Pharmacokinetics and acute toleration of the beta-carboline derivative abecarnil in man

Plasma levels of the beta-carboline, abecarnil (isopropyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido [3,4-b]indole-3- carboxylate, ZK112119) which is presently under development as an anxiolytic, were measured by HPLC with fluorescence detection in six healthy male volunteers given 30 micrograms/kg i.v. and 5 and 10 mg p.o. Following i.v. injection, plasma levels declined biphasically with half-lives of 6 min and 3.4 h. The total clearance was 13 ml/min/kg. After oral administration, maximum concentrations were reached after 2 h. The bioavailability was approximately 60%. The terminal half-life after p.o. administration was 7 h. No clinically relevant changes in ECG, vital signs or standard laboratory measurements occurred. Eight different adverse reactions were noted by the subjects. The most frequently reported side-effects were tiredness, dizziness, unsteady gait and lack of concentration.     

Investigation of the morphology of cell clones, derived from the mammalian EBTr cell line and their susceptibility to vaccine avian poxvirus strains FK and Dessau

The ability for replication of vaccine avian pox viral strains FK and Dessau in cell clones, derived from the EBTr cell line, derived from embryonic bovine trachea, was studied. The derived seven cell clones showed different morphological characteristics and diverse sensitivity to both vaccine avian pox viral strains. Hence, the EBTr-derived cell clones could be used for cultivation, as well as for differentiation of vaccine avian pox viral strains. In addition, studies have been undertaken to elucidate the possible use of cultivated strains in these heterologous cell culture system's vaccine avian pox viral strains for biotechnology, as well as for solving problems, related to infection of people with avian viruses.     

Integrin expression in correlation to clinicopathological features and prognosis of prostate cancer: A systematic review and meta-analysis

Background: The prompt identification of patients with poor prognosis is essential in order to improve the treatment outcomes in prostate cancer (CaP); as a novel approach, several molecular markers, including integrins, have been discussed as prognostic biomarkers. Our aim was to comprehensively examine aberrant expression of integrins in correlation with clinicopathological features and prognosis in CaP by synthesizing all available evidence, in a systematic review and meta-analysis. Methods: A systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Scientific literature databases (Pubmed, Embase, and Scopus) were systematically searched until May 10, 2020. Random-effects (DerSimonian-Laird) models were used to estimate pooled odds ratios (ORs) for cross-sectional correlations with clinicopathological characteristics and relative risks for longitudinal associations with prognosis. Results: Fourteen studies were included with a total number of 3,194 CaP cases examined (13 cross-sectional and four longitudinal cohort study arms). Correlation of low expression of α₆ (pooled OR = 0.10, 95% confidence interval [CI]: 0.04–0.28, P < 0.001) and β₁ (pooled OR = 0.45; 95% CI: 0.21–1.00, P = 0.049) integrin with high Gleason score was noted. A borderline trend between reduced expression of α₆ integrin and an advanced clinical stage of CaP (pooled OR = 0.48; 95% CI: 0.22-1.03, P = 0.06) was observed. No associations with biochemical recurrence and survival were documented. Conclusions: Evidence on the association of low expression of integrins α₆ and β₁ and more advanced CaP exist, whereas significant results on survival were not documented; further studies are warranted.     

The use of third-party packed red blood cells during ex situ normothermic machine perfusion of organs for transplantation: Underappreciated complexities?

Ex situ normothermic machine perfusion (NMP) is being used increasingly in the assessment of higher risk deceased donor organs and to facilitate prolonged organ storage. Third-party packed red blood cells (pRBCs) are often used as an oxygen carrier in the perfusate of ex situ NMP. Despite the increasing interest in NMP, comparatively little attention has been paid to the appropriate selection of pRBCs. This includes the choice of ABO blood group and Rhesus D status, the need for special requirements for selected recipients, and the necessity for traceability of blood components. Flushing organs with cold preservation solution after NMP removes the overwhelming majority of third-party allogeneic pRBCs, but residual pRBCs within the organ may have biologically relevant effects following implantation as they enter the recipient's circulation. This review considers these issues, and suggests that national transplant and blood transfusion agencies work together to develop a co-ordinated approach within each country. This is especially important given the possibility of organ re-allocation between centers after ex situ NMP, and the ongoing development of organ perfusion hubs.     

Left-hemispheric superiority for visuospatial orientation in homing pigeons

To test for lateralisation of visuospatial orientation during homing, pigeons who had binocularly learned the homeward route from remote release sites were tested monocularly on either their left or their right eye for homing performance. In two experiments with three different release sites, birds using their right eye showed considerably better homing performance. If sun compass information was available, there was no difference in the direction of vanishing. Without this information, a difference between pigeons using their left or right eye emerged. Results show that visuospatial orientation in birds can be lateralised in favour of the left brain hemisphere and lend further support to the view that vision is important for pigeons homing on a familiar route. Cognitive mechanisms which might account for the observed pattern of lateralisation are discussed.     

