CNS 7056: A Novel Ultra-short-acting Benzodiazepine

Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo.

Methods: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes ([alpha]1[beta]2[gamma]2, [alpha]2[beta]2[gamma]2, [alpha]3[beta]2[gamma]2, [alpha]5[beta]2[gamma]2) of the [gamma]-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test.

Results: CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 [mu]m) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil.     

Hybrid Anterior Cruciate Ligament Reconstruction: Introduction of a New Technique for Anatomic Anterior Cruciate Ligament Reconstruction

Recently, anatomic or double-bundle reconstruction of the anterior cruciate ligament (ACL) has been presented in an effort to more accurately restore the native anatomy. These techniques create 2 tunnels in both the femur and tibia to reproduce the bundles of the ACL. However, the increased number of tunnels, particularly on the femoral side, has raised some concerns among authors and surgeons. We describe a technique to reconstruct the 2 distinct bundles of the ACL by using a single femoral tunnel and 2 tibial tunnels, the “hybrid” ACL reconstruction. The femoral tunnel is drilled through an anteromedial arthroscopy portal, which allows placement in a more anatomic position. Fixation in the femur is achieved with a novel device that separates a soft-tissue graft into 2 independently functioning bundles. Once fixed in the femur, the anteromedial and posterolateral bundles of the graft are passed through respective tunnels at the anatomic footprint on the tibia. These bundles are independently tensioned, which creates a reconconstruction that is similar to the native ACL. The technique presented provides surgeons with an alternative to other double-bundle techniques involving 4 tunnels.     

Deliberate hypotension in orthopedic surgery reduces blood loss and transfusion requirements: A meta-analysis of randomized controlled trials

PURPOSE: To determine if deliberate hypotension decreases blood loss and transfusion requirements in patients undergoing orthopedic surgery, a systematic review of all randomized trials addressing this issue was undertaken. METHODS: Electronic databases, citations lists and review articles were searched for potential articles. Relevant articles met the following inclusion criteria: English language, humans undergoing orthopedic surgery, deliberate hypotension used by any method, intraoperative blood loss measured as an outcome, and the trial methodology being randomized and controlled. Four outcomes were analyzed, including estimated blood loss, blood transfused, surgery duration, and quality of the surgical field. For all analyses, the random-effects model was used. RESULTS: Seventeen articles met the inclusion criteria. The surgeries studied included total hip arthroplasty (seven), orthognathic surgery (eight), total knee arthroplasty (one) and spinal fusion (one). A total of 636 patients were randomized across all studies. For blood loss, the overall weighted mean difference favoured treatment, with a savings of about 287 mL of blood [95% confidence interval (CI): -447, -127]. The mean differences also showed a statistically significant benefit for deliberate hypotension in reducing transfusion requirements (-667 mL of blood transfused; 95% CI: -963, -370). Deliberate hypotension was not shown to reduce the duration of surgery (-1.9 min of surgery; 95% CI: -7.2, 3.5) or improve surgical conditions (surgical field quality rating -0.5; 95% CI: -1.1, 0.2). CONCLUSION: This review provides some support for the use of deliberate hypotension in reducing blood loss and transfusion requirements in orthopedic surgery, but these results are tempered by the small sample sizes and poor methodological quality of published studies.     

L’électroencéphalogramme n’est pas un examen légitime pour la confirmation du diagnostic de mort cérébrale

PURPOSE: In France, legislation mandates that the clinical diagnosis of brain death be confirmed by one paraclinical test before organ donation is allowed. That test may be either the electroencephalogram (EEG) or cerebral angiography. We report a case in which the clinical diagnosis of brain death was first confirmed by two EEGs performed according to the French guidelines, but ruled out by cerebral angiography. Considering that the EEG is no longer recommended to establish the diagnosis of brain death, we discuss the relevance of maintaining the EEG for brain death diagnosis in France. CLINICAL FINDINGS: A 58 yr-old man was admitted to the intensive care unit because of coma secondary to a massive subarachnoid hemorrhage with herniation below the falx shown by computed tomography. Clinical criteria of brain death were rapidly present. Two EEGs first confirmed the diagnosis but a four-vessel cerebral angiography was finally performed because the patient moved spontaneously. This cerebral angiography showed flow in the right internal carotid artery. A computed tomography performed the next day definitely confirmed the absence of brain death and organ donation did not occur. CONCLUSIONS: This case demonstrates the limitations of the EEG for this indication and suggests that angiography should be preferred. French legislation is probably maladjusted and would benefit by incorporating guidelines of other countries like Canada. International harmonization of criteria for brain death diagnosis would also be welcome.     

Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study.

