Increased Risk of Surgical Field Contamination from Acute Pre-operative Treatment of Pediculosis Capitis (Lice) Infestation - A Case Report of Two Twin Pediatric Patients.

Introduction: Little is known about the perioperative management of Pediculus capitis (lice) infestations, including risk of contamination to the sterile field, whether to delay surgery, and optimal time to treat and/or operate. Case Report: Two identical twin patients presented for elective in situ percutaneous pinning of chronic slipped capital femoral epiphyses. Active pediculosis capitis was noted intraoperatively by the anesthesia team during the first patient's surgery. Meticulous examination of the sterile field at that time demonstrated no organisms or other sources of contamination. The second patient's surgery was delayed to discuss her case with the infectious disease team. Scant literature exists to guide recommendations. Ultimately, a single permethrin treatment immediately before surgery was recommended and followed by our team. After careful prepping and draping, a louse was observed on the sterile field near the planned pin insertion site. The case was immediately canceled and delayed indefinitely. After two additional treatments over the next 4 days, only eggs (but no active insects) were observed in the patient's hair. We elected to proceed to surgery at that time, which concluded without issue. Conclusion: The surgical implications of an active lice infestation are numerous. Administration of antiparasitic medication in the immediate pre-operative period causes increased movement in pediculosis capitis, which may increase risk of sterile field contamination. Elective procedures should be postponed to complete multiple rounds of permethrin. In cases of urgent/emergent surgery, or in which treatment delay is unfeasible, foregoing delousing treatment in the immediate pre-operative period may be recommended.

Suture Anchor-Based Quadriceps Tendon Repair May Result in Improved Patient-Reported Outcomes but Similar Failure Rates Compared to the Transosseous Tunnel Technique.

PURPOSE: The purpose of this study was to compare failure rates and patient-reported outcomes between transosseus (TO) suture and suture anchor (SA) quadriceps tendon repairs. METHODS: Following institutional review board approval, patients who underwent primary repair for quadriceps tendon rupture with TO or SA techniques between January 2009 and August 2018 were identified from an institutional database and retrospectively reviewed. Patients were contacted for satisfaction (1-10 scale), current function (0-100 scale), failure (retear), and revision surgeries; International Knee Documentation Committee (IKDC) score and Knee Injury and Osteoarthritis Outcomes Score (KOOS) were also collected to achieve a minimum of 2-year follow-up. RESULTS: Sixty-four patients (34 SA, 30 TO) were available by phone or e-mail at a mean of 4.81 ± 2.60 years postoperatively. There were 10 failures, for an overall failure rate of 15.6%. Failure incidence did not significantly differ between treatment groups (P = .83). Twenty-seven patients (47% of nonfailed patients) had completed patient-reported outcomes. The SA group reported higher subjective function (SA: 90 [85-100] vs TO: 85 [60-93], 95% CI of difference: -19.9 to -2.1 × 10-5, P = .042), final IKDC (79.6 [50.0-93.6] vs 62.1 [44.3-65.5], 95% CI of difference: -33.0 to -0.48, P = .048), KOOS Pain (97.2 [84.7-97.2] vs 73.6 [50.7-88.2], 95% CI of difference: -36.1 to -3.6 × 10-5, P = .037), Quality of Life (81.3 [56.3-93.8] vs 50.0 [23.4-56.3], 95% CI of difference: -50.0 to -6.2, P = .026), and Sport (75.0 [52.5-90.0] vs 47.5 [31.3-67.5], 95% CI of the difference: -45.0 to -4.1 × 10-5, P = .048). CONCLUSIONS: There is no significant difference in failure rate between transosseus and suture anchor repairs for quadriceps tendon ruptures (P = .83). Most failures occur secondary to a traumatic reinjury within the first year postoperatively. Despite the lack of difference in failure rates, at final follow-up, patients who undergo suture anchor repair may report significantly greater subjective function and final IKDC, KOOS Pain, Quality of Life, and Sport scores. LEVEL OF EVIDENCE: III, retrospective cohort study.

