The role of the craniospinal nerves in mediating the antinociceptive effect of transcranial electrostimulation in the rat

Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, but its mechanism of action has not been elucidated. In a recently introduced clinically relevant rat model of TES we have validated and characterized the TES antinociceptive effect, suggesting involvement of the sensory nerves of the rat's scalp in mediating that effect. In this study, we have further investigated the role of the craniospinal nerves by attempting to block the TES antinociceptive effect with local anesthetic injected under the TES electrodes. We also applied different transcutaneous electrical nerve stimulation modalities through the TES electrodes and compared the elicited antinociceptive effect to that of TES. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick latency test in awake, unrestrained male rats. Data were analyzed by one-way analysis of variance followed by the Bonferroni t-test. The TES antinociceptive effect was significantly reduced after local anesthetic injection, and administration of 100 Hz transcutaneous electrical nerve stimulation was, over time, capable of eliciting the same degree of antinociceptive effect as TES. We conclude that sensory craniospinal nerves play a critical role in mediating the TES antinociceptive action and offer a hypothesis on the underlying mechanism(s) responsible for this action.     

A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management

BACKGROUND: Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain. METHODS: Patients (aged 18-75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose. RESULTS: Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P < 0.001). There were also significant trends across the escalating dose groups for decreasing pain intensity at rest (P = 0.01), increasing sedation (P = 0.03), and more adverse events (P = 0.002). The number needed to treat to prevent one rescue analgesia request for the 10-mg and 15-mg doses, relative to 5 mg, were 2.0 (95% confidence interval, 1.5-3.1) and 1.3 (95% confidence interval, 1.1-1.7), respectively. The study was terminated because of a serious vasovagal adverse event in a patient receiving 15 mg. CONCLUSION: These significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.     

Molecular mechanisms transducing the anesthetic, analgesic, and organ-protective actions of xenon

The anesthetic properties of xenon have been known for more than 50 yr, and the safety and efficacy of xenon inhalational anesthesia has been demonstrated in several recent clinical studies. In addition, xenon demonstrates many favorable pharmacodynamic and pharmacokinetic properties, which could be used in certain niche clinical settings such as cardiopulmonary bypass. This inert gas is capable of interacting with a variety of molecular targets, and some of them are also modulated in anesthesia-relevant brain regions. Besides these anesthetic and analgesic effects, xenon has been shown to exert substantial organoprotective properties, especially in the brain and the heart. Several experimental studies have demonstrated a reduction in cerebral and myocardial infarction after xenon application. Whether this translates to a clinical benefit must be determined because preservation of myocardial and cerebral function may outweigh the significant cost of xenon administration. Clinical trials to assess the impact of xenon in settings with a high probability of injury such as cardiopulmonary bypass and neonatal asphyxia should be designed and underpinned with investigation of the molecular targets that transduce these effects.     

In vitro biophysical strain model for understanding mechanisms of osteopathic manipulative treatment

CONTEXT: Normal physiologic movement, pathologic conditions, and osteopathic manipulative treatment (OMT) are believed to produce effects on the shape and proliferation of human fibroblasts. Studies of biophysically strained fibroblasts would be useful in producing a model of the cellular mechanisms underlying OMT. OBJECTIVE: To investigate the effects of acyclic in vitro biophysical strain on normal human dermal fibroblasts and observe potential changes in cellular shape and proliferation, as well as potential changes in cellular production of nitric oxide, interleukin (IL) 1beta, and IL-6. DESIGN AND METHODS: Randomized controlled trial. Human fibroblasts were subjected in vitro to control conditions (no strain) or biophysical strain of various magnitudes (10%-30% beyond resting length) and durations (12-72 hours). After control or strain stimuli, fibroblasts were analyzed for potential changes in cell shape, proliferative capacity, nitric oxide secretion, and cytokine (IL-1beta, IL-6) secretion. RESULTS: Low strain magnitudes (<20%) induced mild cellular rounding and pseudopodia truncation. High strain magnitudes (>20%) decreased overall cell viability and the mitogenic response, and induced cell membrane decomposition and pseudopodia loss. No basal or strain-induced secretion of IL-1beta was observed. Interleukin 6 concentrations increased two-fold, while nitric oxide levels increased three-fold, in cells strained at 10% magnitude for 72 hours (P<.05). CONCLUSION: Human fibroblasts respond to in vitro strain by secreting inflammatory cytokines, undergoing hyperplasia, and altering cell shape and alignment. The in vitro biophysical strain model developed by the authors is useful for simulating a variety of injuries, determining in vivo mediators of somatic dysfunction, and investigating the underlying mechanisms of OMT.     

Predictors of surgical outcome in Wilms' tumor: a single-institution comparative experience

Background

The merits of primary nephrectomy (PN) vs preoperative chemotherapy (PC) for patients with Wilms' tumor (WT) are much debated. Early data from the International Society of Pediatric Oncology suggested decreased intraoperative spillage but increased risk of local recurrence after PC. Patients with WT at our institution were managed with PC until 1996; subsequently, they underwent PN. This study compares these approaches as they affect tumor spillage, local recurrence, and survival.

Methods

Patients with WT diagnosed at the Hospital for Sick Children from 1985 to 2003 were reviewed.

