Surgical timing and complications, with body image, quality of life, sexual function and genital sensation in patients with congenital adrenal hyperplasia.

INTRODUCTION: The aim of this project was to document the long-term outcomes relating to sexual function, genital sensation, body image and quality of life, in an Australian cohort of adolescent and adult women with congenital adrenal hyperplasia (CAH) who have undergone feminising genitoplasty in infancy, childhood or adolescence. MATERIALS AND METHODS: Identification and follow-up of women with CAH aged 12-40 years who had their first feminising genitoplasty or ongoing management at a single tertiary referral center with multidisciplinary care (n = 80). Medical records were reviewed for Prader stage, and operative outcomes. The prospective component of the study included tracing indivudals aged 12-40 years (n = 69), of whom 34 were contactable. Twenty-one responded to the invitation to participate in the study, completing some or all of a series of validated standardized questionnaires and/or participation in examination of external genital with sensation testing. Results were compared to a control population of similar age distribution (n = 23). RESULTS: The median Prader stage was 3, median age at surgery was four months, median hospital stay of three days with 80 % of surgery undertaken by one surgeon. There was one major and eight minor complications. Re-operation rates were low. There was no difference between participants and controls in terms of sexual function, quality of life, or body image outcomes including genital appearance. Participants had increased sensitivity to soft touch on genital sensation testing compared to controls. Most participants (71 %) reported that early timing of surgery was 'good', four (19 %) felt their surgery was too late, one felt their surgery was too early, and one was unsure. Most were happy with the outcome of their surgery. DISCUSSION: Outcomes after feminising genitoplasty are mixed and influenced not only by the surgery itself, but also the ongoing management of the condition alongside each patient's own cultural and social context. At present there is no comparative data available on the sexual, mental, body image and quality of life outcomes of young females with CAH who have had their operation delayed until adulthood. Our study is limited by low participant response rate, and difficulty recruiting 1:1 control population for all participants, but nevertheless provides some insight into the outcomes of these patients for which limited data is available. CONCLUSION: In the population studied feminising genitoplasty in infancy and childhood had overall positive outcomes. This occurred in a tertiary center with expert multidisciplinary individualised care.

Nonstenotic Carotid Plaques and Embolic Stroke of Undetermined Source: A Multimodality Review.

Symptomatic nonstenotic carotid artery disease has been increasingly recognized as a thromboembolic source in patients who would otherwise be classified as having embolic stroke of undetermined source. Evidence suggests that certain plaque features seen on sonography, CT, and MR imaging in nonstenotic carotid artery disease may predispose to recurrent stroke in patients with embolic stroke of undetermined source. We performed a focused literature review to further study plaque features in the context of embolic stroke of undetermined source and to determine which plaque features may be associated with ipsilateral ischemic events in such patients. Plaque thickness as seen on both ultrasound and CT appears to have a consistent association with ipsilateral stroke in patients with embolic stroke of undetermined source across multiple studies. Intraplaque hemorrhage as seen on MR imaging is now understood to have a strong association with ipsilateral stroke in patients with embolic stroke of undetermined source. Continued study of various plaque features as seen on different modalities is warranted to uncover other potential associations.

Average SAR prediction, validation, and evaluation for a compact MR scanner head-sized RF coil.

A recently developed compact 3 T (C3T) MRI scanner with high performance gradients [1, 2] has a dedicated radiofrequency (RF) transmit coil that exposes only the head, neck and a small portion of the upper body region during head-first scanning. Due to the unique coil geometry and patient positioning, the established SAR model used for a conventional whole-body scanner cannot be directly translated to the C3T. Here a specific absorption rate (SAR) estimation and validation framework was developed and used to implement a dedicated and accurate SAR prediction model for the C3T. Two different SAR prediction models for the C3T were defined and evaluated: one based on an anatomically derived exposed mass, and one using a fixed anatomical position located caudally to the RF coil to determine the exposed mass. After coil modeling and virtual human body simulation, the designed SAR prediction model was implemented on the C3T and verified with calorimetry and in vivo scan power monitoring. The fixed-demarcation exposed mass model was selected as appropriate exposed mass region to accurately estimate the SAR deposition in the patient on the C3T.

