Measuring the potency labelling of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin (®)) in an LD50 assay.

The biological potency of botulinum toxin (BT) drugs is determined by a standardised LD50 assay. However, the potency labelling varies vary amongst different BT drugs. One reason for this may be differences in the LD50 assays applied. When five unexpired batches of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin(®)) are compared in the Xeomin(®) batch release assay, the potency variability of both BT drugs fell within the range allowed by the European Pharmacopoiea. Statistical analyses failed to detect differences in the potency labelling of both products. Although the existence of a conversion ratio has been questioned recently, our experimental data are in line with previous clinical experience showing that Botox(®) and Xeomin(®) can be compared using a 1:1 conversion ratio. Identical potency labelling allows easy exchange of both BT drugs in a therapeutic setting, and direct comparison of efficacy, adverse effects and costs.

Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.

Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.

Stress worsens endothelial function and ischemic stroke via glucocorticoids.

BACKGROUND AND PURPOSE: Chronic stress is associated with increased stroke risk. However, the underlying pathophysiological mechanisms are poorly understood. We examined the effects of chronic stress on endothelial function and ischemic brain injury in a mouse model. METHODS: 129/SV mice were treated with glucocorticoid receptor antagonist mifepristone (25 mg kg(-1)/d) or vehicle and exposed to 28 days of chronic stress consisting of exposure to rat, restraint stress, and tail suspension. Heart rate and blood pressure were continuously recorded by telemetry. Endothelial nitric oxide synthase mRNA and protein expression as well as superoxide production and lipid hydroperoxides were quantified. Endothelium-dependent vasorelaxation was measured in aortic rings. Ischemic lesion volume was quantified after 30 minutes filamentous middle cerebral artery occlusion and 72 hours reperfusion. RESULTS: Chronic stress caused a significant increase in heart rate, impaired endothelium-dependent vasorelaxation, increased superoxide production, and reduced aortic and brain endothelial nitric oxide synthase levels. Animals exposed to chronic stress showed major increases in ischemic lesion size. These deleterious effects of stress were completely reversed by treatment with mifepristone. CONCLUSIONS: Chronic stress increases stroke vulnerability likely through endothelial dysfunction, which can be reversed by a glucocorticoid receptor antagonist.

Expression of the non-gastric H+/K+ ATPase ATP12A in normal and pathological human prostate tissue.

Altered cellular proton handling and cell volume regulation are hallmarks of tumorigenesis. To investigate a possible involvement of the non-gastric H(+)/K(+) ATPase ATP12A (ATP1AL1) in prostate cancer, we performed immunohistochemistry in formalin-fixed, paraffin-embedded histological sections from benign and malignant human prostate lesions. Normal prostate tissue displayed a membrane-bound ATP12A staining with focal accumulated pattern, whereas in the benign prostate hyperplasia (BPH) and cancerous prostate tissue (tumor grade I-III) the protein appears to be displaced in the luminal cells of the glandular epithelium. Hence, the expression pattern of ATP12A is markedly altered in BPH and prostate cancer. To test for altered gene expression of ATP12A we performed quantitative reverse transcriptase PCR (QRT-PCR) in normal (tumor-free) prostate tissue, BPH and tumor stages I-III using a prostate cancer cDNA array. However, no significantly different expression levels could be detected in the various disease states compared to normal tissue, which contrasts the findings from immunohistochemistry and points to the possibility of altered post-translational processing and/or sorting of the protein. We further show that ATP12A mRNA is expressed at different levels in PC-3 and LNCaP prostate cancer cells, with a significant ~26-fold higher expression in the latter cell type. Protein expression in these tumor cell lines was verified by Western blot.

Amantadine Inhibits SARS-CoV-2 In Vitro.

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

Addition of lidocaine suppositories to periprostatic nerve block enhances pain control in prostate biopsies: a placebo-controlled randomized trial.

PURPOSE: The aim of this study was to evaluate the efficacy of a combined topical and local anesthesia consisting of a transrectal lidocaine suppository followed by periprostatic nerve block (PNB) in comparison to the combination of transrectally applied lidocaine gel followed by PNB and PNB alone as methods of reducing pain during transrectal prostate biopsy. PATIENTS AND METHODS: 100 patients were randomized to four groups and received either a placebo suppository or 10 ml of 2% lidocaine gel or a suppository containing 60 or 120 mg of lidocaine 1 h before biopsy. Additionally, every patient received a PNB using 5 ml 2% lidocaine. After performing an extensive transrectal ultrasound-guided biopsy, pain was evaluated using a visual pain scale. RESULTS: The mean pain score in the placebo group was 3.4, in the lidocaine gel group it was 3.7, and in the 60 or 120 mg lidocaine suppository groups it was 2.4 and 2.5, respectively. No patient showed vegetative symptoms like sweating or symptomatic hypotonia and no patient had severe pain. CONCLUSION: The addition of lidocaine suppositories to PNB as a form of combined anesthesia showed a significantly better pain reduction than the addition of lidocaine gel to PNB or PNB alone.

Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of toll-like receptor 9.

AIMS: Myocardial function is severely compromised during sepsis. Several underlying mechanisms have been proposed. The innate immune system, i.e. toll-like receptor (TLR) 2 and 4, significantly contributes to cardiac dysfunction. Little is known regarding TLR9 and its pathogenic ligand bacterial DNA in the myocardium. We therefore studied the role of TLR9 in myocardial inflammation and cardiac contractility. METHODS AND RESULTS: Wild-type (WT, C57BL/6) and TLR9-deficient (TLR9-D) mice and isolated cardiomyocytes were challenged with synthetic bacterial DNA (CpG-ODN). Myocardial contractility as well as markers of inflammation/signalling were determined. Isolated cardiomyocytes incorporated fluorescence-marked CpG-ODN. In WT mice, CpG-ODN caused a robust response in hearts demonstrated by increased levels of tumour necrosis factor (TNF-alpha), interleukin (IL)-1beta, IL-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappaB activity. This inflammatory response was absent in TLR9-D mice. Under similar conditions, contractility measurements of isolated ventricular cardiomyocytes demonstrated a TLR9-dependent loss of sarcomeric shortening after CpG-ODN exposure. This observation was iNOS dependent as the application of a specific iNOS inhibitor reversed sarcomeric shortening to normal levels. CONCLUSION: Our data suggest that bacterial DNA contributes to myocardial cytokine production and loss of cardiomyocyte contractility via TLR9.

Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow.

Physical activity upregulates endothelial nitric oxide synthase (eNOS), improves endothelium function, and protects from vascular disease. Here, we tested whether voluntary running would enhance neovascularization and long-term recovery following mild brain ischemia. Wild-type mice were exposed to 30 minutes of middle-cerebral artery occlusion (MCAo) and reperfusion. Continuous voluntary running on wheels conferred long-term upregulation of eNOS in the vasculature and of endothelial progenitor cells (EPCs) in the spleen and bone marrow (BM). This was associated with higher numbers of circulating EPCs in the blood and enhanced neovascularization. Moreover, engraftment of TIE2/LacZ-positive BM-derived cells was increased in the ischemic brain. Four weeks after the insult, trained animals showed higher numbers of newly generated cells in vascular sites, increased density of perfused microvessels and sustained augmentation of cerebral blood flow within the ischemic striatum. Moreover, running conferred tissue sparing and improved functional outcome at 4 weeks. The protective effects of running on angiogenesis and outcome were completely abolished when animals were treated with a NOS inhibitor or the antiangiogenic compound endostatin after brain ischemia, and in animals lacking eNOS expression. Voluntary physical activity improves long-term stroke outcome by eNOS-dependent mechanisms related to improved angiogenesis and cerebral blood flow.

Comparison of lidocaine suppositories and periprostatic nerve block during transrectal prostate biopsy.

The aim of this randomized prospective and partially double-blind study was to evaluate the efficacy of transrectal lidocaine applied as suppositories in comparison to periprostatic infiltration as methods of reducing pain during transrectal prostate biopsy. 100 patients were randomized to four groups and received either a suppository containing 60 mg of lidocaine 2 h before biopsy, a 120-mg lidocaine suppository 1 h before biopsy, a 120-mg lidocaine suppository 2 h before biopsy, or they were anaesthetized with a periprostatic infiltration of 5 ml 2% lidocaine. In all patients the same 10-core transrectal biopsy technique was performed. Pain was evaluated using a visual pain scale ranging from 0 to 10 points. The mean pain score in the 60-mg (2 h), 120-mg (1 h), and 120-mg (2 h) lidocaine suppository groups was 3.63, 3.56, and 3.58 respectively. The mean pain score of patients receiving periprostatic infiltration was 1.80. No patient showed vegetative symptoms like sweating or hypotonia. No patient had severe pain. Eight of the 9 patients with no pain were in the periprostatic injection group. Thus, all lidocaine suppositories showed a good analgesic effect although a significantly better pain reduction was achieved by periprostatic lidocaine infiltration.

