Olecranon Osteotomy Exposure for Distal Humeral Fracture Treatment.

Background: Olecranon osteotomy (OO) is commonly utilized to improve exposure when treating intra-articular distal humeral fractures. A chevron-shaped osteotomy facilitates reduction and increases surface area for healing1. Following distal humeral fracture reduction and fixation, the OO fragment is fixed with a precontoured plate. The OO technique yields comparable outcomes to alternative techniques1,2. Description: The technique is performed as follows. (1) Imaging is reviewed and preoperative planning is performed. (2) The patient is positioned in the lateral decubitus position with the operative extremity placed over a bolster. (3) A longitudinal posterior skin incision is centered just medial or lateral to the tip of the olecranon. Full-thickness skin flaps are raised medially and laterally. (4) The ulnar nerve is identified and mobilized for later anterior subcutaneous transposition. (5) An OO is performed at the non-articular "bare area" of the trochlear notch with an oscillating saw and completed with an osteotome. (6) Open reduction and internal fixation of the distal humerus is performed. (7) The osteotomy fragment is reduced, and a precontoured plate is applied. (8) A small longitudinal slit in the distal triceps over the proximal edge of the plate decreases plate prominence and is repaired with suture. (9) The subcutaneous tissues and skin are closed in the usual manner. Alternatives: Alterative techniques include extra-articular OO, triceps splitting, triceps reflecting, and lateral para-olecranon combined with a medial approach. Multiple drill holes and a thin osteotome can help mitigate the kerf created by the oscillating saw. Alternative fixation methods include a predrilled 6.5-mm intramedullary screw, a tension band construct, suture fixation, or a one-third tubular plate. Rationale: The OO technique provides improved exposure when compared with alternative techniques, enabling accurate reduction and fixation of distal humeral fractures1-3. Wilkinson and Stanley found that OO exposed the distal humeral articular surface to a greater degree than the triceps-splitting and triceps-reflecting approaches3. OO has not been associated with triceps weakness, unlike some of the alternative techniques2. Expected Outcomes: The incidence of good-to-excellent outcomes is similar when comparing the techniques for exposure of intra-articular distal humeral fractures4. Osteotomies united in all patients in 2 reported series, totaling 84 cases1,2. Removal of symptomatic hardware used in OO fragment fixation can occur in a small subset of patients1,2. Important Tips: Provisionally size a precontoured plate and fix it on the olecranon to aid in later reduction and fracture fixation.The bare area is the desired position for the OO because of its natural lack of cartilage5,6. This non-articular bare area is located just distal to the deepest portion of the trochlear notch, approximately 2 to 2.5 cm distal to the olecranon tip5,6.An (apex-distal) chevron osteotomy angle of ∼130° will help to keep the osteotomy within the non-articular bare area6.Beginning on the dorsal surface of the ulna, directly posterior to the bare area, an oscillating saw is utilized to create a chevron osteotomy to subchondral bone, perpendicular to the long axis of the ulna5,6.The OO is completed by fracturing through the osteochondral surface, which leaves an irregular chondral cancellous surface that can accurately interdigitate. This facilitates later reduction and stability of the osteotomy.Anatomic articular reduction of the OO is not solely judged on the dorsal cortical bone because of the kerf removed by the saw blade. Instead, examination of the articular surface of the trochlear notch is the primary assessment of reduction.Placement of suture through the proximal portion of the plate aids in the repair of the longitudinal split of the distal triceps.Successful treatment of distal humeral fractures requires accurate reduction and rigid fixation aided by adequate exposure achieved through OO. Acronyms and Abbreviations: ORIF = open reduction and internal fixationOT = occupational therapyHWR = hardware removalK-wire = Kirschner wireROM = range of motion.

Distinct expression patterns of Hedgehog signaling components in mouse gustatory system during postnatal tongue development and adult homeostasis.

