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Notizen: Vectors constructed from recombinant herpes simplex virus (HSV) have special utility for gene transfer to the nervous system. Nonreplicating vectors created by deletion of essential immediate early genes can be propagated to high titers on complementing cell lines that provide the missing gene product(s) in trans. Direct inoculation of these vectors into neural parenchyma is effective in rodent models of brain tumor, Parkinson disease, spinal cord injury, and spinal root trauma. Subcutaneous inoculation of the HSV vectors can be used to transduce neurons of the dorsal root ganglion to provide a therapeutic effect in models of polyneuropathy and chronic regional pain. In human trials, direct injection of replication-competent HSV into brain tumors has proven safe. Human trials of nonreplicating HSV gene transfer by direct inoculation for treatment of glioblastoma and HSV gene transfer by subcutaneous inoculation for the treatment of chronic intractable pain should commence soon.

Notizen: 1. In North America, the invasive predatory cladoceran Cercopagis pengoi was first detected in Lake Ontario. We explored the impact of Cercopagis on the lower food web of Lake Ontario through assessments of historical and seasonal abundance of the crustacean zooplankton, by conducting feeding experiments on the dominant prey of the invader, and by estimating its food requirements.2. Between 1999 and 2001, a decrease in the abundance of dominant members of the Lake Ontario zooplankton community (Daphnia retrocurva, Bosmina longirostris and Diacyclops thomasi) coincided with an increase in the abundance of Cercopagis. Daphnia retrocurva populations declined despite high fecundity in all 3 years, indicating that food limitation was not responsible. Chlorophyll a concentration generally increased, concomitant with a decline in the herbivorous cladoceran zooplankton in the lake.3. Laboratory experiments demonstrated that Cercopagis fed on small-bodied species including D. retrocurva and B. longirostris.4. Consumption demand of mid-summer populations of Cercopagis, estimated from a bioenergetic model of the confamilial Bythotrephes, was sufficient to reduce crustacean abundance, although the degree of expected suppression varied seasonally and interannually.5. Predatory effects exerted by Cercopagis on the Lake Ontario zooplankton, while initially very pronounced, have decreased steadily as the species became established in the lake.

Notizen: The distinct distribution of trkA receptors on small neurons and trkC receptors on large neurons in the dorsal root ganglion correlates with the dependence of these two classes of neurons on nerve growth factor and neurotrophin-3, respectively, for survival during development. In adult animals, the distribution of high affinity neurotrophin (trk) is complex and overlapping; neurotrophins are not required for cell survival, but may influence cell phenotype and the response to injury. In order to test the functional activity of trkA receptors in the sensory ganglia of adult animals in vivo, we examined the ability of a nerve growth factor-expressing recombinant replication-defective herpes simplex virus-based vector to prevent the selective degeneration of large sensory fibres caused by intoxication with pyridoxine. Transduction of dorsal root ganglion neurons in vivo by subcutaneous inoculation of the nerve growth factor-expressing vector prevented the development of pyridoxine-induced neuropathy measured by electrophysiological, morphological and behavioural measures. These results demonstrate a functional activity of trkA receptors expressed on large neurons in the dorsal root ganglion in mature animals; this observation has important implications for the choice of neurotrophic factors for treatment of peripheral nerve disease.

Notizen: In the Xenopus laevis retina, a principal model for retinal circadian organization, photoreceptors have all the properties of circadian oscillators. However, rhythmic oscillations of Per1 gene expression in the inner retina (but not photoreceptors) have been reported in mice with the suggestion that mice and frogs have a different retinal circadian organization. Although it is known that two period genes (xPer1 and xPer2) exhibit different temporal patterns of expression in the Xenopus retina, and that one (xPer2) is directly responsive to light and dopamine, it is not known whether this reflects the properties of period genes within photoreceptor oscillators or among distinct retinal cell populations. We addressed this by determining the cellular site of light and dopamine regulated xPer2 expression, and the diurnal expression of both xPer1 and xPer2 using in situ hybridization. Our data show that both xPer1 and xPer2 are expressed in most cell types in the retina, including inner nuclear neurons and ganglion cells. However, light and quinpirole, a dopamine agonist, increase xPer2 levels specifically in photoreceptors, and the effect of quinpirole, but not light, is blocked by pCPT-cAMP. Furthermore, antiphasic diurnal expression of xPer1 and xPer2 also occurs in photoreceptors. Our analysis does not provide insight into the near constitutive expression of period genes in the inner retina, but supports a model in which light- and dopamine regulated-xPer2 and rhythmic xPer1 play critical roles in entrainment and circadian oscillations within photoreceptors.

