Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects

Summary The effects of barbiturates on the GABA-receptor complex and the A₁ adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [³⁵S]t-butylbicyclophosphorothionate ([³⁵S]TBPT) and enhanced the binding of [³H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [³⁵S]TBPT binding, they showed varying degrees of maximal enhancement of [3H]diazepam binding; (±)methohexital was identified as the most efficacious compound for this enhancement. At the A₁ adenosine receptor all barbiturates inhibited the binding of [³H]N⁶-phenylisopropyladenosine ([³H]PIA) in a competitive manner. The comparison of the effects on [³H]diazepam and [³H]PIA binding showed that excitatory barbiturates interact preferentially with the A₁ adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/anaesthetic properties of barbiturates.Abbreviations GABA -aminobutyric acid - TBPT t-butylbicyclophosphorothionate 1073 - DMBB 5-(1,3-dimethyl)butyl-5-ethylbarbituric acid - MCB N-methyl-5-(1-cyclohexen-1-yl)-5-ethylbarbituric acid - MPPB N-methyl-5-phenyl-5-propylbarbituric acid - PIA N⁶-phenylisopropyladenosine Send offprint requests to M. J. Lohse at the above address     

Tula Virus as Causative Agent of Hantavirus Disease in Immunocompetent Person,Germany

We report molecular evidence of Tula virus infection in an immunocompetent patient from Germany who had typical signs of hantavirus disease. Accumulating evidence indicates that Tula virus infection, although often considered nonpathogenic, represents a threat to human health.     

Is the Parkland formula still the best method for determining the fluid resuscitation volume in adults for the first 24 hours after injury? — A retrospective analysis of burn patients in Germany

BackgroundR Rapid fluid resuscitation is a crucial therapy during the treatment of patients with extensive burns. In 1968, the Parkland Formula was introduced for the calculation of the estimated volume of the resuscitation fluid. Since then, different methods for the calculation of fluid resuscitation volume have been developed. We aimed to evaluate if the Parkland formula is still the most effective method for fluid resuscitation volume calculation in burn patients.MethodsIn the period between January 2015 and January 2019, data from 569 patients over 16 years old with burns of more than 20% total body surface area (TBSA) and at least 15% TBSA full thickness burns were entered in the German burn registry. The patients were divided into 5 groups (0, +1, ?1, +2, ?2) according to the volume of the resuscitation fluid they received. Group 0 patients received the amount of fluid calculated according to the Parkland formula (n = 83). The 4 other groups received reduced (-1, -2) or increased (+1, +2) fluid volumes in comparison to the value obtained by the Parkland formula.ResultsPatients in Group 0 presented a significantly lower mortality in the first week (4.5%) compared to groups –2 (16.7%) and group +2 (19.5%) (p = 0.021). Furthermore, the mean number of operations in group +2 (5.81) was higher than in group ?2 (3.81). Surviving patients from group +2 presented a longer hospital stay (68.1 days) compared to the other groups. Additionally, the logistic regression analysis showed a higher survival of patients in groups ?2 and ?1 (regression coefficients ?0.11 and ?0.086; Odds Ratio 0.896 and 0.918; 95% Confidence Interval (CI) 0,411–1.951 and 0.42–2.004).ConclusionIn this retrospective study, register based analysis a restrictive fluid regime was associated with a higher survival compared to the liberal Parkland guided fluid regime.     