The use of Duloxetine in the treatment of male stress urinary incontinence.

Stress urinary incontinence (SUI) is a known complication after prostate surgery. To date no pharmacologic treatment is available. Currently Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is available for women with SUI. This study investigates the effect of Duloxetine on men with SUI after prostate surgery. 56 patients were included in our study. 49 after radical prostatectomy and 7 after TURP. All patients were initially treated with pelvic floor exercises. Thereafter 40 mg Duloxetine was administered twice daily. When taking Duloxetine, the average use of incontinence pads decreased from 3.3 to 1.5 per day. 14 patients needed no and 18 a single pad per day. Most patients reported mild and temporary side effects, 13 patients assessed them to be moderate and 9 being severe. The results of this off-label use show that Duloxetine is effective in men with SUI after prostate surgery even if standard pelvic floor exercises have failed.

[The influence of bone quality and the fixation procedure on the primary stability of cementless implanted tibial plateaus]. / Der Einfluss der Knochenmineraldichte und des Verankerungsverfahrens auf die Primärstabilitat von zementfrei implantierten Tibiakomponenten.

BACKGROUND: An overview of prospective studies on cementless and cemented primary knee joint endoprosthetics carried out between 1988 and 2004 reveals that the aseptic tibial loosening rate of cemented prostheses implanted with fixed meniscal bearings amounts to 2-6% within a period of 4-14 years, while cementless implanted prostheses show loosening rates of up to 28% within a period of 4-10 years. If these results arise from a lack of proper initial osseointegration as a result of insufficient primary stability, and how this is influenced by the tibial bone quality and the tibial fixation procedure has not yet been investigated. MATERIALS AND METHODS: Tibial plateaus were press-fit implanted, both screwed and unscrewed, into each of six pairs of tibial heads from corpses. Stability testing was conducted applying eccentric axial load, shear and torsion. RESULTS: The average amounts of relative movement at the medial and lateral plateau are clearly different in the screwed version and the unscrewed version when loaded axially, but the difference was significant (p = 0.016) only at the medial plateau. Relative movements under shear and torsion showed no significant differences. The bone density of the tibial metaphyses had no significant effect on the primary stability of the cementless implanted tibial plateau. CONCLUSION: When using cementless knee endoprostheses, the fixation of the tibial plateau with screws--in addition to a flawless press-fit and form-fit customization of the tibial head--appears indispensable for guaranteeing proper osseointegration under physiological axial loads.

The cytoskeleton in 'couch potato-ism': Insights from a murine model of impaired actin dynamics.

Evidence for a critical pathophysiological role of aberrant cytoskeletal dynamics is being uncovered in a growing number of neuropsychiatric syndromes. A sedentary lifestyle as well as overt psychopathology is prevalent in patients with the metabolic syndrome. Using mice deficient in gelsolin (Gsn-/-), a crucial actin-severing protein, we here investigated reduced actin turnover as a potential common driver of metabolic disturbances, sedentary behavior, and an anxious/depressive phenotype. Gelsolin deficiency resulted in reduced lifespan. As compared to wildtype controls, Gsn-/- mice (~ 9 weeks) fed a high-fat diet (HFD) over a span of 12 weeks showed increased body weight gain, fat mass, hepatic steatosis, and adipocyte hypertrophy as well as a significantly reduced respiratory quotient. Moreover, increased rigidity of the actin cytoskeleton in mice on HFD induced mRNA expression of Acc1, Acc2, Fasn, and Lipe, key genes involved in fatty acid metabolism in the liver. Glucose tolerance and insulin sensitivity were worsened in Gsn-/- HFD relative to Gsn+/+ HFD mice. Hypertension in Gsn-/- mice was associated with reduced endothelial NO synthase (eNOS) mRNA expression and reduced eNOS protein trafficking to the plasma membrane. Furthermore, acetylcholine-induced cGMP production and relaxation of aortic rings were impaired by actin filament stabilization. Gsn-/- mice on HFD displayed reduced corticosterone concentrations and reduced energy expenditure as compared to Gsn+/+ HFD mice. Moreover, Gsn-/- HFD mice displayed an overall pattern of hypoactive and anxious/depressive-like behavior. In aggregate, our results demonstrate that impaired actin filament dynamics promote the development of key behavioral and physiological aspects of the metabolic syndrome.

The intraindividual agreement of the bone density of the human proximal tibia.