Cav1.3 L-type Ca2+ channel-activated CaMKII/ERK2 pathway in the ventral tegmental area is required for cocaine conditioned place preference.

We have previously demonstrated that pharmacological blockade of ventral tegmental area (VTA) Cav1.3 L-type calcium channels (LTCCs) using Cav1.2 dihydropyridine insensitive (Cav1.2DHP-/-) mutant mice attenuates cocaine conditioned place preference (CPP). However, the molecular mechanisms by which Cav1.3 channels mediate the effects of cocaine in the VTA remain largely unknown. In this study using Cav1.2DHP-/- male mice, we find that cocaine place preference increases CaM kinase IIα, ERK2, and CREB phosphorylation in the VTA, proteins strongly linked to cocaine behaviors. To further explore the causal role of these intracellular signaling proteins in cocaine preference, the CaM kinase II inhibitor, KN93 was directly injected into the VTA of male mice before each cocaine conditioning session. We found that KN93 attenuates conditioned preference for cocaine compared to vehicle treated mice and decreased VTA ERK2 and CREB phosphorylation. Additionally, blockade of the ERK pathway with the MEK inhibitor, U0126 or knockdown of ERK2 using siRNA, attenuated cocaine preference and VTA CREB phosphorylation but not CaMKIIα phosphorylation, suggesting that ERK is activated downstream of CaMKIIα. Examination of postsynaptic density (PSD) GluA1 subunit of AMPA receptors in the nucleus accumbens (NAc) that we have previously shown to be upregulated following long withdrawal periods, was blunted by KN93, U0126 and ERK2 siRNA when examined 30 days following cocaine CPP. Taken together, these findings demonstrate that Cav1.3 channels in the VTA are required for cocaine reward behavior and activation of the CaMKIIα/ERK/CREB signaling pathway in the VTA is necessary for long-lasting changes in the NAc. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'.

Spin in the Abstracts of Meta-analyses and Systematic Reviews: Midshaft Clavicle Fracture.

OBJECTIVES: Spin is a reporting bias that presents the beneficial effect of an experimental treatment as greater than what is found in the results of the study. This bias can result in patient care recommendations that are more subjective than objective. The purpose of this study is to identify the prevalence of spin in meta-analysis and systematic review abstracts regarding treatment of midshaft clavicle fractures. METHODS: Electronic libraries (MEDLINE, Embase, Web of Science, Google Scholar) were systematically searched. Meta-analyses and systematic reviews regarding treatment of midshaft clavicular fractures were analyzed. The nine most severe types of spin commonly found in abstracts were used as an evaluation tool to assess the articles. Other variables analyzed include year of publication, journal impact factor, number of citations, and methodologic quality according to A Measurement Tool to Assess Systematic Reviews (AMSTAR-2). RESULTS: The database search resulted in 401 articles, of which 53 met inclusion criteria. After review, it was found that 52.8% (28/53) of the included articles contained spin within the abstract. Of the nine most severe types of spin found in abstracts, type 3 spin ("selective reporting of or overemphasis on efficacy outcomes or analysis favoring the beneficial effect of the experimental intervention") was found to be the most prevalent 28.3% (15/53). CONCLUSION: This study demonstrated the presence of spin in the majority of meta-analyses and systematic review abstracts pertaining to midshaft clavicular fractures. Orthopedic surgeons should be aware and recognize spin as they review articles when deciding the treatment course for such injuries. LEVEL OF EVIDENCE: Level 3. See Instructions for Authors for a complete description of levels of evidence.

COPD Overdiagnosis and Its Effect on 30-Day Hospital Readmission Rates.