Results

One hundred sixty patients were identified (114 PC and 46 PN). Tumor spill occurred in 6 (5.3%) of 114 PC and 2 (4.3%) of 46 PN patients. Tumor inhomogeneity, tumor size, and inferior vena cava compression/clot at diagnosis did not affect incidence of spill. Of 6 PC patients with surgical spill, 1 (17%) had significant tumor shrinkage, compared with 87 (81%) of 108 without spill (P < .001). Preoperative chemotherapy and PN had equal rates of surgical complications. Preoperative chemotherapy resulted in 12 (10.5%) of 114 local recurrences vs 5 (10.8%) of 46 with PN. Event-free survival and overall survival were 80% and 92% for PC at 129 months vs 85% and 96% for PN at 61 months.

Conclusions

Preoperative chemotherapy and PN are equally effective in the treatment of WT with no difference in tumor spillage. Failure of the tumor to shrink in size with PC was significantly associated with an increase in tumor spillage and would suggest that a more cautious surgical approach be undertaken in these cases.     

Sedation & immunomodulation

As the armamentarium for sedation in the critically ill expands, opportunities will develop to modulate the immune responses of patients by way of the direct immune and neural-immune interactions of the sedatives. Control of autonomic activity through the use of appropriate sedation may be critical in this matter. Likewise analgesic-based sedation, with increased opioid dosage, may not prove beneficial in the setting of infection; whether avoidance of morphine in preference for a fentanyl derivative will help is unclear. However, as the immune effects seem dependent on the m receptor, it is improbable that a significant difference would be uncovered. Similarly, the present evidence suggests benzodiazepines are deleterious in infection; further studies are required urgently to evaluate this evidence. As an alternative to benzodiazepine-based sedation, dexmedetomidine has shown a remarkable 70% mortality benefit in a small secondary analysis of septic patients from the MENDS trial. Further powered clinical studies should now be undertaken to investigate the potential benefit of the α2-adrenoceptor agonist in this setting, with comparisons with propofol.     

Surfactant Protection Efficacy at Surfaces Varies with the Nature of Hydrophobic Materials

Pharmaceutical Research - Monoclonal antibodies are in contact with many different materials throughout their life cycle from production to patient administration. Plastic surfaces are commonly...     

Nitrous Oxide Produces Antinociceptive Response via [small alpha, Greek]2B and/or [small alpha, Greek]2C Adrenoceptor Subtypes in Mice

Background: Opiate receptors in the periaqueductal gray region and [small alpha, Greek]2 adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N2 O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N2 O and investigate which [small alpha, Greek]2 adrenoceptor subtypes mediate this response.

Methods: After obtaining institutional approval, antinociceptive dose-response and time-course to N2 O was measured in wild-type and transgenic mice (D79N), with a nonfunctional [small alpha, Greek]2A adrenoceptor using tail-flick latency. The antinociceptive effect of N2 O was tested after pretreatment systemically with yohimbine (nonselective [small alpha, Greek]2 antagonist), naloxone (opiate antagonist), L659,066 (peripheral [small alpha, Greek]2-antagonist) and prazosin ([small alpha, Greek]2B- and [small alpha, Greek] (2C-selective) antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective [small alpha, Greek]2 agonist, was tested in wild-type and transgenic mice.

Results: N2 O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N2 O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective [small alpha, Greek]2B-/[small alpha, Greek]2C-receptor antagonists but not by a central nervous system-impermeant [small alpha, Greek]2 antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective [small alpha, Greek]2B-/[small alpha, Greek]2C-receptor antagonist.     

Retroviral-mediated expression of the P140A, but not P140A/G156A, mutant form of O6-methylguanine DNA methyltransferase protects hematopoietic cells against O6-benzylguanine sensitization to chloroethylnitrosourea treatment.

O(6)-Benzylguanine (6-BG) inactivates mammalian O(6)-methylguanine DNA methyltransferase (MGMT), an important DNA repair protein that protects cells against chloroethylnitrosourea (CENU) cytotoxicity. 6-BG is being tested as an approach to treat CENU-resistant tumors that overexpress endogenous MGMT. However, in addition to restoring CENU tumor cell sensitivity, 6-BG also increases the cytotoxic effects of CENUs on hematopoietic cells. Several 6-BG-resistant human MGMT mutants have been characterized in Escherichia coli and are predicted to protect mammalian cells against the combination of 6-BG and CENU treatment in vivo. Two mutants, P140A and P140A/G156A, demonstrated 20- and 1200-fold more resistance to 6-BG depletion of MGMT activity compared with wild-type MGMT (WTMGMT). Here, we analyzed retroviral vectors that express either WTMGMT, the P140A or P140A/G156A mutant forms of MGMT. Retroviral-infected L1210 hematopoietic cells demonstrated similar levels of RNA in all transduced clones. However, the amount of MGMT protein and DNA repair activity was reduced in clones expressing the P140A/G156A mutant compared with those expressing WTMGMT or P140A. Expression of P140A was associated with a 4- to 8-fold increase in resistance to 6-BG depletion of MGMT in transduced L1210 clones and a 1, 3-bis(2-chloroethyl)-1-nitrosourea IC(50) of 50 microM (compared with 27.5 microM for WTMGMT) in primary murine hematopoietic cells. These results demonstrate the utility of screening 6-BG-resistant MGMT proteins in hematopoietic cells and provide evidence that the P140A mutant form of MGMT generates 6-BG- and CENU-resistant hematopoietic cells. Retrovirus vectors expressing this mutant may be useful in future human gene therapy trials.