Striatal patch compartment lesions reduce stereotypy following repeated cocaine administration.

Stereotypy can be characterized as inflexible, repetitive behaviors that occur following repeated exposure to psychostimulants, such as cocaine (COC). Stereotypy may be related to preferential activation of the patch (striosome) compartment of striatum, as enhanced relative activation of the patch compartment has been shown to positively correlate with the emergence of stereotypy following repeated psychostimulant treatment. However, the specific contribution of the patch compartment to COC-induced stereotypy following repeated exposure is unknown. To elucidate the involvement of the patch compartment to the development of stereotypy following repeated COC exposure, we determined if destruction of this sub-region altered COC-induced behaviors. The neurons of the patch compartment were ablated by bilateral infusion of the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/µl) into the striatum. Animals were allowed to recover for eight days following the infusion, and then were given daily injections of COC (25mg/kg) or saline for one week, followed by a weeklong drug-free period. Animals were then given a challenge dose of saline or COC, observed for 2h in activity chambers and sacrificed. The number of mu-labeled patches in the striatum were reduced by DERM-SAP pretreatment. In COC-treated animals DERM-SAP pretreatment significantly reduced the immobilization and intensity of stereotypy but increased locomotor activity. DERM-SAP pretreatment attenuated COC-induced c-Fos expression in the patch compartment, while enhancing COC-induced c-Fos expression in the matrix compartment. These data indicate that the patch compartment contributes to repetitive behavior and suggests that alterations in activity in the patch vs matrix compartments may underlie to this phenomenon.

D-Amphetamine withdrawal-induced decreases in brain-derived neurotrophic factor in sprague-dawley rats are reversed by treatment with ketamine.

Withdrawal from chronic D-amphetamine (D-AMPH) can induce negative emotional states, which may contribute to relapse and the maintenance of addiction. Diminished levels of brain-derived neurotrophic factor (BDNF), particularly in the hippocampus has been observed after exposure to stress, and recent data indicate that treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine may reverse these changes. However, it is unclear whether BDNF levels in the hippocampus or other regions of the limbic system are altered following the stress of D-AMPH withdrawal and it is not currently known if treatment with ketamine has any effect on these changes. The goals of this study were to examine BDNF levels throughout the limbic system following D-AMPH withdrawal and determine whether ketamine treatment would alter D-AMPH-induced changes in BDNF. Sprague-Dawley rats were treated with D-AMPH and BDNF protein examined in the prefrontal cortex, nucleus accumbens, amygdala and hippocampus at 24 h and 4 days of withdrawal. Our data show that at 24 h post-D-AMPH, BDNF levels were increased in the nucleus accumbens and decreased in the hippocampus. At 4 d post-D-AMPH, BDNF protein levels were decreased in all areas examined, and these decreases were reversed by treatment with ketamine. These data suggest that diminished BDNF may contribute to the negative affect seen following D-AMPH withdrawal, and that ketamine treatment could offer relief from these symptoms.

Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells.

Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.

Striatal patch compartment lesions alter methamphetamine-induced behavior and immediate early gene expression in the striatum, substantia nigra and frontal cortex.

Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/µl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c-Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon.

Stress and withdrawal from d-amphetamine alter 5-HT2A receptor mRNA expression in the prefrontal cortex.

Psychostimulant withdrawal results in emotional, behavioral, and cognitive impairments, which may be exacerbated by stress. However, little is known about the neurochemical changes that occur when these two conditions are experienced concomitantly. 5-HT2A receptor (5-HT2AR) mRNA expression in the prefrontal cortex (PFC) is diminished following withdrawal from d-amphetamine (AMPH) and may underlie the emotional and cognitive impairments observed in psychostimulant withdrawal, but whether stress affects 5-HT2AR mRNA expression during psychostimulant withdrawal is unknown. The goal of this study was to examine the impact of forced swim test (FST) exposure during AMPH withdrawal on 5-HT2AR mRNA expression in PFC. Animals were treated 3 times a day for 4 days with escalating doses of AMPH (1-10mg/kg) and 24h or 4 days after the final injection, animals were subjected to FST. At 24h of withdrawal, AMPH-treated animals showed greater immobility in FST and at 4 days of withdrawal, AMPH-treated animals did not show immobility. At 24h of withdrawal, animals showed lower 5-HT2AR mRNA expression in the PFC relative to saline-treated animals, and exposure to FST did not further decrease expression in these animals. At 4 days of withdrawal, AMPH-treated animals showed greater 5-HT2AR mRNA expression relative to saline-treated animals in the PFC, an effect that was diminished by exposure to FST. These data indicate that stress and short-term AMPH withdrawal affect prefrontal 5-HT2AR mRNA expression to a similar degree, and stress experienced during long-term AMPH withdrawal can diminish the recovery of 5-HT2AR mRNA expression. Together, these data suggest that exposure to stress during extended AMPH withdrawal could prolong withdrawal-induced, 5-HT2AR mRNA expression which could be related to 5-HT2AR mediated deficits.