BACKGROUND: Although specific guidelines exist for diagnosing COPD on the basis of spirometry testing data (FEV1/FVC < 0.70 or above the lower limit of normal), the literature suggests that overdiagnosis is common. Whether overdiagnosis increases 30-d readmission rates has not yet been explored. The objective of this study was to determine the prevalence of COPD overdiagnosis and its effect on 30-d hospital readmission rates in our institution. METHODS: We retrospectively identified all subjects who were coded with a COPD hospital discharge in 2018 at Cleveland Clinic main campus and had spirometry data available, including FEV1 and FVC. FEV1/FVC was calculated and compared with the predicted lower limit of normal values. Hospital discharge diagnosis and 30-d hospital readmission data were captured along with comorbidities and other demographics. RESULTS: In 2018, there were 424 hospital discharges with a COPD diagnosis with spirometry testing available. Of these subjects, 124 (29%) were overdiagnosed in the lower limit of normal group and 99 (23.3%) were in the ≥ 0.70 group. One hundred subjects (23.6%) had a 30-d hospital readmission. Of these subjects, 35 had FEV1/FVC that was greater than their predicted lower limit of normal on spirometry. Of the 324 subjects who were not readmitted within 30 d, 89 (27.5%) had FEV1/FVC greater than the lower limit of normal. If the 35 readmitted subjects had not been coded with COPD, the 30-d readmission rate would have decreased significantly from 23.6% to 16.7% (100 of 424 vs 65 of 389, P = .01). Even if all of the 124 subjects who had pulmonary function test data greater than the lower limit of normal had not been counted, the readmission rate would still have decreased from 23.6% to 21.7%, but this was not significant (from 100 of 424 to 65 of 300, P = .3). CONCLUSIONS: COPD was overdiagnosed in our cohort of subjects; this was true whether the FEV1/FVC < 0.70 standard or the lower limit of normal standard was used. Furthermore, this overdiagnosis artificially inflated the 30-d readmission rate. These results illustrate the caution providers should use when making a COPD diagnosis.

Loss of Cav1.2 channels impairs hippocampal theta burst stimulation-induced long-term potentiation.

CACNA1 C, which codes for the Cav1.2 isoform of L-type Ca2+ channels (LTCCs), is a prominent risk gene in neuropsychiatric and neurodegenerative conditions. A role forLTCCs, and Cav1.2 in particular, in transcription-dependent late long-term potentiation (LTP) has long been known. Here, we report that elimination of Cav1.2 channels in glutamatergic neurons also impairs theta burst stimulation (TBS)-induced LTP in the hippocampus, known to be transcription-independent and dependent on N-methyl D-aspartate receptors (NMDARs) and local protein synthesis at synapses. Our expansion of the established role of Cav1.2channels in LTP broadens understanding of synaptic plasticity and identifies a new cellular phenotype for exploring treatment strategies for cognitive dysfunction.

Electronic inhaler monitoring and healthcare utilization in chronic obstructive pulmonary disease.

INTRODUCTION: The effect of electronic inhaler monitoring (EIM) on healthcare utilization in chronic obstructive pulmonary disease (COPD) has not been studied. We hypothesized that the use of EIM in conjunction with a disease management program reduces healthcare utilization in patients with COPD. METHODS: This is a retrospective pre- and post-analysis of a quality improvement project. Patients with COPD and high healthcare utilization (≥one hospitalization or emergency room visit during the year prior to enrolment) were provided with electronic monitoring devices for monitoring controller and rescue inhaler utilization for one year. Patients were contacted when alerts were triggered, indicating suboptimal adherence to controller inhaler or increased use of rescue inhalers, potentially signalling an impending exacerbation. Healthcare utilization was assessed pre- and post-monitoring, with each subject serving as his/her own control. RESULTS: Patients with COPD and high healthcare utilization (n = 39) were recruited. Mean EIM duration was 280.5 (±120.6) days. The mean age was 68.6 (±9.9) years, FEV1 (mean forced expiratory volume in one second) was 1.1 (±0.4) L, and mean Charlson Comorbidity index was 5.6 (±2.7). Average adherence was 44.4% (28.4%). Compared with the year prior to enrolment, EIM was associated with a reduction in COPD-related healthcare utilization per year (2.2 (±2.3) versus 3.4 (±3.2), p = 0.01). Although there was a reduction in all-cause healthcare utilization, this was not statistically significant (3.4 (±2.6) versus 4.7 (±4.1), p = 0.06). DISCUSSION: EIM in conjunction with a disease management program may play a role in reducing healthcare utilization in COPD patients with a history of high healthcare utilization.