The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH ligand SHH, HH receptors, and GLI transcription factors in FP, CVP and FOP in early and late postnatal and adult stages. In adults we also studied the soft palate, and the geniculate and trigeminal ganglia, which extend afferent fibers to the anterior tongue. Shh and Gas1 are the only components that were consistently expressed within taste buds of all three papillae and the soft palate. In the first postnatal week, we observed broad expression of HH signaling components in FP and adjacent, non-taste filiform (FILIF) papillae in epithelium or stroma and tongue muscles. Notably, we observed elimination of Gli1 in FILIF and Gas1 in muscles, and downregulation of Ptch1 in lingual epithelium and of Cdon, Gas1 and Hhip in stroma from late postnatal stages. Further, HH receptor expression patterns in CVP and FOP epithelium differed from anterior FP. Among all the components, only known positive regulators of HH signaling, SHH, Ptch1, Gli1 and Gli2, were expressed in the ganglia. Our studies emphasize differential regulation of HH signaling in distinct postnatal developmental periods and in anterior versus posterior taste organs, and lay the foundation for functional studies to understand the roles of numerous HH signaling components in postnatal tongue development.

Interaction between corticosterone and PER2 in regulating emotional behaviors in the rat.

Circadian rhythms play a prominent role in psychiatric health with disruption in rhythms associated with poor mental health. Corticosterone (CORT) is an important hormone in entraining the biological rhythms of many cells throughout the body and coordinating peripheral rhythms with the central master clock. Here, we tested the hypothesis that excess CORT during the circadian trough would lead to a flattening of period genes (Per1 and Per2) rhythms in limbic brain areas, and thus impact emotional behaviors. Male rats were injected daily with 2.5 mg/kg CORT or vehicle for 21 days at either ZT0 or ZT12 and sucrose preference, open field, and forced swim behaviors measured during the dark phase of the light cycle. After three weeks of injections, a reduction in sucrose preference was observed in animals injected with CORT at ZT0 and the reduction significantly correlated with reductions in Per2 mRNA expression in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). No changes in behavior or period gene expression were observed in animals injected with CORT at ZT12. DsiRNA was used to directly reduce Per2 levels in either the CeA or BNST and behavior was assessed. Despite reductions in Per2 expression in the CeA, no behavioral changes were observed. In contrast, a reduction in Per2 expression in the BNST was sufficient to reduce sucrose preference. The results demonstrate that CORT significantly contributes to the circadian expression of Period genes in certain limbic brain areas and disruption in diurnal CORT or Per2 expression can lead to impaired emotional behavioral responses.

Arthroscopic Versus Open Anterior Shoulder Stabilization: A Prospective Randomized Clinical Trial With 15-Year Follow-up With an Assessment of the Glenoid Being "On-Track" and "Off-Track" as a Predictor of Failure.

BACKGROUND: Recent studies have demonstrated equivalent short-term results when comparing arthroscopic versus open anterior shoulder stabilization. However, none have evaluated the long-term clinical outcomes of patients after arthroscopic or open anterior shoulder stabilization, with inclusion of an assessment of preoperative glenoid tracking. PURPOSE: To compare long-term clinical outcomes of patients with recurrent anterior shoulder instability randomized to open and arthroscopic stabilization groups. Additionally, preoperative magnetic resonance imaging (MRI) studies were used to assess whether the shoulders were "on-track" or "off-track" to ascertain a prediction of increased failure risk. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A consecutive series of 64 patients with recurrent anterior shoulder instability were randomized to receive either arthroscopic or open stabilization by a single surgeon. Follow-up assessments were performed at minimum 15-year follow-up using established postoperative evaluations. Clinical failure was defined as any recurrent dislocation postoperatively or subjective instability. Preoperative MRI scans were obtained to calculate the glenoid track and designate shoulders as on-track or off-track. These results were then correlated with the patients' clinical results at their latest follow-up. RESULTS: Of 64 patients, 60 (28 arthroscopic and 32 open) were contacted or examined for follow-up (range, 15-17 years). The mean age at the time of surgery was 25 years (range, 19-42 years), while the mean age at the time of this assessment was 40 years (range, 34-57 years). The rates of arthroscopic and open long-term failure were 14.3% (4/28) and 12.5% (4/32), respectively. There were no differences in subjective shoulder outcome scores between the treatment groups. Of the 56 shoulders, with available MRI studies, 8 (14.3%) were determined to be off-track. Of these 8 shoulders, there were 2 surgical failures (25.0%; 1 treated arthroscopically, 1 treated open). In the on-track group, 6 of 48 had failed surgery (12.5%; 3 open, 3 arthroscopic [P = .280]). CONCLUSION: Long-term clinical outcomes were comparable at 15 years postoperatively between the arthroscopic and open stabilization groups. The presence of an off-track lesion may be associated with a higher rate of recurrent instability in both cohorts at long-term follow-up; however, this study was underpowered to verify this situation.