We sought whether microdamage could rise in postmenopausal osteoporotic women on long-term bisphosphonates, as suggested by recent animal studies. We found few microcracks in iliac bone biopsies, despite a marked reduction in bone turnover. INTRODUCTION: Animal studies suggest that bisphosphonates (BPs) could increase microdamage frequency in a dose-dependent manner, caused by excessively suppressed bone turnover. However, there is limited data in humans receiving BP therapeutic doses for >3 yr. MATERIALS AND METHODS: We measured microcrack frequency and histomorphometry parameters on transiliac bone biopsies in 50 postmenopausal osteoporotic women (mean age = 68 yr) who had received BP therapy (3 on intravenous pamidronate, 37 on oral alendronate, and 10 on oral risedronate) for at least 3 yr (mean treatment duration = 6.5 yr). We compared these results with transiliac bone biopsies obtained from 12 cadavers. We used bulk staining with green calcein as a fluorochrome. The microcracks were quantified in three 100-microm-thick sections using optic microscopy and were confirmed by laser confocal microscopy. Microcrack frequency (number of microcracks/mm2 of bone tissue) was compared between treated women and controls using nonparametric tests. We also explored predictors of microcrack frequency, including age, duration of BP therapy, and activation frequency. RESULTS: Among treated women, cancellous bone microcrack frequency was low (mean, 0.13 microcracks/mm2) and did not differ significantly from that observed in controls (0.05 microcracks/mm2; p = 0.59). Of note, 54% of the treated women and 58% of the controls had no observable microcracks. There was no association between microcrack frequency and the duration of BP therapy (for microcracks/mm2 and duration, Spearman r = 0.04, p = 0.80) and between patients' ages and the number of microcracks (Spearman r = -0.09, p = 0.61). Although bone remodeling parameters were suppressed in treated women, we found no relationship between microcrack density and activation frequency (Spearman r = -0.003, p = 0.99). Also, microcrack frequency was not increased in women with prevalent vertebral fracture compared with those without fractures. CONCLUSIONS: Among postmenopausal osteoporotic women on long-term BPs, microcrack frequency in the iliac bone is low, despite a marked reduction of bone turnover.     

Significance of beaten copper appearance on skull radiographs in children with isolated sagittal synostosis

Aims and Objectives The significance of beaten copper appearance (BCA) on skull radiographs in children following surgery for isolated sagittal craniosynostosis has not been studied. This study was designed to look for any correlation between BCA and symptoms suggestive of intracranial hypertension in this group of patients. Materials and Methods Forty-eight consecutive children, who were operated for isolated sagittal synostosis from1987 to 2000 and had postoperative skull radiographs, were included. Patients were divided into: (a) BCA group (n = 20), consisting of children who had beaten copper appearance on skull radiographs at last follow up, and (b) Non-BCA group (n = 28), consisting of children who did not have this finding. Records were reviewed to look for symptoms suggestive of intracranial hypertension, such as headache, head banging, and irritability. Results Median age at surgery was 4.8 months for BCA group and 4 months for the non-BCA group. Follow up ranged from 4 to 156 months with a mean of 36.2 months. Total of 28.6% (n = 6) of the children with follow up radiographs done at ≤18 months of age had BCA. The incidence of BCA increased to 83.3% in children with skull radiographs performed after 48 months of age. In 18 (90%) children, the BCA was ‘diffuse’ with 5 (25%) children having the maximum possible score of 8. In the BCA group, 45% (n = 9) had symptoms compared to 10.7% (n = 3) in the control group (p = 0.0068). Conclusions This study suggests a significant number of children with BCA on radiographs develop symptoms suggestive of raised ICP following surgical treatment in infancy and prolonged follow up may be warranted in this group of patients.     

Treatment of anxiety disorders in older adults: a meta-analytic comparison of behavioral and pharmacological interventions.

OBJECTIVE: To reduce the morbidity attributable to anxiety disorders in old age and to improve the quality of care, data on the effectiveness of current treatments are needed. METHODS: A comparative meta-analysis of 32 studies of treatments focused on anxiety disorders in older adults (N = 2,484) receiving behavioral interventions or pharmacotherapy was conducted. RESULTS: In separate analyses of the effects of interventions, stronger improvements of anxiety symptoms are found in pharmacotherapy than in behavioral interventions (d = 1.76 versus d = 0.81 SD units). This difference disappears when computing effect sizes that control for nonspecific change in the control group (d = 0.80 and d = 0.83 SD units) because effect sizes are greater in pill-placebo controls of pharmacological studies than in control groups (e.g., wait list) of behavioral interventions (d = 1.06 versus d = 0.10 SD units). Both interventions also yield moderate reductions in depressive symptoms (d = 0.59 versus d = 0.61 SD units), and dropout rates were comparable. CONCLUSIONS: Available pharmacotherapy and behavioral interventions are reasonably effective. Given the higher average treatment effects of pharmacological interventions, pharmacotherapy may be the first choice of treatment as long as medical conditions and patients' preferences do not preclude this form of treatment.