Disrupted resting-state brain network properties in obesity: decreased global and putaminal cortico-striatal network efficiency.

BACKGROUND: The efficient organization and communication of brain networks underlie cognitive processing and their disruption can lead to pathological behaviours. Few studies have focused on whole-brain networks in obesity and binge eating disorder (BED). Here we used multi-echo resting-state functional magnetic resonance imaging (rsfMRI) along with a data-driven graph theory approach to assess brain network characteristics in obesity and BED. METHOD: Multi-echo rsfMRI scans were collected from 40 obese subjects (including 20 BED patients) and 40 healthy controls and denoised using multi-echo independent component analysis (ME-ICA). We constructed a whole-brain functional connectivity matrix with normalized correlation coefficients between regional mean blood oxygenation level-dependent (BOLD) signals from 90 brain regions in the Automated Anatomical Labeling atlas. We computed global and regional network properties in the binarized connectivity matrices with an edge density of 5%-25%. We also verified our findings using a separate parcellation, the Harvard-Oxford atlas parcellated into 470 regions. RESULTS: Obese subjects exhibited significantly reduced global and local network efficiency as well as decreased modularity compared with healthy controls, showing disruption in small-world and modular network structures. In regional metrics, the putamen, pallidum and thalamus exhibited significantly decreased nodal degree and efficiency in obese subjects. Obese subjects also showed decreased connectivity of cortico-striatal/cortico-thalamic networks associated with putaminal and cortical motor regions. These findings were significant with ME-ICA with limited group differences observed with conventional denoising or single-echo analysis. CONCLUSIONS: Using this data-driven analysis of multi-echo rsfMRI data, we found disruption in global network properties and motor cortico-striatal networks in obesity consistent with habit formation theories. Our findings highlight the role of network properties in pathological food misuse as possible biomarkers and therapeutic targets.

Impaired awareness of motor intention in functional neurological disorder: implications for voluntary and functional movement.

BACKGROUND: Functional neurological disorders (FNDs), also known as conversion disorder, are unexplained neurological symptoms unrelated to a neurological cause. The disorder is common, yet poorly understood. The symptoms are experienced as involuntary but have similarities to voluntary processes. Here we studied intention awareness in FND. METHOD: A total of 26 FND patients and 25 healthy volunteers participated in this functional magnetic resonance study using Libet's clock. RESULTS: FND is characterized by delayed awareness of the intention to move relative to the movement itself. The reporting of intention was more precise, suggesting that these findings are reliable and unrelated to non-specific attentional deficits. That these findings were more prominent with aberrant positive functional movement symptoms rather than negative symptoms may be relevant to impairments in timing for an inhibitory veto process. Attention towards intention relative to movement was associated with lower right inferior parietal cortex activity in FND, a region early in the processing of intention. During rest, aberrant functional connectivity was observed with the right inferior parietal cortex and other motor intention regions. CONCLUSIONS: The results converge with observations of low inferior parietal activity comparing involuntary with voluntary movement in FND, emphasizing core deficiencies in intention. Heightened precision of this impaired intention is consistent with Bayesian theories of impaired top-down priors that might influence the sense of involuntariness. A primary impairment in voluntary motor intention at an early processing stage might explain clinical observations of slowed effortful voluntary movement, heightened self-directed attention and underlie functional movements. These findings further suggest novel therapeutic targets.

Relationships between depression, anxiety, and motivation in the real-world: Effects of physical activity and screentime.

