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RationaleFollowing acute respiratory distress syndrome (ARDS), joblessness is common but poorly understood.ObjectivesTo evaluate the timing of return to work after ARDS, and associated risk factors, lost earnings, and changes in healthcare coverage Methods: Over 12-month longitudinal follow-up, ARDS survivors from 43 U.S. ARDSNet hospitals provided employment and healthcare coverage data via structured telephone interviews. Factors associated with the timing of return to work were assessed using Fine and Gray regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data.Measurements and main resultsOf 922 consenting survivors, 386 (42%) were employed before ARDS (56% male; mean ± SD age, 45 ± 13 yr), with seven dying by 12-month follow-up. Of 379 previously employed 12-month survivors, 166 (44%) were jobless at 12-month follow-up. Accounting for competing risks of death and retirement, half of enrolled and previously employed survivors returned to work by 13 weeks after hospital discharge, with 68% ever returning by 12 months. Delays in return to work were associated with longer hospitalization and older age among nonwhite survivors. Over 12-month follow-up, 274 (71%) survivors accrued lost earnings, averaging $26,949 ± $22,447 (60% of pre-ARDS annual earnings). Jobless survivors experienced a 14% (95% confidence interval, 5-22%; P = 0.002) absolute decrease in private health insurance (from 44% pre-ARDS) and a 16% (95% confidence interval, 7-24%; P

Background: Stereotactic radiosurgery is being increasingly used to treat patients with early-stage non-small cell lung cancers (NSCLC) who are not candidates for surgical resection. Stereotactic radiosurgery usually needs fiducial markers (FMs) for the tracking process. FMs have generally been placed using percutaneous computed axial tomography scan guidance. We report the results of FM placement using endobronchial ultrasound (EBUS) in 43 patients., Methods: A multidisciplinary tumor board evaluates NSCLC patients before they are offered stereotactic radiosurgery. In patients selected for stereotactic radiosurgery, FMs were inserted into peripheral, central, and mediastinal tumors using EBUS and, in selected patients, navigational bronchoscopy. Patients underwent repeat computed axial tomography chest scans 2 weeks later to ensure stability of the FMs before beginning stereotactic radiosurgery., Results: Included were 43 consecutive patients (21 men, 22 women; mean age, 74.4 years). Forty-two (98%) had NSC carcinomas (5 recurrences); 1 had a carcinoid tumor. Twenty-two tumors were located in the left lung, 19 in the right lung, 1 at the carina, and 1 pretracheal. Two to 5 FMs were placed in and around all tumor masses using EBUS and, for peripheral lesions, EBUS combined with navigational bronchoscopy. Thirty patients had no displacement of FMs. In the 13 who had displaced 1 or more FMs, the ability to use the remaining FMs for stereotactic radiosurgery was unimpaired., Conclusions: EBUS and navigational bronchoscopy are safe and effective methods to position FMs for preparing patients with both central and peripheral lung cancers for stereotactic radiosurgery., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We examined the effect of (+/-)-gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of the enzyme GABA transaminase, on the acquisition and expression of cocaine-induced sensitization in albino male Sprague-Dawley rats. Animals received a single injection of 1 ml/kg i.p. of 0.9% saline or 15 mg/kg i.p. of (-)-cocaine and locomotor activity was assessed using automated locomotor cages and stereotyped behaviors were scored using a 4-point rating scale (Day 1). Subsequently, animals were given 15 mg/kg i.p. of cocaine every 48 h in their home cage for 1 week (Days 3, 5, and 7) and then given no treatment for 1 week. A challenge injection of 15 mg/kg i.p. of cocaine, but not vehicle, produced a significant increase in locomotor activity and stereotyped behaviors on Day 15 compared to animals that received cocaine on Day 1. Administration of 75 mg/kg i.p. of GVG 2.5 h before the cocaine injections did not significantly alter the acquisition of cocaine-induced locomotor sensitization. However, 150 mg/kg i.p. of GVG significantly attenuated the acquisition of cocaine-induced locomotor sensitization. Administration of 150 mg/kg i.p. of GVG 2.5 h before the cocaine challenge injection on Day 15 significantly attenuated the expression of cocaine-induced locomotor sensitization. Acquisition and expression of cocaine-induced sensitization of stereotypy was also significantly attenuated by 150 mg/kg i.p. of GVG. Since sensitization may be one of the factors involved in relapse to drug use, the present results, in combination with previous findings that GVG blocks the rewarding and incentive motivating effects of cocaine, suggest that GVG might prove useful in the treatment of cocaine addiction., (Copyright 2002 Wiley-Liss, Inc.)

