Safety and efficacy of botulinum toxin type A following long-term use

Botulinum toxin serotype A (BoNT-A) has long heritage of use leading to confidence in its safety and efficacy. The application of BoNT-A does not lead to persistent histological changes in the nerve terminal or the target muscle. Clinical trials defined the safety and tolerability profile of BoNT-A across common therapeutic indications and showed an incidence of adverse events of approximately 25% in the BoNT-A-treated group compared with 15% in the control group. Focal weakness was the only adverse event to occur more often following BoNT-A treatment. Long-term BoNT-A administration has been assessed in various treatment settings, with the level and duration of BoNT-A efficacy response being maintained over repeated rounds of injection with no major safety concerns. The treatment of children with cerebral palsy often require long-term, repeated, multimuscle BoNT-A injections that lead to the administration of comparably higher toxin doses. Despite the high total body doses used, their distribution over multiple muscles and injection sites means that systemic side effects are rare. Recent formulation changes have reduced the incidence of antibody development following treatment with BOTOX^®. These findings show long-term BoNT-A treatment to be both safe and efficacious for a wide variety of indications.     

Long-term neurotoxicity of chlorpyrifos: spatial learning impairment on repeated acquisition in a water maze.

Organophosphate compounds are cholinesterase inhibitors widely used in agriculture, industry, household products, and even as chemical weapons. Their major mechanism of acute toxic action is the inhibition of acetylcholinesterase, which is responsible for the degradation of the neurotransmitter acetylcholine. An organophosphorus ester-induced chronic neurotoxicity (OPICN) syndrome has been proposed. The OPICN syndrome could result from both long-term exposure to subclinical doses of OPs and after acute poisoning. Development of animal models for the cognitive decline are required and could later help to elucidate the mechanisms involved in this long-term effect on the central nervous system. Previously, we have found performance decrements in a four-trial repeated acquisition spatial task in a water maze. The present study includes two experiments to extend the long-term behavioral effects observed. Rats were injected either once or twice with chlorpyrifos (CPF) and then tested months after in a two-trial repeated acquisition task in a water maze. Our results confirm and extend the long-term behavioral effects of subcutaneous administration of CPF. The two treatments used produced performance decrements that suggest functional central nervous system alterations.     

Ineffectiveness of organic calcium channel blockers in antagonizing long-term potentiation

Evidence has accumulated suggesting that the presence of calcium is critical for development of hippocampal long-term potentiation (LTP). However, there is a paucity of information about whether calcium's role in LTP is pre- or postsynaptic. In the present study, we examined the effectiveness of nitrendipine, verapamil, flunarizine and the benzodiazepine diazepam in: blocking voltage-dependent calcium channels; blocking synaptic transmission; and preventing development of LTP. Using the in vitro slice preparation, we obtained intracellular and extracellular recordings from guinea pig hippocampal CA1 pyramidal cells. At the cellular level, all 4 drugs were ineffective in blocking voltage-dependent calcium spikes (TTX resistant) and the calcium-dependent afterhyperpolarization. Verapamil and diazepam appeared to antagonize synaptic transmission, as reflected in smaller population spike amplitudes. Development of long-term potentiation was not affected by the presence of verapamil, flunarizine and diazepam. Nitrendipine appeared to reduce the percentage of slices exhibiting LTP; however, ethanol, the vehicle used to dissolve nitrendipine, was shown in separate experiments to reduce the percentage of slices exhibiting LTP. These results suggest that neither the organic calcium channel blockers--nitrendipine, verapamil, and flunarizine--nor micromolar concentrations of diazepam are potent blockers of extrasynaptic voltage-sensitive calcium channels in hippocampus. They thus cannot be used to demonstrate a specific pre- or postsynaptic calcium role in LTP.     

上胸椎骨折手术治疗方法的探讨

目的 探讨上胸椎骨折的特点及治疗。方法 15例病人按AO分型，A型2例、B型10例、C型3例。均经后路切开复位、脊髓减压、长节段内固定、取髂骨植骨融合术治疗。结果 随访18-24个月，后路长节段固定随访时无一例失败，完全瘫的患者9例中有1例神经功能改善I级．不完全瘫的5例均有Ⅲ级改善，1例无神经损伤。结论 上胸椎骨折损伤严重，后路长节段固定技术是一种合理的有效治疗方法。     

Long-term effectiveness and quality of life improvement in entacapone-treated Parkinson's disease patients: the effects of an early therapeutic intervention

To evaluate the long-term effects of entacapone on both mean daily 'on' time and health-related quality of life (QoL) in patients with Parkinson's disease (PD) experiencing 'end-of-dose' motor fluctuations and the benefits of an early therapeutic intervention. A prospective, multicenter, observational, 12-month study was performed with an initial 3-month intervention phase, consisting of a phone call to half of the patients from randomly selected investigators to assess if dose adjustment was necessary. Effectiveness was determined by home diaries ('on' time), subscales II and III of the Unified Parkinson's Disease Rating Scale (UPDRS), and the Parkinson's Disease Questionnaire (PDQ-8). After 3 months of treatment, 4.0% of the intervention group patients discontinued the study, versus 18.4% in the control group ( P  < 0.01). The improvement in 'on' time was significantly increased since the 3-month visit (21%, P  < 0.0001) until the end of the study (23% at 12 months, P  < 0.0001). Entacapone also induced significant reductions in the UPDRS scores for subscales II and III and in the PDQ-8 score. 11.2% of patients experienced at least one adverse reaction. This study confirms the effectiveness of entacapone in reducing motor fluctuations by increasing 'on' time, and in improving QoL of PD patients. An early adjustment of entacapone and levodopa doses reduces the number of treatment discontinuations during the first months of treatment.     

