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PubMedDate not supplied

Effects of phosphodiesterase (PDE) inhibitors on human ether-a-go-go related gene (hERG) channel activity.

It is presumed that phosphodiesterase (PDE) inhibitors have two mechanisms for inhibition of hERG currents in the acute applications to cells: direct channel block, and downregulation of human ether-a-go-go related gene (hERG) activities by PKA-dependent pathway mediated phosphorylation through their inhibitory effects against PDE enzymes. However, it is unknown whether PDE inhibition contributes to the inhibitory effects of PDE inhibitors on hERG currents. This study examined the effects of various PDE inhibitors on hERG currents using both the whole-cell and perforated patch-clamp techniques in hERG transfected CHO-K1 cells. The study also investigated the contribution of the PKA-dependent pathway to the inhibitory effects of PDE inhibitors on hERG currents. Of the PDE inhibitors tested, vinpocetine, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), vesnarinone, rolipram and dipyridamole decreased hERG currents in a concentration-dependent manner. Vinpocetine and vesnarinone markedly decreased the hERG current with an IC (50)of 0.13 and 20.6 microm, respectively, at comparatively low concentrations. Furthermore, vinpocetine caused a cumulative block of hERG currents. Milrinone, amrinone and zaprinast had no effect on the hERG current up to 100 microm. Of the PDE3 inhibitors (vesnarinone, amrinone and milrinone), only vesnarinone showed an hERG inhibitory effect. The inhibitory effects of vinpocetine and vesnarinone were not significantly affected by the co-application of protein kinase inhibitors. Furthermore, the protein kinase activators had no effect on hERG currents. It is concluded that vinpocetine and vesnarinone block the hERG channel directly, and that the inhibitory effect on intracellular PDE in the PKA-dependent pathway may not be involved in the inhibition of hERG currents in hERG transfected CHO-K1 cells.

Adenine↗
PubMedDate not supplied

1980 Volvo award winner in basic science. Nutritional pathways of the intervertebral disc. An experimental study using hydrogen washout technique.

The pathways of material transfer to the intervertebral disc were studied in adult dogs by measuring diffusion of hydrogen molecules in the nucleus pulposus before and after disruption of the route through the annulus fibrosus and before and after disruption of the end-plate route. The interfaces was only in the central two-thirds of one side, caused significantly greater decrease in the rate of hydrogen washout than the disruption of the annulus route. Histologically, the bone-cartilage interface was frequently perforated by marrow cavity and vascular buds. These findings suggest that the end-plate route is a major pathway for material transfer to the intervertebral disc.

Animals↗
PubMed1993

Biocytin pellets: an alternative technique for massive anterograde labeling of neuronal pathways in vivo and in vitro.

The present study demonstrates that biocytin suspended in pellets of either coagulated chicken plasma (plasmaclot) or gelatine, produces intense anterograde axonal and terminal labeling and dense retrograde Golgi like labeling of neurons when injected into the brain parenchyma of young adult rats. The technique worked perfectly on hippocampal pathways like the mossy fiber system, the hilodentate associational and commissural fiber systems, CA3 Schaffer collaterals, the entorhinal perforant path to fascia dentata and hippocampus, as well as frontal motor cortical efferent and afferent fiber tracts. This pellet tracer delivery technique also proved very useful when applied on hippocampal slice cultures, where small pellets of plasmaclot embedded biocytin resulted in very discrete uptake sites with dense labeling of small groups of neurons and their projections.

Animals↗
PubMed1997

cAMP increases K+ secretion via activation of apical IsK/KvLQT1 channels in strial marginal cells.

