Examining the relationship between blast-induced mild traumatic brain injury and posttraumatic stress-related traits.

Emerging evidence suggests that mild traumatic brain injury (mTBI) resulting from blast exposure may contribute to the occurrence of posttraumatic stress disorder (PTSD) and related affective sequelae, such as anxiety and depression. Many studies have used survey techniques to describe blast exposure leading to comorbid mTBI and related persistent postconcussive symptoms (PPCS) with PTSD in military populations. Despite this, there is a lack of literature that examines possible biological mechanisms by which blast exposure contributes to the development of PTSD sequelae. This Mini-Review addresses the current literature on potential neurophysiological changes that may contribute to PTSD-like traits as a result of a single or multiple exposures to blast events. Evidence from clinical blast-induced mTBI populations and animal models of blast-induced mTBI was evaluated with an emphasis on behavioral and physiological symptoms similar to those seen in PTSD populations and models. From the analysis, we propose potential mechanisms that merit further investigation for better understanding of how blast exposures may produce a higher rate of comorbid PPCS, PTSD, and affective phenomena. An improved understanding of PTSD-like outcomes resulting from blast exposure will ultimately help facilitate the development of future treatments and contribute to a better understanding of PTSD sequelae that develop from physical trauma.

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses.

BACKGROUND: The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. METHODS: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. RESULTS: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP. CONCLUSIONS: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).

Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy.

BACKGROUND: Chronic thoracic pain after cardiac surgery is a serious condition affecting many patients. The aim of this study was to identify predictors for chronic thoracic pain after sternotomy in cardiac surgery patients by analysing patient and perioperative characteristics. METHODS: A follow-up study was performed in 120 patients who participated in a clinical trial on pain levels in the early postoperative period after cardiac surgery. The presence of chronic thoracic pain was evaluated by a questionnaire 1 yr after surgery. Patients with and without chronic thoracic pain were compared. Associations were studied using multivariable logistic regression analysis. RESULTS: Questionnaires of 90 patients were analysed. Chronic thoracic pain was reported by 18 patients (20%). In the multivariable regression model, remifentanil during cardiac surgery, age below 69 yr, and a body mass index above 28 kg m(-2) were independent predictors for chronic thoracic pain {odds ratios 8.9 [95% confidence interval (CI) 1.6-49.0], 7.0 (95% CI 1.6-31.7), 9.1 (95% CI 2.1-39.1), respectively}. No differences were observed in patient and perioperative characteristics between patients receiving remifentanil (58%, n=52) compared with patients not receiving remifentanil (42%, n=38). The association between remifentanil and chronic thoracic pain appeared dose-dependent, both for total dose and for dose corrected for kilogram lean body mass and duration of surgery (P-value for trend: <0.01 and <0.005, respectively). CONCLUSIONS: In this follow-up study in cardiac surgery patients, intraoperative remifentanil was predictive for chronic thoracic pain in a dose-dependent manner. Randomized studies designed to evaluate the influence of intraoperative remifentanil on chronic thoracic pain are needed to confirm these results.

Ge(1-x) Mn(x) clusters: central structural and magnetic building blocks of nanoscale wire-like self-assembly in a magnetic semiconductor.

Controlled nanoscale self-assembly of magnetic entities in semiconductors opens novel perspectives for the tailoring of magnetic semiconductor films and nanostructures with room temperature functionality. We report that a strongly directional self-assembly in growth direction in Mn-alloyed Ge is due to a stacking of individual Ge(1-x)Mn(x) clusters. The clusters represent the relevant entities for the magnetization of the material. They are formed of a core-shell structure displaying a Mn concentration gradient. While the magnetic moments seem to be carried by the shells of the clusters, their core is magnetically inactive.

Adherence to All Steps of a Pain Management Protocol in Intensive Care Patients after Cardiac Surgery Is Hard to Achieve.

Purpose. To investigate adherence to our pain protocol considering analgesics administration, number and timing of pain assessments, and adjustment of analgesics upon unacceptably high (NRS ≥ 4) and low (NRS ≤ 1) pain scores. Material and Methods. The pain protocol for patients in the intensive care unit (ICU) after cardiac surgery consisted of automated prescriptions for paracetamol and morphine, automated reminders for pain assessments, a flowchart to guide interventions upon high and low pain scores, and reassessments after unacceptable pain. Results. Paracetamol and morphine were prescribed in all 124 patients. Morphine infusion was stopped earlier than protocolized in 40 patients (32%). During the median stay of 47 hours [IQR 26 to 74 hours], 702/706 (99%) scheduled pain assessments and 218 extra pain scores were recorded. Unacceptably high pain scores accounted for 96/920 (10%) and low pain scores for 546/920 (59%) of all assessments. Upon unacceptable pain additional morphine was administered in 65% (62/96) and reassessment took place in 15% (14/96). Morphine was not tapered in 273 of 303 (90%) eligible cases of low pain scores. Conclusions. Adherence to automated prescribed analgesics and pain assessments was good. Adherence to nonscheduled, flowchart-guided interventions was poor. Improving adherence may refine pain management and reduce side effects.