Background: Mood and anxiety disorders are highly prevalent and comorbid worldwide, with variability in symptom severity that fluctuates over time. Digital phenotyping, a growing field that aims to characterize clinical, cognitive and behavioral features via personal digital devices, enables continuous quantification of symptom severity in the real world, and in real-time. Methods: In this study, N=114 individuals with a mood or anxiety disorder (MA) or healthy controls (HC) were enrolled and completed 30-days of ecological momentary assessments (EMA) of symptom severity. Novel real-world measures of anxiety, distress and depression were developed based on the established Mood and Anxiety Symptom Questionnaire (MASQ). The full MASQ was also completed in the laboratory (in-lab). Additional EMA measures related to extrinsic and intrinsic motivation, and passive activity data were also collected over the same 30-days. Mixed-effects models adjusting for time and individual tested the association between real-world symptom severity EMA and the corresponding full MASQ sub-scores. A graph theory neural network model (DEPNA) was applied to all data to estimate symptom interactions. Results: There was overall good adherence over 30-days (MA=69.5%, HC=71.2% completion), with no group difference (t(58)=0.874, p=0.386). Real-world measures of anxiety/distress/depression were associated with their corresponding MASQ measure within the MA group (t's > 2.33, p's < 0.024). Physical activity (steps) was negatively associated with real-world distress and depression (IRRs > 0.93, p's ≤ 0.05). Both intrinsic and extrinsic motivation were negatively associated with real-world distress/depression (IRR's > 0.82, p's < 0.001). DEPNA revealed that both extrinsic and intrinsic motivation significantly influenced other symptom severity measures to a greater extent in the MA group compared to the HC group (extrinsic/intrinsic motivation: t(46) = 2.62, p < 0.02, q FDR < 0.05, Cohen's d = 0.76; t(46) = 2.69, p < 0.01, q FDR < 0.05, Cohen's d = 0.78 respectively), and that intrinsic motivation significantly influenced steps (t(46) = 3.24, p < 0.003, q FDR < 0.05, Cohen's d = 0.94). Conclusions: Novel real-world measures of anxiety, distress and depression significantly related to their corresponding established in-lab measures of these symptom domains in individuals with mood and anxiety disorders. Novel, exploratory measures of extrinsic and intrinsic motivation also significantly related to real-world mood and anxiety symptoms and had the greatest influencing degree on patients' overall symptom profile. This suggests that measures of cognitive constructs related to drive and activity may be useful in characterizing phenotypes in the real-world.

Dimensionality of Cognitions in Behavioral Addiction.

Cognitive constructs provide conceptual frameworks for transpathological characterization and improved phenotyping of apparently disparate psychiatric groups. This dimensional approach can be applied to the examination of individuals with behavioral addictions, for example, towards gambling, video-games, the internet, food, and sex, allowing operationalization of core deficits. We use this approach to review constructs such as impulsivity, compulsivity, and attention regulation, which may be most relevant, applicable, and successful for the understanding and subsequent treatment of the addictions.

Minichromosome maintenance proteins as biological markers of dysplasia and malignancy.

Dysplasia, an intermediate stage in the progression from normal tissue to neoplasia, is defined morphologically by a loss of normal orientation between epithelial cells, with changes in cellular and nuclear shape and size. However, little is known about the functional properties of dysplastic cells, including their replicative state, largely due to a lack of available biological markers. We have used novel antibodies against minichromosome maintenance (MCM) proteins to examine the proliferative status of a range of histological lesions and to characterize dysplastic cells in functional terms. Immunoperoxidase staining was used to localize the MCM proteins, components of the prereplicative complex that is essential for initiating eukaryotic DNA replication. These proteins are down-regulated in cells undergoing differentiation or quiescence and, thus, serve as specific markers for proliferating cells. In normal and some reactive tissues, MCM expression was present only in restricted proliferative compartments, consistent with our published findings in the uterine cervix. In dysplastic and malignant tissues, in contrast, MCM proteins were expressed in the majority of cells, extending to surface layers of dysplastic stratified epithelia. In carcinomas, the frequency of expression of MCM proteins showed an inverse correlation with the degree of tumor differentiation. Thus, we suggest that dysplastic cells may be characterized in functional terms as remaining in cell cycle, due to deregulation of normal controls over cell proliferation. Antibodies against MCM proteins have potential clinical applications, for example, in the assessment of tumor prognosis in histological sections and the identification of proliferating cells in clinical samples using biochemical or cytological assays.

Motivation and value influences in the relative balance of goal-directed and habitual behaviours in obsessive-compulsive disorder.

