Multinational comparison study of aircraft pilot healthcare avoidance behaviour.

BACKGROUND: US and Canadian pilots are required to meet medical standards to secure their active flying status, but a subgroup exhibit healthcare avoidance behaviour due to fear of loss of that status. This phenomenon has the potential to impact pilot health, aeromedical screening and aviation safety. No international comparison study of pilot healthcare avoidance currently exists between US and Canadian pilots. AIMS: To compare the rate and subtypes of healthcare avoidance behaviour secondary to fear for loss of flying status between US and Canadian pilots. METHODS: A comparison analysis of data collected during two independent, non-probabilistic, cross-sectional internet surveys including any individual certified to perform flying duties in the USA (US survey) or Canada (Canadian survey). RESULTS: There were 4320 US pilots and 1415 Canadian pilots who completed informed consent and 3765 US pilots and 1405 Canadian pilots were included in the results. There were 56% of US pilots who reported a history of healthcare avoidance behaviour compared to 55% of Canadian pilots (P = 0.578). A multivariable logistic regression that included age, pilot type and gender showed that US pilots were slightly more likely than Canadian pilots to report this behaviour (odds ratio 1.22, 95% confidence interval 1.06-1.4). CONCLUSIONS: Healthcare avoidance behaviour due to fear of loss of flying status has a relatively high prevalence in both US and Canadian pilot populations.

Limited impacts of truck-based ultra-low-volume applications of mosquito adulticides on mortality in honey bees (Apis mellifera).

Adulticides applied against mosquitoes can reduce vector populations during times of high arbovirus transmission. However, impacts of these insecticides on pollinators and other non-target organisms are of concern to mosquito control professionals, beekeepers and others. We evaluated mortality of Culex quinquefasciatus and Apis mellifera when caged insects were exposed to low and high label rates of four common adulticides (Aqua-Pursuit™ [permethrin], Duet® [prallethrin + sumithrin], Fyfanon® [malathion] and Scourge® [resmethrin]) at six distances up to 91.4 m from a truck-mounted ultra-low-volume sprayer. Honey bee mortality was both absolutely low (61 m had limited impacts on honey bee mortality while providing effective mosquito control.

Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Heritability analysis of IgG4 antibodies in autoimmune thyroid disease.

A study of IgG4 autoantibody levels in juvenile thyroid disease patients showed evidence of heritability using the ROMP screening method. These levels increased with time despite the fact that total IgG antibody decreased with time. Evidence of heritability was demonstrated only in patients with high titers of autoantibodies to both thyroglobulin (Tg) and thyroperoxidase (TPO) unlike family members who may show high titers of one or the other and be asymptomatic at the time of sampling. Since high and low IgG4 levels give different heritability plots, these findings may represent a more severe fibrotic form of thyroiditis with a distinct genetic background. Hence a simple predictive approach is offered by this screening tool for the disease in patients and family members which may be helpful in the future to identify IgG4-related thyroiditis early in the course of disease without the requirement for biopsy.

Decreased dopamine activity predicts relapse in methamphetamine abusers.

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Effects of sevoflurane on cognitive deficit, motor function, and histopathology after cerebral ischemia in rats.