Arthroscopically Repaired Bucket-Handle Meniscus Tears: Patient Demographics, Postoperative Outcomes, and a Comparison of Success and Failure Cases.

OBJECTIVE: To define patient demographics, preoperative, and intraoperative surgical variables associated with successful or failed repair of bucket-handle meniscal tears. DESIGN: All patients who underwent arthroscopic repair of a bucket-handle meniscus tear at a single institution between May 2011 and July 2016 with minimum 6-month follow-up were retrospectively identified. Patient demographic, preoperative (including imaging), and operative variables were collected and evaluated. A Kaplan-Meier curve was generated to demonstrate meniscus repair survivorship. RESULTS: In total, 75 patients (78 knees) with an average age of 26.53 ± 10.67 years met inclusion criteria. The average follow-up was 23.41 ± 16.43 months. Fifteen knees (19.2%) suffered re-tear of the repaired meniscus at an average 12.24 ± 9.50 months postoperatively. Survival analysis demonstrated 93.6% survival at 6 months, 84.6% survival at 1 year, 78.4% survival at 2 years, and 69.9% survival at 3 years. There was significant improvement from baseline to time of final follow-up in all patient-reported outcome (P < 0.05) except Marx score (P = 0.933) and SF-12 Mental Subscale (P = 0.807). The absence of other knee pathology (including ligament tear, contralateral compartment meniscal tear, or cartilage lesions) noted intraoperatively was the only variable significantly associated with repair failure (P = 0.024). Concurrent anterior cruciate ligament reconstruction (vs. no concurrent anterior cruciate ligament reconstruction) trended toward significance (P = 0.059) as a factor associated with successful repair. CONCLUSIONS: With the exception of the absence of other knee pathology (including ligament tear, contralateral compartment meniscal tear, or cartilage lesions) noted intraoperatively, no other variables were significantly associated with re-tear. The results are relatively durable with 84.6% survival at 1 year. Surgeons should attempt meniscal repair when presented with a bucket-handle tear.

JC virus infection of meningeal and choroid plexus cells in patients with progressive multifocal leukoencephalopathy.

JC virus (JCV) can cause a lytic infection of oligodendrocytes and astrocytes in the central nervous system (CNS) leading to progressive multifocal leukoencephalopathy (PML). JCV can also infect meningeal and choroid plexus cells causing JCV meningitis (JCVM). Whether JCV also infects meningeal and choroid plexus cells in PML patients and other immunosuppressed individuals with no overt symptoms of meningitis remains unknown. We therefore analyzed archival formalin-fixed, paraffin-embedded brain samples from PML patients, and HIV-seropositive and seronegative control subjects by immunohistochemistry for the presence of JCV early regulatory T Ag and JCV VP1 late capsid protein. In meninges, we detected JCV T Ag in 11/48 (22.9%) and JCV VP1 protein in 8/48 (16.7%) PML patients. In choroid plexi, we detected JCV T Ag in 1/7 (14.2%) and JCV VP1 protein in 1/8 (12.5%) PML patients. Neither JCV T Ag nor VP1 protein could be detected in meninges or choroid plexus of HIV-seropositive and HIV-seronegative control subjects without PML. In addition, examination of underlying cerebellar cortex of PML patients revealed JCV-infected cells in the molecular layer, including GAD 67+ interneurons, but not in HIV-seropositive and HIV-seronegative control subjects without PML. Our findings suggest that productive JCV infection of meningeal cells and choroid plexus cells also occurs in PML patients without signs or symptoms of meningitis. The phenotypic characterization of JCV-infected neurons in the molecular layer deserves further study. This data provides new insight into JCV pathogenesis in the CNS.

Reduction of the expression of the late-onset Alzheimer's disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model.

