Gabapentin Activates Spinal Noradrenergic Activity in Rats and Humans and Reduces Hypersensitivity after Surgery

Background: Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the [alpha]2[delta] subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain.

Methods: Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin.

Results: Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the [alpha]2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements.     

Burkholderia gladioli: five year experience in a cystic fibrosis and lung transplantation center.

BACKGROUND: The impact of infection with Burkholderia gladioli in cystic fibrosis, other chronic airway diseases and immunosuppressed patients is unknown. METHODS: A six-year retrospective review of all patients with B. gladioli infection was performed in a tertiary referral center with cystic fibrosis and lung transplantation programs. In addition, a targeted survey of all 251 lung transplant recipients was performed. Available B. gladioli isolates were analyzed via pulsed field gel electrophoresis. RESULTS: Thirty-five patients were culture positive for B. gladioli, including 33 CF patients. No bacteremia was identified. Isolates were available in 18 patients and all were genetically distinct. Two-thirds of these isolates were susceptible to usual anti-pseudomonal antibiotics. After acquisition, only 40% of CF patients were chronically infected (> or =2 positive cultures separated by at least 6 months). Chronic infection was associated with resistance to > or =2 antibiotic groups on initial culture and failure of eradication after antibiotic therapy. The impact of acquisition of B. gladioli infection in chronic infection was variable. Three CF patients with chronic infection underwent lung transplantation. One post-transplant patient developed a B. gladioli mediastinal abscess, which was treated successfully. CONCLUSIONS: The majority of patients' culture positive for B. gladioli at our center have CF. B. gladioli infection is often transient and is compatible with satisfactory post-lung transplantation outcomes.     

Biphasic Dose Response in Low Level Light Therapy

The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.     

Intraoperative somatosensory evoked potential monitoring during anterior cervical discectomy and fusion in nonmyelopathic patients--a review of 1,039 cases.

BACKGROUND CONTEXT: Intraoperative somatosensory evoked potential (SSEP) monitoring has been shown to reduce the incidence of new postoperative neurological deficits in scoliosis surgery. However, its usefulness during cervical spine surgery remains a subject of debate. PURPOSE: To determine the utility of intraoperative SSEP monitoring in a specific patient population (those with cervical radiculopathy in the absence of myelopathy) who underwent anterior cervical discectomy and fusion (ACDF) surgery. STUDY DESIGN: Retrospective review. PATIENT SAMPLE: A total of 1,039 nonmyelopathic patients who underwent single or multilevel ACDF surgery. The control group (462 patients) did not have intraoperative SSEP monitoring, whereas the monitored group (577 patients) had continuous intraoperative SSEP monitoring performed. OUTCOME MEASURE: A new postoperative neurological deficit. METHODS: SSEP tracings were reviewed for all 577 patients in the monitored group and all significant signal changes were noted. Medical records were reviewed for all 1,039 patients to determine if any new neurological deficits developed in the immediate postoperative period. RESULTS: None of the patients in the control group had any new postoperative neurological deficits. In the monitored group there were six instances of transient SSEP changes (1 due to suspected carotid artery compression; 5 thought to be due to transient hypotension) which resolved with the appropriate intraoperative intervention (repositioning of retractors; raising the arterial blood pressure). Upon waking up from anesthesia, one patient in the monitored group had a new neurological deficit (partial central cord syndrome) despite normal intraoperative SSEP signals. CONCLUSIONS: ACDF appears to be a safe surgical procedure with a low incidence of iatrogenic neurological injury. Transient SSEP signal changes, which improved with intraoperative interventions, were not associated with new postoperative neurological deficits. An intraoperative neurological deficit is possible despite normal SSEP signals.     

A Complication of Stellate Ganglion Block?

Abstract: Stellate ganglion block is commonly used to treat the sympathetically maintained pain which may occur in one‐third of patients with complex regional pain syndrome type 1. A complication that followed a single block and presented a diagnostic dilemma for the ophthalmologist is reported.     

Comparison of survival by allocation to medical therapy, surgery, or heart transplantation for ischemic advanced heart failure.

BACKGROUND: To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation. METHODS: Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score. RESULTS: From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation. CONCLUSIONS: Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.     

Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors.

CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14alpha-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius(2) receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.     

PET network abnormalities and cognitive decline in patients with mild cognitive impairment.

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps<0.01-0.001). In summary, a resting PET covariance pattern previously reported to discriminate AD patients from control subjects was applied prospectively to an independent sample of MCI patients and found to predict cognitive decline. Independent replication in larger samples is needed before clinical application can be considered.