Our decisions are based on parallel and competing systems of goal-directed and habitual learning, systems which can be impaired in pathological behaviours. Here we focus on the influence of motivation and compare reward and loss outcomes in subjects with obsessive-compulsive disorder (OCD) on model-based goal-directed and model-free habitual behaviours using the two-step task. We further investigate the relationship with acquisition learning using a one-step probabilistic learning task. Forty-eight OCD subjects and 96 healthy volunteers were tested on a reward and 30 OCD subjects and 53 healthy volunteers on the loss version of the two-step task. Thirty-six OCD subjects and 72 healthy volunteers were also tested on a one-step reversal task. OCD subjects compared with healthy volunteers were less goal oriented (model-based) and more habitual (model-free) to reward outcomes with a shift towards greater model-based and lower habitual choices to loss outcomes. OCD subjects also had enhanced acquisition learning to loss outcomes on the one-step task, which correlated with goal-directed learning in the two-step task. OCD subjects had greater stay behaviours or perseveration in the one-step task irrespective of outcome. Compulsion severity was correlated with habitual learning in the reward condition. Obsession severity was correlated with greater switching after loss outcomes. In healthy volunteers, we further show that greater reward magnitudes are associated with a shift towards greater goal-directed learning further emphasizing the role of outcome salience. Our results highlight an important influence of motivation on learning processes in OCD and suggest that distinct clinical strategies based on valence may be warranted.

Altered expression of desmosomal components in high-grade squamous intraepithelial lesions of the cervix.

We have used immunohistochemistry to test the hypothesis that components of the desmosome are disrupted during neoplastic progression of squamous epithelial cells in the uterine cervix. Sections of normal cervix and squamous intraepithelial lesions (SILs) were immunostained for desmosomal proteins and glycoproteins, and results were assessed using a semi-quantitative grading system. No difference between normal cervix and low-grade SIL (LSIL) was found. A significant reduction in expression of desmogleins was seen between high-grade SIL (HSIL) and LSIL (P<0.01) and normal cervix (P<0.001). Desmocollin expression was not reduced significantly, although scores showed significantly greater variation in HSIL compared with LSIL (P<0.05) and normal cervix (P<0.05). There was no significant difference in desmoplakin expression among the three groups. The results suggest that there may be sequential disruption of desmosomal function during neoplastic progression of cervical squamous intraepithelial cells, with downregulation of desmogleins during the progression from LSIL to HSIL and loss of desmocollin expression occurring in some cases of established HSIL.

Medication compliance: the patient's perspective.

There has been increasing interest in using outcomes-based research to evaluate quality of care. Compliance with prescribed regimens is an intermediate outcome measure that presumes that a positive health outcome will follow, which is why clinicians and researchers are interested in compliance. Patients, however, use a variety of criteria to determine the value of medication. They may place equal or greater value on personal and often competing nonclinical outcomes. A small but growing literature explores the influence of physical, economic, psychological, and social factors that influence medication use behavior. This literature supports the notion that patients evaluate medication based not only on its clinical effectiveness, but also how it affects all aspects of their lives. Outcomes research on compliance with prescribed medicine should recognize the outcomes valued from the patient's perspective.

Hysterectomy vs. resectoscopic endometrial ablation for the control of abnormal uterine bleeding. A cost-comparative study.

This study compared the costs of endometrial ablation using the uterine resectoscope to those of hysterectomy in a group of patients treated for abnormal uterine bleeding who were enrolled in a national managed health care organization. The cost of endometrial ablation during the periprocedural period was significantly lower than that of hysterectomy, with much of the difference coming from the hospitalization required for the latter procedure. The postprocedural cost for ablation was higher than for hysterectomy owing to the need for second ablations or hysterectomy in 13 of the 85 ablation patients. Preprocedure costs were not different between ablation and hysterectomy. A reanalysis of the data, however, that excluded patients who required a second ablation or hysterectomy suggested that these additional procedures were responsible for the higher postprocedural costs in the ablation group. Resectoscopic endometrial ablation for the treatment of abnormal uterine bleeding resulted in lower periprocedure costs and lower overall treatment costs to the health plan in the groups studied as compared with hysterectomy. Greater familiarity with the technique of resectoscopic endometrial ablation, improved patient selection for the procedure and the use of appropriate pharmacotherapy for suppressing endometrial growth prior to ablation probably substantially improve the rate of success, reduce postprocedural costs and further enhance the cost advantage of this procedure.