Alzheimer's disease (AD) is pathologically characterized by the deposition of the ß-amyloid (Aß) peptide in senile plaques in the brain, leading to neuronal dysfunction and eventual decline in cognitive function. Genome-wide association studies have identified the bridging integrator 1 (BIN1) gene within the second most significant susceptibility locus for late-onset AD. BIN1 is a member of the amphiphysin family of proteins and has reported roles in the generation of membrane curvature and endocytosis. Endocytic dysfunction is a pathological feature of AD, and endocytosis of the amyloid precursor protein is an important step in its subsequent cleavage by ß-secretase (BACE1). In vitro evidence implicates BIN1 in endosomal sorting of BACE1 and Aß generation in neurons, but a role for BIN1 in this process in vivo is yet to be described. Here, using biochemical and immunohistochemistry analyses we report that a 50% global reduction of BIN1 protein levels resulting from a single Bin1 allele deletion in mice does not change BACE1 levels or localization in vivo, nor does this reduction alter the production of endogenous murine Aß in nontransgenic mice. Furthermore, we found that reduction of BIN1 levels in the 5XFAD mouse model of amyloidosis does not alter Aß deposition nor behavioral deficits associated with cerebral amyloid burden. Finally, a conditional BIN1 knockout in excitatory neurons did not alter BACE1, APP, C-terminal fragments derived from BACE1 cleavage of APP, or endogenous Aß levels. These results indicate that BIN1 function does not regulate Aß generation in vivo.

Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates with Tau pathology. In contrast, the loss of BIN1 expression in cultured cells elevates Aß production and Tau propagation by insfluencing endocytosis and recycling. Here, we show that BIN1 accumulates adjacent to amyloid deposits in vivo. We found an increase in insoluble BIN1 and a striking accrual of BIN1 within and near amyloid deposits in the brains of multiple transgenic models of AD. The peri-deposit aberrant BIN1 localization was conspicuously different from the accumulation of APP and BACE1 within dystrophic neurites. Although BIN1 is highly expressed in mature oligodendrocytes, BIN1 association with amyloid deposits occurred in the absence of the accretion of other oligodendrocyte or myelin proteins. Finally, super-resolution microscopy and immunogold electron microscopy analyses highlight the presence of BIN1 in proximity to amyloid fibrils at the edges of amyloid deposits. These results reveal the aberrant accumulation of BIN1 is a feature associated with AD amyloid pathology. Our findings suggest a potential role for BIN1 in extracellular Aß deposition in vivo that is distinct from its well-characterized function as an adaptor protein in endocytosis and membrane remodeling.

Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase-mTORC1 Translational Pathway.

A homozygous nonsense mutation in the cereblon (CRBN) gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male Crbn knock-out (CrbnKO) mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knock-out of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior. Cellular studies identify deficits in long-term potentiation at Schaffer collateral CA1 synapses. We further show that Crbn is robustly expressed in the mouse hippocampus and CrbnKO mice exhibit hyperphosphorylated levels of AMPKα (Thr172). Examination of processes downstream of AMP-activated protein kinase (AMPK) finds that CrbnKO mice have a selective impairment in mediators of the mTORC1 translation initiation pathway in parallel with lower protein levels of postsynaptic density glutamatergic proteins and higher levels of excitatory presynaptic markers in the hippocampus with no change in markers of the unfolded protein response or autophagy pathways. Acute pharmacological inhibition of AMPK activity in adult CrbnKO mice rescues learning and memory deficits and normalizes hippocampal mTORC1 activity and postsynaptic glutamatergic proteins without altering excitatory presynaptic markers. Thus, this study identifies that loss of Crbn results in learning, memory, and synaptic defects as a consequence of exaggerated AMPK activity, inhibition of mTORC1 signaling, and decreased glutamatergic synaptic proteins. Thus, CrbnKO mice serve as an ideal model of intellectual disability to further explore molecular mechanisms of learning and memory.SIGNIFICANCE STATEMENT Intellectual disability (ID) is one of the most common neurodevelopmental disorders. The cereblon (CRBN) gene has been linked to autosomal recessive, nonsyndromic ID, characterized by an intelligence quotient between 50 and 70 but devoid of other phenotypic features, making cereblon an ideal protein for the study of the fundamental aspects of learning and memory. Here, using the cereblon knock-out mouse model, we show that cereblon deficiency disrupts learning, memory, and synaptic function via AMP-activated protein kinase hyperactivity, downregulation of mTORC1, and dysregulation of excitatory synapses, with no changes in social or repetitive behaviors, consistent with findings in the human population. This establishes the cereblon knock-out mouse as a model of pure ID without the confounding behavioral phenotypes associated with other current models of ID.