Rationale: Intermittent footshock reinstates drug-taking behavior in rats, but not behaviors previously maintained by food reinforcers. Here we tested further the generality of this phenomenon by determining whether restraint and food deprivation stressors would reinstate heroin seeking, whether the environment in which footshock is given modulates footshock-induced reinstatement, and whether footshock would reinstate operant responding previously maintained by brain stimulation reward (BSR)., Methods: Groups of rats were trained to self-administer for 10 days either heroin (0.05-0.1 mg/kg/infusion, IV, three 3-h sessions/day) or brain stimulation into the septal area (trains of monopolar cathodal pulses of 100 micros for 500 ms, one 60-min session/day). After extinction of the heroin-reinforced behavior (10-13 days), the rats were tested for reinstatement after exposure to food deprivation (1 and 21 h), restraint given outside the self-administration environment (5, 15 and 30 min), or intermittent footshock (0.8 mA, 15 min) given in the self-administration environment or in a novel (non-drug) environment. For BSR-trained rats, the effect of footshock on reinstatement after extinction (6-10 days) was compared with that induced by noncontingent brain stimulation (three or six discrete stimulations at the start of the test sessions)., Results: Food deprivation reinstated heroin seeking. Footshock reliably reinstated heroin seeking when given in the drug environment, but not when given in a non-drug environment. Similarly, restraint given outside the self-administration environment failed to reinstate heroin seeking. In addition, footshock was as effective as priming brain stimulation in reinstating operant responding previously maintained by BSR., Conclusions: The effect of footshock on reinstatement of heroin seeking generalizes to food deprivation, and appears to be dependent on the environment in which the stressor is given. The data with BSR indicate that the phenomenon of footshock-induced reinstatement is not selective for drug reinforcers.

Intermittent footshock stress has been shown to reinstate extinguished drug-taking behaviour in rats, but the brain areas involved in this effect are to a large degree unknown. Here we studied the role of the septum in stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin for 9-10 days (three 3-h sessions per day, 0.1 mg/kg per infusion). Following training, extinction sessions were given for 8-13 days by substituting saline for heroin, and then tests for reinstatement of heroin seeking were carried out. Reversible inactivation of the medial septum with tetrodotoxin (TTX; 1-5 ng, infused 25-40 min before the test sessions) reliably reinstated heroin seeking, mimicking the effect of 15 min of intermittent footshock. This effect of TTX was not observed after infusions made 1.5 mm dorsally into the lateral septum. In other experiments, it was found that infusions of a low, subthreshold dose of TTX (0.5 ng) into the medial septum, when combined with 2 min of footshock that in itself was ineffective, reinstated heroin seeking. Furthermore, electrical stimulation (400 microA pulses, 100 micros duration, 100 Hz frequency) of the medial septum during exposure to 10 min of intermittent footshock attenuated footshock-induced reinstatement of heroin seeking. These data suggest a role for the medial septum in stress-induced relapse to drug seeking. The septum is thought to be involved in neuronal processes underlying behavioural inhibition, thus we speculate that stressors provoke relapse by interfering with these processes.

Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10-40 microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3 microram). Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6-diethylphenylamino]-2-imidazole (ST-91, 0.5-1 microgram per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress-induced reinstatement of heroin seeking.

