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K Fink

Publications and source records attributed to K Fink.

At least 37 records · Page 2Linked to original sources
PubMed1997

Prostate carcinoma screening in the county of Tyrol, Austria: experience and results.

BACKGROUND: This article summarizes the experience and results of different prostate carcinoma screening projects using total prostate specific antigen (PSA) as the initial test and different diagnostic tests to improve specificity. METHODS: The seven projects studied included 1) a mass screening study using PSA as the initial test in 21,079 volunteers; 2) an investigation of the usefulness of normal and age-referenced PSA cutoffs in 1618 men; 3) a PSA-based screening study of 2272 asymptomatic blood donors; 4) an investigation of the incidence and clinical significance of transitional zone carcinoma in 340 men with negative rectal examination findings and clearly visible prostatic zones on three-dimensional transrectal ultrasound; 5) determination of percent free PSA in one retrospective and two prospective screening studies to define the optimal range of total PSA and determine the appropriate cutpoints for percent free PSA within this range; 6) evaluation of the diagnostic benefit of PSA transitional zone density in 308 screening volunteers; and 7) a study of the impact of PSA-based screening on the percentage of incidental prostate carcinoma diagnosed in 1543 men undergoing transurethal resection of the prostate. RESULTS: 1) Of the 21,078 volunteers, 1618 (8%) had elevated PSA levels. Of these men, 778 (48%) underwent biopsies; 197 biopsies (25%) were positive for prostate carcinoma and 135 patients underwent radical prostatectomy. Ninety-five of the 135 pathologically staged lesions (70%) were found to be organ-confined. 2) A PSA cutoff of 2.5 ng/mL in men age 45-49 years and of 3.5 ng/mL in men age 50-59 years with normal digital rectal examination findings resulted in an 8% increase in both the number of biopsies (66 of 778) and the detection rate of organ-confined disease. 3) Of the 2272 men, 284 had elevated PSA levels and prostate carcinoma was detected in 62 men. All patients underwent radical prostatectomy and histologic examination revealed organ-confined disease in all but eight men. 4) Ninety-eight of 340 men (28.8%) had biopsies positive for carcinoma; 28 of these patients (28.5%) had carcinoma that originated in the transitional zone only. 5) In the retrospective study, receiver operating characteristic curve analysis showed that by using a percent free PSA of 18% as a biopsy criterion in men with an elevated PSA serum level, 37% of the negative biopsies could be eliminated although 94% of all carcinomas would still be detected. In the first prospective study, 106 of 158 men with elevated total PSA values between 2.5 and 10.0 ng/mL were further evaluated and 37 prostate carcinomas were detected. By using a percent free PSA of < or =22% as a biopsy criterion, 30% of the negative biopsies could be eliminated although 98% of the carcinomas would still be detected. In the second prospective study, 120 of 465 men with total PSA levels between 1.25 and 6.49 ng/mL, a percent free PSA of <18%, and normal digital rectal examination findings were further evaluated and 27 (22.5%) were found to have prostate carcinoma. 6) Receiver operating characteristic curve analysis for PSA transitional zone density showed that by using a PSA transitional zone density of >0.22 ng/mL/cc as a biopsy criterion, 24.4% of negative biopsies could be avoided without missing the detection of a single carcinoma. 7) In the prescreening era the incidence of T1a Grade 1 and 2 carcinomas was 3.1% and the incidence of T1a Grade 3 and T1b carcinoma was 2.3%, whereas in the years after the establishment of PSA-based screening the incidence was 4.6% and 1.03%, respectively. CONCLUSIONS: These data suggest that PSA-based screening increases the detection rate of clinically significant and organ-confined tumors. Percent free PSA and PSA transitional zone density provide an additional diagnostic benefit over total PSA.

Age Factors↗
PubMed1997

[Acute renal failure in IgM plasmocytoma with hyperviscosity syndrome].