In the cochlea, K+ is secreted by electrodiffusion across the apical membrane of strial marginal cells via the IsK/KvLQT1 ('IsK') channel. This channel complex has been reported to be activated in other systems by adenosine 3',5'-cyclic monophosphate (cAMP). Since several reports had suggested that cAMP is a second messenger in the cochlea, the effect of the cAMP pathway on transepithelial K+ secretion by strial marginal cells of the gerbil was studied. Both the transepithelial current (Isc) and K+ flux (JK) across strial marginal cell epithelium were measured; Isc in a micro-Ussing chamber and JK as the gradient of K+ concentration near the apical membrane. The apical membrane current (IIsK) and conductance (gIsK) of IsK channels were recorded with the on-cell macro-patch and the nystatin-perforated whole-cell patch clamp techniques. It has previously been shown that the apical IsK channel constitutes the primary pathway for K+ secretion. Cytoplasmic cAMP was elevated by applying dibutyryl cyclic-AMP (dbcAMP) or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) at 37 degrees C. dbcAMP (1 mM) increased Isc by 51 +/- 4% and IIsK in on-cell and whole-cell recordings increased by 214 +/- 63% and 390 +/- 61% above the control value, respectively. IBMX (1 mM) caused transient increases of Isc by 53 +/- 3% and IIsK in on-cell recordings by 177 +/- 75% above the control value. The leak conductance due to all non-IsK channel sources did not change in the presence of dbcAMP or IBMX. dbcAMP (1 mM at 24 degrees C) increased JK by 53 +/- 16% and Isc by 18 +/- 4%. IBMX (1 mM at 24 degrees C) had no effect, suggesting reduced activity of adenylate cyclase at this temperature. Our results demonstrate that the cAMP pathway is constitutively active in strial marginal cells and that the cAMP pathway stimulates transepithelial K+ secretion by increasing IsK channel current rather than by altering another transport pathway.

1-Methyl-3-isobutylxanthine↗
PubMed1977

Long-lasting morphological changes in dendritic spines of dentate granular cells following stimulation of the entorhinal area.

Stimulation of the perforant path induces a long-lasting increase in the area of dendritic spines, which are sites of termination of the stimulated pathway in the distal third of the dentate molecular layer. No enlarged spines were found in the proximal third of the dentate molecular layer, where the commissural afferents terminate. Following a single tetanic stimulus of 30 sec duration at 30/sec, spines became significantly larger by 15%, 38%, 35% and 23% within poststimulation intervals of 2-6 min, 10-60 min, 4-8 h, and 23 h, respectively. Axon terminals decreased their area by 15% within the 2-6 min interval and the vesicle density was decreased by 19% within the 10-60 min interval. Both changes were reversible and terminals resumed their prestimulation condition at longer intervals (greater than 4 h). The initial enlargement of spines was interpreted as being due to a glutamate-induced increase in the sodium permeability of the spine membrane, whereas for the long-lasting enlargement an increase in protein synthesis was postulated. The long-lasting enlargement of dendritic spines in the dentate molecular layer following a short train of stimuli delivered to the perforant path, supports the postulate which links such a change to the mechanism of long-lasting postactivation potentiation observed in this pathway.

Animals↗
PubMed1989

Calcium-binding protein (calbindin-D28k) and parvalbumin immunocytochemistry: localization in the rat hippocampus with specific reference to the selective vulnerability of hippocampal neurons to seizure activity.

