Search

Background This study characterizes the outcomes and complications of surgical reconstruction of distal radioulnar joint (DRUJ) instability using the extensor retinaculum (Herbert sling). Our hypothesis was that extensor retinaculum reconstruction is a reliable method of DRUJ stabilization in adolescents. Methods This was a retrospective study of pediatric patients treated surgically using the Herbert sling for DRUJ instability at a single institution. We identified 22 subjects who underwent surgery at an average of 16.2 years of age (range, 12-18 years). Medical records and available imaging were reviewed for all subjects, and patients were contacted to participate in the prospective completion of the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. Results Preoperative symptoms were more commonly pain (95%) than feelings of DRUJ instability (45%), although 100% had instability on physical examination. Eight (36%) patients demonstrated limited supination preoperatively. Twenty-one subjects (95%) noted prior injury to that wrist, 15 of which were distal radius fractures. Surgery consisted of stabilization of the DRUJ using extensor retinaculum, in concert with other procedures to address all potential causes of wrist pain. Postoperatively, DRUJ stability was maintained in 21 of 22 subjects. Of the 12 patients who provided functional outcome scores, median QuickDASH score was 7.6 (range, 0-45). Conclusions Distal radioulnar joint instability in adolescents is often preceded by fracture of the distal radius. Surgeons must maintain a high level of suspicion to appropriately diagnose DRUJ instability, which is often not an isolated pathoanatomical problem. The Herbert sling technique using extensor retinaculum can successfully confer DRUJ stability in this population.

PURPOSE OF REVIEW: In the absence of antiretroviral therapy (ART), more than 50% of perinatally HIV infected children die by two years of age. Early ART from infancy is therefore a global recommendation and significantly improves immune health, child survival and disease outcome. However, even early treatment does not prevent or eradicate the latent reservoir necessitating life-long ART. Adherence to life-long ART is challenging for children and longstanding ART during chronic HIV infection led to higher risks of non-AIDS co-morbidities and virologic failure in infected children. Thus, HIV-infected children are an important population for consideration for immune-based interventions to achieve ART-free remission and functional cure. This review summarizes how the uniqueness of the early life immune system can be harnessed for the development of ART-free remission and functional cure, which means complete virus control in absence of ART. In addition, recent advances in therapeutics in the HIV cure field and their potential for the treatment of pediatric HIV infections are discussed. RECENT FINDINGS: Preclinical studies and clinical trials demonstrated that immune-based interventions target HIV replication, limit size of virus reservoir, maintain virus suppression, and delay time to virus rebound. However, these studies have been performed so far only in carefully selected HIV-infected adults, highlighting the need to evaluate the efficacy of immune-based therapeutics in HIV-infected children and to design interventions tailored to the early life maturing immune system. SUMMARY: Immune-based therapeutics alone or in combination with ART should be actively explored as potential strategies to achieve viral remission and functional cure in HIV-infected pediatric populations.

Background: Chronotype is an individual's preferred timing of sleep and activity, and is often referred to as a later chronotype (or evening-type) or an earlier chronotype (or morning-type). Having an evening chronotype is associated with more severe depressive and anxiety symptoms. Based on these findings it is has been suggested that chronotype is a stable construct associated with vulnerability to develop depressive or anxiety disorders. To examine this, we test the stability of chronotype over 7 years, and its longitudinal association with the change in severity of depressive and anxiety symptoms. Methods: Data of 1,417 participants with a depressive and/or anxiety disorder diagnosis and healthy controls assessed at the 2 and 9-year follow-up waves of the Netherlands Study of depression and anxiety were used. Chronotype was assessed with the Munich chronotype questionnaire. Severity of depressive and anxiety symptoms were assessed with the inventory of depressive symptomatology and Beck anxiety inventory. Results: Chronotype was found to be moderately stable (r = 0.53) and on average advanced (i.e., became earlier) with 10.8 min over 7 years (p

