Karzinomassoziierte Retinopathie (CAR) bei Mammakarzinom und Karzinoid

Fragestellung: Die Karzinomassoziierte Retinopathie (CAR) stellt ein seltenes paraneoplastisches Syndrom dar, das bislang am h?ufigsten bei kleinzelligen Bronchialkarzinomen beschrieben wurde. Wir berichten über 3 Patientinnen mit CAR in Gegenwart eines Mammakarzinoms bzw. eines Karzinoids der Cervix uteri. Patienten und Methode: Es wurden biomikroskopische, perimetrische, angiographische und elektrophysiologische Befunde erhoben. Au?erdem erfolgte eine Testung der Immunreaktivit?t der Seren an humaner Retina. Ergebnisse: Die Befunde umfa?ten ringf?rmige Gesichtsfelddefekte mit statokinetischer Dissoziation und eine pathologische St?bchen- und Zapfenantwort im ERG. Bei 1 Patientin wurde immunhistochemisch eine Reaktion im Bereich der Photorezeptorinnensegmente, der ?u?eren K?rnerschicht sowie der ?u?eren plexiformen Schicht bei fehlendem Nachweis von Antik?rpern gegen Recoverin gefunden. Diskussion: Neben dem kleinzelligen Bronchialkarzinom k?nnen auch andere Prim?rtumoren mit einer CAR vergesellschaftet sein. Der Nachweis von retinalen Autoantik?rpern unterstützt die Annahme einer tumorinduzierten Immunantwort aufgrund der Expression identischer Epitope durch die Tumorzellen. Dabei kommen offensichtlich verschiedene retinale Proteine als Autoantigene in Betracht.      

Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog

The influence of angiotensin II (ANGII) on the dynamic characteristics of renal blood flow (RBF) was studied in conscious dogs by testing the response to a step increase in renal artery pressure (RAP) after a 60 s period of pressure reduction (to 50 mmHg) and by calculating the transfer function between physiological fluctuations in RAP and RBF. During the RAP reduction, renal vascular resistance (RVR) decreased and upon rapid restoration of RAP, RVR returned to baseline with a characteristic time course: within the first 10 s, RVR rose rapidly by 40 % of the initial change (first response, myogenic response). A second rise began after 20–30 s and reached baseline after an overshoot at 40 s (second response, tubuloglomerular feedback (TGF)). Between both responses, RVR rose very slowly (plateau). The transfer function had a low gain below 0.01 Hz (high autoregulatory efficiency) and two corner frequencies at 0.026 Hz (TGF) and at 0.12 Hz (myogenic response). Inhibition of angiotensin converting enzyme (ACE) lowered baseline RVR, but not the minimum RVR at the end of the RAP reduction (autoregulation-independent RVR). Both the first and second response were reduced, but the normalised level of the plateau (balance between myogenic response, TGF and possible slower mechanisms) and the transfer gain below 0.01 Hz were not affected. Infusion of ANGII after ramipril raised baseline RVR above the control condition. The first and second response and the transfer gain at both corner frequencies were slightly augmented, but the normalised level of the plateau was not affected. It is concluded that alterations of plasma ANGII within a physiological range do not modulate the relative contribution of the myogenic response to the overall short-term autoregulation of RBF. Consequently, it appears that ANGII augments not only TGF, but also the myogenic response.     

Molecular Interaction of Droperidol with Human Ether-a-go-go-related Gene Channels: Prolongation of Action Potential Duration without Inducing Early Afterdepolarization

Background: The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes.

Methods: Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique.

Results: Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 [mu]m. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nm prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed.     

Aquaporin-1 and HCO3−-Cl− transporter-mediated transport of CO2 across the human erythrocyte membrane

Recent studies have suggested that aquaporin-1 (AQP1) as well as the HCO₃⁻-Cl⁻ transporter may be involved in CO₂ transport across biological membranes, but the physiological importance of this route of gas transport remained unknown. We studied CO₂ transport in human red blood cell ghosts at physiological temperatures (37 °C). Replacement of inert with CO₂-containing gas above a stirred cell suspension caused an outside-to-inside directed CO₂ gradient and generated a rapid biphasic intracellular acidification. The gradient of the acidifying gas was kept small to favour high affinity entry of CO₂ passing the membrane. All rates of acidification except that of the approach to physicochemical equilibrium of the uncatalysed reaction were restricted to the intracellular environment. Inhibition of carbonic anhydrase (CA) demonstrated that CO₂-induced acidification required the catalytic activity of CA. Blockade of the function of either AQP1 (by HgCl₂ at 65 μM) or the HCO₃⁻-Cl⁻ transporter (by DIDS at 15 μM) completely prevented fast acidification. These data indicate that, at low chemical gradients for CO₂, nearly the entire CO₂ transport across the red cell membrane is mediated by AQP1 and the HCO₃⁻-Cl⁻ transporter. Therefore, these proteins may function as high affinity sites for CO₂ transport across the erythrocyte membrane.     