Two neuronal calcium-binding proteins, calbindin-D28k (CaBP) and parvalbumin (PV), were localized in the normal rat hippocampus by using immunocytochemical methods to determine 1) their location and 2) whether a correlation exists between the presence of these two calcium-binding proteins and the selective vulnerability of different hippocampal neuronal populations to experimental seizure activity. CaBP-like immunoreactivity (CaBP-LI) is present in all dentate granule cells and some, but not all, CA1 and CA2 pyramidal cells. Some CA1 pyramidal cells lack CaBP-LI, and those that do are lightly stained compared to the dentate granule cells. CA3 pyramidal cells appear to contain neither CaBP- nor PV-LI, and no granule or pyramidal cells exhibit PV-LI. CaBP-LI is present in distinct populations of dentate and hippocampal interneurons but absent from others. In area dentata, CaBP-LI is present in a small number of interneurons of the molecular and granule cell layers and in a small population of presumed basket cells in or below the granule cell layer. Conversely, more presumed dentate basket cells exhibit PV-LI than CaBP-LI. In the hilus of area dentata, few cells are CaBP- or PV-immunoreactive. The hilar somatostatin/neuropeptide Y (NPY)-immunoreactive cells and hilar mossy cells, two distinct and large populations, lack CaBP- and PV-LI. In the CA3 region, CaBP-LI is present in a relatively small number of interneurons in each stratum. PV-immunoreactive interneurons in area CA3 are more numerous. In area CA1, CaBP-LI is present in many interneurons in strata radiatum and lacunosum-moleculare. Some, but relatively fewer, CaBP-positive interneurons are present in strata pyramidale and oriens. Conversely, PV-immunoreactive interneurons are numerous in strata pyramidale and oriens but rare in strata radiatum and lacunosum-moleculare. Staining with the particulate chromagen benzidine hydrochloride revealed a previously undescribed dense band of CaBP-LI in the inner dentate molecular layer, a lamina enriched with kainate-displaceable glutamate-binding sites and innervated by the apparently excitatory ipsilateral associational/commissural (IAC) pathway that originates in the CaBP-negative hilar mossy cells. Bilateral electrical stimulation of the perforant path was performed in order to destroy the hilar mossy cells and to determine if this band of CaBP-LI is normally present within the mossy cell terminals. Perforant path stimulation that destroyed hilar mossy cells throughout the dorsal portions of both hippocampi did not abolish the dense CaBP-like immunoreactivity in the inner molecular layer.

Animals↗
PubMed1983

Effects of kainic and other amino acids on synaptic excitation in rat hippocampal slices: 1. Extracellular analysis.

The actions of kainic acid on excitatory synaptic responses in rat hippocampal slices have been investigated and compared with the effects of other excitatory amino acids. Kainate administered iontophoretically or via the superfusate produced a large and long lasting potentiation of the population spike evoked in the CA1 region by Schaffer collateral-commissural stimulation. This potentiation was associated with a reduction in the field EPSP recorded in the dendritic region (stratum radiatum) but with no change in the presynaptic fibre volley or with any long lasting alteration in the antidromic population spike. The results suggest that one effect of kainate may be to produce dendritic depolarisation in CA1 pyramidal neurones. Kainate in equivalent amounts elicited similar potentiations of the population spike recorded in the dentate gyrus in response to either lateral or medial perforant path stimulation. Smaller amounts of kainate than those required to affect either CA1 or dentate pathways were able to potentiate the mossy fibre-evoked population spike in the CA3 region. Folic acid, which shares kainate's ability to produce seizures and distant brain damage when injected into the brain, elicited similar potentiations of synaptic excitation. Higher doses of folate than of kainate were required which is consistent with its weaker epileptogenic actions in vivo. In contrast, N-methyl-aspartate, ibotenate, L-glutamate and L-aspartate were unable to mimic kainate's potentiating action. In higher doses the substances depressed the population spike for long periods. These data suggest that potentiation of synaptic events may underlie the ability of kainate (and folate) to elicit seizures and distant brain damage.

Amino Acids↗
PubMed2003

Anatomical relationship between arteries and veins in the paraumbilical region.

Veins in the paraumbilical region were investigated in eight fresh cadavers, in which radiopaque materials were injected into both the arterial and the venous systems, to determine their locational relationship to the arteries. Veins in the skin and subcutaneous tissue consisted of venae comitantes and non-venae comitantes. The main trunk of the non-venae comitantes was the superficial inferior epigastric vein, and it formed a polygonal venous network in the skin layer. A large communicating vein, which did not accompany an artery, connected the venous network to a vena comitans of a large paraumbilical arterial perforator. Venous blood that had perfused the dermis of the paraumbilical region had two kinds of pathways to a deep vein: through the superficial inferior epigastric vein to the femoral vein and through the vena comitans to the deep inferior epigastric vein.