Anterograde amnesia induced by hyperthermia in rats.

Anterograde amnesia (AA), forgetting of events that occur following a traumatic episode, has recently been demonstrated by using a mild decrease in temperature (hypothermia) as the amnestic agent. However, no data currently exist to indicate if an increase in body temperature (hyperthermia) might affect memory processing in a similar manner. Experiments 1 and 2 demonstrated that increasing the colonic body temperature of the rat to 3-4 degrees C or more above normal during avoidance training produced a significant retention loss when the test occurred 24 hr after training. Slight hyperthermia to 1-2 degrees C above normal did not impair retention. In Experiment 3, AA resulting from an elevation in temperature was reversed by reheating "amnestic" subjects just prior to the 24-hr test. By rapidly reversing hyperthermia immediately after the training trial with a cooling procedure, Experiment 4 demonstrated that hyperthermia-induced AA was not the result of retrograde influences of the heating treatment. Implications of these results are discussed in terms of possible retention deficits which could conceivably follow environmental heat stress or fever hyperthermia resulting from bacterial infection.

Administration of dexamethasone prior to training blocks ACTH-induced recovery of an extinguished avoidance response.

Pretest administration of ACTH has been shown to produce recovery of an extinguished avoidance response. Presumably this effect is found because endogenous ACTH is a component of the original training memory. However, another possible explanation of this finding is that administration of the peptide acts as a novel stimulus that "disinhibits" the extinguished response. In order to test this "disinhibitory" hypothesis of ACTH-induced recovery of an extinguished avoidance response, some subjects were given dexamethasone 2 hr prior to training and extinction. This synthetic glucocorticoid is effective in blocking endogenous release of ACTH. Thus, ACTH should not be a component of the training memory in subjects given dexamethasone prior to training and extinction but would be a relatively novel stimulus condition at testing. Pretest administration of ACTH was found to be effective in alleviating performance deficits induced by extinction only for subjects given saline prior to training and extinction. Administration of ACTH had no effect on the avoidance responding of subjects given dexamethasone. These findings suggest that pretest administration of ACTH affects retrieval processes rather than acts as a disinhibitor.

Tyrosine ameliorates a cold-induced delayed matching-to-sample performance decrement in rats.

Exposure to cold stress has been shown to impair short-term, or working, memory which may be related to a reduction in brain catecholamines. Administration of the catecholamine precursor tyrosine may alleviate a cold-stress-induced memory impairment by preventing a deficit in brain catecholamine levels. To test this hypothesis, eight rats performed a delayed matching-to-sample (DMTS) task at an ambient temperature of either 2 degrees C (cold) or 22 degrees C, following intraperitoneal administration of saline or tyrosine (50, 100 or 200 mg/kg). Rats administered saline prior to 22 degrees C exposure demonstrated a characteristic delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 1 to 16 s. Consistent with previous research, and relative to 22 degrees C exposure sessions, matching accuracy during 2 degrees C exposure sessions was reduced, which is attributed to the effect of cold on short-term, or working, memory. In particular, during cold exposure sessions matching accuracy was significantly reduced at the longer delay intervals, relative to matching accuracy at 22 degrees C. Additional analysis of cumulative matching errors within sessions showed that during exposure to cold, errors occurred at a constant rate throughout the session, indicating rats' performance was equally debilitated by the stressor over the entire session. During cold exposure sessions, the higher doses of 100 and 200 mg/kg tyrosine significantly improved overall matching accuracy relative to saline, but did not completely reverse the effect of cold exposure, as overall matching accuracy did not increase entirely to levels obtained at 22 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic responses to cognitive activity in a cold environment.