HISTORY AND CLINICAL FINDINGS: Two days after starting withdrawal treatment for alcohol and drug abuse a 56-year-old woman developed acute renal failure. The patient was in a poor general condition and disoriented as to time and place. She had uraemic oral fetor and leg oedema. She had previously fractured both arms 3 months before. INVESTIGATIONS: Biochemical tests indicated renal failure: creatine 1791 mumol/l, urea 51.7 mmol/l, potassium 5.3 mmol/l, phosphate 1.86 mmol/l. Serum protein electrophoresis suggested paraproteinaemia with M gradients in the gamma-fraction. Immune fixation electrophoresis demonstrated monoclonal IgM gammopathy of kappa-type (IgM 44.1 g/l). Haemoglobin level was reduced to 66 g/l. Bone marrow biopsy showed replacement of normal haematopoiesis by highly atypical plasma cells (> 30% of cell population). Magnetic resonance imaging revealed diffuse changes in the pelvis and vertebrae suggesting plasmacytoma, confirming the diagnosis of IgM plasmacytoma of kappa-type. TREATMENT AND COURSE: Focal neurological symptoms (e.g. intermittent anisocoria and visual disturbances) suggested a hyperviscosity syndrome, although the serum protein level was nearly normal. Plasma viscosity was 2.2 mPas (normal range 1.2-1.38 mPas), lowered to 1.5 mPas by plasmapheresis, after which the neuropsychiatric symptoms improved. Chemotherapy for the plasmacytoma in stage IIIB was initiated (VAD scheme) and dialysis became necessary for terminal renal failure. CONCLUSION: Due to the raised level of IgM protein level and its high molecular size a hyperviscosity syndrome with paraproteinemic coma may occur, even though total plasma protein is nearly normal.

Acute Kidney Injury↗
PubMed1997

Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage.

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.

Animals↗
PubMed1997

Effects of selective h5-HT1B (SB-216641) and h5-HT1D (BRL-15572) receptor ligands on guinea-pig and human 5-HT auto- and heteroreceptors.

Human cerebral cortical slices and synaptosomes, guinea-pig cerebral cortical slices and human right atrial appendages were used to study the effects of SB-216641, a preferential h5-HT1B receptor ligand, and of BRL-15572, a preferential h5-HT1D receptor ligand, on the presynaptic h5-HT1B and h5-HT1B-like autoreceptors in the human and guinea-pig brain preparations, respectively, and on the presynaptic h5-HT1D heteroreceptors in the human atrium. The brain preparations, preincubated with [3H]serotonin ([3H]5-HT), and the segments of atrial appendages, preincubated with [3H]noradrenaline, were superfused with modified Krebs' solution and tritium overflow was evoked electrically (human and guinea-pig cerebral cortex slices and human atrial appendages) or by high K+ (human cerebral cortex synaptosomes). The electrically evoked tritium overflow from guinea-pig cerebral cortex slices was reduced by the 5-HT receptor agonist 5-carboxamidotryptamine (5-CT). This effect was not modified by BRL-15572 (2 microM; concentration 154 times higher than its Ki at h5-HT1D receptors) but was antagonized by SB-216641 (0.1 microM; concentration 100 times higher than its Ki at h5-HT1B receptors; apparent pA2 8.45). SB-216641 (0.1 microM) by itself facilitated, whereas BRL-15572 (2 microM) did not affect, the evoked overflow. In human cerebral cortex slices SB-216641 (0.1 microM) also facilitated, and BRL-15572 (2 microM) again failed to affect, the electrically evoked tritium overflow. In human cerebral cortical synaptosomes, 5-CT reduced the K+-evoked tritium overflow. This response was unaffected by BRL-15572 (300 nM) but antagonized by SB-216641 (15 nM; drug concentrations 23 and 15 times higher than their Ki at h5-HT1D and h5-HT1B receptors, respectively). Both drugs, given alone, did not modify the K+-evoked tritium overflow. In human atrial appendages, the electrically evoked tritium overflow was inhibited by 5-HT in a manner susceptible to antagonism by BRL-15572 (300 nM; 23 times Ki at h5-HT1D receptors) but not by SB-216641 (30 nM; 30 times Ki at h5-HT1B receptors). Both drugs by themselves did not change the electrically evoked tritium overflow. In conclusion, SB-216641 behaves as a preferential antagonist at native human 5-HT1B receptors and BRL-15572 as a preferential antagonist at native human 5-HT1D receptors. These compounds are clearly useful tools for the differentiation between human 5-HT1B and 5-HT1D receptors in functional studies.

Animals↗
PubMed1997

Involvement of different calcium channels in K+- and veratridine-induced increases of cytosolic calcium concentration in rat cerebral cortical synaptosomes.