Arteries↗
PubMed1981

[An anatomical and technical note for microsurgery of the MCA aneurysm (author's transl)].

Several basic anatomical and technical principles helpful in selecting and planning the surgical treatment of the aneurysm of middle cerebral artery were discussed. 1. Superficial sylvian vein (SSV) usually runs on the temporal opercular bank, therefore, frontal opercular side may be preferred in opening the sylvian fissure(SF). In approximately 10% of specimens, there are two separate SSV lying close together in the SF which only rarely have communicating channels to each other. It should be kept in mind a vein of the one opercular bank may course to the surface, pass beneath the nearest sylvian vein on its side of the fissure and join the more distally located sylvian vein. 2. Deep sylvian vein (deep middle cerebral vein) which closely accompanies the trunk of MCA must be preserved. Surgical occlusion of this venous pathway may result in unanticipated serious postoperative complication, such as consciousness deterioration, hemiparesis or aphasia. 3. Perforators leaving the M1 over its posterosuperior surface form a loop which hang anteriorly. The loop occasionally comes forward and extends quite anteriorly where the sylvian fissure opens and therefore is in danger of injury. It is important to avoid tearing these fine vessels while exposing the middle cerebral artery. 4. The parent artery should be exposed proximally to the aneurysm to allow control of flow to the aneurysm if it ruptures during dissection in any way of approaching the aneurysm. 5. The aneurysm usually points in the direction of the long axis of the prebifurcation segment. 6. After the clip is applied, the area should be inspected to make certain the clip does not kink or obstruct the major vessels and that no perforating branches are included in it.

Cerebral Arteries↗
PubMed1976

[Pathways of transcranial blood flow].

The injection of the injectional mass into the internal and external carotid arteries has shown the presence of perforant arteries in the bones of the cranial fornix. The method of impregnation of vessels by silver nitrate in sections of decalcified cranium bones enabled the author to establish the penetration of thin blood vessels into the cranial cavity through sutures. Blood vessels simultaneously found to be present in the spongy and compact substance of the cranial fornix bones. The totalities of the above vessels are considered as transcranial vascular communications. Their possible significance in hemodynamics is discussed.

Adult↗
PubMed2005

Acquired arteriovenous fistula and chronic occlusion of the left anterior descending coronary artery in a patient with previous ablation of a left-sided accessory pathway.

Endocardial catheter ablation of accessory pathways is now considered as therapy of first choice in symptomatic patients. Success rates depend on the location of the accessory pathway itself and the operators experience in catheter ablation procedures. In patients with a left-sided pathway the retrograde transaortic catheter approach is used routinely in most centers. Besides occasional injuries of the vessels used for catheter placement and perforation of the cardiac chambers, there have been only a few case reports in the literature reporting rare procedure-specific complications such as catheter entrapment within the mitral valve apparatus and occlusion of the left circumflex coronary artery. We report a case of primary successful endocardial catheter ablation of a left lateral accessory pathway in a patient with normal coronary arteries at that time. Many years later progressive deterioration of systolic left ventricular function was observed. Coronary angiography revealed occlusion of LAD next to a arteriovenous (AV) fistula between the LAD and the anterior right ventricle. Endocardial catheter ablation was the only known cardiac manipulation in this patient raising the possibility that unintended catheter manipulations within the LAD had led to this rare and severe complication.

Arteriovenous Fistula↗
PubMed1998

Identification of two regions in apolipoprotein B100 that are exposed on the cytosolic side of the endoplasmic reticulum membrane.