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. ß-Amyloid peptides (Aß), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. ß-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Aß production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state Aß levels were similar, synaptic activity-induced endogenous Aß production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.

Impact of a Post-Discharge Integrated Disease Management Program on COPD Hospital Readmissions.

BACKGROUND: Readmission following a hospitalization for COPD is associated with significant health-care expenditure. METHODS: A multicomponent COPD post-discharge integrated disease management program was implemented at the Cleveland Clinic to improve the care of patients with COPD and reduce readmissions. This retrospective study reports our experience with the program. Groups of subjects who were exposed to different components of the program were compared regarding their readmission rates. Multivariate logistic regression analysis was performed to build predictive models for 30- and 90-d readmission. RESULTS: One hundred sixty subjects completed a 90-d follow-up, of which, 67 attended the exacerbation clinic, 16 subjects received care coordination, 51 subjects completed both, and 26 subjects did not participate in any component despite referral. Thirty- and 90-d readmission rates for the entire group were 18.1 and 46.2%, respectively. Thirty- and 90-d readmission rates for the individual groups were: exacerbation clinic, 11.9 and 35.8%; care coordination, 25.0 and 50.0%; both, 19.6 and 41.2%; and neither, 26.9 and 80.8%, respectively. The model with the best predictive ability for 30-d readmission risk included the number of hospitalizations within the previous year and use of noninvasive ventilation (C statistic of 0.84). The model for 90-d readmission risk included receiving any component of the post-discharge integrated disease management program, the number of hospitalizations, and primary care physician visits within the previous year (C statistic of 0.87). CONCLUSIONS: Receiving any component of a post-discharge integrated disease management program was associated with reduced 90-d readmission rate. Previous health-care utilization and lung function impairment were strong predictors of readmission.

Altered reward sensitivity in female offspring of cocaine-exposed fathers.

Recent rodent studies have demonstrated that parental cocaine exposure can influence offspring behavior, supporting the idea that environmental insults can impact subsequent generations. However, studies on the effects of paternal cocaine exposure are limited and multiple inconsistencies exist. In the current study, we behaviorally characterize the effects of paternal cocaine exposure in a C57BL/6J intergenerational mouse model. Male sires were administered cocaine hydrochloride (20mg/kg) or saline (0.01mL/g) once a day for 75days, and bred with drug naïve females twenty-four hours after the final injection. Offspring, separated by sex, were tested in a battery of behaviors. We found that paternal cocaine exposure altered sensitivity to the rewarding and stimulant effects of psychostimulants and natural reward (sucrose) in female offspring; female cocaine-sired offspring showed blunted cocaine preference using cocaine conditioned place preference (CPP) at a low dose (5mg/kg), but displayed similar preference at a higher dose (10mg/kg) compared to saline-sired controls. Additionally, cocaine-sired female offspring exhibited higher psychomotor sensitivity to cocaine (10mg/kg) and amphetamine (2mg/kg) and consumed more sucrose. Cocaine-sired males exhibited increased psychomotor effects of cocaine and amphetamine. Male offspring also displayed an anxiety-like phenotype. No effect of paternal cocaine exposure was observed on depressive-like, learning and memory or social behavior in male or female offspring. Collectively, our findings show that paternal, chronic cocaine exposure induces intergenerational behavioral effects in male and female offspring with greatest impact on sensitivity to psychostimulants and sucrose in females.