Intracellular calcium ion concentrations ([Ca2+]i) in rat cerebral cortical synaptosomes were measured, using the calcium chelating fluorescence dye fura-2. The synaptosomes were depolarized by elevation of the extracellular K+ concentration or by addition of veratridine, which opens voltage-dependent Na+-channels and prevents their inactivation. Both enhancement of the concentration of extracellular K+ (up to 60 mM) and veratridine (1-100 microM) increased the [Ca2+]i in a concentration-dependent manner. In the absence of extracellular Ca2+, the K+- and veratridine-induced increases in [Ca2+]i were abolished, indicating that the increase in [Ca2+]i was due to an influx of extracellular Ca2+. Tetrodotoxin (TTX), a blocker of the voltage-dependent Na+ channel, inhibited the veratridine-induced (10 microM) Ca2+ influx by more than 80%, while the K+-evoked (30 mM) increase of [Ca2+]i was TTX-resistant. Both the K+- and the veratridine-induced Ca2+ influx were not reduced by nifedipine (1 microM), a blocker of L-type Ca2+ channels. Blockade of the voltage dependent N-type Ca2+ channels with omega-conotoxin GVIA (omega-CTx GVIA; 0.1 microM) and of the voltage-dependent P/Q-type channels with omega-agatoxin IVA (omega-AgaTx IVA; 0.2 microM) inhibited the K+-induced increase in [Ca2+]i by about 30 and 55%, respectively; these effects were additive. Omega-conotoxin MVIIC (omega-CTx MVIIC) at a concentration of 0.2 microM, which may be assumed to block predominantly the Q-type Ca2+ channel, inhibited the K+-induced increase in [Ca2+]i by 50%. The veratridine-induced increase in [Ca2+]i was reduced by about 25% by omega-CTx GVIA (0.1 microM), but was resistant to omega-AgaTx IVA (0.2 microM) and omega-CTx MVIIC (0.2 omegaM). Mibefradil (former designation Ro 40-5967), a Ca2+ antagonist which blocks all types of voltage-dependent Ca2+ channels including the T and R channels, led to a concentration-dependent inhibition of the K+- and veratridine-induced increase in [Ca2+]i (abolition at 10 microM mibefradil). Ifenprodil, another non-specific blocker of voltage-dependent Ca2+ channels, also inhibited the K+- and veratridine-induced increase in [Ca2+]i in concentration-dependent manner and abolished it at 320 microM ifenprodil. In contrast, KB-R 7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate; 1 and 3 microM), a highly potent and selective inhibitor of the Na+/Ca2+ exchanger (NCX1), failed to inhibit the K+- and veratridine-induced increase in [Ca2+]i. It is concluded that the K+-induced increase in free cytosolic Ca2+ results from Ca2+ influx through voltage-dependent N- and, above all, Q-type Ca2+ channels. N-type Ca2+ channels also play a minor role in the veratridine-induced increase in [Ca2+]i, but P/Q-type channels do not appear to be involved at all. The inhibition of the veratridine-induced, omega-CTx GVIA- and omega-AgaTx IVA-resistant increase in [Ca2+]i by mibefradil and the failure of KB-R 7943 to inhibit this response are compatible with the suggestion that in rat cerebral cortical synaptosomes, Ca2+ influx via the R-type Ca2+ channel and/or another so far uncharacterized Ca2+ channel may substantially contribute to the veratridine-induced increase in [Ca2+]i.

Adenosine Triphosphatases↗
PubMed1997

Reversion to a previously learned foreign accent after stroke.

Foreign accent syndrome occurs rarely after stroke. Most patients with this syndrome develop an aphasia characterized by a new accent. This report presents a 48-year-old man who sustained a left parietal hemorrhagic stroke resulting in right hemiparesis and the inability to speak. As spontaneous speech emerged several weeks later, he was noted to have a Broca's aphasia and a Dutch accent. Analysis of his speech demonstrated final consonant deletion, substitution of "d" for "th" sounds, vowel distortions, additional "uh" syllables added at the end of words, and errors in voicing. This speech pattern has persisted for more than 5 years after the stroke. Elicitation of additional history found that the patient was born in Holland and lived there until the age of 5 years, when he moved to the United States with his family. Before his stroke, he had no foreign accent. This report illustrates the importance of considering foreign accent syndrome during aphasia recovery and suggests several pathogenetic mechanisms that may contribute to the development of this syndrome.