Idiopathic Intracranial Hypertension is Associated with a Higher Burden of Visible Cerebral Perivascular Spaces: The Glymphatic Connection.

BACKGROUND AND PURPOSE: Research suggests a connection between idiopathic intracranial hypertension and the cerebral glymphatic system. We hypothesized that visible dilated perivascular spaces, possible glymphatic pathways, would be more prevalent in patients with idiopathic intracranial hypertension. This prevalence could provide a biomarker and add evidence to the glymphatic connection in the pathogenesis of idiopathic intracranial hypertension. MATERIALS AND METHODS: We evaluated 36 adult (older than 21 years of age) patients with idiopathic intracranial hypertension and 19 controls, 21-69 years of age, who underwent a standardized MR imaging protocol that included high-resolution precontrast T2- and T1-weighted images. All patients had complete neuro-ophthalmic examinations for papilledema. The number of visible perivascular spaces was evaluated using a comprehensive 4-point qualitative rating scale, which graded the number of visible perivascular spaces in the centrum semiovale and basal ganglia; a 2-point scale was used for the midbrain. Readers were blinded to patient diagnoses. Continuous variables were compared using a Student t test. RESULTS: The mean number of visible perivascular spaces overall was greater in the idiopathic intracranial hypertension group than in controls (4.5 [SD, 1.9] versus 2.9 [SD, 1.9], respectively; P = .004). This finding was significant for centrum semiovale idiopathic intracranial hypertension (2.3 [SD, 1.4] versus controls, 1.3 [SD, 1.1], P = .003) and basal ganglia idiopathic intracranial hypertension (1.7 [SD, 0.6] versus controls, 1.2 [SD, 0.7], P = .009). There was no significant difference in midbrain idiopathic intracranial hypertension (0.5 [SD, 0.5] versus controls, 0.4 [SD, 0.5], P = .47). CONCLUSIONS: Idiopathic intracranial hypertension is associated with an increased number of visible intracranial perivascular spaces. This finding provides insight into the pathophysiology of idiopathic intracranial hypertension, suggesting a possible relationship between idiopathic intracranial hypertension and glymphatic dysfunction and providing another useful biomarker for the disease.

Changes in Ventricular and Cortical Volumes following Shunt Placement in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: While changes in ventricular and extraventricular CSF spaces have been studied following shunt placement in patients with idiopathic normal pressure hydrocephalus, regional changes in cortical volumes have not. These changes are important to better inform disease pathophysiology and evaluation for copathology. The purpose of this work is to investigate changes in ventricular and cortical volumes in patients with idiopathic normal pressure hydrocephalus following ventriculoperitoneal shunt placement. MATERIALS AND METHODS: This is a retrospective cohort study of patients with idiopathic normal pressure hydrocephalus who underwent 3D T1-weighted MR imaging before and after ventriculoperitoneal shunt placement. Images were analyzed using tensor-based morphometry with symmetric normalization to determine the percentage change in ventricular and regional cortical volumes. Ventricular volume changes were assessed using the Wilcoxon signed rank test, and cortical volume changes, using a linear mixed-effects model (P < .05). RESULTS: The study included 22 patients (5 women/17 men; mean age, 73 [SD, 6] years). Ventricular volume decreased after shunt placement with a mean change of -15.4% (P < .001). Measured cortical volume across all participants and cortical ROIs showed a mean percentage increase of 1.4% (P < .001). ROIs near the vertex showed the greatest percentage increase in volume after shunt placement, with smaller decreases in volume in the medial temporal lobes. CONCLUSIONS: Overall, cortical volumes mildly increased after shunt placement in patients with idiopathic normal pressure hydrocephalus with the greatest increases in regions near the vertex, indicating postshunt decompression of the cortex and sulci. Ventricular volumes showed an expected decrease after shunt placement.

Carotid Intraplaque Hemorrhage and Stenosis: At What Stage of Plaque Progression Does Intraplaque Hemorrhage Occur, and When is It Most Likely to Be Associated with Symptoms?

