Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Human Molecular Genetics     

Safety of thrombolysis during cardiopulmonary resuscitation.

The prognosis is generally poor for patients who experience a cardiac arrest. The most common causes of sudden cardiac arrest are massive pulmonary embolism (PE) and acute myocardial infarction (MI). While thrombolysis is a first-line treatment option in massive PE and acute MI, cardiopulmonary resuscitation (CPR) has been regarded as a relative contraindication for thrombolysis because of the anticipated bleeding risk caused by traumatic cardiocompressions. However, an increasing number of case reports and clinical studies on thrombolysis during and after CPR highlight an increased frequency of the return of spontaneous circulation and a better neurological outcome of surviving patients. These effects are mainly due to the thrombolysis of macroscopic blood clots and the amelioration of microcirculatory reperfusion.This article reviews case reports and clinical studies of thrombolysis during and shortly after CPR in order to estimate the risk of severe bleeding events caused by CPR in association with thrombolysis compared with CPR without thrombolysis.Although thrombolysis per se can cause severe and potentially fatal haemorrhage, there is no evidence that severe bleeding events occur more often when thrombolysis is combined with cardiocompressions. In addition, by far the majority of bleeding complications can be treated effectively. Thus, in many cases, the possible benefit of thrombolysis during CPR seems to outweigh the potential risks. However, there may be a publication bias in some case reports and studies towards reporting successful rather than unsuccessful CPRs. In addition, not enough controlled clinical trials have yet been conducted. Therefore, data from large randomised, multicentre studies are needed to definitely answer the question of the relationship between safety and efficacy of this promising treatment option.We conclude that the currently available data do not indicate that thrombolysis contributes to a significant increase in bleeding complications when administered during CPR.     

Structural modification of receptor-binding technetium-99m complexes in order to improve brain uptake

Low brain uptake is a generally accepted problem in developing technetium-99m brain receptor imaging agents. For a class of potential 5-HT_2A receptorbinding agents we tried to improve the original low brain uptake of 0.4% injected dose (ID) in rats 5 min p.i. by modifying the lipophilic properties of the molecules. Because of the presence of a protonable nitrogen, which according to the pK _a value leads to ionization of the molecule at blood pH, the pK _a value was considered to be the parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of five candidates lowers the apparent pK _a value from 10.0 to 8.3 and dramatically increases the brain uptake to 1.3% ID at 5 min. The direct relationship between brain uptake and apparent pK _a cannot be simply explained by the increase in the pK _a-governed proportion of the neutral species.     

Recurrent salzmann’s corneal degeneration

Three keratoplasties were carried out on two patients because of nodular degeneration of the cornea. Progress after keratoplasty could be followed up in one eye for 17 months and in the other two eyes, for 2.5 and 9 years, respectively. The implant with the short follow-up of only 17 months remained glass-clear; nothing abnormal was discovered during the checkups. In the case of the other patient in whom a longer follow-up period was possible, the following findings were evident: (1) a remarkably late epithelial immune response in one eye (after 18 months) with subsequent incomplete reepithelisation and formation of fine, superficial, cloudy opacity (observation period 2.5 years); (2) formation of dense but flat, superficial areas of opacity in the cornea of the other eye (observation period 9 years). These areas may be regarded as a precursor of Salzmann’s corneal degeneration. No difference could be found between the histological findings in the explants and those in a degenerative pannus or an older scar caused by inflammation of the Bowman membrane.     

Neuron-like cells in long-term neural crest cultures are not targets of nerve growth factor

It has been shown previously that a subpopulation of long-term (7-14 days) cultured neural crest cells undergoing differentiation possesses receptors for nerve growth factor (NGF). These cells are likely to be targets of NGF during the early stages of embryonic development. This study was conducted to determine whether cells exhibiting neuron-like characteristics (i.e. process formation, presence of putative neurotransmitters) in neural crest cultures have NGF receptors. This was accomplished by combining 125I-NGF radioautography and immunocytochemistry using antibodies against tyrosine hydroxylase, serotonin, and vasoactive intestinal polypeptide. Examination of light microscopic radioautographs revealed that none of the neuron-like cells with tyrosine hydroxylase-like, serotonin-like, or vasoactive intestinal polypeptide-like immunoreactivity bound 125I-NGF, and, therefore, do not possess NGF receptors. It is not known whether the lack of NGF receptors on neuron-like cells is due to the early developmental stage of these cells, or is caused by a difference in the microenvironment in vitro as compared to in vivo. The identity of the cultured neural crest cells which do possess NGF receptors remains to be determined.     