BACKGROUND: The volatile anesthetic sevoflurane exhibits neuroprotective properties when assessed for motor function and histopathology after cerebral ischemia in rats. Damage of hippocampal neurons after ischemia relates to a number of cognitive deficits that are not revealed by testing animals for motor function. Therefore, the present study evaluates cognitive and behavioral function as well as hippocampal damage in rats subjected to cerebral ischemia under sevoflurane compared with fentanyl/nitrous oxide (N(2)O)/O(2) anesthesia. METHODS: Thirty-four rats were trained for 10 days using a hole-board test to detect changes in cognitive and behavioral function. Rats were randomly assigned to the following groups: (A) sham/fentanyl/N(2)O/O(2) (n=7); (B) ischemia/fentanyl/N(2)O/O(2) (n=10); (C) sham/2.0 vol% sevoflurane in O(2)/air (n=7); and (D) ischemia/2.0 vol% sevoflurane in O(2)/air (n=10). Cerebral ischemia was produced by unilateral common carotid artery occlusion combined with hemorrhagic hypotension (mean arterial blood pressure 40 mmHg for 45 min). Temperature, arterial blood gases, and pH were maintained constant. Cerebral blood flow was measured using laser-Doppler flowmetry. After surgery, cognitive and behavioral function was re-evaluated for 10 days. On day 11, the brains were removed for histopathologic evaluation (hematoxylin/eosin-staining). RESULTS: Cognitive testing revealed deficits in declarative and working memory in ischemic rats anesthetized with fentanyl/N(2)O. Rats anesthetized with sevoflurane during ischemia showed a significantly better outcome. Hippocampal damage was significantly worse with fentanyl/N(2)O. CONCLUSION: The present data add to previous investigations showing that sevoflurane prevents a deficit in cognitive function and histopathological damage induced by cerebral ischemia in rats.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Increased brain oxygenation during intubation-related stress.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine whether brain oxyhaemoglobin-deoxyhaemoglobin coupling was altered by anaesthesia or intubation-induced stress. METHODS: This was a prospective observational study in the operating room. Thirteen patients (ASA I and II) undergoing spinal or peripheral nerve procedures were recruited. They were stabilized before surgery with mask ventilation of 100% oxygen. Anaesthesia was induced with 2 microg kg(-1) fentanyl and 3 mg kg(-1) thiopental. Laryngoscopy and intubation were performed 4 min later. After intubation, desflurane anaesthesia (FiO2=1.0) was adjusted to maintain response entropy of the electroencephalogram at 40-45 for 20 min. Prefrontal cortex oxyhaemoglobin and deoxyhaemoglobin were determined every 2 s using frequency domain near-infrared spectroscopy. Blood pressure, heart rate and response entropy were collected every 10 s. RESULTS: Awake oxyhaemoglobin and deoxyhaemoglobin were 18.9 +/- 2.3 micromol (mean +/- SD) and 12.7 +/- 0.8 micromol, respectively, and neither changed significantly during induction. Intubation increased oxyhaemoglobin by 37% (P < 0.05) and decreased deoxyhaemoglobin by 16% (P < 0.05), and both measures returned to baseline within 20 min of desflurane anaesthesia. Blood pressure, heart rate and electroencephalogram response entropy increased during intubation, and the increase in heart rate correlated with the increase in brain oxygen saturation (r = 0.48, P < 0.05). CONCLUSIONS: Intubation-related stress increased oxyhaemoglobin related to electroencephalogram and autonomic activation. Stress-induced brain stimulation may be monitored during anaesthesia using frequency domain near-infrared spectroscopy.

Bispectral index system (BIS) monitoring reduces time to extubation and discharge in children requiring oral presedation and general anesthesia for outpatient dental rehabilitation.

PURPOSE: Pediatric oral rehabilitation patients who receive presedation with oral Versed and general anesthesia (GA) occasionally experience prolonged sedation and delayed discharge. The Bispectral Index System (BIS) is an EEG monitor that measures the anesthesia level. The purpose of this study was to compare the effects of monitoring the BIS to not monitoring the BIS on time from discontinuation of GA to extubation and to discharge. METHODS: Twenty-nine children were enrolled. BIS was monitored from admission until discharge. Each child received 0.7 mg/kg of oral Versed. In the operating room, GA with sevoflurane (IH), rocuronium 1 mg/kg (IV), fentanyl 1 microg/kg (IV), and ondansetron 0.15 mg/kg (IV) was administered. Randomly, in half the patients, the anesthesiologist maintained the level of anesthesia and BIS by adjusting sevoflurane. In the rest, the anesthesiologist did not know BIS. The time from turning off sevoflurane to discharge was compared. RESULTS: Group 1 patients were extubated 5+/-2 minutes sooner than group 2 patients (P=.04). The post-anesthesia care unit stay for group 1 patients was 47+/-17 minutes compared to 63+/-17 minutes in group 2. (p=0.02). CONCLUSIONS: Monitoring anesthesia with BIS promotes earlier extubation and discharge for pediatric dental patients who receive oral Versed and sevoflurane GA.