Sensitized corticosterone responses do not mediate the enhanced fear memories in chronically stressed rats.

Following a stressful event, the hypothalamus-pituitary-adrenal axis mediates the release of the stress hormone cortisol (corticosterone in rodents; CORT). Elevated CORT binds to glucocorticoid receptors to mediate physiological responses including facilitating memory formation. Previous work from our laboratory demonstrated that male rats exposed to chronic stress demonstrate enhanced contextual fear memories and sensitized CORT responses to subsequent stress exposure; however, this is unknown in female rats. The experiments here tested whether chronic stress enhances fear memory formation in female rats and whether the sensitized CORT response in chronic stress rats contributes to their enhanced fear memory. Studies first examined CORT responses to contextual fear conditioning in male and female rats and examined whether chronic stress enhanced the formation of contextual fear memories 24 h later. Studies then used metyrapone, a CORT synthesis inhibitor, to investigate whether blockade of plasma CORT would eliminate the chronic stress-induced enhancement in contextual fear memory. Results show that female rats have greater CORT responses than males, and chronic stress sensitizes the CORT response to fear conditioning in both sexes. However, female rats do not show enhanced contextual fear memory following chronic stress. Chronically stressed male rats show greater memory acquisition and show greater contextual fear memory 24 h later following fear conditioning. Metyrapone dampens contextual fear memory in all rats but does not eliminate the enhancement in freezing behavior in chronic stress rats. Collectively, these studies indicate sensitized CORT responses in chronically stressed rats is likely not the mechanism by which chronic stress facilitates memory formation.

Neuroendocrine Regulation of Brain Cytokines After Psychological Stress.

There is growing evidence that stress-induced brain cytokines are important in the etiology of depression and anxiety. Here, we review how the neuroendocrine responses to psychological stressors affect the immediate and long-term regulation of inflammatory cytokines within the brain and highlight how the regulation changes across time with repeated stress exposure. In doing so, we report on the percentage of studies in the literature that observed increases in either IL-1ß, TNF-α, or IL-6 within the hypothalamus, hippocampus, or prefrontal cortex after either acute or chronic stress exposure. The key takeaway is that catecholamines and glucocorticoids play critical roles in the regulation of brain cytokines after psychological stress exposure. Central catecholamines stimulate the release of IL-1ß from microglia, which is a key factor in the further activation of microglia and recruitment of monocytes into the brain. Meanwhile, the acute elevation of glucocorticoids inhibits the production of brain cytokines via two mechanisms: the suppression of noradrenergic locus coeruleus neurons and inhibition of the NFκB signaling pathway. However, glucocorticoids and peripheral catecholamines facilitate inflammatory responses to future stimuli by stimulating monocytes to leave the bone marrow, downregulating inhibitory receptors on microglia, and priming inflammatory responses mediated by peripheral monocytes or macrophages. The activation of microglia and the elevation of peripheral glucocorticoid and catecholamine levels are both necessary during times of stress exposure for the development of psychopathologies.

Sex differences in the regulation of brain IL-1ß in response to chronic stress.

Elevations in brain interleukin-1 beta (IL-1ß) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1ß production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: ß-AR) IL-1ß production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the "yin-yang" balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1ß. To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (ß-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1ß mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1ß expression in non-stressed controls but significantly reduced IL-1ß in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1ß in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1ß mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1ß in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1ß indicating the increase in brain IL-1ß following metyrapone treatment was due to increase ß-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL-1ß. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1ß by the norepinephrine-ß-AR pathway, while stress had no effect in the regulation of brain IL-1ß in female rats.

The Influence of Sport-Field Properties on Muscle-Recruitment Patterns and Metabolic Response.