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique to treat psychiatric disorders, such as obsessive-compulsive disorder (OCD). However, the rTMS response varies across subjects.OBJECTIVE/HYPOTHESIS: We hypothesize that baseline network properties of the rTMS target may help understand this variation and predict response.METHODS: Excitatory rTMS to the dorsolateral prefrontal cortex (dlPFC) was applied in 19 unmedicated OCD patients, while inhibitory dlPFC-rTMS was applied in 17 healthy controls. The vertex was used as an active control target (19 patients, 18 controls). The rTMS response was operationalized as the individual change in state distress rating during an emotion regulation task. At baseline, subjects underwent resting-state functional MRI. The brain network was constructed by calculating wavelet coherence between regional activity of regions in the Brainnetome atlas. Local and integrative static connectivity and the dynamic network role of the target were calculated. Baseline target region network features were non-parametrically correlated to rTMS response.RESULTS: In the dlPFC-stimulated patients, greater local connectivity (Kendall's Tau = -0.415, p = 0.013) and less promiscuous role of the target (Kendall's Tau = 0.389, p = 0.025) at baseline were related to greater distress reduction after excitatory rTMS. There were no significant associations in healthy subjects nor in the active control stimulated patients.CONCLUSIONS: Pre-treatment network topological indices predict rTMS-induced emotional response changes in OCD, such that greater baseline resting-state local connectivity and less temporal integration of the target region imply greater stimulation effects. These results may lead the way towards personalized neuromodulation in OCD.

Background: Exposure and response prevention is an effective treatment for obsessive-compulsive disorder (OCD), but it is unclear how symptom reduction is related to changes in the brain. We aimed to determine the effects of a 4-day concentrated exposure and response prevention program (Bergen 4-day treatment) on the static and dynamic functional connectome in patients with OCD. Methods: Thirty-four patients with OCD (25 unmedicated) underwent resting-state functional magnetic resonance imaging the day before the Bergen 4-day treatment, and 28 (21 unmedicated) were rescanned after 1 week. Twenty-eight healthy control subjects were also scanned for baseline comparisons and 19 of them were rescanned after 1 week. Static and dynamic graph measures were quantified to determine network topology at the global, subnetwork, and regional levels (including efficiency, clustering, between-subnetwork connectivity, and node flexibility in module allegiance). The Yale-Brown Obsessive Compulsive Scale was used to measure symptom severity. Results: Twenty-four patients (86%) responded to treatment. We found significant group × time effects in frontoparietal-limbic connectivity (η p 2 = 0.19, p =.03) and flexibility of the right subgenual anterior cingulate cortex (η p 2 = 0.18, p =.03), where, in both cases, unmedicated patients showed significant decreases while healthy control subjects showed no significant changes. Healthy control subjects showed increases in global and subnetwork efficiency and clustering coefficient, particularly in the somatomotor subnetwork. Conclusions: Concentrated exposure and response prevention in unmedicated patients with OCD leads to decreased connectivity between the frontoparietal and limbic subnetworks and less flexibility of the connectivity of the subgenual anterior cingulate cortex, suggesting a more independent and stable network topology. This may represent less limbic interference on cognitive control subnetworks after treatment.