Periodic (high peak) exposure to alcohol during early infancy in the rat has been shown to disrupt the partial reinforcement extinction effect (PREE), a measure of persistence learning, when rats were tested at weaning age. The current study examined the effects of d-amphetamine (0.3 mg/kg, i.p.) on the PREE after early postnatal exposure to alcohol (4.5 mg/kg) delivered in a milk-based diet or an isocaloric control diet via oral intubation once a day on postnatal days 4 to 9. On postnatal days 20 and 21, rats were trained on either a continuously reinforced or partially reinforced schedule of food reward, followed by extinction. Rats were randomly assigned to eight conditions, depending on diet, drug, and reward schedule. The results were (1) a replication of the finding that periodic (high peak) exposure to alcohol diminishes the PREE, and (2) that amphetamine restores the PREE to normal levels in alcohol-treated animals, and may reduce the PREE in control subjects. The possible role of noradrenergic and dopaminergic systems in situations of extinction and nonreward are discussed.

Early postnatal exposure to alcohol during early development produces deficits in learned persistence, as reflected in the partial reinforcement extinction effect (PREE) in weanling rats, and deficits memory-based learning, as shown by patterned single alternation (PSA) discrimination learning in preweanling rats. We report a partial replication of these effects using the intubation method instead of artificial rearing. Rat pups were intubated once per day with 4.5 g/kg/day alcohol in a milk-based diet or control diet on postnatal days (PNDs) 4 to 9, and then assessed for the PREE on PNDs 20 and 21 or PSA learning on PNDs 17 and 18. Compared with previous artificial rearing reports, the intubation method produced healthier and heavier pups, and yielded a consistently lower and less variable blood alcohol levels. Even with the lower alcohol levels, intubation with alcohol eliminated the PREE. Intubation with alcohol had a weaker but still detrimental effect on PSA learning. These results suggest that alcohol exposure during development can produce behavioral deficits in the absence of the more severe effects on brain and body growth typically associated with fetal alcohol syndrome.

Ng-nitro-L-arginine (L-NArg), a potent nitric oxide synthase inhibitor, has been implicated as a potential mechanism for attenuating the development of tolerance to opioid drugs and for suppressing opioid withdrawal. Neurons in the locus coeruleus (LC) express opioid receptors and these neurons exhibit both tolerance to chronic administration of opioids and antagonist-precipitated withdrawal hyperactivity. This study tested the hypothesis that L-NArg would attenuate the development of opioid tolerance in LC neurons. Challenge doses of morphine were administered while recording single-cell extracellular activity in brain slices from rats who had been concurrently treated for 5 days with morphine (75 mg morphine sulfate base pellets) and L-NArg (10 mg/kg, i.p., bid). The average ED50 for morphine of cells from rats who received L-NArg injections and morphine pellets was similar to that in cells from rats who had been implanted with sham pellets (14.5-18 nM). In contrast, the average ED50 of cells from morphine pelleted animals who received saline injections was substantially higher (34.5 nM). These results demonstrate that L-NArg attenuates the development of tolerance to morphine in LC neurons.

The N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor has been implicated in several kinds of learning and memory, as well as in long-term potentiation (LTP), a putative cellular mechanism for learning and memory. This experiment examined the role of the NMDA receptor in patterned single-alternation (PSA) learning in preweanling rats following intraperitoneal injections of 0.05 mg/kg MK-801, a selective NMDA antagonist. MK-801 significantly inhibited PSA at both 60-s and 30-s intertrial intervals (ITIs), and attenuated, but did not block, learning at 8-s ITI. These results are compared with effects on PSA, a form of nonspatial, memory-based learning, observed after early postnatal exposure to alcohol, infant hippocampal lesions, and infant exposure to X-irradiation, and they add strongly to these earlier demonstrations of the role of the hippocampus in learning and memory that is clearly nonspatial and non-cognitive-map-related.