BACKGROUND AND PURPOSE: The relationship between carotid intraplaque hemorrhage and luminal stenosis severity is not well-established. We sought to determine whether intraplaque hemorrhage is related to carotid stenosis and at what degree of stenosis intraplaque hemorrhage most likely contributes to ischemic symptoms. MATERIALS AND METHODS: Consecutive patients who underwent MR carotid plaque imaging with MPRAGE sequences to identify intraplaque hemorrhage were retrospectively reviewed. Degrees of stenoses were categorized as minimal (<30%), moderate (30%-69%), and severe (>70%). Arteries were categorized into 2 groups: symptomatic (ipsilateral to a cerebral ischemic event) and asymptomatic (from a patient without an ischemic event). Multiple regression analyses were used to determine independent associations between the degree of stenosis and intraplaque hemorrhage and the presence of intraplaque hemorrhage with symptoms among categories of stenosis. RESULTS: We included 449 patients with 449 carotid arteries: Two hundred twenty-five (50.1%) were symptomatic, and 224 (49.9%) were asymptomatic. An increasing degree of stenosis was independently associated with the presence of intraplaque hemorrhage (OR = 1.02; 95% confidence interval, 1.01-1.03). Intraplaque hemorrhage was independently associated with ischemic events in arteries with <30% stenosis (OR = 5.68; 95% CI, 1.49-21.69). No such association was observed in arteries with >30% stenosis. Of symptomatic arteries with minimal stenosis, 8.7% had intraplaque hemorrhage versus 1.7% of asymptomatic arteries (P = .02). No differences in intraplaque hemorrhage prevalence were found between symptomatic and asymptomatic groups with moderate (P = .18) and severe stenoses (P = .99). CONCLUSIONS: The presence of intraplaque hemorrhage on high-resolution plaque imaging is likely most useful in identifying symptomatic plaques in cases of minimal stenosis.

Associations between disordered eating and intimate partner violence mediated by depression and posttraumatic stress disorder symptoms in a female veteran sample.

OBJECTIVE: This study established a link between intimate partner violence (IPV) and eating disorders (EDs) via mediators of depression and posttraumatic stress disorder (PTSD) symptoms in female veterans. METHOD: A nationally representative sample of female veterans (N = 190, Mean age = 48.41 years) completed online surveys assessing IPV and symptoms of depression, PTSD, and EDs, at three time points from 2014 to 2017. RESULTS: Approximately 14.11% of participants met criteria for any ED (7.83% Bulimia Nervosa; 6.28% Binge Eating Disorder), and 49.42% reported lifetime histories of IPV. Eating disorder symptoms were significantly associated with lifetime IPV, PTSD and depression symptoms at the bivariate level. Mediation model results revealed that lifetime IPV was indirectly associated with EDDS scores, via PTSD symptoms and depression symptoms. CONCLUSION: Findings confirmed elevated rates of probable EDs and lifetime IPV among female veterans; significant associations between EDs, lifetime IPV, depression, and PTSD; and mediation of the association between IPV and EDs by PTSD and depression symptoms. Implications for screening, treatment and research are discussed.

Associations between healthcare use and disordered eating among female veterans.

OBJECTIVE: Individuals with eating disorders (EDs) have considerable medical and psychiatric comorbidity as well as increased healthcare use and associated costs. However, EDs remain largely undetected and understudied among veteran populations, and EDs are not routinely screened for or treated in Veterans Affairs (VA) medical settings. Research elucidating the links between disordered eating and VA and non-VA healthcare use is needed to inform policy and practice for ED screening and treatment. METHOD: Data regarding probable EDs and VA and non-VA healthcare use was obtained through a mail survey of 198 female veterans receiving care from VA. RESULTS: A total of 21 participants (10.6%) met probable criteria for subthreshold anorexia nervosa, bulimia nervosa, or binge-eating disorder. Negative binomial regression models revealed that female veterans with EDs reported higher frequency of VA mental healthcare use and substance use disorder treatment, above and beyond the association of comorbid PTSD and depression symptoms. DISCUSSION: These findings confirm the high probability that female veterans with EDs are utilizing significant VA mental health resources. Screening for EDs may be particularly important in VA medical and mental health settings.

