A novel GalR2-specific peptide agonist

The galanin peptide family and its three receptors have with compelling evidence been implicated in several high-order physiological disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. In the current study we present data on receptor binding and functional response for a novel galanin receptor type 2 (GalR2) selective chimeric peptide, M1145 [(RG)₂-N-galanin(2-13)-VL-(P)₃-(AL)₂-A-amide]. The M1145 peptide shows more than 90-fold higher affinity for GalR2 over GalR1 and a 76-fold higher affinity over GalR3. Furthermore, the peptide yields an agonistic effect in vitro, seen as an increase in inositol phosphate (IP) accumulation, both in the absence or the presence of galanin. The peptide design with a N-terminal extension of galanin(2-13), prevails new insights in the assembly of novel subtype specific ligands for the galanin receptor family and opens new possibilities to apply the galanin system as a putative drug target.     

Pathologische Anatomie (Sektionstechnik) und Physiologie

Ohne Zusammenfassung     

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m², three patients were treated at 90 mg/m², and five patients received 120 mg/m². A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m². Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Post‐traumatic reactions among rescue personnel 96 hours after the Hilton Hotel bombing in Sinai: The effect of previous exposure

This paper considers the immediate post‐traumatic reactions of rescue personnel who were exposed to the Hilton Hotel bombing in Sinai. The entire rescue personnel (n = 26) were assessed and separated into two groups on the basis of previous exposure to the same type of trauma. The results suggest that among rescue personnel, those with previous exposure had a lower level of post‐traumatic symptoms than those who were being exposed for the first time. This supports the hypothesis that previous exposure to the same type of trauma has an immunizing effect for subsequent same type of traumatic event among rescue personnel. Copyright © 2005 John Wiley & Sons, Ltd.     

Learning-induced enhancement of postsynaptic potentials in pyramidal neurons

We studied the effect of olfactory learning-induced modifications in piriform (olfactory) cortex pyramidal neurons on the propagation of postsynaptic potentials (PSPs). Rats were trained to distinguish between odors in pairs, in an olfactory discrimination task. Three days after training completion, PSPs were evoked in layer II pyramidal cells in piriform cortex brain slices by electrical stimulation of two pathways. Stimulation of layer Ib activated the intra-cortical fibers that terminate on the proximal region of the apical and basal dendrites. Stimulation of layer Ia activated the afferent axons that originate from the olfactory bulb and terminate on the distal apical dendrites. We have previously shown that olfactory training is accompanied by enhanced synaptic transmission in the intrinsic pathway, but not in the afferent pathway at 3 days after training. Here we show that at this stage, in both pathways PSPs evoked in neurons from trained rats had significantly faster rise time measured at the soma compared with PSPs in neurons from pseudo-trained and naive rats. Activation of the slow afterhyperpolarization (AHP), which is generated by potassium channels probably located at the proximal region of both apical and basal dendrites, reduced the amplitude measured at the soma of the proximal intrinsic pathway PSPs more effectively than PSPs that were generated distally by the afferent fibers. Thus the amount of reduction by AHP was used as a measure for the relative distance of PSP-generating sites from the soma. In neurons from trained rats, despite the previously reported reduction in AHP amplitude, AHP conductance shunted the PSPs from both synaptic pathways more efficiently compared with neurons from the control rats. We suggest that in neurons from trained rats PSPs are electrotonicly closer to the soma.     

A stage-specific calcium-binding protein from microfilariae of Brugia malayi (Filariidae)

The monoclonal antibody MF1 has been shown to cause transient clearance of blood-borne microfilariae in gerbils infected with Brugia malayi. The present study demonstrates that the MF1 antibody recognizes a proteinaceous determinant on two polypeptides of 70 and 75 kDa. Both the monoclonal antibody and antisera raised to the gel-purified antigen show binding restricted to mature microfilariae. Intrauterine and recently shed microfilariae apparently lack the MF1 molecules. Prominent 45Ca-binding molecules comigrate with the MF1 antigens in one-dimensional electrophoresis (under both reducing and non-reducing conditions), and co-purify through ion exchange chromatography. The MF1 antigen thus appears to be a developmentally regulated calcium-binding protein(s).     

Pathophysiology of cardiac extracorporeal membrane oxygenation

The treatment of cardiogenic shock using inotropic agents and vascular volume expansion places an added burden on the heart. The resultant increase in cardiac work may cause myocardial ischemia and lead to cardiac arrest. Extracorporeal membrane oxygenation (ECMO) may be used to treat cardiogenic shock. It supports systemic circulation, assures diastolic perfusion of the myocardium, and reduces cardiac workload. The rise in blood pressure associated with restoring systemic circulation afterloads the heart and can cause left atrial hypertension and pulmonary edema. ECMO does not automatically reduce cardiac work, especially in the presence of residual shunts. Left atrial drainage or decompression may be essential in certain patients both to avert pulmonary edema and to reduce cardiac work.     

Reliability of reciprocal isokinetic testing of the knee extensors and flexors

This study was conducted to assess the reliability of torque measurements across different trials and different test sessions. Each trial consisted of three maximal, reciprocal contractions of the knee extensors and flexors at test velocities of 60 and 180 degrees /sec. Three trials were conducted on each of three test sessions, with each session separated by 48 hours. Results indicate that reliability of reciprocal isokinetic testing of the knee can be improved by 1) testing in more than one occasion, 2) testing more than three trials during a single session if testing during more than one session is impossible, and 3) allowing the subject to become familiar with the isokinetic test procedure and to warm up adequately. Data obtained in this study indicated performance variability was predominantly associated with between subject differences and secondarily related to within subject changes over trials and days. Dynamometer calibration remained stable across all test sessions, indicating that the method was reliable for recording torque output during all testing procedures. J Orthop Sports Phys Ther 1991;14(3):121-127.