Immunohistochemical estimation of cell cycle phase in laryngeal neoplasia.

We previously developed an immunohistochemical method for estimating cell cycle state and phase in tissue samples, including biopsies that are too small for flow cytometry. We have used our technique to examine whether primary abnormalities of the cell cycle exist in laryngeal neoplasia. Antibodies against the markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67, and putative markers of cell cycle phase, cyclin D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis) were applied to paraffin-embedded sections of normal larynx (n = 8), laryngeal dysplasia (n = 10) and laryngeal squamous cell carcinoma (n = 10). Cells expressing each marker were determined as a percentage of total cells, termed the labelling index (LI), and as a percentage of Mcm-2-positive cells, termed the labelling fraction (LF). The frequency of coexpression of each putative phase marker was investigated by confocal microscopy. There was a correlation between Mcm-2 and Ki67 LIs (rho = 0.93) but Mcm-2 LIs were consistently higher. All cells expressing a phase marker coexpressed Mcm-2, whereas Ki67 was not expressed in a proportion of these cells. The putative phase markers showed little coexpression. Labelling index values increased on progression from normal larynx through laryngeal dysplasia to squamous cell carcinoma for Mcm-2 (P = 0.001), Ki67 (P = 0.0002), cyclin D1 (P = 0.015), cyclin A (P = 0.0001) and cyclin B1 (P = 0.0004). There was no evidence of an increase in the LF for any phase marker. Immunohistochemistry can be used to estimate cell cycle state and phase in laryngeal biopsies. Our data argues against primary cell cycle phase abnormalities in laryngeal neoplasia.

A minimally invasive immunocytochemical approach to early detection of oral squamous cell carcinoma and dysplasia.

Squamous dysplasia of the oral cavity indicates increased risk of progression to squamous cell carcinoma (SCC). An important advance would be the development of a minimally invasive assay for identification of oral SCC and dysplasia. We have investigated the suitability in this context of immunostaining oral smears for minichromosome maintainance proteins (MCMs), sensitive and specific biomarkers of cell cycle entry. Immunohistochemical examination of 66 oral tissue samples showed a greater frequency of Mcm-2 expression in surface layers of moderate/severe dysplasia and SCC compared to benign keratosis/mild dysplasia. Immunocytochemistry for Mcm-2/Mcm-5 was performed on 101 oral smears. Conventional smears included 23 from normal mucosa, benign proliferative disease and mild dysplasia, all of which were MCM negative. Of 52 conventional smears of SCC tissue samples, 18 were inadequate. However, MCM-positive cells were present in 33/34 adequate samples. Of 26 liquid-based cytology smears, 19 out of 20 smears from SCC were adequate and all were MCM positive. Six smears from benign lesions were adequate and MCM negative. We conclude that MCMs are promising markers for early detection of oral SCC and dysplasia, particularly in a liquid-based cytology platform. Detection of MCMs would be amenable to automation and potentially applicable in the developing world. Further studies are now warranted.

Coprescription of terfenadine and erythromycin or ketaconazole: an assessment of potential harm.

PURPOSE: In a retrospective study, the authors used a pharmacy claims database to analyze the rate of coprescription of terfenadine and erythromycin or ketaconazole. STUDY PERIOD: The investigators reviewed claims filed for these drugs between January 1, 1990, and June 30, 1993. The time period allowed for comparison of coprescription rates before and after the Food and Drug Administration (FDA) required the manufacturer of terfenadine to inform the medical community of potentially serious adverse interactions. RESULTS: There were 5,802 coprescription events for terfenadine and erythromycin and 150 coprescription events for terfenadine and ketaconazole. Rates per 100,000 terfenadine users demonstrated large declines about 18 months after initial regulatory action. Coprescription events of terfenadine with either erythromycin or ketaconazole continued to occur despite regulatory action. CONCLUSIONS: Results of this study suggest important roles for the pharmacist as a risk manager, disseminating information about newly published drug interactions. Both health providers and patients are audiences for the pharmacist's drug expertise. The delay in physician reaction to new information from pharmaceutical companies and the federal government suggests an early, strong role for the pharmacist in changing prescribing behavior.