The Functional Status of the ACL in Varus OA of the Knee: The Association With Varus Deformity and Coronal Tibiofemoral Subluxation

BackgroundThe present article analyzes the association of the functional anterior cruciate ligament (ACL) status and the overall varus deformity and coronal tibiofemoral subluxation (CTFS) in varus OA of the knee.MethodsOne hundred consecutive knees with varus OA in 84 patients were prospectively included. Knees were divided into two groups, in accordance with the ACL status (functionally sufficient or insufficient). All included patients were potential candidates for unicompartmental knee arthroplasty with predominantly medial compartment OA. Knees with Kellgren/Lawrence ≥ grade 3 in the lateral compartment were excluded leaving 79 knees to be included in this study. Mechanical varus deformity and CTFS were evaluated on AP radiographs and valgus stress radiographs, and compared between the two groups.ResultsKnees with a functionally insufficient ACL had significantly more varus deformity on hip-to-ankle AP standing radiographs (P = .001) and on valgus stress radiographs (P = .017). CTFS on AP standing radiographs was significantly higher (P = .045) in knees with a functionally insufficient ACL. Seventy-three percent (8/11) of the ACL-insufficient knees had a varus deformity of ≥10° and 64% (7/11) of ACL-insufficient knees had CTFS ≥ 6mm. By contrast, only one patient (2%, 1/41) with an insufficient ACL had< 10° varus deformity and a CTFS of < 6mm.ConclusionFunctional ACL insufficiency in osteoarthritic varus knees is associated with greater varus deformity and more advanced CTFS. Seventy-three percent of ACL-insufficient knees had a varus deformity of ≥10° and 64% of ACL-insufficient knees a CTFS of ≥ 6mm. In the work-up for medial unicompartmental knee arthroplasty, functional ACL insufficiency is likely in knees with varus deformity of ≥10° and CTFS of ≥ 6mm.     

Experimental Induction of Emotional and Sexual Intimacy: Exploring the Validity of the German Fast Friends Procedure in Individuals with and without Childhood Maltreatment

The Fast Friends Procedure (FFP) is a widely used experimental paradigm to induce emotional intimacy. Besides exploring the validity of a German translation of the paradigm (n?=?46), we developed an extension of the FFP that induces sexual intimacy and assessed heart rate, high-frequency heart rate variability, and electrodermal activity responses to the FFP and its extension. Furthermore, we examined its applicability to individuals with childhood maltreatment (n?=?56), who frequently suffer from intimacy-related difficulties. Intimacy, positive affect, liking, and attraction increased during the FFP and partly during the sexual intimacy extension in both study groups. Moreover, both groups showed physiological responses consistent with positive social interactions. The use of the German FFP and its sexual intimacy extension can thus be recommended for research in the general population and in individuals with childhood maltreatment, although more studies are needed to further validate the paradigms.

     

Human V5/MT+: comparison of functional and cytoarchitectonic data

To date, the delineation of the human visual “motion area” still relies on functional paradigms originally devised to identify monkey area MT. Using fMRI, we have identified putative human area V5/MT+ in normals by modelling the BOLD responses to alternating radially moving and stationary dot patterns. Functional activations were compared with cytoarchitectonic probability maps of its putative correlate area hOc5, which was calculated based upon data from histological sections of ten human post-mortem brains. Bilateral visual cortex activations were seen in the single subject dynamic versus stationary contrasts and in the group random-effects analysis. Comparison of group data with area hOc5 revealed that 19.0%/39.5% of the right/left functional activation was assigned to the right/left hOc5. Conversely, 83.2%/53.5% of the right/left hOc5 was functionally activated. Comparison of functional probability maps (fPM) with area hOc5 showed that 28.6%/18.1% of the fPM was assigned to hOc5. In turn, 84.9%/41.5% of the area hOc5 was covered by the respective fPM. Thus, random-effects data and fPMs yielded similar results. The present study shows for the first time the correspondence between the functionally defined human V5/MT+ and the post-mortem cytoarchitectonic area hOc5.     