Background Population segmentation and risk stratification are important strategies for allocating resources in public health, health care and social care. Social exclusion, which is defined as the cumulation of disadvantages in social, economic, cultural and political domains, is associated with an increased risk of health problems, low agency, and as a consequence, a higher need for health and social care. The aim of this study is to test social exclusion against traditional social stratifiers to identify high-risk/high-need population segments. Methods We used data from 33,285 adults from the 2016 Public Health Monitor of four major cities in the Netherlands. To identify at-risk populations for cardiovascular risk, cancer, low self-rated health, anxiety and depression symptoms, and low personal control, we compared relative risks (RR) and population attributable fractions (PAF) for social exclusion, which was measured with the Social Exclusion Index for Health Surveys (SEI-HS), and four traditional social stratifiers, namely, education, income, labour market position and migration background. Results The analyses showed significant associations of social exclusion with all the health indicators and personal control. Particular strong RRs were found for anxiety and depression symptoms (7.95) and low personal control (6.36), with corresponding PAFs of 42 and 35%, respectively. Social exclusion was significantly better at identifying population segments with high anxiety and depression symptoms and low personal control than were the four traditional stratifiers, while the two approaches were similar at identifying other health problems. The combination of social exclusion with a low labour market position (19.5% of the adult population) captured 67% of the prevalence of anxiety and depression symptoms and 60% of the prevalence of low personal control, as well as substantial proportions of the other health indicators. Conclusions This study shows that the SEI-HS is a powerful tool for identifying high-risk/high-need population segments in which not only ill health is concentrated, as is the case with traditional social stratifiers, but also a high prevalence of anxiety and depression symptoms and low personal control are present, in addition to an accumulation of social problems. These findings have implications for health care practice, public health and social interventions in large cities.

BACKGROUND: Functional neuroimaging endophenotypes of obsessive-compulsive disorder (OCD) have been suggested during executive tasks. The purpose of this study was to investigate whether behavioral and neural responses during emotion processing and regulation also represent an endophenotype of OCD.METHODS: Forty-three unmedicated adult OCD patients, 19 of their unaffected siblings, and 38 healthy control participants underwent 3T functional magnetic resonance imaging during an emotion regulation task including neutral, fear-inducing, and OCD-related visual stimuli. Stimuli were processed during natural appraisal and during cognitive reappraisal, and distress ratings were collected after each picture. We performed between-group comparisons on task behavior and brain activation in regions of interest during emotion provocation and regulation.RESULTS: Siblings reported similar distress as healthy control participants during provocation, and significantly less than patients. There was no significant three-group difference in activation during fear provocation or regulation. Three-group comparisons showed that patients had higher amygdala and dorsomedial prefrontal cortex activation during OCD-related emotion provocation and regulation, respectively, while siblings were intermediate between patients and control participants but not significantly different from either. Siblings showed higher left temporooccipital activation (compared with both healthy control participants and patients) and higher frontolimbic connectivity (compared with patients) during OCD-related regulation.CONCLUSIONS: Unaffected siblings do not show the same distress and amygdala activation during emotional provocation as OCD patients. Siblings show distinct activation in a temporo-occipital region, possibly related to compensatory cognitive control. This suggests that emotion regulation is not a strong endophenotype for OCD. When replicated, this contributes to our understanding of familial risk and resilience for OCD.

The norm-based face space model (nMDFS) predicts that perceived typicality decreases with distance to the norm. Accordingly, an original face and its corresponding anti-face (deviating in exactly opposite direction from the norm) should inherit equivalent levels of typicality. Similarly, varying distance-to-norm (DTN, in absolute values) should have equivalent effects on typicality for both unfamiliar faces and their anti-faces. Here we reasoned that familiar faces would not follow this rule, due to the special nature of their mental representations. We investigated event-related brain potentials (ERPs) to familiar and unfamiliar faces and their anti-faces with different DTN (±0.33, ±0.66, and ±0.99). Across DTN, rated typicality was highest for original familiar faces, whereas all other face stimuli exhibited the expected gradual decrease of typicality with increasing DTN. ERPs showed pronounced DTN effects in the occipitotemporal P200 (190–260 ms), with progressively smaller amplitudes for faces with higher DTN, for all face types. By contrast, prominent effects of familiarity were found for the subsequent N250 (260–400 ms) and a late occipitotemporal negativity (LN, 400–800 ms). A large increase of occipitotemporal negativity was observed for original familiar faces versus their non-recognizable anti-faces. Analogous effects were small or absent for unfamiliar faces versus their anti-faces. These results confirm the N250 and LN as correlates of the processing of the identity of known faces, and show for the first time that the face-sensitive P200 is primarily modulated by DTN of a face in nMDFS.