The interindividual variability in the biomechanical properties of cadaver bones has remained an unsolved problem in biomechanical investigation procedures. For this reason, it is postulated to use matched bone pairs from the same individual for comparative biomechanical tests. The rationale behind this procedure is based on the assumption that biomechanically similar behaviour is to be expected in an intraindividual rather than an interindividual comparison. Systematic studies confirming this thesis were performed on the human femur. However, investigations regarding the intraindividual properties of the proximal tibial metaphysis with respect to the underlying bone densities, have not yet been performed. In order to verify the hypothesis that matched proximal tibial metaphyses from the same donor imply corresponding bone density values, densitometric measurements (pQCT) were performed in 14 matched cadaver tibias (average age 61 years, 9 men, 5 women) which were fresh-frozen at -40 degrees C after removal. After statistical analysis of the bone density values, five tibial pairs were identified as differing on the basis of missing correlations and the existence of systematic differences within the pairwise data. In other words, only about 2/3 of the data in the random sample available was classified as comparable. As the bone density measured by pQCT technique significantly correlates with the biomechanical properties of the bone, it can be concluded from the test result available that matched human tibiae show no concurring bone density values in 1/3 of cases. Thus the pairing of corpse tibiae does not necessarily imply suitability for comparative biomechanical experiments.

Supervision, transference and countertransference.

The author discusses supervision, transference and countertransference as seen in the context of the clinical case of a patient who had been first seen as a training analysis case and who later, in a fortuitous way, was treated by the supervisor of the training analysis. The supervisor, who in the first instance did not recognize the patient, discusses the reasons for this unusual experience in terms of the presence and absence of transference during the analysis of this patient as a training case and the problems inherent in the task of supervising. The patient's feelings towards the first and the second analyst and the vicissitudes of transference and countertransference during the supervision of the training analysis and its influence on the presentation of the analytical sessions by the student are also detailed and discussed. The question of recorded supervision presentations and their possible influence on the dynamics of supervision is raised.

Female mice lacking estrogen receptor beta display prolonged ventricular repolarization and reduced ventricular automaticity after myocardial infarction.

BACKGROUND: Major gender-based differences in the incidence of ventricular tachyarrhythmia after myocardial infarction have been shown in humans. Although the underlying mechanisms are unclear, earlier studies suggest that estrogen receptor-mediated effects play a major role in this process. METHODS AND RESULTS: We examined the effect of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) on the electrophysiological phenotype in female mice with and without chronic anterior myocardial infarction. There was no significant difference in overall mortality, infarct size, and parameters of left ventricular remodeling when we compared infarcted ERalpha-deficient and ERbeta-deficient mice with infarcted wild-type animals. In the 12-hour telemetric ECG recording 6 weeks after myocardial infarction, surface ECG parameters did not show significant differences in comparisons of ERalpha-deficient mice versus wild-type controls, infarcted versus noninfarcted ERalpha-deficient mice, and infarcted ERalpha-deficient versus infarcted wild-type mice. However, infarcted ERbeta-deficient versus noninfarcted ERbeta-deficient mice showed a significant prolongation of the QT (61+/-6 versus 48+/-8 ms; P<0.05) and QTc intervals (61+/-7 versus 51+/-9 ms; P<0.05) and the JT (42+/-6 versus 31+/-4 ms; P<0.05) and JTc intervals (42+/-7 versus 33+/-4 ms; P<0.05). Furthermore, infarcted ERbeta-deficient versus infarcted wild-type mice showed a significant prolongation of the QT (61+/-6 versus 53+/-8 ms; P<0.05) and QTc intervals (61+/-7 versus 53+/-7 ms; P<0.05) and the JT (42+/-6 versus 31+/-5 ms; P<0.05) and JTc intervals (42+/-7 versus 31+/-5 ms; P<0.05), accompanied by a significant decrease of ventricular premature beats (7+/-21/h versus 71+/-110/h; P<0.05). Finally, real-time polymerase chain reaction-based quantitative analysis of mRNA levels showed a significantly lower expression of Kv4.3 (coding for I(to)) in ERbeta-deficient mice (P<0.05). CONCLUSIONS: Estrogen receptor beta deficiency results in prolonged ventricular repolarization and decreased ventricular automaticity in female mice with chronic myocardial infarction.

Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia.