Efficient propagation of single gene deleted recombinant Sendai virus vectors

Recombinant Sendai virus vectors (SeVV) have become an attractive tool for basic virological as well as for gene transfer studies. However, to (i) reduce the cellular injury induced by basic recombinant SeV vectors (encoding all six SeV genes as being present in SeV wild-type (wt) genomes) and to (ii) improve SeV vector safety, deletions of viral genes are necessary for the construction of superior SeVV generations. As a strong expression system recombinant replication-incompetent adenoviruses, coding for SeV proteins hemagglutinin-neuraminidase (HN), fusion (F), or matrix (M), were generated and successfully employed for the propagation of single gene deleted (DeltaHN, DeltaF, DeltaM) recombinant SeVV. Further investigations of the propagation procedures required for single gene deleted recombinant SeVV demonstrated (i) modifications of the cell culture medium composition as well as (ii) incubation with vitamin E as crucial steps for the enhancement of SeVV-DeltaHN, -DeltaF, or -DeltaM viral particle yield. Such optimized propagation procedures even led to a successful propagation of HN-deleted viral particles (SeVV-DeltaHN), which has not been reported before.     

In situ dormancy of B lymphocytes programmed for an IgE antibody response and their sudden release from unresponsiveness under in vitro conditions

Priming of CBA/J mice with different doses of antigen has aprofound effect on the ratio of IgE versus IgG antibodies appearingupon Immunization. Repeated injections of minute doses induceIgG and high titers of IgE antibodies. Large doses elicit ahigh IgG but a very low IgE antibody titer. In order to studythe modalities for activation and inactivation of IgE-producingB cells, an in vitro culture system was established in whichspleen cells from animals primed with keyhole limpet hemocyaninwere re-stliulated with antigen. In contrast to the expectationfrom the in vivo situation, spleen cells from animals Immunizedwith large doses of antigen and virtually lacking IgE antibodiesproduce high amounts of IgE antibodies upon re-stimulation invitro. The titers in spleen cell cultures from mice primed withminute doses remain proportional to the response measured asserum antibodies. In accordance with the induction of high amountsof IgE antibodies in spleen cell cultures from mice primed withlarge doses, the frequency of IgE antibody-secreting cells wasraised drastically, 1000-fold. The in vitro response is a trueanamnestic response. The sudden appearance in high frequencyof IgE antibody-forming cells among spleen cells isolated fromprimed mice which have high IgG but virtually no IgE antibodytiters is as yet unexplained and the origin of the B memorycells has not yet been traced. The answer might be crucial forour understanding of the down-regulation of the IgE Immune responses.     

Differentiation and expansion of beta cell mass in porcine neonatal pancreatic cell clusters transplanted into nude mice

Neonatal porcine pancreas has considerable capacity for growth and differentiation, making it an attractive potential source of islet tissue for xenotransplantation. Pancreases from 1-3-day-old newborn pigs were digested with collagenase and cultured for 8 days. The resulting cellular aggregates are called porcine neonatal pancreatic cell clusters (NPCCs). The mean yield of NPCCs from a newborn pig was 28,200 +/- 1700 islet equivalents. Cytokeratin 7 (CK7) was used as a marker for the immunostaining of pancreatic duct cells. In neonatal pancreas, 18% of the insulin-positive cells co-stained for CK7, thus being protodifferentiated. NPCCs also contained protodifferentiated cells; insulin/PP and insulin/somatostatin co-stained cells were more common than insulin/glucagon cells. Between 1 and 8 days of culture, the DNA content of the NPCCs fell to 16% and the insulin content to 33% of the starting value, mainly due to the preferential loss of exocrine cells. Transplantation of 2000 or 4000 NPCCs into diabetic nude mice typically normalized glucose values in 10-20 weeks. Mice with successful grafts had lower fasting blood glucose levels than normal mice and accelerated glucose clearance after an i.p. glucose load. The starting NPCCs consisted of 17% insulin-staining cells, but the grafts of mice with reversed diabetes consisted of 94% beta cells, with some co-stained for CK7, indicating that the grafts still contained immature cells. The mass of insulin-producing cells rose from 0.22 +/- 0.08 mg 1 week after transplantation to 4.34 +/- 0.27 mg in mice sacrificed at 27-35 weeks. In summary, NPCCs contain mostly islet precursor cells, which when transplanted into nude mice undergo striking differentiation and beta cell expansion.     

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.