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine.

Extensive 3' alternative splicing of the mu opioid receptor gene OPRM1 creates multiple C-terminal splice variants. However, their behavioral relevance remains unknown. The present study generated 3 mutant mouse models with truncated C termini in 2 different mouse strains, C57BL/6J (B6) and 129/SvEv (129). One mouse truncated all C termini downstream of Oprm1 exon 3 (mE3M mice), while the other two selectively truncated C-terminal tails encoded by either exon 4 (mE4M mice) or exon 7 (mE7M mice). Studies of these mice revealed divergent roles for the C termini in morphine-induced behaviors, highlighting the importance of C-terminal variants in complex morphine actions. In mE7M-B6 mice, the exon 7-associated truncation diminished morphine tolerance and reward without altering physical dependence, whereas the exon 4-associated truncation in mE4M-B6 mice facilitated morphine tolerance and reduced morphine dependence without affecting morphine reward. mE7M-B6 mutant mice lost morphine-induced receptor desensitization in the brain stem and hypothalamus, consistent with exon 7 involvement in morphine tolerance. In cell-based studies, exon 7-associated variants shifted the bias of several mu opioids toward ß-arrestin 2 over G protein activation compared with the exon 4-associated variant, suggesting an interaction of exon 7-associated C-terminal tails with ß-arrestin 2 in morphine-induced desensitization and tolerance. Together, the differential effects of C-terminal truncation illustrate the pharmacological importance of OPRM1 3' alternative splicing.

Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1.

The CACNA1C gene that encodes the L-type Ca2+ channel (LTCC) Cav1.2 subunit has emerged as a candidate risk gene for multiple neuropsychiatric disorders including bipolar disorder, major depressive disorder, and schizophrenia, all marked with depression-related symptoms. Although cacna1c heterozygous (HET) mice have been previously reported to exhibit an antidepressant-like phenotype, the molecular and circuit-level dysfunction remains unknown. Here we report that viral vector-mediated deletion of cacna1c in the adult prefrontal cortex (PFC) of mice recapitulates the antidepressant-like effect observed in cacna1c HET mice using the sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST). Molecular studies identified lower levels of REDD1, a protein previously linked to depression, in the PFC of HET mice, and viral-mediated REDD1 overexpression in the PFC of these HET mice reversed the antidepressant-like effect in SPT and TST. Examination of downstream REDD1 targets found lower levels of active/phosphorylated Akt (S473) with no change in mTORC1 phosphorylation. Examination of the transcription factor FoxO3a, previously linked to depression-related behavior and shown to be regulated in other systems by Akt, revealed higher nuclear levels in the PFC of cacna1c HET mice that was further increased following REDD1-mediated reversal of the antidepressant-like phenotype. Collectively, these findings suggest that REDD1 in cacna1c HET mice may influence depression-related behavior via regulation of the FoxO3a pathway. Cacna1c HET mice thus serve as a useful mouse model to further study cacna1c-associated molecular signaling and depression-related behaviors relevant to human CACNA1C genetic variants.

Lateral Thoracic Osteoplastic Rib-Sparing Technique Used for Lateral Spine Surgery: Technical Note.

Of patients who have undergone lateral approaches to the thoracic spine, surgical site postoperative pain appears to be greater among those who have undergone transection and removal of a rib segment than those who have not. Therefore, techniques that conserve anatomical position and minimize tissue disruption would theoretically result in less pain and a quicker recovery. Herein, we describe a rib-sparing osteoplastic technique used when rib segments need to be displaced in order to create an unobscured corridor to the operative target. Our approach minimizes soft tissue disruption and restores the anatomical function of the rib. Based on our experience, these patients report less pain, mobilize earlier, and are discharged sooner than those who have had rib segments sacrificed as part of a lateral approach to the spine.

Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts.

BACKGROUND: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD. METHODS: In this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. RESULTS: Here, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions. CONCLUSION: Our study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.