The histaminergic system of the brain: its roles in arousal and autonomic regulation.
Szabadi E, Bradshaw CM, Freeman C, Scaife J, Hou RH, Langley RW.
Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.


Anesthesia for cesarean section in a patient with spinal muscular atrophy.

We describe the anesthetic management for cesarean section and tubal ligation of a 23-year-old primipara with type II spinal muscular atrophy (benign Werdnig Hoffmann). She was wheelchair-bound, had severe restrictive lung disease, and severe kyphoscoliosis, with Harrington rods extending from the thoracic to the sacral spines. A general anesthetic was given. We used propofol and alfentanil for rapid-sequence induction of anesthesia. We did not use any muscle relaxants / relaxant intraoperatively. Postoperative care was provided in the intensive care unit. The patient made a good recovery.

Effects of ephedrine on intubating conditions following priming with rocuronium.
Leykin Y, Pellis T, Lucca M, Gullo A.
Department of Anaesthesia, Pain, Perioperative Medicine and Intensive Care, Santa Maria degli Angeli Hospital, Pordenone, Italy.
Background: Onset of action of muscle relaxants / relaxant is influenced by cardiac output and muscle blood flow. Ephedrine reduces the onset time of rocuronium. Onset is also shortened by priming. Accordingly, we hypothesized that priming combined with ephedrine is superior to either technique used separately. Methods: Four groups of randomly allocated patients (n = 31), ASA I - II, were induced with propofol 2.5 mg kg(-1). In groups I and II, 0.04 mg kg(-1) of rocuronium was followed by a 3-min priming interval. Induction was followed by an intubation dose of 0.04 mg kg(-1). Then a 30-s intubation was attempted. In groups III and IV the same sequence was repeated except for sham priming and an intubation dose of 0.44 mg kg(-1). In groups I and II, ephedrine (210 microg kg(-1)) was injected before propofol. In groups II and V, an equivalent volume of normal saline was injected. Jaw relaxation, vocal cord position, and diaphragmatic response were used to assess intubating conditions. Results: All patients of group I were intubated 30 s after the intubating dose and within a 20-s interval compared with 74% of patients in groups II and III, and 84% of patients in group IV. Intubating conditions were graded good to excellent in all patients in group I compared with 42% of those in group II, 35% in group III and 52% in group IV (P < 0.01 vs. group I). During the priming interval, no adverse effects were observed or reported. Conclusions: Ephedrine in combination with propofol significantly improved clinical intubating conditions at 30 s following priming with rocuronium compared with priming with ephedrine without priming.


Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study.
Whyte J, Katz D, Long D, DiPasquale MC, Polansky M, Kalmar K, Giacino J, Childs N, Mercer W, Novak P, Maurer P, Eifert B.
Moss Rehabilitation Research Institute/Albert Einstein Healthcare Network, Philadelphia, PA, USA. jwhyte@einstein.edu
OBJECTIVES: To develop predictive models of recovery from the vegetative state (VS) and minimally conscious state (MCS) after traumatic brain injury (TBI) and to gather preliminary evidence on the impact of various psychotropic medications on the recovery process to support future randomized controlled trials. Design Longitudinal observational cohort design, in which demographic information, injury and acute care history, neuroimaging data, and an initial Disability Rating Scale (DRS) score were collected at the time of study enrollment. Weekly follow-up data, consisting of DRS score, current psychoactive medications, and medical complications, were gathered until discharge from inpatient rehabilitation. SETTING: Seven acute inpatient rehabilitation facilities in the United States and Europe with specialized programs for treating patients in the VS and MCS. PARTICIPANTS: People with TBI (N=124) who were in the VS or MCS 4 to 16 weeks after injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: DRS score at 16 weeks after injury and time until commands were first followed (among those participants demonstrating no command following at study enrollment). Results DRS score at enrollment, time between injury and enrollment, and rate of DRS change during the first 2 weeks of poststudy observation were all highly predictive of both outcomes. No variables related to injury characteristics or lesions on neuroimaging were significant predictors. Of the psychoactive medications, amantadine hydrochloride was associated with greater recovery and dantrolene sodium was associated with less recovery, in terms of the DRS score at 16 weeks but not the time until commands were followed. More detailed analysis of the timing of functional improvement, with respect to the initiation of amantadine provided suggestive, but not definitive, evidence of the drug's causal role. CONCLUSIONS: These findings show the feasibility of improving outcome prediction from the VS and MCS using readily available clinical variables and provide suggestive evidence for the effects of amantadine and dantrolene, but these results require confirmation through randomized controlled trials.