Protease protection assays of apolipoprotein B100 (apoB) in digitonin-permeabilized HepG2 cells indicated that multiple domains of apoB are exposed to the cytosol through an extensive portion of the secretory pathway. The intracellular orientation of apoB in the secretory pathway was confirmed by immunocytochemistry using antibodies recognizing specific domains of apoB in streptolysin-O (STP-O)- and saponin-permeabilized HepG2 cells. Lumenal epitopes on marker proteins in secretory pathway compartments (p63, p53, and galactosyltransferase) were not stained by antibodies in STP-O-treated cells, but were brightly stained in saponin-treated cells, confirming that internal membranes were not perforated in STP-O-treated cells. An anti-apoB peptide antibody (B4) recognizing amino acids 3221-3240 caused intense staining in close proximity to the nuclear membrane, and less intensely throughout the secretory pathway in STP-O-permeabilized cells. Staining with this antibody was similar in STP-O- and saponin-treated cells, indicating that this epitope in apoB is exposed to the cytosol at the site of apoB synthesis and throughout most of the remaining secretory pathway. Similar results indicating a cytosolic orientation were obtained with monoclonal antibody CC3.4, which recognizes amino acids 690-797 (79-91 kD) in apoB. Two polyclonal antibodies made to human LDL and two monoclonal antibodies recognizing amino acids 1878-2148 (D7.2) and 3214-3506 (B1B6) in apoB did not produce a strong reticular signal for apoB in STP-O-treated cells. The anti-LDL and B1B6 antibodies produced almost identical punctate patterns in STP-O-treated cells that overlapped with LAMP-1, a membrane marker for lysosomes. These observations suggest that the B1B6 epitope of apoB is exposed on the surface of the lysosome. The results identify two specific regions in apoB that are exposed to the cytosol in the secretory pathway.

Amino Acid Sequence↗
PubMed2006

Laparoscopic appendectomy significantly reduces length of stay for perforated appendicitis.

INTRODUCTION: Though ruptured appendicitis is not a contraindication to laparoscopic appendectomy (LA), most surgeons have not embraced LA as the first-line approach to ruptured appendicitis. In fact, in 2002, the Cochrane Database Review concluded: 1) the clinical effects of LA are "small and of limited clinical relevance," and 2) the effects of LA in perforated appendicitis require further study. OBJECTIVE: To study the effects of LA vs open appendectomy (OA) among adults with appendicitis. METHODS: In 2003, 272 adults underwent appendectomy at a large County hospital, and were enrolled in a prospective clinical pathway that detailed their hospital course from time of diagnosis to discharge. Data included patient demographics, time elapse from diagnosis to surgery, surgical technique (LA vs. OA), operative diagnosis (acute vs perforated appendicitis) and post-operative length of stay (LOS). RESULTS: Complete data was obtained for 264 (97%) patients. Patient demographics were similar in the LA and OA groups (p > 0.05). Patients with LA had a significantly shorter LOS than OA by 1.6 days (p < 0.05). This LOS was significantly shorter among those with ruptured appendicitis vs. non-ruptured appendicitis (2.0 days vs. 0.3 day reduction, p = 0.0357). Rank-order multiple regression analysis, controlling for all other factors, showed laparoscopy to have a significant effect on postoperative LOS in all appendicitis cases, especially ruptured appendicitis. CONCLUSIONS: The two-day reduction in LOS among those with ruptured appendicitis who underwent LA was significant enough to overcome the smaller benefit of LA in acute appendicitis. From a hospital utilization point of view, LA should be considered as the first-line approach for all patients with appendicitis.

Adult↗
PubMed2006

Akt/GSK3beta survival signaling is involved in acute brain injury after subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: Apoptotic cell death is associated with acute brain injury after subarachnoid hemorrhage (SAH). The Akt/glycogen synthase kinase-3beta (GSK3beta) pathway plays an important role in the cell death/survival pathway after a variety of cell death stimuli. However, its role in acute brain injury after SAH remains unknown. METHODS: We used an endovascular perforation model of SAH in rats. Phospho-Akt and phospho-GSK3beta expression was examined by Western blot analysis and immunohistochemistry. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) and a cell death assay were used for detection of apoptosis. We administered LY294002 to examine the role of the Akt/GSK3beta pathway in the phosphoinositide 3-kinase pathway after SAH. RESULTS: Phosphorylation of Akt and GSK3beta was accelerated after SAH. In the cerebral cortex, where acute brain injury was the most severe, phosphorylation of these proteins was observed in the early phase after SAH. Cortical neurons with continuous Akt phosphorylation did not colocalize with TUNEL-positive cells at 24 hours. LY294002 reduced Akt and GSK3beta phosphorylation and increased brain injury after SAH. CONCLUSIONS: The present study suggests that the Akt/GSK3beta pathway might be involved in neuronal survival in acute brain injury after SAH.