Safety and feasibility of robotic-assisted Ivor-Lewis esophagectomy.

Esophagectomy is associated with substantial morbidity. Robotic surgery allows complex resections to be performed with potential benefits over conventional techniques. We applied this technology to transthoracic esophagectomy to assess safety, feasibility, and reliability of this technology. A retrospective cohort study of all patients undergoing robotic-assisted Ivor-Lewis esophagectomy (RAIL) from 2009 to 2014 was conducted. Clinicopathologic factors and surgical outcomes were recorded and compared. All statistical tests were two-sided and a P-value of <0.05 was considered statistically significant. We identified 147 patients with an average age 66 ± 10 years. Neoadjuvant therapy was administered to 114 (77.6%) patients, and all patients underwent a R0 resection. The mean operating room (OR) time was 415 ± 84.6 minutes with a median estimated blood loss (EBL) of 150 (25-600) mL. Mean intensive care unit (ICU) stay was 2.00 ± 4.5 days, median length of hospitalization (LOH) was 9 (4-38) days, and readmissions within 90 days were low at 8 (5.5%). OR time decreased from 471 minutes to 389 minutes after 20 cases and a further decrease to mean of 346 minutes was observed after 120 cases. Complications occurred in 37 patients (25.2%). There were 4 anastomotic (2.7%) leaks. Thirty and 90-day mortality was 0.68% and 1.4%, respectively. This represents to our knowledge the largest series of robotic esophagectomies. RAIL is a safe surgical technique that provides an alternative to standard minimally invasive and open techniques. In our series, there was no increased risk of LOH, complications, or death and re-admission rates were low despite earlier discharge.

MR Elastography Analysis of Glioma Stiffness and IDH1-Mutation Status.

BACKGROUND AND PURPOSE: Our aim was to noninvasively evaluate gliomas with MR elastography to characterize the relationship of tumor stiffness with tumor grade and mutations in the isocitrate dehydrogenase 1 (IDH1) gene. MATERIALS AND METHODS: Tumor stiffness properties were prospectively quantified in 18 patients (mean age, 42 years; 6 women) with histologically proved gliomas using MR elastography from 2014 to 2016. Images were acquired on a 3T MR imaging unit with a vibration frequency of 60 Hz. Tumor stiffness was compared with unaffected contralateral white matter, across tumor grade, and by IDH1-mutation status. The performance of the use of tumor stiffness to predict tumor grade and IDH1 mutation was evaluated with the Wilcoxon rank sum, 1-way ANOVA, and Tukey-Kramer tests. RESULTS: Gliomas were softer than healthy brain parenchyma, 2.2 kPa compared with 3.3 kPa (P < .001), with grade IV tumors softer than grade II. Tumors with an IDH1 mutation were significantly stiffer than those with wild type IDH1, 2.5 kPa versus 1.6 kPa, respectively (P = .007). CONCLUSIONS: MR elastography demonstrated that not only were gliomas softer than normal brain but the degree of softening was directly correlated with tumor grade and IDH1-mutation status. Noninvasive determination of tumor grade and IDH1 mutation may result in improved stratification of patients for different treatment options and the evaluation of novel therapeutics. This work reports on the emerging field of "mechanogenomics": the identification of genetic features such as IDH1 mutation using intrinsic biomechanical information.

'It makes the patient's spirit weaker': tuberculosis stigma and gender interaction in Dar es Salaam, Tanzania.

SETTING: Dar es Salaam, Tanzania. OBJECTIVES: To describe tuberculosis (TB) related stigma and to understand how it interacts with gender to affect access to care. DESIGN: Eight focus group discussions were held among 48 TB patients and their household members, and a thematic content analysis was carried out. RESULTS: The main components of stigma were fear, self-isolation, ostracization, loss of status in the community, and discrimination by providers. Participants described the cultural context in which stigma operated as characterized by a general lack of health knowledge, cultural beliefs about TB, and engendered beliefs about disease in general. Both genders described some similar effects of stigma, including relationship difficulties and specifically challenges forming new relationships, but many effects of stigma were distinct by gender: women described challenges including assumptions about promiscuity and infidelity, as well as rejection by partners, while men described survival challenges. Stigma acted as a barrier to care through a cyclical pattern of stigma and fear, leading to health-seeking delays, with resulting continued transmission and poor health outcomes that further reinforced stigma. CONCLUSION: TB-related stigma is prevalent in this setting and operates differently for men and women. Interventions designed to increase case detection must address stigma and its interaction with gender.