PURPOSE: To investigate different sport-field properties' influence on muscle-recruitment patterns and metabolic response during a series of running and agility drills. METHODS: Eleven male athletes were fitted with a standard multipurpose training shoe. The test protocol consisting of 4 high-intensity trials with 60-s rests between trials performed on 2 fields with different properties. Time-dependent field properties were measured using the American Standards for Testing and Materials protocol (F-1936). A 30-m pretest and posttest sprint determined fatigue and player performance. Electromyography (EMG) recorded muscle activity for vastus medialis, biceps femoris, gastrocnemius medial head, and tibialis anterior, and metabolic activity analyzed maximal oxygen consumption, heart rate, respiratory exchange ratio, metabolic equivalent, and energy expenditure. RESULTS: A difference was calculated for muscle activity across trials (P = .01) for both surfaces. Muscle activity was <13% on the field with less energy return (P = .01). Metabolic components (maximal oxygen consumption, heart rate, respiratory exchange ratio, metabolic equivalent, and energy expenditure) were significantly different across trials (P = .01) but not significantly different between fields. The participants completed the agility course (5.2%) faster on the field with greater energy return, while caloric expenditure was similar between fields. CONCLUSIONS: The findings indicate that field mechanical properties influence muscle-activation patterns. The field demonstrating the greatest magnitude of energy return produces the lowest sprint and agility course times; however, performing on a field exhibiting unfamiliar mechanical properties could cause the athlete to produce atypical movement patterns that might contribute to overuse of the neuromuscular system.

Does Clinical Exam and Ultrasound Compare With MRI Findings When Assessing Tendon Approximation in Acute Achilles Tendon Tears? A Clinical Study.

The purpose of this study was to determine if clinical palpation and ultrasound determination of apposition compares with magnetic resonance imaging (MRI) findings in patients with an acute Achilles tendon rupture. A review of 18 consecutive patients presenting with an acute Achilles tendon tear was performed. All tears were diagnosed by clinical exam and confirmed by ultrasound. Ankles were then plantarflexed to a point where tendon apposition was achieved as determined by palpation and ultrasound. Dorsally based equinus splints were applied, and approximation was reconfirmed by palpation and ultrasound. MRI was performed on all patients for comparison to the exam/ultrasound for any residual gapping after splinting. Demographic and clinical comparisons were made between those with <0.5 cm and ≥0.5 cm of residual gapping found on MRI. Eighteen patients with acute Achilles tears were splinted at a mean of 41° ± 11°, with presumed, complete tendon approximation confirmed with palpation and ultrasound. Post-splinting MRI demonstrated that 9/18 (50%) of these patients had residual gapping at a mean of 2.2 ± 1 cm. Mean time to MRI from splinting was not different between those with gapping (1.3 ± 2 days) and those without (1.2 ± 1 days). No other clinical or demographic differences were observed between these groups. In conclusion, clinical exam and ultrasound did not routinely relate to MRI in assessing tendon approximation after splinting of an acute Achilles tendon tear. For surgeons who use approximation as a determination of nonoperative treatment, varying results can be obtained depending on the clinical utility used.

Return to Duty Following Open Reduction and Internal Fixation of Unstable Ankle Fractures in the Active Duty Population.

INTRODUCTION: Literature on functional outcomes after ankle surgery is for the most part limited to return to sport studies. The purpose of this study was to determine occupational and functional outcomes following operative treatment of unstable ankle fractures in the active duty military population. MATERIALS AND METHODS: All ankle fractures treated with open reduction internal fixation at a single institution from 2013 to 2015 were reviewed. Inclusion criteria included active duty personnel with a single-sided injury requiring operative management. All patients had a minimum of 6 months follow-up. Forty-seven records were reviewed with 43 patients fitting these criteria. Patients were predominantly male (91%) with an average age of 26 years at the time of fracture. Functional outcomes were evaluated using AOFAS and SANE scores. Occupational outcomes were determined in reference to a service member's ability to return to full duty. RESULTS: Of the 43 subjects, 81% (n = 35) returned to active duty. Of the eight individuals who did not return to active duty, six were medically boarded out of the military. Looking at demographic, surgical, and functional variables, only the SANE and AFAOS scores functional outcomes showed a significant correlation with individual return to duty. Individuals who reported less pain and increased functional outcomes had increased return to duty rates. CONCLUSION: This study sought to determine predictors for return to duty within an active duty military population after ORIF of unstable ankle fractures. Given the paucity of military literature on this subject, the end goal was to provide realistic recovery expectations for both injured service members and their command teams. Overall, 81% of patients were able to return to active duty following operative treatment of unstable ankle fractures. There were no associations found between age, gender, military rank, or fracture patterns and return to duty.