Gamma-secretase activity of presenilin 1 regulates acetylcholine muscarinic receptor-mediated signal transduction.

Familial Alzheimer's disease (FAD) presenilin 1 (PS1) mutations give enhanced calcium responses upon different stimuli, attenuated capacitative calcium entry, an increased sensitivity of cells to undergo apoptosis, and increased gamma-secretase activity. We previously showed that the FAD mutation causing an exon 9 deletion in PS1 results in enhanced basal phospholipase C (PLC) activity (Cedazo-Minguez, A., Popescu, B. O., Ankarcrona, M., Nishimura, T., and Cowburn, R. F. (2002) J. Biol. Chem. 277, 36646-36655). To further elucidate the mechanisms by which PS1 interferes with PLC-calcium signaling, we studied the effect of two other FAD PS1 mutants (M146V and L250S) and two dominant negative PS1 mutants (D257A and D385N) on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular calcium concentrations ([Ca2+]i) in SH-SY5Y neuroblastoma cells. We found a significant increase in basal PI hydrolysis in PS1 M146V cells but not in PS1 L250S cells. Both PS1 M146V and PS1 L250S cells showed a significant increase in carbachol-induced [Ca2+]i as compared with nontransfected or wild type PS1 transfected cells. The elevated carbachol-induced [Ca2+]i signals were reversed by the PLC inhibitor neomycin, the ryanodine receptor antagonist dantrolene, the general aspartyl protease inhibitor pepstatin A, and the specific gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. The cells expressing either PS1 D257A or PS1 D385N had attenuated carbachol-stimulated PI hydrolysis and [Ca2+]i responses. In nontransfected or PS1 wild type transfected cells, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester and pepstatin A also attenuated both carbachol-stimulated PI hydrolysis and [Ca2+]i responses to levels found in PS1 D257A or PS1 D385N dominant negative cells. Our findings suggest that PS1 can regulate PLC activity and that this function is gamma-secretase activity-dependent.

Ryanodine receptors in peritoneal mast cells: possible role in the modulation of exocytotic activity.

Previous studies have shown that ryanodine in low concentrations and caffeine increase intracellular [Ca(2+)] in the absence of external Ca(2+), suggesting Ca(2+) release from intracellular stores through ryanodine receptors (RyR). In the present study we employed amperometry to examine the effect of RyR agonists and antagonists on serotonin release elicited with compound 48/80 (10 micro g/ml). Ryanodine (1 micro M) or, similarly, 20 mM caffeine, in the absence of external Ca(2+), enhanced the amperometric response to compound 48/80 and all the individual amperometric spike parameters. Ryanodine (50 micro M), dantrolene (20 micro M) and tetracaine (50 micro M), putative antagonists of the RyR, attenuated the amperometric response significantly, decreasing the number and frequency of events as well as their amplitude. This is the first demonstration that Ca(2+) availability from RyR-operated Ca(2+) sources may contribute to the modulation of secretory activity in mast cells, affecting not only the cellular exocytotic response, but also the characteristics of single amperometric events. Immunocytochemical labelling, using a monoclonal RyR antibody, confirmed the presence of RyR in this preparation.

A fatality involving Metaxalone ( Skelaxin ).
Moore KA, Levine B, Fowler D.
Office of the Chief Medical Examiner, State of Maryland, 111 Penn St., Baltimore, MD 21201, USA. kamoore2@juno.com
A case is presented of a 54-year-old white female found dead in a secured apartment. Postmortem toxicologic analysis of the heart blood identified acetaminophen (97 mg/L), citalopram (0.4 mg/L), gabapentin (24 mg/L) and Metaxalone ( Skelaxin ) (21 mg/L). The Metaxalone ( Skelaxin ) concentration is within the range of previously reported fatalities involving Metaxalone ( Skelaxin ). The medical examiner ruled that the cause of death was Metaxalone ( Skelaxin ) and gabapentin intoxication and the manner of death was suicide.