Brain↗
PubMed1997

Effects of imidazolines on noradrenaline release in brain: an investigation into their relationship to imidazoline, alpha 2 and H3 receptors.

The present study was carried out to clarify whether the imidazolines clonidine, moxonidine and cirazoline as well as the guanidine aganodine inhibit noradrenaline release in the rat and rabbit brain via imidazoline receptors, alpha 2-adrenoceptors and/or histamine H3 receptors. Slices or synaptosomes from the rat or the rabbit brain were incubated with 3H-noradrenaline and exposed to phenoxybenzamine, which irreversibly blocks presynaptic alpha 2-adrenoceptors and, at considerably lower potency, imidazoline receptors. Tritium overflow in the superfused preparations was evoked electrically (3 Hz; slices) or by K+ 15 mmol/l (synaptosomes). Noradrenaline and rauwolscine, which possess low affinity, if any, for imidazoline receptors, were used as reference drugs. The evoked overflow in rat brain cortex slices and synaptosomes and in rat medulla oblongata slices, not exposed to phenoxybenzamine, was inhibited by clonidine, moxonidine and noradrenaline. Phenoxybenzamine markedly attenuated the effect of each drug to about the same extent. In rabbit brain cortex slices, not exposed to phenoxybenzamine, the evoked overflow was inhibited by clonidine, moxonidine, aganodine and noradrenaline, facilitated by BDF 6143 (4-chloro-2-(2-imidazoline-2-yl-amino)-isoindoline), idazoxan and rauwolscine and not affected by cirazoline. In slices exposed to phenoxybenzamine, the inhibitory effects of the imidazolines, of aganodine and of noradrenaline were again attenuated by about the same high degree, the facilitatory effects of BDF 6143, idazoxan and rauwolscine were abolished and cirazoline produced a slight inhibition of the evoked overflow. The latter effect was not affected by high concentrations of rauwolscine and idazoxan (at which these drugs act antagonistic at imidazoline receptors in other models). The specific binding of 3H-N alpha-methylhistamine to H3 receptors in rat brain cortex membranes was displaced only by high concentrations of moxonidine (pKi = 6.16) and at even lower affinity by aganodine, BDF 6143, cirazoline, clonidine and idazoxan (pKi < 5). Histamine, which was used as a reference drug, proved to be very potent (pKi = 8.20). In conclusion, imidazolines affect noradrenaline release in the rat and rabbit brain cortex and medulla oblongata via alpha 2-adrenoceptors but not via imidazoline receptors resembling the presynaptic imidazoline receptors previously identified in peripheral tissues of the rabbit. In addition, the involvement of I1- or I2-imidazoline binding sites or of H3 receptors is very improbable in view of the low affinity of aganodine, moxonidine and/or clonidine for these recognition sites and/or incompatibility of the rank order of their affinities with the potencies of the drugs in inhibiting noradrenaline release.

Adrenergic alpha-Agonists↗
PubMed1997

Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein.

We used transgenic mice expressing a dominant negative mutation of interleukin-1 beta converting enzyme (ICE) (C285G) in a model of transient focal ischemia in order to investigate the role of ICE in ischemic brain damage. Transgenic mutant ICE mice (n = 11) and wild-type littermates (n = 9) were subjected to 3 h of middle cerebral artery occlusion followed by 24 h of reperfusion. Cerebral infarcts and brain swelling were reduced by 44% and 46%, respectively. Neurological deficits were also significantly reduced. Regional CBF, blood pressure, core temperature, and heart rate did not differ between groups when measured for up to 1 h after reperfusion. Increases in immunoreactive IL-1 beta levels, observed in ischemic wild-type brain at 30 min after reperfusion, were 77% lower in the mutant strain, indicating that proIL-1 beta cleavage is inhibited in the mutants. DNA fragmentation was reduced in the mutants 6 and 24 h after reperfusion. Hence, endogenous expression of an ICE inhibitor confers resistance to cerebral ischemia and brain swelling. Our results indicate that downregulation of ICE expression might provide a useful therapeutic target in cerebral ischemia.

Animals↗
PubMed1996

Presynaptic 5-HT autoreceptors modulate N-methyl-D-aspartate-evoked 5-hydroxytryptamine release in the guinea-pig brain cortex.