The surgical Infection Society Revised Guidelines on the management of intra-abdominal infection

BACKGROUND: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. METHODS: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. RESULTS: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. SUMMARY: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline.(AU)

Gradient nonlinearity calibration and correction for a compact, asymmetric magnetic resonance imaging gradient system.

Due to engineering limitations, the spatial encoding gradient fields in conventional magnetic resonance imaging cannot be perfectly linear and always contain higher-order, nonlinear components. If ignored during image reconstruction, gradient nonlinearity (GNL) manifests as image geometric distortion. Given an estimate of the GNL field, this distortion can be corrected to a degree proportional to the accuracy of the field estimate. The GNL of a gradient system is typically characterized using a spherical harmonic polynomial model with model coefficients obtained from electromagnetic simulation. Conventional whole-body gradient systems are symmetric in design; typically, only odd-order terms up to the 5th-order are required for GNL modeling. Recently, a high-performance, asymmetric gradient system was developed, which exhibits more complex GNL that requires higher-order terms including both odd- and even-orders for accurate modeling. This work characterizes the GNL of this system using an iterative calibration method and a fiducial phantom used in ADNI (Alzheimer's Disease Neuroimaging Initiative). The phantom was scanned at different locations inside the 26 cm diameter-spherical-volume of this gradient, and the positions of fiducials in the phantom were estimated. An iterative calibration procedure was utilized to identify the model coefficients that minimize the mean-squared-error between the true fiducial positions and the positions estimated from images corrected using these coefficients. To examine the effect of higher-order and even-order terms, this calibration was performed using spherical harmonic polynomial of different orders up to the 10th-order including even- and odd-order terms, or odd-order only. The results showed that the model coefficients of this gradient can be successfully estimated. The residual root-mean-squared-error after correction using up to the 10th-order coefficients was reduced to 0.36 mm, yielding spatial accuracy comparable to conventional whole-body gradients. The even-order terms were necessary for accurate GNL modeling. In addition, the calibrated coefficients improved image geometric accuracy compared with the simulation-based coefficients.

Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits.

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

MR Elastography Demonstrates Increased Brain Stiffness in Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Normal pressure hydrocephalus is a reversible neurologic disorder characterized by a triad of cognitive impairment, gait abnormality, and urinary incontinence that is commonly treated with ventriculoperitoneal shunt placement. However, multiple overlapping symptoms often make it difficult to differentiate normal pressure hydrocephalus from other types of dementia, and improved diagnostic techniques would help patient management. MR elastography is a novel diagnostic tool that could potentially identify patients with normal pressure hydrocephalus. The purpose of this study was to assess brain stiffness changes in patients with normal pressure hydrocephalus compared with age- and sex-matched cognitively healthy individuals. MATERIALS AND METHODS: MR elastography was performed on 10 patients with normal pressure hydrocephalus and 21 age- and sex-matched volunteers with no known neurologic disorders. Image acquisition was conducted on a 3T MR imaging scanner. Shear waves with 60-Hz vibration frequency were transmitted into the brain by a pillowlike passive driver. A novel postprocessing technique resistant to noise and edge artifacts was implemented to determine regional brain stiffness. The Wilcoxon rank sum test and linear regression were used for statistical analysis. RESULTS: A significant increase in stiffness was observed in the cerebrum (P = .001), occipital lobe (P < .001), parietal lobe (P = .001), and the temporal lobe (P = .02) in the normal pressure hydrocephalus group compared with healthy controls. However, no significant difference was noted in other regions of the brain, including the frontal lobe (P = .07), deep gray and white matter (P = .43), or cerebellum (P = .20). CONCLUSIONS: This study demonstrates increased brain stiffness in patients with normal pressure hydrocephalus compared with age- and sex-matched healthy controls; these findings should motivate future studies investigating the use of MR elastography for this condition and the efficacy of shunt therapy.