Bispectral Index System (BIS) monitoring reduces time to discharge in children requiring intramuscular sedation and general anesthesia for outpatient dental rehabilitation.

PURPOSE: Pediatric patients who receive both intramuscular (i.m.) sedation and general anesthesia (GA) for oral rehabilitation occasionally experience prolonged sedation and delayed discharge. The Bispectral Index System (BIS) is an EEG monitor that measures the level of sedation. The authors compared discharge times of patients who had BIS monitoring to those who did not to determine if the use of BIS speeded discharge. METHODS: After IRB approval, 20 children were enrolled. BIS was monitored continuously from admission until discharge. Each child received ketamine, midazolam, and glycopyrrolate i.m. Once sedated, the patient was transferred to the operating room, monitored, and i.v. access was established. GA proceeded with sevoflurane, rocuronium, and fentanyl. Randomly, in half the patients, the anesthesiologist knew and maintained the BIS at GA level of sedation by adjusting sevoflurane. In the rest, the anesthesiologist did not know BIS. Time from turning of sevoflurane to discharge was noted and compared. RESULTS: Patients where the BIS was known and used were discharged 60+/-13 minutes after the end of GA. Patients where BIS was unknown were discharged 90+/-11 minutes after the end of GA (P<.001). CONCLUSIONS: Based on the data, the authors recommend the use of BIS to facilitate faster discharge of pediatric patients who require i.m. sedation and GA for oral rehabilitation.

Reversed latissimus dorsi muscle flap for repair of recurrent congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Neonates with large congenital diaphragmatic hernias (CDH) require prosthetic patch closure of the defect because of the paucity of native diaphragmatic tissue. As the child grows, patch separation can occur necessitating reoperation. Use of vascularized autologous tissue may decrease the incidence of reherniation as tissue incorporation and growth may be improved. The authors report our early experience using a local muscle advancement flap with microneural anastomosis for those children in whom reherniation develops after prosthetic patch placement. METHODS: Seven patients with CDH (6 left and 1 right) whose synthetic diaphragmatic patch separated from the chest wall resulting in a clinically significant recurrent hernia were followed up with prospectively. After dissecting the ipsilateral latissimus dorsi off the chest wall and dividing the thoracodorsal neurovascular bundle (based on its lumbar blood supply), the synthetic patch was removed via an eighth intercostal incision. The muscle flap was placed into the hemithorax through the bed of the tenth rib and sutured in place over a Vicryl mesh scaffold. The thoracodorsal nerve was anastomosed to the phrenic nerve. Functional analysis of the flap was performed in 4 patients. RESULTS: Age at placement of the muscle graft ranged from 2 months to 48 months (median, 24 months). There has been no evidence of reherniation after placement of the muscle graft. Long-term outcome and functional analysis of the flap was available in 4 patients (mean, 19 months). Two infants had fluoroscopic and sonographic evidence of nonparadoxical neodiaphragmatic motion. In one of these, electromyographic evidence of function was documented with a phrenic nerve conduction velocity of 22 meters per second. The third infant showed no evidence of neodiaphragmatic motion, and the fourth infant had paradoxical motion. CONCLUSIONS: This is the first direct documentation of phrenic nerve function in an infant with CDH. An innervated reversed latissimus dorsi (RLD) flap reconstruction for recurrent CDH provides an alternative to prosthetic patch repair. This technique offers the advantages of autologous vascularized tissue with potential phrenic nerve innervation and physiologic neodiaphragmatic motion.

Glyburide decreases myocardial oxygen pressure in dogs.