Patient compliance--an overview.

This article reviews the major topic areas of compliance research. Much of the research in the area has focused on measurement, extent, and determinants of non-compliance. Research on the effectiveness of educational and behavioural strategies to improve compliance suggests the need to combine them. While some authors have attempted to model compliance or medication-taking behaviours, these models cannot be applied widely. After decades of compliance research, very little consistent information is available, except that people do not take their medications as prescribed. The methodological rigour of compliance studies may partially contribute to this situation. Methodological flaws have included design features and study execution. In addition, researchers have proceeded with studies without regard to a theoretical framework. Many have argued that much of the existing compliance literature also lacks conceptual rigour. Although we know that people do not take their medications consistently, we do not know specifically why they have done so. One reason for this lack of understanding is that compliance research has been dominated by the perspective of the health professional. To better understand medication-taking behaviour, researchers need to examine the patient's perspective. Consequently, future research needs to investigate a patient's decision-making process and the reasons for those decisions.

Agency for Health Care Policy and Research clinical practice guidelines.

OBJECTIVE: To review and summarize past activities of guidelines development at the Agency for Health Care Policy and Research (AHCPR) to enhance understanding of its new role and facilitate the development of new guidelines. DATA SYNTHESIS: The current Congressional climate and past criticisms of the guidelines development process have caused the AHCPR to reevaluate the way it produces guidelines. This assessment has resulted in the AHCPR restructuring its role to serve now as a science partner with private and public organizations. CONCLUSIONS: The development and role of evidence-based clinical practice guidelines are discussed, and the new roles of the AHCPR are described.

Human atherosclerotic plaques express DC-SIGN, a novel protein found on dendritic cells and macrophages.

The association of autoimmune phenomena with atherosclerosis suggests that plaques may contain specialized antigen-presenting cells, dendritic cells (DCs). DC-SIGN is a C-type lectin expressed by DCs. This study assessed whether human atherosclerotic plaques expressed DC-SIGN and several other macrophage/DC markers. Plaques from human coronary and carotid arteries and aorta contained DC-SIGN-immunoreactive cells. Double-labelling showed co-expression of DC-SIGN and macrophage/DC lineage markers CD14, CD68, HLA-DR, and S100. There was no immunoreactivity for the DC activation markers CD83 or CMRF-44. Since DC-SIGN mediates adhesion to T-lymphocytes and endocytosis, its expression in atherosclerotic plaques may have functional implications. Activated DCs migrate quickly from areas of inflammation to regional lymph nodes, possibly explaining the paucity of activated DCs in atherosclerotic plaques. In conclusion, this study has shown that DC-SIGN is expressed in atherosclerosis.

Assessment of cell cycle state may facilitate the histopathological diagnosis of malignant mesothelioma.

AIMS: The differentiation of benign pleural conditions from malignant mesothelioma may be difficult, especially with a small biopsy. We have tested the hypothesis that assessment of the cell cycle status is of value in the histopathological diagnosis of such biopsies, by comparing 33 malignant mesotheliomas with 36 cases of reactive mesothelial hyperplasia and reactive pleural fibrosis. METHODS AND RESULTS: Biopsies were investigated for proliferative status by immunostaining for a novel antibody, MCM2, all of which showed nuclear expression of MCM2 at higher frequency than Ki67 (P < 0.0001). Counts in areas of maximum tumour staining showed significantly higher labelling indices (LIMax) in epithelioid and sarcomatoid mesotheliomas compared with reactive mesothelial hyperplasia and reactive pleural fibrosis (P < 0.0001 for both). Average counts (LIAve) revealed a significant increase in epithelioid mesothelioma compared with reactive mesothelial hyperplasia (P < 0.0001). CONCLUSION: We consider MCM2 to be a useful adjunct in the differential diagnosis of malignant mesothelioma.