Adrenergic responses during physical stress such as cold exposure have been reported to differ from those responses observed during cognitive activity. Both the separate and the combined effects of cold and cognitive activity on catecholamine activity were examined in six male subjects. Alterations in plasma epinephrine and norepinephrine showed different patterns as a function of exposure to a 4 degrees C cold environment, a cognitive performance assessment battery (PAB), and the two conditions combined. Plasma epinephrine was not altered by exposure to cold and only slightly increased by PAB performance when given at 23 degrees C. However, epinephrine was substantially elevated by exposure to combined cold and PAB. Heart rate changes paralleled observed changes in epinephrine. Norepinephrine release was predominantly increased by cold exposure and was not altered by PAB performance.

Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats.

Exposure to stress has previously been found to impair long-term potentiation (LTP) in the hippocampus. Exposure to stress has also been proposed to induce an LTP-like effect. We examined the effect of acute cold stress on synaptic transmission, neuronal excitability, and LTP induction in the medial perforant path-granule cell synapse of freely moving rats. After obtaining baseline recordings of evoked field potentials at room temperature (23 degrees C), rats were transferred to an environmental cage maintained at 4 degrees C (cold group) or 23 degrees C (control group) and, 90 min later, high-frequency stimulation (HFS) was applied to the medial perforant path. Serum corticosterone measured in trunk blood from rats without implanted electrodes was significantly elevated in cold exposed (28. 7 microg/dl) rats relative to control (6.6 microg/dl). Despite increased corticosterone levels indicative of stress activation, cold exposed rats exhibited LTP of the fEPSP slope and population spike of similar magnitude and time course as controls. In addition, there was no stress-specific effect on the fEPSP slope or population spike and no effect on paired-pulse plasticity. Surprisingly, despite extensive cage acclimation, transferring rats to the environmental cage was associated with a reduction in population spike amplitude and an enhancement in paired-pulse facilitation. The results show that acute cold stress leading to elevated serum corticosterone levels neither induces LTP-like increases in synaptic efficacy nor impairs tetanus-evoked LTP in the dentate gyrus of freely moving rats. Thus, impaired working memory during cold stress is not due to an inability of perforant path synapses to express LTP.

Tyrosine pretreatment alleviates suppression of schedule-controlled responding produced by corticotropin releasing factor (CRF) in rats.

Disruption of performance observed when animals are exposed to physical stressors which deplete brain catecholamines can be alleviated by pretreatment with the catecholamine precursor tyrosine. Central administration of the stress hormone corticotropin releasing factor (CRF) has been shown to affect a variety of behaviors and also to potently increase the release of central catecholamines. Since CRF-induced disruption of behavior may involve CRF-induced depletion of brain catecholamines, the present study examined whether tyrosine would alleviate suppression of schedule-controlled responding in rats resulting from ICV administration of CRF. Administration of CRF (1.0 microgram-10 micrograms) produced dose-dependent suppression of response rate and total number of earned reinforcers in rats responding on a multiple fixed-interval 60 s/fixed-ratio 20 schedule for food reinforcement. Pretreatment with 200 mg/kg tyrosine (IP) administered with ICV saline decreased response rate but did not lower total reinforcers, whereas 400 mg/kg of tyrosine decreased both. Injection of 400 mg/kg tyrosine reduced, but did not completely restore, CRF-induced suppression of behavior. The 200 mg/kg tyrosine dose was less effective in alleviating CRF-induced suppression of performance. These data indicate that pretreatment with the catecholamine precursor tyrosine can partially ameliorate performance decrements resulting from CRF administration.

Thermal stress modulates temporal patterns of responding on a multiple DRL-FR schedule.

To investigate temporal changes in behavior induced by moderate cold temperatures, rats performing on a multiple differential-reinforcement-of-low-rate (DRL) fixed-ratio (FR) schedule were exposed to ambient temperatures of 2, 8, 16, and 24 degrees C. DRL response rates markedly increased with decreasing cold temperatures, while FR response rates remained unchanged. In addition, as ambient temperatures decreased, the interresponse time (IRT) distribution of DRL responses shifted toward shorter times and short IRT bursts increased. Compared with cold effects, exposure to 38 degrees C heat induced decreases in both DRL and FR response rates which were associated with increases in long IRTs. Decreases in reinforcement frequency was associated only with the DRL schedule in cold, and with both DRL and FR schedules during heat exposures. The distinct effects of cold and heat on both DRL and FR responding suggest that the increases in DRL response rates and shifts in IRT distribution are unique to cold, and are not due to general effects of nonspecific thermal change in the ambient environment.

The effects of preexposure to the drug on state dependent retention.