Notizen: Multisite Electroanatomic Mapping. Ablation of intra-atrial reentrant tachycardia following Mustard or Senning procedures has low success rates. The Biosense Carto system was used to map intra-atrial reentry in a 22-year-old woman who had undergone a Mustard procedure. A line of block was created connecting a Mustard baffle suture line to the tricuspid valve annulus, which terminated the arrhythmia and prevented its reinitiation. Multisite electoanatomic mapping was invaluable in defining atrial anatomy and the intra-atrial reentrant pathway, and in creating a contiguous line of block. This mapping may improve ablation success rates in patients following the Mustard or Senning repair.

Notizen: Background: Careful assessment of QT interval prolongation is required before novel drugs are approved by regulatory authorities. The choice of the most appropriate method of electrocardiogram (ECG) acquisition and QT/RR interval measurement in clinical trials requires better understanding of the differences among currently available approaches. This study compared standard and Holter-derived 12-lead ECGs for utility in detecting sotalol-induced QT/QTc and RR changes. Manual methods (digitizing pad and digital on-screen calipers) were compared for precision of QT and RR interval measurement. Methods and Results: Sixteen hundred pairs of serial 12-lead digital ECGs were recorded simultaneously by standard resting ECG device and by continuous 12-lead digital Holter over 3 days in 39 healthy male and female volunteers. No therapy was given on the 1st day followed by 160 mg and 320 mg of sotalol on the 2nd and 3rd day, respectively. Holter-derived and standard ECGs produced nearly identical sotalol-induced QT/QTc and RR changes from baseline, as did the manual digipad and on-screen caliper measurements. The variability of on-screen QT measurement in this study was greater than that of digipad. Conclusions: Digital 12-lead Holter and standard 12-lead ECG recorders, as well as the manual digitizing pad and digital on-screen calipers, are of equal utility for the assessment of drug-induced change from baseline in QT and RR interval, although the variability of the on-screen method in this study was greater than of the digipad.

Notizen: Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets.Pharmacokinetic studies demonstrated that reboxetine is suitable for twice daily administration (8–10 mg/day) and that it exhibits minimal drug-drug interactions. The starting dose of reboxetine should be reduced in the elderly, in patients with renal or hepatic impairment, or in patients receiving potent CYP3A inhibitors. A total of 20 phase II/III clinical studies comprising placebo-controlled, active comparator-controlled and open-label uncontrolled studies in both short-term and long-term treatment of major depression have been conducted. In the treatment of major depression, reboxetine was superior to placebo in 5 of 12 short- or long-term placebo-controlled studies and was comparable in efficacy to active comparators in 3 out of 3 active-controlled studies. Unlike conventional tricyclic antidepressants (TCAs), reboxetine had only minimal sedative and cardiovascular liabilities, probably due to increased pharmacological specificity of reboxetine as compared with TCAs. Unlike serotonin reuptake inhibitors, this selective and specific norepinephrine reuptake inhibitor demonstrated a distinct side-effect profile with diminishing sexual dysfunction and GI side effects. The availability of this agent has afforded patients suffering from major depressive disorder a new class of agents to combat the debilitating consequence of this psychiatric disease. The demonstrated pharmacological specificity of this compound has provided the psychopharmacology community with a tool to elucidate the role of norepinephrine in brain functions. Testing this agent in different animal models has enabled the exploration of the role of modulation of norepinephrine tone in the therapy of CNS disorders beyond depression.

Notizen: Background: The aim of this study was to compare the reproducibility and sensitivity of four commonly used methods for QT interval assessment when applied to ECG data obtained after infusion of ibutilide. Methods: Four methods were compared: (1) 12-lead simultaneous ECG (12-SIM), (2) lead II ECG (LEAD II), both measured on a digitizing board, (3) 3-LEAD ECG using a manual tangential method, and (4) a computer-based, proprietary algorithm, 12SL™ ECG Analysis software (AUT). QT intervals were measured in 10 healthy volunteers at multiple time points during 24 hours at baseline and after single intravenous doses of ibutilide 0.25 and 0.5 mg. Changes in QT interval from baseline were calculated and compared across ECG methods, using Bland–Altman plots. Variability was studied using a mixed linear model. Results: Baseline QT values differed between methods (range 376–395 ms), mainly based on the number of leads incorporated into the measurement, with LEAD II and 3-LEAD providing the shortest intervals. The 3-LEAD generated the largest QT change from baseline, whereas LEAD II and 12-SIM generated essentially identical result within narrow limits of agreement (0.4 ms mean difference, 95% confidence interval ± 20.5 ms). Variability with AUT (standard deviation 15.8 ms for within-subject values) was clearly larger than with 3-LEAD, LEAD II, and 12-SIM (9.6, 10.0, and 11.3 ms). Conclusion: This study demonstrated significant differences among four commonly used methods for QT interval measurement after pharmacological prolongation of cardiac repolarization. Observed large differences in variability of measurements will have a substantial impact on the sample size required to detect QT prolongation in the range that is currently advised in regulatory guidance.