Neurochemical correlates of caudate atrophy in Huntington's disease

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy (¹H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous ¹H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two ¹H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized ¹H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N‐acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease‐related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches. © 2014 International Parkinson and Movement Disorder Society     

Mood Instability and Psychosis: Analyses of British National Survey Data

Background: We used British national survey data to test specific hypotheses that mood instability (1) is associated with psychosis and individual psychotic phenomena, (2) predicts the later emergence of auditory hallucinations and paranoid ideation, and (3) mediates the link between child sexual abuse and psychosis. Methods: We analyzed data from the 2000 and 2007 UK national surveys of psychiatric morbidity (N = 8580 and 7403, respectively). The 2000 survey included an 18-month follow-up of a subsample (N = 2406). Mood instability was assessed from the Structured Clinical Interview for DSM-IV Axis II (SCID-II) questionnaire. Our dependent variables comprised auditory hallucinations, paranoid ideation, the presence of psychosis overall, and a 15-item paranoia scale. Results: Mood instability was strongly associated in cross-sectional analyses with psychosis (2000: OR: 7.5; 95% CI: I 4.1–13.8; 2007: OR: 21.4; CI: 9.7–41.2), paranoid ideation (2000: OR: 4.7; CI: 4.1–5.4; 2007: OR: 5.7; CI: 4.9–6.7), auditory hallucinations (2000: OR: 3.4; CI: 2.6–4.4; 2007: OR 3.5; CI: 2.7–4.7), and paranoia total score (2000: Coefficient: 3.6; CI: 3.3–3.9), remaining so after adjustment for current mood state. Baseline mood instability significantly predicted 18-month inceptions of paranoid ideation (OR: 2.3; CI: 1.6–3.3) and of auditory hallucinations (OR: 2.6; CI: 1.5–4.4). Finally, it mediated a third of the total association of child sexual abuse with psychosis and persecutory ideation and a quarter of that with auditory hallucinations. Conclusions: Mood instability is a prominent feature of psychotic experience and may have a role in its genesis. Targeting mood instability could lead to innovative treatments for psychosis.Key words: epidemiology, psychopathology, paranoia, auditory hallucination, child sexual abuse     

The clinical spectrum of anxiety in Parkinson's disease

Anxiety is common in Parkinson's disease (PD), and contributes to increased disability and poorer quality of life. In spite of its significant impact, the symptomatology, chronology, and neurobiology of anxiety in PD are all poorly understood, and this hinders accurate diagnosis and development of effective treatment strategies. This review investigates and updates literature related to the clinical spectrum of anxiety in PD. The reported prevalence of anxiety in PD varies considerably, with emerging interest in the frequency of the DSM‐IV residual category of “Anxiety disorder, not otherwise specified” (Anxiety disorder NOS), which is observed in up to 25% of PD patients. By design, there are no standardized diagnostic criteria for Anxiety disorder NOS, because this is the category applied to individuals who do not meet diagnostic criteria for any other current anxiety disorder. Anxiety rating scales incompletely capture anxiety symptoms that relate specifically to PD symptoms and the complications arising from PD therapy. Consequently, these scales have been deemed inappropriate for use in PD, and there remains a need for the development of a new PD‐specific anxiety scale. Research establishing accurate symptom profiles of anxiety in PD is sparse, although characterizing such symptomatology would likely improve clinical diagnosis and facilitate targeted treatment strategies. Research into the neurobiological and psychological underpinnings of anxiety in PD remains inconclusive. Anxiety can precede the onset of PD motor symptoms or can develop after a diagnosis of PD. Further investigations focused on the chronology of anxiety and its relationship to PD diagnosis are required. © 2014 International Parkinson and Movement Disorder Society     

Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR‐1A,mMOR‐1O,and mMOR‐1P

Extensive alternative pre‐mRNA splicing of the mu opioid receptor gene, OPRM1, has demonstrated an array of splice variants in mice, rats and humans. Three classes of splice variants have been identified: full‐length seven transmembrane (TM) domain variants with C‐terminal splicing, truncated 6TM variants and single TM variants. The current studies isolates and characterizes an additional three full‐length C‐terminal splice variants generated from the mouse OPRM1 gene: mMOR‐1A, mMOR‐1O, and mMOR‐1P. Using RT‐qPCR, we demonstrated differential expression of these variants' mRNAs among selected brain regions, supporting region‐specific alternative splicing. When expressed in Chinese Hamster Ovary cells, all the variants displayed high mu binding affinity and selectivity with subtle differences in the affinities toward some agonists. [³⁵S]γGTP binding assays revealed marked differences in agonist‐induced G protein activation in both potency and efficacy among the variants. Together with the previous studies of mu agonist‐induced phosphorylation and internalization in several carboxyl terminal splice variants, the current studies further suggest the existence of biased signaling of various agonists within each individual variant and/or among different variants. Synapse 68:144–152, 2014 . © 2013 Wiley Periodicals, Inc.     