Sympathetic nervous system contributes to enhanced corticosterone levels following chronic stress.

Exposure to chronic stress often elevates basal circulating glucocorticoids during the circadian nadir and leads to exaggerated glucocorticoid production following exposure to subsequent stressors. While glucocorticoid production is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis, there is evidence that the sympathetic nervous system can affect diurnal glucocorticoid production by direct actions at the adrenal gland. Experiments here were designed to examine the role of the HPA and sympathetic nervous system in enhancing corticosterone production following chronic stress. Rats were exposed to a four-day stress paradigm or control conditions then exposed to acute restraint stress on the fifth day to examine corticosterone and ACTH responses. Repeated stressor exposure resulted in a small increase in corticosterone, but not ACTH, during the circadian nadir, and also resulted in exaggerated corticosterone production 5, 10, and 20min following restraint stress. While circulating ACTH levels increased after 5min of restraint, levels were not greater in chronic stress animals compared to controls until following 20min. Administration of astressin (a CRH antagonist) prior to restraint stress significantly reduced ACTH responses but did not prevent the sensitized corticosterone response in chronic stress animals. In contrast, administration of chlorisondamine (a ganglionic blocker) returned basal corticosterone levels in chronic stress animals to normal levels and reduced early corticosterone production following restraint (up to 10min) but did not block the exaggerated corticosterone response in chronic stress animals at 20min. These data indicate that increased sympathetic nervous system tone contributes to elevated basal and rapid glucocorticoid production following chronic stress, but HPA responses likely mediate peak corticosterone responses to stressors of longer duration.

Interaction of metabolic stress with chronic mild stress in altering brain cytokines and sucrose preference.

There is growing evidence that metabolic stressors increase an organism's risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight 2-bottle sucrose test (food ad libitum) on Day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1-hr sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to nonstressed controls in an overnight sucrose test, and 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously "resilient" animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta (IL-1ß) expression in limbic brain areas. Although all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared with food-deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1ß while food and water deprivation only increased hypothalamus IL-1ß in stress-susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses.

Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion.

Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (ß-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and ß-AR signaling within the amygdala, which led to the hypothesis that some stress-induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety-like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making.

Beta-adrenergic receptor activation primes microglia cytokine production.

Exaggerated pro-inflammatory cytokine production by primed microglia is thought to mediate pathology during stress, aging, and neurodegeneration. Recently, it was demonstrated that beta-adrenergic receptor (ß-AR) antagonism prevents priming of microglia in mice exposed to chronic stress. To determine if ß-AR stimulation is sufficient to prime microglia, rats were intra-cerebroventricularly administered isoproterenol (ß-AR agonist) or vehicle and 24 h later hippocampal microglia were placed in culture with media or LPS. Prior isoproterenol treatment significantly enhanced IL-1ß and IL-6, but not TNF-α production following LPS stimulation. These data suggest that central ß-AR stimulation is sufficient to prime microglia cytokine responses.

Repeated stressor exposure regionally enhances beta-adrenergic receptor-mediated brain IL-1ß production.

It has been proposed that increased brain cytokines during repeated stressor exposure can contribute to neuropathological changes that lead to the onset of depression. Previous studies demonstrate that norepinephrine acting via beta-adrenergic receptors (ß-ARs) mediate brain IL-1 production during acute stressor exposure. The aim of the current studies was to examine how the regulation of brain cytokines by adrenergic signaling might change following repeated stressor exposure. Fischer rats were exposed to four days of chronic mild stress and 24h after the last stressors ß-AR expression, norepinephrine turnover, and ß-AR-mediated induction of brain IL-1 were measured in limbic areas (e.g. hypothalamus, hippocampus, amygdala, and prefrontal cortex) and brainstem. Repeated stressor exposure resulted in decreases in ß-AR expression (B(max)) measured by saturation binding curves in many limbic brain areas, while an increase was observed in the brainstem. This coincided with significant increases in norepinephrine turnover in the prefrontal cortex, hypothalamus, and amygdala, a significant increase in norepinephrine turnover was not observed in the hippocampus or brainstem. Stress increased overall IL-1 production in the amygdala (both basal and stimulated). While stress did not affect basal IL-1 levels in any other brain area, central administration of isoproterenol (a ß-AR agonist) augmented IL-1 production in the hypothalamus of stressed animals. These data indicate that repeated stressor exposure results in brain area specific enhancements in ß-AR-mediated IL-1 production and extends current knowledge of stress-induced enhancement of brain cytokine beyond sensitized response to immunological stimuli.

