Glucocorticoid receptor enhancement of pregnane X receptor-mediated CYP2B6 regulation in primary human hepatocytes.

Although the glucocorticoid receptor (GR) facilitates the xenobiotic-induced expression of CYP2B in rodents, its role in the regulation of human CYP2B6 is unclear. In this report, the role of human GR in the regulation of CYP2B6 was evaluated using primary human hepatocytes and transfection assays with Huh7 cells. CYP2B6 expression was not induced in primary hepatocytes treated with dexamethasone (DEX) concentrations (0.01-1 microM) known to activate GR. In contrast, treatment with 0.1 microM DEX enhanced CYP2B6 induction by different pregnane X receptor (PXR) activators, including rifampin, phenytoin, clotrimazole, and phenobarbital. In Huh7 cells, cotransfection of human (h)GR and hPXR with CYP2B6-phenobarbital-responsive enhancer module (PBREM) reporter constructs revealed that all hPXR ligands induce CYP2B6 reporter gene activity, and this ligand-dependent activation is greatly enhanced by activated hGR. CYP2B6 reporter gene expression was not induced in the presence of hPXR ligands when hGR alone was cotransfected with CYP2B6 reporter construct. In hGR and human constitutive androstane receptor (hCAR) cotransfection assays, activated hGR increased the constitutive activation of PBREM reporter constructs by hCAR in the absence of inducers. In the presence of activated hGR and known inducers of CYP2B6, only PB treatment caused a further 2-fold activation of hCAR compared with control. These studies show that hGR is involved synergistically in the xenobiotic-responsive regulation of human CYP2B6 by hPXR and hCAR. Moreover, the results suggest that the GR-enhanced expression of CYP2B6 is mediated through an indirect mechanism that does not require increased expression of nuclear receptor.     

Ergotamine/caffeine treatment of orthostatic hypotension in parkinsonism with autonomic failure

Eight patients with parkinsonism who developed severe orthostatic sypotension, were treated with oral ergotamine/caffeine. Significant long-term improvement in standing systolic blood pressure and symptoms of syncope and light-headedness were observed in four of these patients. One patient in whom the drug was effective discontinued it because of nausea. Another lost benefit after 2 weeks of sucessful therapy. Significant supine systolic hypertension occureed in only one patient, which was easily managed by nifedipine given at night. Symptoms or signs of ergotism were not observed. Oral ergotamine/caffeine should be considered as a cost-effective teratment for refactory orthostatic hypotension in carefully selected patients with parkinsonism.     

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).     

Combined tool approach is 100% successful for emergency football face mask removal.

OBJECTIVE: To compare effectiveness of two techniques for removing football face masks: cutting loop straps [cutting tool: FMXtractor (FMX)] or removing screws with a cordless screwdriver and using the FMXtractor as needed for failed removals [combined tool (CT)]. Null hypotheses: no differences in face mask removal success, removal time or difficulty between techniques or helmet characteristics. DESIGN: Retrospective, cross-sectional. SETTING: NOCSAE-certified helmet reconditioning plants. PARTICIPANTS: 600 used high school helmets. INTERVENTIONS: Face mask removal attempted with two techniques. MAIN OUTCOME MEASUREMENTS: Success, removal time, rating of perceived exertion (RPE). RESULTS: Both techniques were effective [CT 100% (300/300); FMX 99.4% (298/300)]. Use of the backup FMXtractor in CT trials was required in 19% of trials. There was significantly (P<0.001) less call for the backup tool in helmets with silver screws (6%) than in helmets with other screws (31%). Mean removal time was 44.51+/-18.79s (CT: 37.84+/-15.37s, FMX: 51.21+/-19.54s; P<0.001). RPE was different between techniques (CT: 1.83+/-1.20, FMX: 3.11+/-1.27; P<0.001). Removal from helmets with silver screws was faster (Silver=33.38+/-11.03, Others=42.18+/-17.64; P<0.001) and easier (Silver=1.42+/-0.89, Other=2.23+/-1.33; P<0.001). CONCLUSIONS: CT was faster and easier than FMX. Most CT trials were completed with the screwdriver alone; helmets with silver screws had 94% screwdriver success. Clinically, these findings are important because this and other research shows that compared to removal with cutting tools, screwdriver removal decreases time, difficulty and helmet movement (reducing potential for iatrogenic injury). The combined-tool approach captures benefits of the screwdriver while offering a contingency for screw removal failure. Teams should use degradation-resistant screws. CLINICAL RELEVANCE: Sports medicine professionals must be prepared with appropriate tools and techniques to efficiently remove the face mask from an injured football player's helmet.     

Gender-specific response to isoflurane preconditioning in focal cerebral ischemia.