BACKGROUND: Reports show that glyburide, an adenosine triphosphate sensitive potassium (K+ATP) channel blocker, will reverse the myocardial protective effect of inhalational anesthesia. We evaluated the effect of glyburide on myocardial tissue oxygen pressure (PmO2) in dogs anesthetized with desflurane. METHODS: Twelve dogs were anesthetized with 8% end-tidal desflurane for baseline anesthesia. A flow probe was placed on the left anterior descending (LAD) artery. A probe that measured PmO2 was inserted into the middle myocardium in the LAD region. After baseline measures, six dogs received i.v. 1 mg kg(-1) of glyburide and six dogs received sham vehicle treatment. After the glyburide or sham treatment, each dog received an i.v. infusion of adenosine 0.1 microg kg(-1) x min(-1), sodium nitroprusside (SNP) 2-4 microg kg(-1) x min(-1) and 14% end-tidal desflurane in random order. RESULTS: Glyburide decreased LAD artery flow from 59 +/- 9 ml min(-1) to 30 +/- 6 ml min(-1) (P < 0.05) and PmO2 from 44 +/- 16 mmHg to 30 +/- 9 mmHg (P < 0.05). Adenosine infusion increased LAD artery blood flow 180% in the sham-treated dogs but produced no change in the glyburide-treated dogs. Sodium nitroprusside infusion increased LAD artery flow and decreased PmO2 in both the glyburide- and sham-treated dogs. Desflurane (14%) did not reverse the glyburide-induced vasoconstriction but increased PmO2 to 38 +/- 20 mmHg (P < 0.05). CONCLUSION: Glyburide produced myocardial tissue hypoxia, which was not changed by adenosine, worsened by SNP and improved by 14% desflurane. The improvement in PmO2 with desflurane occurred without a change in myocardial blood flow.

Nearly space-filling fractal networks of carbon nanopores.

Small-angle x-ray scattering, nitrogen adsorption, and scanning tunneling microscopy show that a series of activated carbons host an extended fractal network of channels with dimension D(p) = 2.8-3.0 (pore fractal), channel width 15-20 A (lower end of scaling), network diameter 3000-3400 A (upper end of scaling), and porosity of 0.3-0.6. We interpret the network as a stack of quasiplanar invasion percolation clusters, formed by oxidative removal of walls between closed voids of diameter of approximately 10 A and held in registry by fibrils of the biological precursor, and point out unique applications.

Brain compared to heart tissue oxygen pressure during changes in arterial carbon dioxide in the dog.

Myocardial tissue oxygen pressure (PmO2 ) and left anterior descending (LAD) artery blood flow were measured in dogs anesthetized with 1.5% isoflurane, and were then compared to brain tissue oxygen pressure (PbO2 ) and middle cerebral artery (MCA) blood flow during normocapnia, hypocapnia, and hypercapnia. A craniotomy was performed and a tissue probe (Codman, Inc.) that measures PO2, PCO2, and pH was inserted into the brain cortex in the MCA region (n = 8). Separately, after a thoracotomy, a probe was inserted into the middle myocardium of the left ventricle, within the distribution of the LAD, in eight dogs. Blood flow probes were placed on the LAD or MCA. Blood flow and tissue gases were measured during normocapnia (PaCO2 = 38 mm Hg), hypocapnia (PaCO2 = 26 mm Hg), and hypercapnia (PaCO2 = 53 mm Hg). Mean arterial pressure, heart rate, arterial gases, and pH were not different between brain and heart measurements. PbO2 was 21 +/- 9 mm Hg (mean +/- SD ), 40 +/- 16 mm Hg, and 47 +/- 11 mm Hg. PmO2 was 35 +/- 12 mm Hg, 40 +/- 14 mm Hg, and 48 +/- 15 mm Hg during hypocapnia, normocapnia, and hypercapnia respectively. During hypercapnia, LAD and MCA flow increased 50% and tissue oxygenation increased 20% ( P < .05). During hypocapnia, MCA flow and PbO2 decreased 50% ( P < .05), but LAD flow and PmO2 did not significantly change. These results indicated that LAD flow and myocardial PO2 were less responsive to hypocapnia than MCA flow and PbO2.

Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure.

We report a patient who presented with anophthalmia, panhypopituitarism, early onset of end stage renal failure, and craniofacial abnormalities. MRI at age 3 revealed that the pituitary was absent and renal biopsy demonstrated nephronophthisis as the cause of the renal failure. A similar syndrome has been associated with interstitial deletions of chromosome 14q22 and in one case hemizygosity for SIX6 was demonstrated. The patient reported here had a normal karyotype and Southern blot did not reveal loss of one copy of SIX6. We discuss other possible candidate genes that could be implicated in this syndrome.

Reconstruction with rectus abdominis myocutaneous free flap after orbital exenteration in children.

OBJECTIVE: To present a 1-stage technique for orbital reconstruction after exenteration with the use of myocutaneous rectus abdominis free flap in children. SURGICAL TECHNIQUE: After orbital exenteration, a myocutaneous rectus abdominis free flap with long vascular pedicle is harvested from the abdomen. The flap is transferred to the orbit and the vascular pedicle is passed through an opening made in the lateral orbital wall, where it is anastomosed to superficial temporal vessels. The skin of the flap is trimmed to correspond to the eyelid defect and the incisions are closed. METHODS: After informed consent was obtained, 2 children, 3 and 8 years old, underwent orbital reconstruction with a rectus abdominis free flap after exenteration for orbital rhabdomyosarcoma and orbital osteosarcoma in the setting of retinoblastoma. RESULTS: This technique allowed easy postoperative wound care. Viability of the flap was excellent. The technique provided sufficient volume to fill the orbit, with improved aesthetic results and minimal donor site deformity. CONCLUSIONS: The postoperative care and aesthetic outcome in patients with rectus abdominis free flap after exenteration are much improved over those provided with traditional surgical techniques. This primary reconstruction is recommended for any patient requiring orbital exenteration, but particularly for pediatric patients who tolerate debridement of traditional exenteration sites poorly.

Sodium nitroprusside compared with isoflurane-induced hypotension: the effects on brain oxygenation and arteriovenous shunting.

UNLABELLED: We compared sodium nitroprusside (SNP)-induced hypotension with 3% isoflurane-induced hypotension with regard to brain tissue oxygen pressure (PtO(2)), middle cerebral artery (MCA) blood flow, and cerebral arteriovenous shunting. Eight dogs were anesthetized with 1.5% isoflurane. After a craniotomy, a probe was inserted into the left frontoparietal brain cortex to mea-sure tissue gases and pH. Blood flow was measured in a secondary branch of the MCA by a flowprobe. Measurements were made during baseline 1.5% isoflurane, during 1.5% isoflurane and SNP-induced hypotension or 3% isoflurane-induced hypotension to a mean pressure of 60-65 mm Hg, and during continued treatment with SNP or 3% isoflurane with blood pressure support to baseline levels with phenylephrine. Shunting was calculated from arterial, sagittal sinus, and tissue (indicating capillary) oxygen content. During hypotension with SNP, PtO(2) decreased 50%, and shunting increased 50%. During hypotension with 3% isoflurane, PtO(2) and shunting did not change. Blood pressure support increased PtO(2) and MCA flow during both SNP and 3% isoflurane treatment. These results show that SNP is a cerebrovasodilator but that hypotension will decrease PtO(2), probably because of an increase in arteriovenous shunting and a decrease in capillary perfusion. IMPLICATIONS: We measured brain arteriovenous shunting and tissue oxygen pressure(PtO(2))during a 40% decrease in blood pressure induced by sodium nitroprusside (SNP)or 3% isoflurane. Large-dose isoflurane maintainedPtO(2) with no change in shunting. SNP infusion decreasedPtO(2) 50%and increased shunting 50%. This suggests that SNP-induced hypotension decreases PtO(2) because of a decrease in capillary perfusion.

