhibition by MB was unaltered in oocytes injected with the Ca2+ chelator 1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid and perfused with Ca2+-free bathing solution containing 2 mM Ba2+. MB decreased the maximal ACh-induced responses without significantly affecting ACh potency. Furthermore, specific binding of [125I] α-bungarotoxin, a radioligand selective for the α7 nAChR, was not altered by MB (10 µM), indicating that MB acts as a noncompetitive antagonist on α7 nAChRs. In hippocampal slices, whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the γ-aminobutyric acid-mediated spontaneous postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for α7 nAChRs, were abolished after 10 min application of 3 μM MB. These results demonstrate that MB inhibits the function of human α7 nAChRs expressed in Xenopus oocytes and of α7 nAChR-mediated responses in rat hippocampal neurons.
The effects of three types of behavior on c-fos activation in different brain regions of the muds... more The effects of three types of behavior on c-fos activation in different brain regions of the mudskipper, Periophthalmus cantonensis, were studied by immunocytochemistry. Animals were divided into four groups: The control group did not undergo any specific treatment. The second group consisted of animals that were agitated for an hour with a glass rod at an irregular speed. The third group contained animals showing aggressive behavior during an hour of monitoring, i.e. documented territorial hostility by raising of dorsal fins and pursuit of intruders. In contrast to these three groups, which had last been fed 24h earlier, the fourth group included animals that had been nourished 1h prior to sacrifice. Results showed that, in most brain regions of control animals, there were relatively few c-fos positive cells. After fish had been agitated, however, very prominent c-fos label was seen in the lateral and medial parts of the telencephalon, the thalamus, hypothalamus, pituitary and medulla. In aggressive fish, a significant increase in the number of c-fos positive sites, as compared to control fish, was observed in the diencephalons, pons and medulla, but not in the telencephalon. After feeding, there was a less substantial increase in c-fos protein expression in the diencephalon, but an even more prominent c-fos activation in the pons and medulla. Our present results support the hypothesis that, in fish, the medial telencephalon is involved in avoidance reaction and the lateral telencephalon in spatial memory, whereas rhombencephalic activation may reflect activity of cranial nerve nuclei.
Journal of Cancer Research and Clinical Oncology, 1985
In order to study structural changes in the lymph node architecture in the course of metastatic i... more In order to study structural changes in the lymph node architecture in the course of metastatic involvement by carcinoma, 70 axillary lymph nodes of 45 female patients affected by breast carcinoma were examined. The following growth pattern of the metastasis was observed: (1) Involvement of vasa afferentia and (marginal) sinuses; (2) lysis of sinus wall and infiltration, causing replacement and lysis of reticulin fibres; (3) appearance of fibrillary fibronectin (FN) as the first noticeable sign of tumor stroma; (4) immigration of fibroblasts along these fibres, appearance of argyrophilic fibres codistributed with fibrillary FN; (5) formation of the complete tumor stroma, neovessels included. The appearance of FN is thus the first step of stroma formation and is interpreted as an "in situ" precipitation of soluble plasma FN.
Trisomy 19 (ts19) of the mouse permits detailed studies on the influence of an extra autosome upo... more Trisomy 19 (ts19) of the mouse permits detailed studies on the influence of an extra autosome upon the postnatal development of the central nervous system. To examine gliogenesis and myelinogenesis, the optic nerves of 19 ts19 pugs aged 1-15 days have been examined by light and electron microscopy and compared to those of litter-mate controls. Differentiation of astrocytes and oligodendrocytes, myelinogenesis as well as the opening of the eyes are each delayed by about 2 days. Myelin sheaths are normally structured in ts19. There is a decrease in the percentage of myelinated fibres. The cross-sectional area of the ts19 optic nerve is reduced. The fibre density, which decreases with age both in ts19 and control mice, is higher in ts19 mice. Both with ts19 and control animals, the distribution of fibre diameters of myelinated axons overlaps with that of promyelinated and unmyelinated fibres, but myelinated axons cannot be observed below a diameter of 0.3 micron, and unmyelinated axons are always smaller than 1 micron. The mean diameter of promyelinated axons is identical in ts19 and control animals. Myelination is therefore not severely disturbed in the ts19 optic nerve. As retinal differentiation in ts19 is delayed by 2 days as well, reports on an asynchronous development of neurons and myelin sheaths cannot be confirmed for the visual system.
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Papers by Dietrich Lorke