Scopolamine-induced amnesia in humans: lack of effects of the benzodiazepine receptor antagonist β-carboline ZK 93426

It has been suggested from pharmacological studies in animals that ZK 93426 may improve memory and other cognitive processes in humans. Scopolamine has been used to model aspects of memory impairment. To test the effects of ZK 93426 alone and in combination with scopolamine, ZK 93426 (0.04 mg/kg) or vehicle (Intralipid R) was administered intravenously (i.v.) to normal controls, pre-treated with either scopolamine 0.5 mg administered subcutaneously (s.c.) or the same volume of saline. A visual (presentation of pictures) and a verbal (words list) memory test were applied. Both drugs on their own and in combination were found to be safe and well tolerated. ZK 93426 did not antagonize the scopolamine-induced impairment of acquisition of the words list. Scopolamine did not impair delayed recall of visual or verbal material. ZK 93426 alone improved performance in delayed recall of visual material presented after drug application, whereas it impaired performance in delayed recall of visual material presented before drug administration.     

Hemispheric lateralisation in a manual-verbal task combination: the role of modality and gender

Differences in hemispheric lateralisation between males and females were tested using a manual-verbal task combination. The manual task was finger tapping and the verbal task required reciting words. Words were presented either visually or aurally in order to examine a possible role of modality of presentation on hemispheric lateralisation. The influence of the verbal task on motor task performance was evaluated by changes in the number of taps from single to dual-task condition. The influence of the motor task performance on the verbal task was examined by changes in the number of words recalled. Cognitive performance differences between males and females were also examined in a mental rotation task. The results showed a greater right finger (RH) tapping than left finger (LH) tapping interference, but only when the verbal task was presented in the visual mode. There was no difference in this pattern between males and females, both showing a greater RH tapping than LH tapping interference. The interference in finger tapping for both RH and LH was greater when the verbal task was presented aurally than when presented visually. Furthermore, females compared to males showed a greater interference in finger tapping when the verbal task was presented aurally than when presented visually. Later recall of verbal information was impaired equally by concurrent RH or LH tapping; however, later recall was better when the verbal task was presented visually than when presented aurally. No gender differences were found in delayed recall. Performance in the mental rotation task was better in males than in females. The data are discussed on the basis of theories of dual task interference and/or of brain asymmetry.     

The relationship between Rarebit perimetry and OCT‐derived retinal nerve fibre layer thickness in glaucoma

Purpose: To examine the association between measures of neuroretinal matrix integrity as determined with Rarebit perimetry and optical coherence tomography (OCT)‐derived retinal nerve fibre layer thickness. Methods: One randomly selected eye of 30 White primary open‐angle glaucoma patients (age: 60.9 ± 11.7 years; MD: ?3.2 ± 5.1 dB) and 16 healthy White individuals (age: 33.2 ± 6.4 years; MD: ?0.8 ± 0.8 dB) were included in the study. Participants underwent Rarebit perimetry testing (central field, software version 4) and an OCT fast retinal nerve fibre layer (RNFL) scan. Correlation was investigated between hemifield Rarebit scores and the corresponding RNFL values, as well as between global Rarebit scores and the respective RNFL measures. Results: Statistically significant correlations of average hit rate (HR) < 90 and mean hit rate (MHR) were detected with Max–Min and average thickness (Pearson’s r ranging from 0.393 to 0.474). Number HR < 90 showed a moderate correlation only with Max–Min (r = ?0.396, P = 0.030). Regarding the association between hemifield hit rates and the corresponding OCT thickness parameters, only inferior maximum correlated moderately with HR superior (r = 0.385, P = 0.035). A tendency was detected for the relationship of superior maximum with HR inferior (r = 0.345, P = 0.062). For the control group, no significant correlation was found for any of the global or hemifield indices and the corresponding thickness values. Conclusion: Although Rarebit perimetry is based on a physiological principle distinctly different from conventional perimetry, it provides global indicators of neuroretinal matrix integrity that correlate with some OCT‐derived RNFL thickness measures.     

Endogenous versus exogenous cell replacement for Parkinson’s disease: where are we at and where are we going?

Parkinson’s disease is the second most common neurodegenerative disease and has currently no effective treatment, one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars compacta. In addition, Parkinson’s disease diagnosis is typically done when a significant percentage of the dopaminergic neurons is already lost. In neurodegenerative disorders, some therapeutic strategies could be effective only at inhibiting further degeneration; on the other hand, cell replacement therapies aim at replacing lost neurons, an approach that would be ideal for the treatment of Parkinson’s disease. Many cell replacement therapies have been tested since the 1970s in the field of Parkinson’s disease; however, there are still significant limitations prohibiting a successful clinical application. From the first fetal midbrain intrastriatal graft to the most recent conversion of astrocytes into dopaminergic neurons, we have gained equally, significant insights and questions still looking for an answer. This review aims to summarize the main milestones in cell replacement approaches against Parkinson’s disease. By focusing on achievements and failures, as well as on the additional research steps needed, we aim to provide perspective on how future cell replacement therapies treats Parkinson’s disease.Key Words: endogenous, neurodegenerative disease, neurogenesis, neurotrophic factors, Parkinson’s disease, stem cells, transdifferentiation, transplantations