Fear conditioning can contribute to behavioral changes observed in a repeated stress model.

Repeated exposure to laboratory stressors often results in behavioral changes that are commonly referred to as depressive-like behaviors. Here, we examined the contribution fear conditioning may play in altering an animals' behavior in a repeated stress paradigm. Fischer rats were exposed daily to different stressors in a complex environment (context A). After four days of stressor exposure, exploratory behavior (10 min in new cage) and social interaction (5 min with juvenile) were tested on day 5 in either the same environment or a new environment (context B). Rats showed decreased exploration and social interaction when tested in context A compared to control rats or rats tested in context B. Additionally, chronic infusion of propranolol (beta-adrenergic receptor antagonist that crosses the blood-brain barrier), but not nadolol (beta-adrenergic receptor antagonist that does not readily cross the blood-brain barrier), prevented the behavioral changes following repeated stressor exposure. Propranolol treatment did not affect the acute or chronic elevation of corticosterone, the decrease in body weight gain, or adrenal hypertrophy observed in animals exposed to stress. These data demonstrate that conditioned fear responses can contribute to behavioral changes in a repeated stress paradigm. Additional studies revealed, Sprague-Dawley rats do not demonstrate decreased exploration or social interaction when testing occurs in the same context as repeated stressor exposure suggesting Fischer rats may have a greater propensity to associate distal cues with aversive events in a complex environment. This may be due to greater stress responses in Fischer animals that are known to enhance consolidation of emotionally arousing events.

Stress-induced facilitation of host response to bacterial challenge in F344 rats is dependent on extracellular heat shock protein 72 and independent of alpha beta T cells.

Activation of the in vivo stress response can facilitate antibacterial host defenses. One possible mechanism for this effect is stress-induced release of heat shock protein 72 (Hsp72) into the extracellular environment. Hsp72 is a ubiquitous cellular protein that is up-regulated in response to cellular stress, and modulates various aspects of immune function including macrophage inflammatory/bactericidal responses and T-cell function when found in the extracellular environment. The current study tested the hypothesis that in vivo extracellular Hsp72 (eHsp72) at the site of inflammation contributes to stress-induced restricted development of bacteria, and facilitated recovery from bacteria-induced inflammation, and that this effect is independent of alpha beta (αß) T cells. Male F344 rats were exposed to either inescapable electrical tail-shocks or no stress, and subcutaneously injected with Escherichia coli (ATCC 15746). The role of eHsp72 was investigated by Hsp72-immunoneutralization at the inflammatory site. The potential contribution of T cells was examined by testing male athymic (rnu/rnu) nude rats lacking mature αß T cells and heterozygous thymic intact control (rnu/+) rats. The results were that stressor exposure increased plasma concentrations of eHsp72 and facilitated recovery from bacterial inflammation. Immunoneutralization of eHsp72 at the inflammatory site attenuated this effect. Stressor exposure impacted bacterial inflammation and eHsp72 equally in both athymic and intact control rats. These results support the hypothesis that eHsp72 at the site of inflammation, and not αß T cells, contributes to the effect of stressor exposure on subcutaneous bacterial inflammation.

Prior laparotomy or corticosterone potentiates lipopolysaccharide-induced fever and sickness behaviors.

Stimulating sensitized immune cells with a subsequent immune challenge results in potentiated pro-inflammatory responses translating into exacerbated sickness responses (i.e. fever, pain and lethargy). Both corticosterone (CORT) and laparotomy cause sensitization, leading to enhanced sickness-induced neuroinflammation or pain (respectively). However, it is unknown whether this sensitization affects all sickness behaviors and immune cell responses equally. We show that prior CORT and prior laparotomy potentiated LPS-induced fever but not lethargy. Prior CORT, like prior laparotomy, was able to potentiate sickness-induced pain. Release of nitric oxide (NO) from peritoneal macrophages stimulated ex vivo demonstrates that laparotomy, but not CORT sensitizes these cells.