Inhalation anesthetics are effective chemical preconditioning agents in experimental cerebral ischemia. However, previous work has been performed exclusively in male animals. We determined if there is a gender difference in ischemic outcome after isoflurane preconditioning (IsoPC), and if this sex-specific response is linked to differences in Akt phosphorylation or expression of neuronal inducible cell-death putative kinase (NIPK), a negative modulator of Akt activation. Young and middle-aged male and female mice were preconditioned for 4 h with air (sham PC) or 1.0% IsoPC and recovered for 24 h. Cortices were subdissected from preconditioned young male and female mice for measurement of Akt phosphorylation (Western blot) and NIPK mRNA (quantitative polymerase chain reaction). Additional cohorts underwent 2 h of reversible middle cerebral artery occlusion. Lastly, male and female Akt1(+/+) and Akt1(-/-) mice were studied to determine if gender differences in ischemic outcome after IsoPC is Akt1-dependent. Infarction volume was determined at 22 h reperfusion (2,3,5-triphenyltetrazolium chloride). As expected, IsoPC decreased ischemic damage as compared with sham PC in young and middle-aged male mice. In contrast, IsoPC markedly increased infarction in young female mice and had no effect in middle-aged female mice. Cortical phospho-Akt was increased by IsoPC versus sham PC only in male mice. No increase was observed in IsoPC female mice. NIPK mRNA was higher in female mice than in male mice regardless of preconditioning status. Male IsoPC neuroprotection was lost in Akt1-deficient male mice. We conclude that IsoPC is beneficial only in ischemic male brain and that sex differences in IsoPC are mediated through Akt activation and basal NIPK expression.     

Changes in treatment of advanced laryngeal cancer 1985-2001

OBJECTIVE: In 1991, a randomized study was published and demonstrated that use of nonsurgical therapy (chemoradiation) provided similar survival to total laryngectomy (the gold standard) for patients with advanced-stage laryngeal cancer. The purpose of this study was to assess how treatment of advanced laryngeal cancer was influenced by such developments in non-surgical therapy. STUDY DESIGN: Patterns of care study using National Cancer Database (1985-2001). RESULTS: The percentage of advanced-stage patients treated with chemoradiation increased from 8.3% to 20.8% while the proportion treated with radiation alone decreased from 38.9% to 23.0%. Use of chemoradiation increased at a significantly faster rate after the 1991 publication at both community cancer centers and teaching research facilities. The use of total laryngectomy decreased slightly during this period. CONCLUSIONS: The use of chemoradiation increased after the 1991 publication. It was impossible to determine from the NCDB whether additional patients who could benefit from chemo-RT were not offered or did not complete this treatment option. We recommend that treatment recommendations discussed at tumor boards be recorded in cancer registries.     

Does an oral appliance reduce palatal flutter and tongue base snoring?

OBJECTIVES: Oral appliances are designed to treat snoring and sleep apnea by advancing the mandible and tongue. We test the hypothesis that an oral appliance affects palatal snoring as well as tongue base obstruction. METHODS: Prospective observational cohort study. Sixty patients with a chief complaint of snoring with or without apnea were enrolled. Each patient underwent a home sleep test followed by 3 weeks sleeping with an oral appliance. Each patient then underwent a repeat home sleep test while using the device. RESULTS: There was a statistically significant improvement in the snores per hour (P = 0.0005), the maximum snoring loudness (P = 0.0001), average snoring loudness (P = 0.00001), and the percentage of palatal snoring (P = 0.0007). There was also a significant decrease in oxygen desaturation events (P = 0.003). CONCLUSIONS: This study suggests oral appliances may be effective treatment for both palatal and tongue base snoring.     

Band-pass response properties of rat SI neurons

Rats typically employ 4- to 12-Hz "whisking" movements of their vibrissae during tactile exploration. The intentional sampling of signals in this frequency range suggests that neural processing of tactile information may be differentially engaged in this bandwidth. We examined action potential responses in rat primary somatosensory cortex (SI) to a range of frequencies of vibrissa motion. Single vibrissae were mechanically deflected with 5-s pulse trains at rates /=3 Hz. In contrast with this low-pass feature of the response, several other characteristics of the response revealed bandpass response properties. While average evoked response amplitudes measured 0-35 ms after stimulus onset typically decreased with increasing frequency, the later components of the response (>15 ms post stimulus) were augmented at frequencies between 3 and 10 Hz. Further, during the steady state, both rate and temporal measures of neural activity, measured as total spike rate or vector strength (a measure of temporal fidelity of spike timing across cycles), showed peak signal values at 5-10 Hz. A minimal biophysical network model of SI layer IV, consisting of an excitatory and inhibitory neuron and thalamocortical input, captured the spike rate and vector strength band-pass characteristics. Further analyses in which specific elements were selectively removed from the model suggest that slow inhibitory influences give rise to the band-pass peak in temporal precision, while thalamocortical adaptation can account for the band-pass peak in spike rate. The presence of these band-pass characteristics may be a general property of thalamocortical circuits that lead rodents to target this frequency range with their whisking behavior.