Biologic significance of surface microroughing in bone incorporation of porous bioactive glass implants

A novel chemical etching method was recently developed to create a controlled microrough surface on porous bioactive glass implants. Our earlier in vitro studies showed enhanced attachment of osteoblast-like MG63 cells on a microrough bioactive glass surface. The purpose of our current study was to confirm the in vivo significance of surface microroughening for bone bonding of bioactive glass. Porous bioactive glass cones made of sintered microspheres were surgically implanted in the anterior cortex of rabbit femurs. Peripheral quantitative computed tomography (pQCT), biomechanical push-out testing, histomorphometry, and electron microscopy (BEI-SEM) were used to analyze bone ingrowth and osseointegration at 7, 10, 14, 28, 56, and 84 days after implantation. The results showed that microroughening of the bioactive glass surface significantly enhanced the bone-bonding response of the biomaterial. The positive response was seen in one of the three bioactive glass compositions studied. The affinity index of new bone on the glass surface was significantly (p = 0.02) increased with a trend (p = 0.10) toward improved mechanical incorporation. New bone formation was dependent on the glass composition, and it was found to occur not only through the mechanism of bone ingrowth but also based on in situ osteogenesis within implant interstices. Based on these results, the procedure of microroughening could enhance the osteopromotive properties of certain bioactive glass compositions.     

Ascending aortic stenosis selectively increases action potential-induced Ca2+ influx in epicardial myocytes of the rat left ventricle

A decrease of the transient outward potassium current (Ito) has been observed in cardiac hypertrophy and contributes to the altered shape of the action potential (AP) of hypertrophied ventricular myocytes. Since the shape and duration of the ventricular AP are important determinants of the Ca2+ influx during the AP (QCa), we investigated the effect of ascending aortic stenosis (AS) on QCa in endo- and epicardial myocytes of the left ventricular free wall using the AP voltage-clamp technique. In sham-operated animals, QCa was significantly larger in endocardial compared to epicardial myocytes (803 +/- 65 fC pF(-1), n = 27 vs. 167 +/- 32 fC pF(-1), n = 38, P < 0.001). Ascending aortic stenosis significantly increased QCa in epicardial myocytes (368 +/- 54 fC pF(-1), n = 42, P < 0.05), but did not alter QCa in endocardial myocytes (696 +/- 65 fC pF(-1), n = 26). Peak and current-voltage relation of the AP-induced Ca2+ current were unaffected by AS. However, the time course of the current-voltage relation was significantly prolonged in epicardial myocytes of AS animals. Model calculations revealed that the increase in QCa can be ascribed to a prolonged opening of the activation gate, whereas an increase in inactivation prevents an excessive increase in QCa. In conclusion, AS significantly increased AP-induced Ca2+ influx in epicardial but not in endocardial myocytes of the rat left ventricle.     

Striatal dopamine transporter density in major depression

Rationale: There are no previous data available regarding [¹²³I]β-CIT binding to the dopamine transporter sites in the basal ganglia in depressed patients. Objective: The present study tested the hypothesis that the brain DAT density in depressed patients is lower than that in matched healthy controls. Methods: Fifteen drug-naive outpatients with major depression and 18 healthy controls were investigated using single photon emission computerized tomography (SPECT) with a high-affinity dopamine transporter specific radioligand, ¹²³I-labeled β-CIT (2β-carbomethoxy-3β-(4-iodophenyl)-tropane). Results: We found a significantly higher [¹²³I]β-CIT uptake in both sides of the basal ganglia in patients with major depression than in the controls (Mann-Whitney U-test, P = 0.002 on the right and P = 0.003 on the left). Conclusions: The radioligand uptake reflecting the DAT density was significantly higher among the patients than in the controls. This finding is unexpected, since it is generally believed that monoaminergic neurotransmission is lower in depression, and therefore it could be assumed that a reduction in dopamine transmission would lead to secondary down-regulation of DAT density. However, it is possible that up-regulation of the DAT may be the primary alteration, which leads to lower intrasynaptic dopamine concentration and to lower dopamine neural transmission. Received: 20 October 1998/Final version: 25 January 1999     

Interaction between nitric oxide and endogenous vasoconstrictors in control of renal blood flow

The level of renal blood flow (RBF) is controlled by opposing vasoconstrictor and vasodilator influences. In a recent investigation in normotensive dogs, we found that combined blockade of endothelin type A (ET(A)) receptors and angiotensin II formation induces marked increases in RBF that were much larger than the effects of blocking either system alone. The aim of the present study was to determine the contribution of nitric oxide (NO) to this vasodilator response. Experiments were made in 6 conscious, chronically instrumented dogs subjected to 5 different experimental treatments on separate days. Blockade of ET(A) receptors alone by the selective antagonist LU 135252 had only minor effects on RBF compared with time-control experiments. Additional blockade of angiotensin II formation by angiotensin-converting enzyme inhibition with trandolaprilat caused a substantial increase of RBF by approximately 50%. This vasodilation was entirely suppressed when NO formation was prevented by inhibition of NO synthase with N(G)-nitro-L-arginine methyl ester HCl. However, when during NO synthase inhibition renal vascular NO concentrations were clamped at control levels by infusing the NO donor S-nitroso-N-acetyl-D, L-penicillamine, the vasodilator response to combined blockade of ET(A) receptors and angiotensin II formation was completely restored (DeltaRBF approximately 60%). These results indicate that the vasodilation after combined ET(A) receptor blockade and angiotensin-converting enzyme inhibition is not mediated by an increase in NO release but results from the unmasking of the tonic influence that is normally exerted by constitutively released NO. Accordingly, the tonic activity of endothelial NO synthase appears to be of major importance in the physiological regulation of renal vascular resistance by determining the vasomotor responses to endothelin and angiotensin II.