Nebulized budesonide versus oral steroid in severe exacerbations of childhood asthma.

The aim of this study was to assess whether nebulized budesonide may substitute for oral prednisolone in the management of children whose asthma is severe enough to warrant hospital admission, but who have no life threatening features. In a prospective, double-blind, randomized study nebulized budesonide (2 mg 8 hourly) was compared with oral prednisolone (2 mg/kg at entry and again at 24 h) in 46 children admitted to hospital with severe asthma exacerbations. Efficacy variables (including lung function measurements such as the primary outcome variable, Forced Expiratory Volume in 1 second (FEV1) and symptoms) were measured 24 h after treatment initiation. FEV1 improved significantly compared to baseline in patients who received nebulized budesonide compared to the prednislone group. The data show nebulized budesonide to be at least as effective as oral steroid in improving lung function and symptom severity in severe exacerbations of childhood asthma.

Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV.

Mechanisms of transplacental transmission of human immunodeficiency virus (HIV) are poorly understood. DC-SIGN is a C-type lectin able to bind HIV gp120 with high affinity, mediating HIV adsorption to the surface of dendritic cells for up to several days. Via this mechanism, DC-SIGN significantly enhances the infection of CD4(+) co-receptor (CCR5 or CXCR4)(+) T lymphocytes in trans. In this study, DC-SIGN-specific serum was developed to investigate the cell type responsible for the high level of DC-SIGN RNA expression previously observed in the placenta. DC-SIGN expression was shown on CD68(+) HLA-II(+) CD14(low) S100(+/-) CD83(-) CD86(-) cmrf-44(-) villous cells consistent with Hofbauer cells and also on CD68(+) HLA-II(+) CD14(high) S100(-) CD83(-) CD86(-) cmrf-44(-) decidual macrophages. The DC-SIGN(+) Hofbauer cells co-express CD4 and the chemokine receptors, CCR5 and CXCR4, observations which may account for the ability of these cells to become infected with HIV. These fetal DC-SIGN(+) cells are separated by only a layer of trophoblast from both DC-SIGN(+) maternal cells and maternal blood, potential sources of HIV in infected mothers. Previous studies have suggested that this trophoblast layer is frequently breached during pregnancy. It is therefore proposed that DC-SIGN may facilitate the transplacental transmission of HIV.

A novel immunohistochemical method for estimating cell cycle phase distribution in ovarian serous neoplasms: implications for the histopathological assessment of paraffin-embedded specimens.

We have investigated whether immunohistochemical markers can identify differences in cell cycle phase distribution in ovarian serous neoplasms, including borderline tumours of different grades. Sections of normal ovary (n=18), serous cystadenoma (n=21), borderline serous tumours (n=21) and serous cystadenocarcinoma (n=15) were analysed by immunohistochemistry using markers of cell cycle entry (Mcm-2) and cell cycle phase, including cyclin D1 (mid-to-late G1), cyclin A (S phase), cyclin B1 (G2 phase) and phosphohistone H3 (mitosis). Double-labelling confocal microscopy confirmed marker phase specificity and phase estimations were corroborated by flow cytometry. On progression from normal ovary through serous cystadenoma and borderline tumours to cystadenocarcinomas, expression of Mcm-2 (P<0.0001), cyclin D1 (P=0.002), cyclin A (P<0.0001), cyclin B1 (P<0.0001) and phosphohistone H3 (P<0.0001) increased, paralleled by an increase in the S-phase fraction (cyclin A : Mcm-2 ratio; P=0.002). Borderline tumours of increasing grade also showed increased Mcm-2 and cyclin A expression, together with an increase in the S-phase fraction. Immunohistochemistry can be used to estimate cell cycle phase distribution in ovarian serous neoplasms, giving results similar to flow cytometric analysis and enabling direct assessment of tumour heterogeneity. Immunohistochemical estimates of the S-phase fraction may identify serous borderline tumours likely to exhibit malignant progression and/or select serous cystadenocarcinomas likely to respond to adjuvant therapy.