The present experiment examined whether previous experience with a drug would decrease the potential of the drug to produce state dependent retention (SDR) for a passive avoidance response in rats. In the first experiment, a single injection of sodium pentobarbital (20 mg/kg) given on six consecutive days before the training day slightly reduced, but did not block, pentobarbital-induced SDR. In Experiment Two, four preexposure injections of 5 IU/kg insulin reduced the magnitude of memory loss produced by administration of the hormone prior to training. As with pentobarbital, however, preexposure to insulin did not completely block the amnestic effect of the hormone. A subsequent experiment demonstrated that the decrease in the strength of insulin-induced SDR in insulin preexposed rats was not the result of enhanced acquisition. Collectively, these data indicate that noncontingent preexposure to an amnestic treatment may decrease the magnitude of memory loss that would normally result from the administration of that treatment during training.

Hippocampal and body temperature changes in rats during delayed matching-to-sample performance in a cold environment.

In order to study the effects of temperature changes induced by cold stress on working memory, telemetry thermistor probes were implanted into the hippocampal region of the brain and into the peritoneal cavity of rats. Temperatures in these regions were monitored while rats performed on a delayed matching-to-sample (DMTS) task at ambient temperatures of 23 degrees C and 2 degrees C. Matching accuracy was significantly decreased during exposure to 2 degrees C, indicating a marked impairment of short-term or working memory. Temperature in the hippocampus increased 2 degrees C during exposure to 23 degrees C, but only 1 degrees C when the environmental temperature was 2 degrees C. Body temperature showed a similar but less pronounced pattern in that cold exposure attenuated the increase in temperature observed when animals performed the DMTS task. These results suggest that cold-induced impairment of working memory may be associated with subtle temperature changes in the brain.

Effects of repeated administration of corticotropin-releasing factor on schedule-controlled behavior in rats.

To examine the effects of repeated administration of corticotropin-releasing factor (CRF) on behavior, rats were administered ICV injections of either CRF or saline on alternate days for 10 days prior to performing on a multiple fixed-interval (FI) 60 s/fixed-ratio (FR) 20 schedule for food reinforcement. A daily session consisted of 10 components of each schedule that alternated, starting with the FI component. CRF doses were individually determined for each rat and were either 1.0, 3.0, or 10 micrograms CRF based upon the dose that occasioned more than a 50% reduction in the rate of responding. Acute administration of CRF decreased the rate of responding in both components well below control rates; this decrease in responding was associated with a 20 or 50% decrease in the number of earned reinforcements in the FI and FR components, respectively. With repeated administration, CRF-induced suppression of responding was attenuated, although CRF continued to decrease response rate. Despite the continued reduction in response rate, subsequent CRF injections did not result in a loss of reinforcements in the FI component, whereas rats continued to lose 20% of the reinforcers in the FR component. After an 18-day hiatus in which no CRF was administered, the baseline rate of responding on the multiple schedule increased, in particular in the FI component. When CRF was readministered, response rates were slightly suppressed relative to a reestablished saline control but significantly higher than CRF-induced suppression on the last day of the chronic regimen. These data demonstrate that with repeated administration tolerance develops to CRF-induced suppression of responding in rats.

Neuropeptide-Y both improves and impairs delayed matching-to-sample performance in rats.

Neuropeptide-Y (NPY) was administered intracerebroventricularly to rats performing on delayed matching-to-sample (DMTS) to determine if NPY modulates short-term (working) memory. Rats administered saline demonstrated a characteristic DMTS delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 2 to 8 to 16 seconds. At 8- and 16-second delays, low doses of NPY (0.25 and 0.5 nmol/kg) increased matching accuracy. As doses increased from 1 to 16 nmol/kg, accuracy decreased in a dose- and delay-dependent manner. NPY effects were specific to working memory, since NPY did not affect accuracy of responses to the sample stimulus (reference memory). At higher doses, a greater decline in accuracy occurred when the correct stimulus was on the opposite side from the response on the previous trial compared to accuracy when the previous response was on the same side. These data show NPY may both improve and impair accuracy on DMTS and that some portion of impairment is due to proactive interference resulting from previous trials.

Repeated exposure to moderate cold impairs matching-to-sample performance.

To study effects of moderate cold (5 degrees C) on complex cognitive performance, subjects were exposed to cold while responding on a conditional discrimination task. The task required a correct choice of which of two simultaneously presented matrices matched a previously presented sample matrix. The effects of task performance in cold and ambient temperatures was examined on three repeated occasions, one pair of conditions per week. Responses accuracy was consistently impaired in each cold session. In addition, choice response latencies lengthened and sample response latencies decreased in all cold exposures. The data show that even moderate cold exposure that does not produce core hypothermia can impair performance of a complex cognitive task and that the magnitude of performance change is not attenuated by a brief series of cold exposures.

