Effect of metabotropic glutamate receptor activity on rhythmic discharges of the neonatal rat spinal cord in vitro

To extend our understanding of the network-based properties which enable a neuronal circuit to produce sustained electrical oscillations, we explored the potential contribution of metabotropic glutamate receptors (mGluRs) to generation of rhythmic discharges. The in vitro spinal cord of the neonatal rat was used as a model to find out if electrical patterns characterized by either alternating or synchronous motor pool discharges (recorded from lumbar ventral roots) required mGluR activation or were modulated by it. Alternating patterns of fictive locomotion (induced by NMDA and 5HT) were slowed down and blocked by the broad spectrum mGluR agonist (±)-1-aminocyclopentane-trans-1, 3-dicarboxylic acid (t-ACPD; 5–50 M) and unaffected by the broad spectrum mGluR antagonist (RS)--methyl-4-carboxyphenylglycine (MCPG; 1 mM). The regular, synchronous bursting emerging in the presence of strychnine and bicuculline was accelerated by t-ACPD with a commensurate decrease in single burst length, an effect antagonized by MCPG which per se did not affect bursting. The action of t-ACPD was selectively inhibited by the L-type Ca²⁺ blocker nifedipine which, however, did not change rhythm acceleration evoked by NMDA. These data suggest that neither alternating nor synchronous oscillatory discharges were apparently dependent on mGluR activation via endogenously released glutamate. However, mGluR activation by the agonist t-ACPD modulated rhythmic patterns, indicating that such receptors are a potential target for pharmacological up- or downregulation of spinal rhythmicity.The first two authors contributed equally to this workDue to an error in the citation line, this revised PDF (published in December 2003) deviates from the printed version, and is the correct and authoritative version of the paper.     

Biopsy Method and Excision Volume Do Not Affect Success Rate of Subsequent Sentinel Lymph Node Dissection in Breast Cancer

Introduction: Sentinel lymph node dissection (SLND) is becoming a recognized technique for accurately staging patients with breast cancer. Its success in patients with large tumors or prior excisions has been questioned. The purpose of this study was to evaluate the effect of biopsy method, excision volume, interval from biopsy to SLND, tumor size, and tumor location on SLND success rate.Methods: Consecutive patients who underwent SLND followed by completion axillary lymph node dissection from October 1991 to December 1995 were analyzed. Included were cases performed early in the series before the technique was adequately developed. Excision volume was derived from the product of three dimensions as measured by the pathologist. Two end points were analyzed: sentinel node identification rate and accuracy of SLND in predicting axillary status. Univariate analyses using x2 or Fishers exact test for categorical variables and Wilcoxon rank sums for continuous variables were performed. Multivariate analysis was performed using logistic regression.Results: There were 284 SLND procedures performed on 283 patients. Median age was 55 years. The most recent biopsy method used before SLND was stereotactic core biopsy in 41 (14%), fine-needle aspiration in 62 (22%), and excision in 181 (64%) procedures. The mean excision volume was 32 ml with a range of 0.3–169 ml. The mean time from biopsy to SLND was 17 days with a range of 0–140 days. The mean tumor size was 2.0 cm (15 Tis [5%], 184 T1 [65%], 72 T2 [25%], and 13 T3 [5%]). Tumors were located in the outer quadrants in 74%, the inner quadrants in 18%, and subareolar region in 8%. The sentinel node was identified in 81%, and 39% had metastases. There were three false-negative cases early in the series. Sensitivity was 97%, and accuracy was 99%. Negative predictive value was 98% in cases in which the sentinel node was identified. On the basis of biopsy method, excisional volume, time from biopsy to SLND, tumor size, and tumor location, there was no statistically significant difference (P..05) in sentinel node identification rate or accuracy of SLND.Conclusions: SLND has a high success rate in breast cancer patients regardless of the biopsy method or the excision volume removed before SLND. In addition, the interval from biopsy to SLND, tumor size, and tumor location have no effect on the success rate of SLND, even in this series which included patients operated on before the technique was adequately defined. Patients with breast cancers located in any quadrant and diagnosed either with a needle or excisional biopsy could be evaluated for trials of SLND.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Oralando, Florida, March 4–7, 1999.     

Minimal effective dose of dysport and botox in a rat model of neurogenic detrusor overactivity

Background

Two botulinum toxins A have been evaluated for the treatment of refractory neurogenic detrusor overactivity (NDO) in humans: Dysport (abobotulinumtoxinA) and Botox (onabotulinumtoxinA). However, these two distinct commercialized products have different potency units and are not interchangeable.

Objective

Assessment of the dose response and determination of minimal effective dose (MED) for Dysport and Botox in spinal cord–injured (SCI) rats with NDO.

Design, setting, and participants

Female, adult, Sprague-Dawley rats (n = 98) underwent T8-T9 spinal cord transection. Nineteen days after spinal cord injury, rats received intradetrusor injections (25 μl injected, eight sites) of vehicle (V); Dysport 2, 5, 7.5, 10, and 12.5 U; and Botox 0.8, 2, 5, 7.5, and 10 U. Two days after injection, continuous cystometry was performed in conscious rats.

Measurements

Voiding contractions (VC) were assessed by duration of VC, intercontraction interval, voided volume, maximal pressure, pressure threshold change, and intravesical baseline pressure (BP), while nonvoiding contractions (NVC) were evaluated by amplitude, frequency, and volume threshold to elicit NVC. MEDs for Dysport and Botox were determined by analysis of variance step-down trend test.

Results and limitations

MEDs for Dysport and Botox were 10 U and 7.5 U, respectively. Regarding VC, only BP significantly decreased after 10 U Dysport and 7.5 U Botox compared to V (from 3.7 ± 0.6 to 1.5 ± 0.1 and 1.4 ± 0.3 mm Hg, respectively; p < 0.01 and p < 0.001, respectively). Dysport (10 U) and Botox (7.5 U) significantly inhibited NVC by decreasing their amplitude (from 7.4 ± 1.1 to 5.8 ± 0.5 and 5.4 ± 0.6 mm Hg, respectively; p < 0.05); frequency (from 2.2 ± 0.4 to 1.5 ± 0.2 and 1.3 ± 0.3 NVC per minute, respectively; p < 0.01); and increasing volume threshold to elicit NVC (from 29.8 ± 3.7 to 47.6 ± 6.9 and 47.7 ± 6.3%, respectively; p < 0.05 and p < 0.001, respectively).

Conclusions

This is the first preclinical dose-ranging study with Dysport and Botox under standardized conditions showing similar inhibiting effects on NDO, albeit at different MEDs. It highlights the importance of distinguishing each preparation for predicted outcomes and doses to be used. Further studies in patients with NDO are warranted to confirm these experimental results.     

Resistance to trypanocidal drugs in cattle populations of Zambezia Province,Mozambique

Parasitology Research - African animal trypanosomosis is a debilitating tsetse-transmitted parasitic disease of sub-Saharan Africa. Therapeutic and prophylactic drugs were introduced more than...     

“Bite-sized” rivaroxaban patient education and its effect on knowledge

International Journal of Clinical Pharmacy -