Activity-dependent Decay of Early LTP Revealed by Dual EPSP Recording in Hippocampal Slices from Young Rats

The early maintenance of long-term potentiation (LTP) was studied in the CA1 region of hippocampal slices from 12- to 18-day-old rats in a low-magnesium solution (0.1 mM). The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of the field excitatory postsynaptic potential were estimated in parallel using early and late measurements of the composite potential. At the normal test stimulus frequency of 0.1 Hz, LTP was seen initially as a predominant increase in the AMPA component, but converted, via a substantial decay of this component and a gradual growth of the NMDA component, into nearly equal changes of the two components. Interrupting the test stimulation for 10 min, changing the test stimulus frequency to 1/60 Hz after LTP induction, or using a test stimulus frequency of 1/60 Hz during the entire experiment significantly reduced the decay of the potentiation of the AMPA component while enhancing the potentiation of the NMDA one. The ratio between the magnitudes of the two excitatory postsynaptic potential (EPSP) components showed a decaying time course that was independent of the manipulations used. Application of the NMDA antagonist D(-)-2-amino-5-phosphonopentanoic acid (50μM) after LTP induction stabilized the LTP of the AMPA component until washout was started. On the other hand, the phosphatase inhibitor okadaic acid (1 μM) resulted in decay of the potentiation of both EPSP components back to around baseline and altered the time course of the ratio between the components. Our results show that the early maintenance of LTP is controlled in an activity-dependent and NMDA-dependent manner. This process accelerates the decay of LTP of both AMPA and NMDA components in parallel, suggesting that it is similar to homosynaptic long-term depression, although it operates at the normal test stimulus frequency. The data support a scenario in which LTP ensues as a selective AMPA receptor modification and subsequently converts to another modification, possibly a presynaptic one.     

Atrial Synchronous Ventricular Pacing with a Single Lead: Reliability of Atrial Sensing During Physical Activities, and Long-term Stability of Atrial Sensing

A VDD pacing system with bipolar single-pass leads, were implanted in 36 consecutive patients (average age 72 ± 2years) with high degree atrioventricular block and normal sinus node function. At implant the atrial signal amplitude was 2.6 ± 0.2mV measured by a pacing system analyser (PSA), 1.8 ± 0.1mV measured peak-to-peak from the telemetered calibrated electrogram, and 1.3 ± 0.1mV measured from the sensing threshold. At one month follow-up the peak-to-peak amplitudes (mV) of the telemetered atrial electrograms were not significantly different measured continuously during resting supine with quiet breathing (1.4 ± 0.1), sitting (1.6 ± 0.2). standing (1.5 ± 0.1), arm swinging (1.4 ± 0.2), hyperventilation (1.3 ± 0.1), Vaisalva manoeuvre (1.4 ± 0.1), and treadmill exercise (1.9 ± 0.6). The telemetered atrial electrogram amplitude and the atrial sensing threshold varied between 1.2 ± 0.09mV and 1.8 ± 0.1mV, and between 0.95 ± 0.07mV and 1.3 ± 0.01mV, respectively at 0.5, 1, 3, 6 and 12 months follow-up, but the changes were statistically nonsignificant. The Event Summary showed sensing of 98% to 99% of the atrial events at the different follow-up periods.     

地膜覆盖条件下红花生长发育规律及其与产量关系的研究

对地膜覆盖条件下红花生长发育规律及其与产量的关系进行了研究。结果表明,地膜红花与露地红花生长发育规律基本一致,但地膜红花生育进程明显提前,各个阶段的生长量明显增多,花的产量及籽粒产量极显著提高。     

Ultrastructural distribution of NADPH-diaphorase in the normal hippocampus and after long-term potentiation

Summary The distribution of the enzyme nitric oxide synthase (NOS) was investigated at the ultrastructural level in synaptic structures of the hippocampal formation in relation to long-term potentiation (LTP), based on the histochemical NADPH-diaphorase (NADPH-d) staining with the tetrazolium salt BSPT. BSPT-formazan, the osmiophilic reaction product, was found to be selectively distributed and predominantly attached to membranes of the endoplasmic reticulum. In synaptic regions mainly the presynaptic sides showed labeling. Although several groups have demonstrated a principal involvement of NO in the LTP-mechanism, we found only a low, statistically insignificant increase in NADPH-d stained presynaptic areas of the dentate gyrus, where LTP was evoked. Postsynaptic elements also did not show any noticeable differences. Based on the present results, the predominantly presynaptic localization of NOS should be preferably considered in models describing a functional role of NO in LTP formation, despite the fact that we failed to reveal any indications for an LTP-related change in synaptically located NADPH-d.