Animals↗
PubMed2003

Protein kinase C is necessary for recovery from the thyrotropin-releasing hormone-induced r-ERG current reduction in GH3 rat anterior pituitary cells.

The biochemical cascade linking activation of phospholipase C-coupled thyrotropin-releasing hormone (TRH) receptors to rat ERG (r-ERG) channel modulation was studied in situ using perforated-patch clamped adenohypophysial GH3 cells and pharmacological inhibitors. To check the recent suggestion that Rho kinase is involved in the TRH-induced r-ERG current suppression, the hormonal effects were studied in cells pretreated with the Rho kinase inhibitors Y-27632 and HA-1077. The TRH-induced r-ERG inhibition was not significantly modified in the presence of the inhibitors. Surprisingly, the hormonal effects became irreversible in the presence of HA-1077 but not in the presence of the more potent Rho kinase inhibitor Y-27632. Further experiments indicated that the effect of HA-1077 correlated with its ability to inhibit protein kinase C (PKC). The hormonal effects also became irreversible in cells in which PKC activity was selectively impaired with GF109203X, Gö6976 or long-term incubation with phorbol esters. Furthermore, the reversal of the effects of TRH, but not its ability to suppress r-ERG currents, was blocked if diacylglycerol generation was prevented by blocking phospholipase C activity with U-73122. Our results suggest that a pathway involving an as yet unidentified protein kinase is the main cause of r-ERG inhibition in perforated-patch clamped GH3 cells. Furthermore, they demonstrate that although not necessary to trigger the ERG current reductions induced by TRH, an intracellular signal cascade involving phosphatidylinositol-4,5-bisphosphate hydrolysis by phospholipase C, activation of an alpha/betaII conventional PKC and one or more dephosphorylation steps catalysed by protein phosphatase 2A, mediates recovery of ERG currents following TRH withdrawal.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMedDate not supplied

Indwelling catheters: developing an integrated care pathway package.

Urinary catheterisation is a common nursing procedure in hospital and in the community, yet there are risks associated with it. Complications include urethral trauma, urinary tract infection, strictures, urethral perforation, encrustation, bladder calculi and neoplastic changes (Lowthian, 1998). The procedure is also linked to nosocomial infection and, in some cases, these catheter-related infections can prove fatal (Pratt et al, 2001). Due to the risks, catheterisation is indicated as a last resort after all other interventions have failed.

Algorithms↗
PubMed1999

[With periosteal "sandwich" suturing and repairing septonasal perforation by nasal columella degloving].

OBJECTIVE: To recommend a new type of repairing septonasal peforation. METHOD: After a seagull's incision is made around the internal edges of anterior nares and the root of nasal columella, the mucoperiost of nasal septum and nasal bottom is widely dissected through the nasal columella degloving pathway. Then, relaxative incisions are made in bilateral mucoperiost at different directions and bilateral peforations are relaxative sutured at different levels respectively. Meanwhile, an autograft of tibil periost is fixed into nasal septum by the "sandwich" technique. Finally, both nasal cavities are carefully packed. RESULTS: Three cases of septonasal perforation were successfully repaired and have been followed up for 1-2 years respectivelly with no recurrence. CONCLUSION: The characteristics of this operation are: style rather fashionable, pathway rather wide, mucoperiost rather relaxed, suture rather firm and failing rather few.

Adult↗