The extracellular electrophysiological properties of neurons in the laterodorsal tegmental nucleus (LDT), a major source of cholinergic afferents to the thalamus, were studied in chloral hydrate-anesthetized rats. A combination of antidromic activation from the thalamus and histological verification of recording sites was used to correlate the identity of extracellular recordings in the rat LDT with cholinergic neurons in that region. All neurons antidromically activated by stimulation of the anteroventral thalamus were histologically verified to be within clusters of cholinergic (NADPH-d-positive) cells in the LDT or in the adjacent nucleus locus coeruleus (LC). The thalamically projecting LDT neurons had a homogeneous neurophysiological profile consisting of long duration action potentials (mean = 2.5 ms), slow conduction velocities (mean = 0.78 m/s), and lengthy chronaxie values (mean = 0.725 ms). The appearance and axonal characteristics of these neurons resembled those of noradrenergic LC neurons, but the two populations exhibited substantially different spontaneous activity patterns and sensory responsiveness. These characteristics may be useful in the preliminary identification of putative cholinergic neurons in vivo, and thereby provide a foundation for exploring the neuropharmacology, afferent modulation, sensory responsiveness and behavioral correlates of the brainstem cholinergic system.

The survival of synchronous G1 or asynchronous Chinese hamster ovary cells in vitro to heat treatment may depend on the cellular population density at the time of heating and/or as the cells are cultured after heating. The addition of lethally irradiated feeder cells may increase survival at 10(-3) by as much as 10- to 100-fold for a variety of conditions when cells are heated either in suspension culture or as monolayers with or without trypsinization. The protective effect associated with feeder cells appears to be associated with close cell-to-cell proximity. However, when cells are heated without trypsinization about 24 hr or later after plating, when adaptation to monolayer has occurred, the protective effect is reduced; i.e., addition of feeder cells enhances survival much less, for example, about 2- to 3-fold at 10(-2)-10(-3) survival. Also, the survival of a cell to heat is independent of whether the neighboring cell in a microcolony is destined to live or die. Finally, if protective effects associated with cell density do occur and are not controlled, serious artifacts can result as the interaction of heat and radiation is studied; for example, survival curves can be moved upward, and thus changed in shape as the number of cells plated is increased with an increase in the hyperthermic treatment or radiation dose following hyperthermia. Therefore, to understand mechanisms and to obtain information relevant to populations of cells in close proximity, such as those in vivo, these cellular population density effects should be considered and understood.

To quantitatively relate heat killing and heat radiosensitization, asynchronous or G1 Chinese hamster ovary (CHO) cells at pH 7.1 or 6.75 were heated and/or X-irradiated 10 min later. Since no progression of G1 cells into S phase occurred during the heat and radiation treatments, cell cycle artifacts were minimized. However, results obtained for asynchronous and G1 cells were similar. Hyperthermic radiosensitization was expressed as the thermal enhancement factor (TEF), defined as the ratio of the D0 of the radiation survival curve to that of the D0 of the radiation survival curve for heat plus radiation. The TEF increased continuously with increased heat killing at 45.5 degrees C, and for a given amount of heat killing, the amount of heat radiosensitization was the same for both pH's. When cells were heated chronically at 42.4 degrees C at pH 7.4, the TEF increased initially to 2.0-2.5 and then returned to near 1.0 during continued heating as thermal tolerance developed for both heat killing and heat radiosensitization. However, the shoulder (Dq) of the radiation survival curve for heat plus radiation did not manifest thermal tolerance; i.e., it decreased continuously with increased heat killing, independent of temperature, pH, or the development of thermotolerance. These results suggest that heat killing and heat radiosensitization have a target(s) in common (TEF results), along with either a different target(s) or a difference in the manifestation of heat damage (Dq results). For clinical considerations, the interaction between heat and radiation was expressed as (1) the thermal enhancement ratio (TER), which is the dose of X rays alone divided by the dose of X rays combined with heat to obtain an isosurvival, e.g., 10(-4), and (2) the thermal gain factor (TGF), the ratio of the TER at pH 6.75 to the TER at pH 7.4. Since low pH reduced the rate of development of thermal tolerance during heating at low temperatures, low pH enhanced heat killing more at 42-42.5 degrees C than at 45.5 degrees C where thermal tolerance did not develop. Therefore, the increase in the TGF after chronic heating at 42-42.5 degrees C was greater than after acute heating at 45.5 degrees C, due primarily to the increase in heat killing causing an even greater increase in heat radiosensitization. These findings agree with animal experiments suggesting that in the clinic, a therapeutic gain for tumor cells at low pH may be greater for temperatures of 42-42.5 degrees C than of 45.5 degrees C.