Serotonergic interaction between medial prefrontal cortex and mesotelencephalic DA system underlies cognitive and affective deficits in hemiparkinsonian rats.

Parkinson's disease (PD) patients not only exhibit motor impairments, but also characteristic deficits in cognitive and affective functions. Such functions have consistently been associated with the medial prefrontal cortex (mPFC). To determine whether there is an interaction between the midbrain dopamine system (MDS) and the mPFC underlying the cognitive and emotional deficits seen in rats, we administered a disconnection procedure of these structures by applying lesions to the mPFC (N-methyl-d-aspartic acid (NMDA)) and the medial forebrain bundle (6-hydroxydopamine (6-OHDA)) either in the same or opposite hemispheres. The results indicate a functional interaction of the MDS and the mPFC: Disconnection effects on behavior were observed with respect to memory-, anxiety- and depression-related behaviors. A disconnection of the mPFC and MDS had promnestic, antidepressant- and anxiolytic-like effects. In order to determine whether this circuit between the mPFC and MDS involves serotonergic mechanisms, we also utilized serotonin-specific disconnections of the mPFC by applying the 5-HT-specific agent 5,7-dihydroxytryptamine (5,7-DHT) into the mPFC and 6-OHDA into the medial forebrain bundle, again either in the same or opposite hemispheres. The behavioral effects observed here resembled those incurred by the unspecific disconnection of the mPFC, demonstrating a significant contribution of serotonergic mechanisms to the interplay between the MDS and the mPFC. Taken together, these experiments provide evidence for an interaction of the MDS and the mPFC in the control of cognitive and affective processes known to be impaired in PD and point toward a prominent involvement of the serotonergic system. A disconnection of the mPFC and the MDS had promnestic, antidepressant- and anxiolytic-like behavioral effects. These findings may impact therapeutic approaches in the treatment of cognitive and neuropsychiatric symptoms seen in PD.

Dopamine in the nucleus accumbens core, but not shell, increases during signaled food reward and decreases during delayed extinction.

UNLABELLED: Microdialysis studies in rat have generally shown that appetitive stimuli release dopamine (DA) in the nucleus accumbens (NAc) shell and core. Here we examined the release of DA in the NAc during delivery of reward (food) and during extinction of food reward in the freely moving animal by use of in vivo microdialysis and HPLC. Fifty-two male Wistar rats were trained to receive food reward associated with appearance of cue-lights in a Skinner-box during in vivo microdialysis. Different behavioral protocols were used to assess the effects of extinction on DA and its metabolites. Results Exp. 1: (a) During a 20-min period of cued reward delivery, DA increased significantly in the NAc core, but not shell subregion; (b) for the next 60min period half of the rats underwent immediate extinction (with the CS light presented during non-reward) and the other half did not undergo extinction to the cue lights (CS was not presented during non-reward). DA remained significantly increased in both groups, providing no evidence for a decrease in DA during extinction in either NAc core or shell regions. (c) In half of the animals of the group that was not subjected to extinction, the cue lights were turned on for 30min, thus, initiating extinction to cue CS at a 1h delay from the period of reward. In this group DA in the NAc core, but not shell, significantly decreased. Behavioral analysis showed that while grooming is an indicator of extinction-induced behavior, glances toward the cue-lights (sign tracking) are an index of resistance to extinction. Results Exp. 2: (a) As in Exp. 1, during a 30-min period of cued reward delivery, DA levels again increased significantly in the NAc core but not in the NAc shell. (b) When extinction (the absence of reward with the cue lights presented) was administered 24h after the last reward session, DA again significantly decreased in the NAc core, but not in the NAc shell. CONCLUSIONS: (a) These results confirm the importance of DA release in the NAc for reward-related states, with DA increasing in the core, but not shell subregion. (b) They provide first evidence that during the withholding of expected reward, DA decreases in the NAc core, but not shell region. (c) This decrease in DA appears only after a delay between delivery of reward and extinction likely due to it being masked by persisting DA release. We hypothesize the decrease in extinction-induced release of DA in the NAc core to be a marker for the despair/depression that is known to accompany the failure to obtain expected rewards/reinforcers.