Inhibition of sarcoplasmic Ca2+-ATPase increases caffeine- and halothane-induced contractures in muscle bundles of malignant hyperthermia susceptible and healthy individuals.
Schuster F, Muller R, Hartung E, Roewer N, Anetseder M.
BACKGROUND: Malignant hyperthermia (MH) is triggered by halogenated anaesthetics and depolarising muscle relaxants, leading to an uncontrolled hypermetabolic state of skeletal muscle. An uncontrolled sarcoplasmic Ca2+ release is mediated via the ryanodine receptor. A compensatory mechanism of increased sarcoplasmic Ca2+-ATPase activity was described in pigs and in transfected cell lines. We hypothesized that inhibition of Ca2+ reuptake via the sarcoplasmic Ca2+-ATPase (SERCA) enhances halothane- and caffeine-induced muscle contractures in MH susceptible more than in non-susceptible skeletal muscle. METHODS: With informed consent, surplus muscle bundles of 7 MHS (susceptible), 7 MHE (equivocal) and 16 MHN (non-susceptible) classified patients were mounted to an isometric force transducer, electrically stimulated, preloaded and equilibrated. Following 15 min incubation with cyclopiazonic acid (CPA) 25 yM, the European MH standard in-vitro-contracture test protocol with caffeine (0.5; 1; 1.5; 2; 3; 4 mM) and halothane (0.11; 0.22; 0.44; 0.66 mM) was performed. Data as median and quartiles; Friedman- and Wilcoxon-test for differences with and without CPA; p < 0.05. RESULTS: Initial length, weight, maximum twitch height, predrug resting tension and predrug twitch height of muscle bundles did not differ between groups. CPA increased halothane- and caffeine-induced contractures significantly. This increase was more pronounced in MHS and MHE than in MHN muscle bundles. CONCLUSION: Inhibition of the SERCA activity by CPA enhances halothane- and caffeine-induced contractures especially in MHS and MHE skeletal muscle and may help for the diagnostic assignment of MH susceptibility. The status of SERCA activity may play a significant but so far unknown role in the genesis of malignant hyperthermia.

Implementation of RCGP guidelines for acute low back pain: a cluster randomised controlled trial.

BACKGROUND: The Royal College of General Practitioners (RCGP) has produced guidelines for the management of acute low back pain in primary care. AIM: To investigate the impact on patient management of an educational strategy to promote these guidelines among general practitioners (GPs). DESIGN OF STUDY: Group randomised controlled trial, using the health centre as the unit of randomisation. SETTING: Primary care teams in north-west England. METHOD: Twenty-four health centres were randomly allocated to an intervention or control arm. Practices in the intervention arm were offered outreach visits to promote national guidelines on acute low back pain, as well as access to fast-track physiotherapy and to a triage service for patients with persistent symptoms. RESULTS: Twenty-four centres were randomised. Two thousand, one hundred and eighty-seven eligible patients presented with acute low back pain during the study period: 1049 in the intervention group and 1138 in the control group. There were no significant differences between study groups in the proportion of patients who were referred for X-ray, issued with a sickness certificate, prescribed opioids or muscle relaxants, or who were referred to secondary care, but significantly more patients in the intervention group were referred to physiotherapy or the back pain unit (difference in proportion = 12.2%, 95% confidence interval [CI] = 2.8% to 21.6%). CONCLUSION: The management of patients presenting with low back pain to primary care was mostly unchanged by an outreach educational strategy to promote greater adherence to RCGP guidelines among GPs. An increase in referral to physiotherapy or educational programmes followed the provision of a triage service.

Subthalamic deep brain stimulation masking possible malignant syndrome in Parkinson disease.

Centro de Neurologia y Neurocirugia funcional, Clinica Quiron, San Sebastian, Spain.