Residual sleepiness after N(2)O sedation: a randomized control trial [ISRCTN88442975]

BACKGROUND: Nitrous oxide (N(2)O) provides sedation for procedures that result in constant low-intensity pain. How long do individuals remain sleepy after receiving N(2)O? We hypothesized that drug effects would be apparent for an hour or more. METHODS: This was a randomized, double blind controlled study. On three separate occasions, volunteers (N = 12) received 100% oxygen or 20% or 40% N(2)O for 30 min. Dependent measures included the multiple sleep latency test (MSLT), a Drug Effects/Liking questionnaire, visual analogue scales, and five psychomotor tests. Repeated measures analysis of variance was performed with drug and time as factors. RESULTS: During inhalation, drug effects were apparent based on the questionnaire, visual analogue scales, and psychomotor tests. Three hours after inhaling 100% oxygen or 20% N(2)O, subjects were sleepier than if they breathed 40% N(2)O. No other drug effects were apparent 1 hour after inhalation ceased. Patients did not demonstrate increased sleepiness after N(2)O inhalation. CONCLUSION: We found no evidence for increased sleepiness greater than 1 hour after N(2)O inhalation. Our study suggests that long-term effects of N(2)O are not significant

Immunotherapy for neuroblastoma using syngeneic fibroblasts transfected with IL-2 and IL-12

Cytokine-modified tumour cells have been used in clinical trials for immunotherapy of neuroblastoma, but primary tumour cells from surgical biopsies are difficult to culture. Autologous fibroblasts, however, are straightforward to manipulate in culture and easy to transfect using nonviral or viral vectors. Here we have compared the antitumour effect of fibroblasts and tumour cells transfected ex vivo to coexpress interleukin-2 (IL-2) and IL-12 in a syngeneic mouse model of neuroblastoma. Coinjection of cytokine-modified fibroblasts with Neuro-2A tumour cells abolished their in vivo tumorigenicity. Treatment of established tumours with three intratumoral doses of transfected fibroblasts showed a significant therapeutic effect with reduced growth or complete eradication of tumours in 90% of mice, associated with extensive leukocyte infiltration. Splenocytes recovered from vaccinated mice showed enhanced IL-2 production following Neuro-2A coculture, and increased cytotoxicity against Neuro-2A targets compared with controls. Furthermore, 100% of the tumour-free mice exhibited immune memory against tumour cells when rechallenged three months later. The potency of transfected fibroblasts was equivalent to that of tumour cells in all experiments. We conclude that syngeneic fibroblasts cotransfected with IL-2 and IL-12 mediate therapeutic effects against established disease, and are capable of generating immunological memory. Furthermore, as they are easier to recover and manipulate than autologous tumour cells, fibroblasts provide an attractive alternative immunotherapeutic strategy for the treatment of neuroblastoma

Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo

Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C–Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living culture

Perioperative and long-term operative outcomes after surgery for trigeminal neuralgia: microvascular decompression vs percutaneous balloon ablation

<p>Abstract</p> <p>Objectives</p> <p>Numerous medical and surgical therapies have been utilized to treat the symptoms of trigeminal neuralgia (TN). This retrospective study compares patients undergoing either microvascular decompression or balloon ablation of the trigeminal ganglion and determines which produces the best long-term outcomes.</p> <p>Methods</p> <p>A 10-year retrospective chart review was performed on patients who underwent microvascular decompression (MVD) or percutaneous balloon ablation (BA) surgery for TN. Demographic data, intraoperative variables, length of hospitalization and symptom improvement were assessed along with complications and recurrences of symptoms after surgery. Appropriate statistical comparisons were utilized to assess differences between the two surgical techniques.</p> <p>Results</p> <p>MVD patients were younger but were otherwise similar to BA patients. Intraoperatively, twice as many BA patients developed bradycardia compared to MVD patients. 75% of BA patients with bradycardia had an improvement of symptoms. Hospital stay was shorter in BA patients but overall improvement of symptoms was better with MVD. Postoperative complication rates were similar (21% vs 26%) between the BA and MVD groups.</p> <p>Discussion</p> <p>MVD produced better overall outcomes compared to BA and may be the procedure of choice for surgery to treat TN.</p

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Relationship between total cerebral blood flow and ICP measured noninvasively with dynamic MRI technique in healthy subjects

Cerebral blood flow and ICP are important neurophysiologic parameters known to be affected by pathology and by trauma. Limited data on the relationship between these parameters following head trauma is inconsistent with regard to whether these parameters are correlated. Data on the relationship between these parameters in the healthy state is not readily available due to a lack of noninvasive means to measure these important parameters. A recently developed noninvasive MRI-based method for simultaneous measurement of total cerebral blood flow and intracranial pressure was applied to establish the relationship between ICP and TCBF values in healthy subjects. Seventy-one simultaneous measurements of CBF and ICP were obtained from 23 healthy young adults. These results demonstrated that CBF values span over a much narrower range compared with ICP. The relationship between the inter-individual CBF and ICP measurements suggest that in the healthy state and in rest these parameters are not correlated