Guinea-pig cerebral cortical slices preincubated with [3H]5-hydroxytryptamine ([3H]5-HT) were superfused with Mg(2+)-free Krebs' solution. N-Methyl-D-aspartate (NMDA) stimulated tritium overflow in a concentration-dependent manner. The NMDA-evoked overflow was abolished by omission of CA2+ or presence of 1.2 mM Mg2+, but only partly inhibited by tetrodotoxin. The competitive and noncompetitive NMDA receptor antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849) and dizocilpine, respectively, also blocked the stimulatory effect of NMDA. Furthermore, the NMDA-evoked tritium overflow was inhibited by 5-carboxamidotryptamine in a manner susceptible to blockade by methiothepin, which given alone facilitated overflow. This facilitatory effect was increased in the presence of 6-nitroquipazine, a selective 5-HT reuptake inhibitor. It is concluded that the release of 5-HT in the guinea-pig cerebral cortex is stimulated via NMDA receptors, which are in part located on the serotoninergic axon terminals, and that the NMDA-evoked 5-HT release is modulated via inhibitory 5-HT autoreceptors.

Animals↗
PubMed1996

Evidence for presynaptic location of inhibitory 5-HT1D beta-like autoreceptors in the guinea-pig brain cortex.

The effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by high K+ were determined in superfused synaptosomes and slices, preincubated with [3H]5-HT, from guinea-pig brain cortex. In addition, we estimated the potencies of 5-HT receptor ligands in inhibiting specific [3H]5-HT binding (in the presence of 8-hydroxy-2(di-n-propylamino)tetralin and mesulergine to prevent binding to 5-HT1A and 5-HT2C sites) to guinea-pig cortical synaptosomes and membranes. 5-HT receptor agonists inhibited the K(+)-evoked tritium overflow from synaptosomes and slices. In synaptosomes the rank order of potencies was 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl] -1H-indole-3-yl] ethylamine (L-694,247) > 5-carboxamidotryptamine (5-CT) > oxymetazoline (in the presence of idazoxan) > or = 5-HT > sumatriptan > or = 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969). The potencies of the agonists in inhibiting tritium overflow from slices correlated with those in synaptosomes, suggesting that the same site of action is involved in both preparations. In synaptosomes the nonselective antagonist at cloned human 5-HT1D alpha and 5-HT1D beta receptors, methiothepin, shifted the concentration-response curve for 5-CT to the right (apparent pA2: 7.87). In contrast, ketanserin at a concentration which should block the 5-HT1D alpha, but not the 5-HT1D beta, receptor did not alter the inhibitory effect of 5-CT on tritium overflow. In cortical synaptosomes and membranes, [3H]5-HT bound to a single site with high affinity. In competition experiments, 5-HT receptor agonists and antagonists inhibited specific [3H]5-HT binding. In synaptosomes the rank order was L-694,247 > methiothepin > 5-CT > 5-methoxytryptamine > 5-HT > or = sumatriptan > or = oxymetazoline > RU 24969 > ketanserin > ritanserin. A very similar rank order was obtained in cerebral cortical membranes. The potencies of the 5-HT receptor agonists in inhibiting tritium overflow from synaptosomes and slices correlated with their potencies in inhibiting [3H]5-HT binding to synaptosomes and membranes. In conclusion, the 5-HT receptors mediating inhibition of 5-HT release in the guinea-pig cortex are located on the serotoninergic axon terminals and, hence, represent presynaptic inhibitory autoreceptors. The [3H]5-HT binding sites in cerebral cortical synaptosomes and membranes exhibit the pharmacological properties of 5-HT1D receptors. The correlation between the functional responses and the binding data confirms the 5-HT1D character of the presynaptic 5-HT autoreceptors. According to the results of the interaction experiment of ketanserin and methiothepin with 5-CT on 5-HT release, the presynaptic 5-HT autoreceptors can be subclassified as 5-HT1D beta-like.

Animals↗
PubMed1996

Presynaptic 5-HT auto- and heteroreceptors in the human central and peripheral nervous system.