Incidence of revision adenoidectomy in children.

OBJECTIVE/HYPOTHESIS: Adenoidectomy is a frequently performed procedure in the pediatric population. Revision rates and indications for a second procedure in children are scarce. STUDY DESIGN: Retrospective cohort study. METHODS: Patient records at a multistate pediatric healthcare system were searched for all CPT codes that included adenoidectomy in children less than 12 years of age for a 5-year period (2005-2010). A subset of patients was identified for whom the same CPT codes appeared more than once in this 5-year period. The indication, age, gender, adenoid size, and technique of adenoidectomy were recorded. RESULTS: A total of 23,612 occurrences of the CPT codes were identified. The subset of patients with multiple CPT codes, indicating revision adenoidectomy, included 304 records (1.3%). Mean age at first procedure was 2.8 years (SD = 1.7 years). Mean age at second procedure was 4.7 years (SD = 1.99 years). Mean interval between procedures was 1.8 years (SD = 1.1 years). CONCLUSIONS: Revision adenoidectomy occurs at a rate of 1.3%. Reasons for revision include persistence symptoms ranging from adenoiditis to recurrent otitis to obstructive sleep apnea.

Reconstruction of the radial forearm free flap donor site using integra artificial dermis.

Autologous skin grafting to the donor site in patients who undergo radial forearm free flap reconstruction (RFFF) is associated with cosmetic and functional morbidity. Integra artificial dermis (Integra Lifesciences, Plainsboro, NJ) is a bovine collagen based dermal substitute that can be used as an alternative to primary autologous skin transplantation of the donor site. We describe a staged reconstruction using Integra followed by ultrathin skin grafting that results in highly aesthetic and functional outcomes for these defects. A retrospective review of 29 patients undergoing extirpative head and neck oncologic resection were examined. Integra graft placement was performed at the time of RFFF harvest followed by autologous split thickness skin grafting at 1 to 5 weeks postoperatively. Healing fully occurred within 4-6 weeks with negligible donor site complications, excellent cosmesis, and minimal scar contracture. Composite reconstruction with Integra artificial dermis offers advantages over traditional methods of coverage for select cases of radial forearm free flap donor site closures.

Degrees of dysplasia and the use of cidofovir in patients with recurrent respiratory papillomatosis.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a benign disease characterized by recurrent lesions in the airway. The prevalence and degree of dysplasia that is present in the natural course of RRP is not well established. Adjuvant therapies, such as cidofovir, have been tried with the goal of decreasing the interval between repeat surgical treatments, the mainstay of therapy. Although, the off-label use of cidofovir to treat RRP has been common, there have been concerns regarding carcinogenic transformation following the use of cidofovir. This study aims to explore the association between increasing degree of papilloma dysplasia and the use of cidofovir in the context of the natural progression of dysplasia in RRP. STUDY DESIGN: Retrospective case series. METHODS: Demographic data and surgical history were obtained through chart reviews for this retrospective case series of 13 patients with RRP who had histopathologic biopsies done before and after exposure to cidofovir. Pathologic data collected over 10 years from serial excisions at the University of Iowa Hospitals were reviewed by a single pathologist, and the highest degree of dysplasia was noted per excision time. RESULTS: Of the 176 specimens collected in these 13 patients with serial papilloma biopsies, 5.7% had no dysplasia, 57.4% had mild dysplasia (grade 1), 28.4% had moderate dysplasia (grade 2), and 8.5% had severe dysplasia (grade 3). A comparison of each patient's multiple biopsies across time suggested that the dysplastic grade was worse in two patients, better in four patients, and virtually unchanged in seven patients. There was no clear-cut pattern between the use of cidofovir and the degree of dysplasia over time. CONCLUSIONS: These results strongly suggest that intralesional cidofovir therapy does not correlate with worsening dysplastic progression. Dysplasia is relatively common in the setting of RRP; however, the prognostic significance of this finding is unknown. Additional research is needed to delineate the natural progression of dysplasia and its clinical significance in RRP, as well as the efficacy of cidofovir.

Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report.

Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.