A novel immune competent murine hypertrophic scar contracture model: A tool to elucidate disease mechanism and develop new therapies

Hypertrophic scar (HSc) contraction following burn injury causes contractures. Contractures are painful and disfiguring. Current therapies are marginally effective. To study pathogenesis and develop new therapies, a murine model is needed. We have created a validated immune‐competent murine HSc model. A third‐degree burn was created on dorsum of C57BL/6 mice. Three days postburn, tissue was excised and grafted with ear skin. Graft contraction was analyzed and tissue harvested on different time points. Outcomes were compared with human condition to validate the model. To confirm graft survival, green fluorescent protein (GFP) mice were used, and histologic analysis was performed to differentiate between ear and back skin. Role of panniculus carnosus in contraction was analyzed. Cellularity was assessed with 4′,6‐diamidino‐2‐phenylindole. Collagen maturation was assessed with Picro‐sirius red. Mast cells were stained with Toluidine blue. Macrophages were detected with F4/80 immune. Vascularity was assessed with CD31 immune. RNA for contractile proteins was detected by quantitative real‐time polymerase chain reaction (qRT‐PCR). Elastic moduli of skin and scar tissue were analyzed using a microstrain analyzer. Grafts contracted to ～45% of their original size by day 14 and maintained their size. Grafting of GFP mouse skin onto wild‐type mice, and analysis of dermal thickness and hair follicle density, confirmed graft survival. Interestingly, hair follicles disappeared after grafting and regenerated in ear skin configuration by day 30. Radiological analysis revealed that panniculus carnosus doesn't contribute to contraction. Microscopic analyses showed that grafts show increase in cellularity. Granulation tissue formed after day 3. Collagen analysis revealed increases in collagen maturation over time. CD31 stain revealed increased vascularity. Macrophages and mast cells were increased. qRT‐PCR showed up‐regulation of transforming growth factor beta, alpha smooth muscle actin, and rho‐associated protein kinase 2 in HSc. Tensile testing revealed that human skin and scar tissues are tougher than mouse skin and scar tissues.     

Perioperative Breast MRI Is Not Associated with Lower Locoregional Recurrence Rates in DCIS Patients Treated With or Without Radiation

Introduction

For women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS), the benefit of magnetic resonance imaging (MRI) remains unknown. Here we examine the relationship of MRI and locoregional recurrence (LRR) and contralateral breast cancer (CBC) for DCIS treated with BCS, with and without radiotherapy (RT).

Methods

A total of 2,321 women underwent BCS for DCIS from 1997 to 2010. All underwent mammography, and 596 (26 %) also underwent perioperative MRI; 904 women (39 %) did not receive RT, and 1,391 (61 %) did. Median follow-up was 59 months, and 548 women were followed for ≥8 years. The relationship between MRI and LRR was examined using multivariable analysis.

Results

There were 184 LRR events; 5- and 8-year LRR rates were 8.5 and 14.6 % (MRI), respectively, and 7.2 and 10.2 % (no-MRI), respectively (p = 0.52). LRR was significantly associated with age, menopausal status, margin status, RT, and endocrine therapy. After controlling for these variables and family history, presentation, number of excisions, and time period of surgery, there remained no trend toward association of MRI and lower LRR [hazard ratio (HR) 1.18, 95 % confidence interval (CI) 0.79–1.78, p = 0.42]. Restriction of analysis to the no-RT subgroup showed no association of MRI with lower LRR rates (HR 1.36, 95 % CI 0.78–2.39, p = 0.28). No difference in 5- or 8-year rates of CBC was seen between the MRI (3.5 and 3.5 %) and no-MRI (3.5 and 5.1 %) groups (p = 0.86).

Conclusions

We observed no association between perioperative MRI and lower LRR or CBC rates in patients with DCIS, with or without RT. In the absence of evidence that MRI improves outcomes, the routine perioperative use of MRI for DCIS should be questioned.     

Impact of Availability of Immediate Breast Reconstruction on Bilateral Mastectomy Rates for Breast Cancer across the United States: Data from the Nationwide Inpatient Sample

Background

Availability of immediate breast reconstruction (IBR) varies among institutions, yet the impact of IBR availability on the rates of bilateral mastectomy (BM) versus unilateral mastectomy (UM) for breast cancer is unknown.

Methods

From the 2002 to 2010 Nationwide Inpatient Sample, we identified women with breast cancer undergoing UM or BM with and without IBR using ICD-9 codes. Hospitals were classified as performing IBR if at least one hospitalization included both mastectomy and reconstruction and then by IBR volume. Statistical comparisons utilized Chi square tests, tests for trend, and multivariable logistic regression.

Results

We identified 130,420 women undergoing UM (76.9 %) or BM (23.1 %) for breast cancer. Of 6,579 hospitals, 3,358 (51.0 %) performed no IBRs, while in the remaining 3,221 hospitals, 1 to 638 IBRs were performed per year. Large, teaching, urban, and Northeastern hospitals were more likely to have higher IBR volumes. BM rates were significantly higher in patients treated at those hospitals with higher IBR volumes, from 33.1 % at hospitals performing ≥24 IBRs per year to 9.0 % at hospitals without IBR (p < 0.001). Upon adjusted analysis, patients who elected BM were more likely to be seen at hospitals performing ≥24 IBRs per year (odds ratio 1.69 vs. UM, p < 0.001).

Conclusions

In this analysis of national data, BM rates were higher in hospitals where IBR was available, suggesting a significant influence of institutional factors on treatment options for breast cancer patients. Efforts are needed to ensure patients have access to IBR when desired and to better understand the reasons for hospital variation in BM rates.