Moderate cold exposure shortens evoked potential latencies in humans.

Visual, auditory event-related potentials, and brainstem auditory-evoked responses were recorded in as many as six young male subjects in order to study the effects of moderate cold air exposure on central nervous system functioning. Evoked potentials were recorded during repeated 50-min exposures to air of 4 and 22 degrees C; these levels of exposure resulted in no change in rectal core temperature. Evoked potentials recorded during exposures to 4 degrees air displayed consistently shorter latencies compared to those recorded at 22 degrees, suggesting faster CNS processing of sensory stimuli in the cold. These results are consistent with recent investigations of cold-induced behavioral response changes which indicate that increased arousal may occur with moderate (nonhypothermic) cold exposure.

Effects of mild TBI from repeated blast overpressure on the expression and extinction of conditioned fear in rats.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are pressing medical issues for the Warfighter. Symptoms of mTBI can overlap with those of PTSD, suggesting the possibility of a causal or mediating role of mTBI in PTSD. To address whether mTBI can exacerbate the neurobiological processes associated with traumatic stress, we evaluated the impact of mTBI from a blast overpressure (BOP) on the expression of a conditioned fear. In the rat, conditioned fear models are used to evaluate the emotional conditioning processes that are known to become dysfunctional in PTSD. Rats were first trained on a variable interval (VI), food maintained, operant conditioning task that established a general measure of performance. Inescapable electric shock (IES) was paired with an audio-visual conditioned stimulus (CS) and followed 1day later by three daily exposures to BOP (75kPa). Subsequently, the CS alone was presented once every 7days for 2months, beginning 4days following the last BOP. The CS was presented during the VI sessions allowing a concurrent measure of performance. Treatment groups (n=10, each group) received IES+BOP, IES+sham-BOP, sham-IES+BOP or sham-IES+sham-BOP. As expected, pairing the CS with IES produced a robust conditioned fear that was quantified by a suppression of responding on the VI. BOP significantly decreased the expression of the conditioned fear. No systematic short- or long-term performance deficits were observed on the VI from BOP. These results show that mTBI from BOP can affect the expression of a conditioned fear and suggests that BOP caused a decrease in inhibitory behavioral control. Continued presentation of the CS produced progressively less response suppression in both fear conditioned treatments, consistent with extinction of the conditioned fear. Taken together, these results show that mTBI from BOP can affect the expression of a conditioned fear but not necessarily in a manner that increases the conditioned fear or extends the extinction process.

Efficacy of an intravenous bolus of morphine 2.5 versus morphine 7.5 mg for procedural pain relief in postoperative cardiothoracic patients in the intensive care unit: a randomised double-blind controlled trial.

As pain in the intensive care unit (ICU) is still common despite important progress in pain management, we studied the efficacy of an intravenous bolus of morphine 2.5 vs 7.5 mg for procedural pain relief in patients after cardiothoracic surgery in the ICU. In a prospective double-blind randomised study, 117 ICU patients after cardiothoracic surgery were included. All patients were treated according a pain titration protocol for pain at rest, consisting of continuous morphine infusions and paracetamol, applied during the entire ICU stay. On the first postoperative day, patients were randomised to intravenous morphine 2.5 (n=59) or 7.5 mg (n=58) 30 minutes before a painful intervention (turning of patient and/or chest drain removal). Pain scores using the numeric rating scale (Numeric Rating Scale, range 0 to 10) were rated at rest (baseline) and around the painful procedure. At rest (baseline), overall incidence of unacceptable pain (Numeric Rating Scale ≥4) was low (Numeric Rating Scale >4; 14 vs 17%, P=0.81) for patients allocated to morphine 2.5 and 7.5 mg respectively. For procedure-related pain, there was no difference in incidence of unacceptable pain (28 vs 22%, P=0.53) mean pain scores (2.6 [95% confidence interval 2.0 to 3.2] vs 2.7 [95% confidence interval 2.0 to 3.4]) between patients receiving morphine 2.5 and 7.5 mg respectively. In intensive care patients after cardiothoracic surgery with low pain levels for pain at rest, there was no difference in efficacy between intravenous morphine 2.5 mg or morphine 7.5 mg for pain relief during a painful intervention.