Acute activation of peripheral lymphocytes during treatment of diabetic ketoacidosis.

Activated peripheral T-lymphocytes are increased in both pre-insulin-dependent diabetes mellitus (IDDM) patients and in recently diagnosed IDDM patients, as well as in various forms of acute stress. We studied the in vivo T-lymphocyte activation in six patients in severe diabetic ketoacidosis (DKA) prior to treatment, after 24 h of treatment and > or =5 days after admission. Five of the six patients showed an increased percentage of activated T-lymphocytes based on the expression of HLA-DR at 24 h of treatment when compared to the admission percentage of activation (P<.05). There was no correlation to the admission serum glucose, osmolality, or electrolytes. Serum pH showed a trend toward an inverse correlation, but was not statistically significant. We speculate that T-lymphocyte activation plays a role in the progression of the acute complications of subclinical brain edema and interstitial pulmonary edema of DKA. This process could also be another factor in the progression of the chronic complications of IDDM in addition to the well-established effects of hyperglycemia and hypertension.

The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation.

While the transactivation function of the tumor suppressor p53 is well understood, less is known about the transrepression functions of this protein. We have previously shown that p53 interacts with the corepressor protein mSin3a (hereafter designated Sin3) in vivo and that this interaction is critical for the ability of p53 to repress gene expression. In the present study, we demonstrate that expression of Sin3 results in posttranslational stabilization of both exogenous and endogenous p53, due to an inhibition of proteasome-mediated degradation of this protein. Stabilization of p53 by Sin3 requires the Sin3-binding domain, determined here to map to the proline-rich region of p53, from amino acids 61 to 75. The correlation between Sin3 binding and stabilization supports the hypothesis that this domain of p53 may normally be subject to a destabilizing influence. The finding that a synthetic mutant of p53 lacking the Sin3-binding domain has an increased half-life in cells, compared to wild-type p53, supports this premise. Interestingly, unlike retinoblastoma tumor suppressor protein, MDMX, and p14(ARF), Sin3 stabilizes p53 in an MDM2-independent manner. The ability of Sin3 to stabilize p53 is consistent with the model whereby these two proteins must exist on a promoter for extended periods, in order for repression to be an effective mechanism of gene regulation. This model is consistent with our data indicating that, unlike the p300-p53 complex, the p53-Sin3 complex is immunologically detectable for prolonged periods following exposure of cells to agents of DNA damage.

Combining median electroencephalography frequency and sympathetic activity in an index to evaluate opioid detoxification in patients.

During rapid opioid detoxification, increased sympathetic activity and a greater median frequency (MF) of activity on electroencephalography (EEG) have been reported. The purpose of this study was to evaluate a new index for detoxification that combines sympathetic activity and MF data. After informed consent was obtained, eight patients were sedated with propofol. The MF of EEG activity derived from frontal electrodes was determined. Heart rate variability was evaluated in 256-second segments by power spectral analysis, and sympathetic activity was determined by the low frequency component. The Hoffman Index for narcotic detoxification was weighted 70% to sympathetic activity and 30% to MF to normalize the difference in scales and to provide adequate weight to the sympathetic component. Opioid detoxification was produced by infusion of 25 mg naloxone for 30 minutes, followed by a 24-hour infusion of 1 mg per hour. The MF showed a rapid increase during high-dose infusion of naloxone, but the peak response occurred 1 to 2 hours later. Sympathetic activation and the Hoffman Index increased more slowly after the start of naloxone infusion, but peak increases in all components occurred at approximately the same time. The peak increases in Hoffman Index (110% of baseline), MF (260%), and sympathetic activity (304%) during administration of naloxone were significant and correlated with respect to time (r = 0.89-0.94). The Hoffman Index showed an early increase related to MF and a well-defined peak response indicative of sympathetic and MF activity. The behavior of the Hoffman Index in relation to the MF and sympathetic activity more clearly indicated the onset of opioid detoxification and the maximum response to opioid reversal than did MF or sympathetic activity alone.