Effects of trapidil-derivatives on calcium channel currents in isolated ventricular cells from mice

Summary A single glass micropipette voltage clamp technique with intracellular dialysis was used to study the effects of the trapidil derivatives AR 12–456 and AR 12–463 on Ca channel currents carried by Bat+ in isolated ventricular cells from mice hearts. Inspite of a more potent inhibition of the cAMP phosphodiesterase from heart (Bartel et al. 1985) a reversible Ca channel blocking action of both compounds could be observed. The concentration of half maximal block was calculated to about 50 mol/l for both derivatives tested. Neither a shift in the current-voltage relationships nor a significant change in the potential for half maximal activation was found. The maximal Ba²⁺ -conductance was reduced. The steady state inactivation was shifted towards more negative potentials by application of 100 mol/l AR 12–463. The decay of the Ba currents was accelerated in the range of the applied test potentials between –20 and +20 mV. It is concluded that the new trapidil derivatives with more potent inhibitory action on cardiac phosphodiesterase than trapidil can block myocardial Ca channels. Send offprint requests to B. Nilius     

Distribution of drugs over whole blood: II. The transport function of whole blood for phenytoin

Phenytoin (DPH) partition between the three main blood compartments, i.e., plasma proteins, erythrocytes, and plasma water, was studied at various concentrations in vitro and in vivo. In vitro, the partition ratio of DPH in a system of erythrocytes in plasma water was 4.5 at concentrations between 0.8 and 100.8 micrograms DPH/ml. In vitro in whole blood (hence, in the presence of plasma proteins), this ratio was approximately 3.9. At 38 degrees C, blank erythrocytes were already in equilibrium with DPH-spiked plasma 3 min after contact, whereas at 20 degrees C, equilibration took 10 minutes or more. By adding blank ultrafiltrate to blood containing DPH, DPH concentrations of blood compartments shifted. It appeared that with the added blank ultrafiltrate, DPH was delivered overproportionally from erythrocytes and less from the protein fraction. In vivo, the elimination half-life of DPH in erythrocytes was 21.4 h and in plasma proteins 67.9 h. These results are similar to those obtained with valproate. It is concluded that erythrocytes have a low affinity for DPH. Their high-capacity transport system, having a "last-come-first-go" mechanism, plays a quantitatively important role in the transport of DPH.     

CGP 6809 — A new nitrosoureido-sugar derivative with activity in human tumor xenografts

Summary CGP 6809 [ethyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)--d-glucofuranoside] is a new methylnitrosoureido-sugar derivative that has been shown to be active against a broad spectrum of transplantable tumours in mice and rats [14]. We investigated the anti-tumour effect of CGP 6809 in ten selected, human tumour xenograft lines growing s. c. in nude mice. The p. o. administration of 125 mg/kg per day for 10–15 days was less toxic (lethality 12% in tumour-bearing nude mice) than the i. p. injection of 62.5 mg/kg per day (lethality 22%). The anti-tumour effect was similar for both application routes; two large bowel cancers responded to treatment with CGP 6809, rectal cancer CXF 158 showed a remission, and the rapidly growing, undifferentiated colonic cancer CXF 280 exhibited a transient no-change. Furthermore, remissions were observed in the epidermoid lung cancer LXF 322 and in thyroid cancer 117. Tumour progression was found in another epidermoid lung cancer and in three stomach cancers, one melanoma, and one soft tissure sarcoma. CGP 6809 is a promising new agent for clinical trials, especially for large bowel and epidermoid lung cancer.Supported in part by grant PTB 8467 from the Bundesminister für Forschung und Technologie, Bonn, FRG     

Inhibitory effect of amiloride and gadolinium on fine afferent nerves in the rat knee: evidence of mechanogated ion channels in joints

Synovial joints are complex sensory organs which provide continuous feedback regarding position sense and degree of limb movement. The transduction mechanisms which convert mechanical forces acting on the joint into an electrochemical signal which can then be transmitted to the central nervous system are not well understood. The present investigation examined the effect of the mechanogated ion channel blockers amiloride and gadolinium on knee joint mechanosensitivity. In deeply anaesthetised rats (sodium thiopental: 100–120 mg/kg, i.p.), single unit extracellular recordings were made from knee joint group III (Aδ) and group IV (C) primary afferents in response to mechanical rotation of the joint. Afferent firing rate was measured before and after topical application of either amiloride (0.1 mM, 1 mM) or gadolinium (250 μM) onto the receptive field of the sensory unit and recording was continued every 10 min up to a total of 50 min. With normal rotation of the knee, joint mechanosensitivity was significantly reduced by both amiloride (P<0.0001; n=10–21) and gadolinium (P=0.001; n=12) and this effect was sustained throughout the recording period. This investigation provides the first in vivo electrophysiological evidence that joint mechanotransduction involves the activation of amiloride and gadolinium-sensitive mechanogated ion channels. Future studies to determine the mechanogated ion channel subtypes present in joints and the modulation of their gating properties during inflammation may yield novel approaches for the control of arthritis pain. Funding: JJMcD is funded by the Alberta Heritage Foundation for Medical Research, the Canadian Institutes for Health Research, and the Arthritis Society of Canada.