In view of the potential pathophysiological and therapeutic implications, presynaptic 5-HT auto- and heteroreceptors have been identified and characterized in isolated human tissues and their functional role has been determined. Such investigations have been carried out in different laboratories including that of the authors. Basic evidence for the involvement of inhibitory 5-HT receptors in modulation of 5-HT release in the cerebral cortex was obtained in slices: exogenous 5-HT inhibited 5-HT release in a manner susceptible to blockade by methiothepin, which given alone facilitated 5-HT release, probably by preventing endogenous 5-HT from activating the inhibitory receptors. The latter receptors are located on the 5-HT nerve terminals themselves, since 5-HT (and sumatriptan) also inhibited 5-HT release from cortical synaptosomes. Their pharmacological properties conform to those of the 5-HT1D class. Subclassification (5-HT1D alpha or 5-HT1D beta) has been tried with ketanserin which has an at least 60 times higher affinity for 5-HT1D alpha (pki = 7.1) than 5-HT1D beta receptors. Since ketanserin (0.32 microM) did not affect the concentration-response curve for 5-carboxamidotryptamine (5-CT), the presynaptic 5-HT autoreceptor may belong to the 5-HT1D beta rather than the 5-HT1D alpha subtype. The sympathetic nerve terminals of the human saphenous vein are endowed with inhibitory 5-HT1D beta heteroreceptors, as indicated by the potency ratio of several 5-HT receptor agonists in inhibiting noradrenaline release in strips of this blood vessels and by the ability of methiothepin, but not of ketanserin 0.3 microM, to act as an antagonist. Noradrenergic nerves in the dura mater, which probably innervate its microvasculature, may also be endowed with inhibitory 5-HT receptors, since 5-HT inhibited noradrenaline release from this tissue. In strips of atrial appendages, 5-HT receptor agonists (e.g. 5-HT, 5-CT and sumatriptan) inhibited noradrenaline release at potencies which are correlated with their ki values at 5-HT1D alpha and 5-HT1D beta receptors. Since this inhibitory effect was antagonized by ketanserin (0.3 but not 0.03 microM) and methiothepin, the presynaptic 5-HT receptor in this tissue may belong to the 5-HT1D alpha subtype. However, this conclusion needs further confirmation by experiments with more potent and subtype-selective antagonists of 5-HT1D alpha and 5-HT1D beta receptors.

Central Nervous System↗
PubMed1996

Usefulness of the ratio free/total prostate-specific antigen in addition to total PSA levels in prostate cancer screening.

OBJECTIVES: Two different studies were performed. The aim of the first study was to define whether the measurement of the ratio between free and total prostate-specific antigen (f/t PSA) in serum may enhance the ability of PSA-based screening for early detection of prostate cancer in men with elevated serum PSA levels. A second study was undertaken to investigate the value of f/t PSA ratio in serum to improve the specificity of prostate cancer screening in men with serum PSA levels between 2.5 and 10.0 ng/mL. METHODS: In a retrospective study of 266 men with elevated PSA levels and proven biopsy results, f/t PSA levels were measured using deep frozen serum samples. In a second study we enrolled 158 men with elevated PSA levels according to age reference ranges apparent from our current PSA screening study with additional measurement of the f/t PSA ratio. All study volunteers with a free f/t PSA ratio cutoff point of < or = 22% underwent digital rectal examination, transrectal ultrasonography, and biopsy of the prostate. Free and total PSA levels were measured with the Delfia PSA dual label f/t PSA kit (Wallac Oy Turku, Finland). RESULTS: 106 of 158 men with elevated total PSA values between 2.5 and 10.0 ng/mL (group 1) have been further evaluated and 37 prostate cancers were detected. Mean percentage of free PSA was 10% in men with cancer and 22% in men with benign prostatic hyperplasia. Using a f/t PSA ratio of < or = 22% as a biopsy criterion 30% of the negative biopsies could be eliminated while still detecting 98% carcinomas. CONCLUSIONS: Measurement of f/t PSA reduces the number of unnecessary biopsies in PSA screening without missing many cancers.

Aged↗
PubMed1995

Stimulation of serotonin release in the rat brain cortex by activation of ionotropic glutamate receptors and its modulation via alpha 2-heteroreceptors.