The molecular mechanisms that mediate gram-negative sepsis-associated myocardial dysfunction remain elusive. Myocardial expression of inflammatory mediators is Toll-like receptor 4 (TLR4) dependent. However, it remains to be elucidated whether TLR4, expressed on cardiac myocytes, mediates impairment of cardiac contractility after lipopolysaccharide (LPS) application. Cardiac myocyte contractility, measured as sarcomere shortening of isolated cardiac myocytes from C3H/HeJ (with nonfunctional TLR4) and C3H/HeN (control), were recorded at stimulation frequencies between 0.5 and 10 Hz and after incubation with 1 and 10 mug/mL LPS for up to 8 h. Control cells treated with LPS were investigated with and without a competitive LPS inhibitor (E5564) and a specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea. In control mice, LPS reduced sarcomere shortening amplitude and prolonged duration of relaxation, whereas sarcomere shortening of C3H/HeJ cells was insensitive to LPS. NFkappaB and iNOS were upregulated after LPS application in control mice compared with C3H/HeJ. Inhibition of TLR4 by E5564 as well as inhibition of iNOS prevented the influence of LPS on contractile activity in control myocytes. LPS-dependent suppression of cardiac myocyte contractility was significantly blunted in C3H/HeJ mice. Competitive inhibition of functional TLR4 with E5564 protects cardiac myocyte contractility against LPS. These findings suggest that TLR4, expressed on cardiac myocytes, contributes to sepsis-induced myocardial dysfunction. E5564, currently under investigation in two clinical phase II trials, seems to be a new therapeutic option for the treatment of myocardial dysfunction in sepsis associated with endotoxemia.

Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

Ca2+ entry via P/Q-type Ca2+ channels and the Na+/Ca2+ exchanger in rat and human neocortical synaptosomes.

Rat or human neocortical synaptosomes were used to study the role of voltage-gated Ca(2+) channels and the Na(+)/Ca(2+) exchanger in (45)Ca(2+) influx into nerve terminals. K(+) depolarization-induced (45)Ca(2+) influx through voltage-gated Ca(2+) channels into rat or human synaptosomes was completely blocked by mibefradil 30 microM or Cd(2+) 100 microM but was not affected by tetrodotoxin 1 microM. It was reduced by omega-agatoxin IVA 0.2 microM by 68% in synaptosomes of either species, whereas omega-conotoxin GVIA 0.1 microM and nifedipine 1 microM had no effect. Veratridine-induced (45)Ca(2+) entry into rat neocortical synaptosomes was completely blocked by mibefradil 30 microM, reduced by 80% by Cd(2+) 100 microM, by 90% by tetrodotoxin 1 microM and by 53% by omega-agatoxin IVA 0.2 microM but not by omega-conotoxin GVIA 0.1 microM or nifedipine 1 microM. Na(+)/Ca(2+) exchanger-mediated (45)Ca(2+) uptake into rat neocortical synaptosomes evoked by replacement of Na(+) by choline(+) in the incubation buffer was reduced by KB-R7943 (3-50 microM), an inhibitor of the Na(+)/Ca(2+) exchanger, in a concentration-dependent manner (maximal inhibition by 46% at 50 microM; IC(23%)=7.1 microM). Mibefradil also inhibited the Na(+)/Ca(2+) exchanger-mediated Ca(2+) uptake, although at 3.7 times lower potency (IC(23%)=26 microM). It is concluded that in rat and human neocortical nerve terminals Ca(2+) entry is mediated under physiological conditions by P/Q-type, but not by N- or L-type Ca(2+) channels or the Na(+)/Ca(2+) exchanger. If the cytosolic Na(+) concentration is increased, Ca(2+) is also taken up via the Na(+)/Ca(2+) exchanger. In addition to the ability of mibefradil to block all voltage-operated Ca(2+) channels, this drug is a low potency inhibitor of the Na(+)/Ca(2+) exchanger.

Magnitude of trauma and personality change.

In this paper the author postulates that, in post-traumatic personality structures caused by overwhelming traumatic experiences, pre-traumatic personality features and childhood experiences are of little or no relevance. Sixty-four survivors of Nazi concentration camps are examined, their concentration camp experiences detailed and pre-persecution histories and post-persecution psychopathology studied. The significance of a concentration camp experience is analytically discussed and evaluated. This study shows that 52 cases (81.2%) of the 64 survivors of concentration camps presented an almost identical depressive personality structure irrespective of their prepersecution life history. The 64 survivors of concentration camps are psychologically compared to 78 cases of people who, in view of the menacing circumstances, decided to emigrate and in this way were spared from becoming victims of the Nazi 'final solution'. Finally, the author discusses the value of psychoanalytical treatment.