Time-dependent bidirectional effects of chronic caffeine on functional recovery of the dorsal light reflex after hemilabyrinthectomy in the goldfish Carassius auratus.

Caffeine works through a variety of complex mechanisms to exert an often bidirectional set of functional and structural neurological changes in vertebrates. We investigated the effects of chronic caffeine exposure on functional recovery of the dorsal light reflex (DLR) in hemilabyrinthectomized common goldfish, Carassius auratus. In this lesion model, the unilateral removal of the vestibular organs results in a temporary loss of gravitationally modulated postural control which is quantifiable via the DLR. We compared the functional recovery over 24 days of post-surgery goldfish continuously held in a caffeine solution of 2.5mg/L (n=10), 5.0mg/L (n=10), 10.0mg/L (n=11), or 0.0mg/L control (n=9). Comparison to a sham surgery group (n=11) indicated statistically significant changes in the DLR of all hemilabyrinthectomized fish on day 1. The control group recovered over the study period and approached, but did not reach sham surgery DLR. Although the caffeine-treated fishes appeared to initiate some postural recovery within the first 2 weeks, beginning on day 10, all caffeine groups diverged from the control group with a deterioration of postural control. All three caffeine groups were significantly deficient in comparison with the control on days 10-24. These results suggest that caffeine exposure can at first be benign, but that high dosage or prolonged exposure hinders functional recovery.

Immunization with DISC1 protein in an animal model of ADHD influences behavior and excitatory amino acids in prefrontal cortex and striatum.

The Disrupted-in-schizophrenia 1 (DISC1) gene is involved in vulnerability to neuropsychiatric disorders. Naples high-excitability (NHE) rat model neuropsychiatric problems characterized by an unbalanced mesocortical dopamine system. Here, we assessed behavioral and neurochemical effects of immunization against multimeric rat DISC1 protein in adult NHE rats, an animal model of attention-deficit hyperactivity disorder and their Random-Bred (NRB) controls. Males of both lines received subcutaneous injections of vehicle (PB), adjuvant only (AD) or recombinant rat DISC1 protein purified from E. coli, suspended in AD (anti-DISC1) at age of 30, 45 and 60 postnatal days (pnd). At 75 pnd, the rats were exposed to a Làt maze and 2 days later to an Olton eight-arm radial maze, and horizontal (HA) and vertical activities (VA) were monitored. Non-selective (NSA) and selective spatial attention (SSA) were monitored in the Làt and in the Olton maze by duration of rearings and working memory, respectively. Post mortem neurochemistry in the prefrontal cortex (PFc), dorsal (DS) and ventral (VS) striatum of L-Glutamate, L-Aspartate and L-Leucine was performed. All immunized rats showed a clear humoral IgM (but not IgG) immune response against the immunogen, indicating that immunological self-tolerance to DISC1 can be overcome by immunization. NHE rats exhibited a higher unspecific IgM response to adjuvant, indicating an immunological abnormality. The sole anti-DISC1 immunization-specific behavioral in the NHE rats was an increased horizontal activity in the Làt maze. Adjuvant treatment increased vertical activity in both lines, but in the NRB controls it increased rearing and decreased horizontal activity. Liquid chromatography/tandem mass spectrometry analysis of soluble or membrane-trapped neurotransmitters aspartate, glutamate and leucine revealed increased soluble aspartate levels in the ventral striatum of NRB controls after anti-DISC1 immunization. Immune activation by adjuvant independent of simultaneous DISC1 immunization led to other specific changes in NHE and control NRB rats. In DISC1-immunized NHE rats, horizontal activity in Lat maze correlated with membrane-trapped glutamate in PFc and in the NRB rats, duration of rearing in Olton maze correlated with membrane-trapped glutamate in PFc and aspartate in dorsal striatum. In addition to non-specific immune activation (by AD), the postnatal anti-DISC1 immune treatment led to behavioral changes related to mechanisms of activity and attention and had influenced amino acids and synaptic markers in striatum and neocortex in the adult NHE as well as control animals.