Rat brain cortex slices were used to study (1) the release of 5-hydroxytryptamine (5-HT) induced by activation of N-methyl-D-aspartate (NMDA) or non-NMDA receptors and (2) the alpha 2-adrenoceptor-mediated modulation of NMDA-evoked 5-HT release. Cortical slices were preincubated with [3H]5-HT in the presence of the selective noradrenaline uptake inhibitor, maprotiline (to avoid false labelling of noradrenergic axon terminals), and the superfused with solution containing the 5-HT reuptake inhibitor, 6-nitroquipazine. In slices superfused with Mg(2+)-free medium, NMDA and L-glutamate, in a concentration-dependent manner, elicited an overflow of tritium. The NMDA-evoked tritium overflow was abolished by omission of Ca2+ ions, almost completely suppressed by 1.2 mM Mg2+ and only partly (by about 60%) inhibited by tetrodotoxin. Dizocilpine (formerly MK-801), an antagonist at the phencyclidine site within the NMDA-gated channel, also decreased the NMDA-evoked overflow. The competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849) caused a parallel shift of the NMDA concentration-response curve to the right. The NMDA-induced tritium overflow was not affected by addition of exogenous glycine but was inhibited by 5,7-dichlorokynurenic acid, an antagonist at the glycine site of the NMDA receptor. Spermidine slightly increased the NMDA-induced tritium overflow whereas arcaine, an antagonist at the polyamine site of the NMDA-receptor, caused a decrease. Ifenprodil and eliprodil, which exhibit different affinities for NMDA receptors composed of different subunits were highly potent (in the nanomolar range) in inhibiting the NMDA-evoked tritium overflow. Noradrenaline reduced, whereas the alpha 2-adrenoceptor antagonist idazoxan facilitated, the NMDA-evoked overflow. Idazoxan shifted the concentration-response curve of noradrenaline to the right. In slices superfused with solution containing 1.2 mM Mg2+, kainic acid or (RS)-alpha-amino-3-hydroxy-5-methyl-4 -isoxazole propionic acid (AMPA) also caused a concentration-dependent overflow of tritium, which again was not completely (by about 75 and 50%, respectively) inhibited by tetrodotoxin. The kainate-evoked tritium overflow was inhibited by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not affected by CGP 37849 or arcaine. The AMPA-evoked tritium overflow was also decreased by CNQX. It is concluded that activation of NMDA or non-NMDA receptors elicits a release of 5-HT in the rat brain cortex. The receptors are at least partly located on the serotoninergic nerve terminals. The results with ifenprodil and eliprodil are compatible with the view that the NMDA receptor involved contains the NR2B subunit. The NMDA-evoked 5-HT release is modulated by presynaptic alpha 2-adrenoceptors.

Animals↗
PubMed1995

Subclassification of presynaptic 5-HT autoreceptors in the human cerebral cortex as 5-HT1D receptors.

Human cerebral cortical synaptosomes were used to determine the 5-hydroxytryptamine (5-HT) receptor subtype to which the inhibitory presynaptic 5-HT autoreceptor belongs. The synaptosomes preincubated with [3H]5-HT were superfused and tritium overflow was stimulated by high K+. The K(+)-evoked tritium overflow, which was Ca(2+)-dependent but tetrodotoxin-resistant, was concentration-dependently inhibited by the nonselective 5-HT 1D alpha/1D beta receptor agonist, 5-carboxamidotryptamine. Ketanserin at a concentration which should block the 5-HT 1D alpha but not the 5-HT 1D beta receptor failed to antagonize the inhibitory effect of 5-carboxamidotryptamine. In contrast, the nonselective 5-HT 1D alpha/1D beta receptor antagonist, methiothepin, at a concentration which should block both the 5-HT 1D alpha and the 5-HT 1D beta receptor abolished the effect of 5-carboxamidotryptamine. It is concluded that the presynaptic 5-HT autoreceptor, which has previously been classified as 5-HT 1D, belongs to the 5-HT1D beta subtype.

Adult↗
PubMed1995

Projection, identification, and bi-logic.

The work and postulations of Matte-Blanco are explained in some detail, especially regarding the logical functioning of the conscious and unconscious mind, asymmetrical and symmetrical logic, and bi-logical thought structures. A case serves as an example for the clinical application of Matte-Blanco's ideas to theoretical conceptualization and to the technique of interpretation.

Adult↗
PubMed1994

N-methyl-D-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors.

In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mumol/l or 0.032 mumol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine and the selective H2 receptor agonist dimaprit (each up to 10 mumol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.

Animals↗