We followed an ERP-based approach to gain knowledge on the dependence and temporal order of two essential processes of face perception: attractiveness and gender. By combining a dual-choice task with a go/nogo-paradigm focusing on the LRP and N200-effect, we could estimate the processing times and onsets of both types of face processing. The analyses of the LRP revealed that gender aspects were processed much earlier than attractiveness. Whereas gender was already analysed 243.9 ms post-stimulus onset, attractiveness came into play 58.6 ms later, i.e. after a post-stimulus onset delay of 302.5 ms. This resulting pattern was mirrored by the analyses of the N200-effect, an effect available mainly frontally which is supposed to correlate with the inhibition of inappropriate responses. Taking the onset of the N200 effect as an estimator for the moment at which information has been processed sufficiently for task decision, we could trace the N200 effect at 152.0 ms for go/nogo-decision on gender, while not as early as 206.7 ms on attractiveness. In sum, processing of facial attractiveness seems to be based on gender-specific aesthetic pre-processing, for instance via activating gender-specific attractiveness prototypes which show focused processing of certain facial aspects.

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term human immunodeficiency virus (HIV) remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth, as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the abilities of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and nonneutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain dependent. Moreover, we observe a strong correlation between the neutralization potencies and nonneutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.

Background: Obsessive-compulsive disorder (OCD) has been related to worse performance, abnormal brain activity, and functional connectivity during response inhibition. Whether these findings are indications of stable traits that contribute to the development of the disorder, or whether they are a result of the state severity of obsessions and anxiety, remains unclear since previous research mainly has employed cross-sectional designs. The present study aimed to assess longitudinal between- and within-person relationships between symptoms, task performance, right inferior frontal gyrus brain activation, and connectivity between the right amygdala and the right pre-supplementary motor area in 29 OCD patients before and after concentrated exposure and response prevention treatment.Method: Patients received exposure and response prevention delivered during 4 consecutive days, following the Bergen 4-day Treatment format. Patients performed a Stop Signal Task during 3T functional Magnetic Resonance Imaging the day before treatment, as well as 1 week and 3 months after treatment completion. Multilevel models were used to analyze disaggregated within- and between-person effects over time. Independent variables were scores on the symptom severity scales for OCD, anxiety, depression, and state distress during scanning. Dependent variables were reaction time for go trials, stop signal response time, task-related brain activation and connectivity.Results: A positive between-person effect was found for obsessive-compulsive, anxiety, and depressive symptom severity on go trial reaction time, indicating that patients with higher symptom scores on average respond slower during accurate go trials. We also found no significant between- or within-person relations between symptom severity and task-related activation or fronto-limbic connectivity.Conclusions: The between-person findings may point toward a general association between slower processing speed and symptom severity in OCD. Longitudinal studies should disaggregate between- and within-person effects to better understand variation over time.

Background There is no clear consensus for the criteria for closed treatment of metacarpal neck fractures. Our objective was to determine whether closed reduction of pediatric fifth metacarpal neck fractures results in a clinically meaningful improvement in radiographic angulation. Methods We performed a retrospective cohort study of pediatric patients with fifth metacarpal neck fractures treated with closed reduction. Radiographs were examined for sagittal fracture angulation measured post-reduction, 2 to 14 days post-reduction, and 21 to 35 days post-reduction. We compared the angulation for open versus closed physes, initial fracture angulation greater than or less than 50°, and immobilization in extension versus intrinsic-plus position. Results Fifty-four subjects were included with an average age of 14.8 years at the time of injury and a mean initial fracture angulation of 42.7°. The improvement in fracture angulation was 8.3° (90% confidence interval [CI], 5.9-10.7) on post-reduction radiographs, 8.5° (90% CI, 6.1-10.9) at 2 to 14 days post-reduction, and 4.3° (90% CI, 1.4-7.2) at 21 to 35 days post-reduction. Subgroup analysis showed that patients with injury angle greater than or equal to 50° had significantly higher mean reductions than those with injury angle less than 50°. In this group, angulation improved 15.6° (90% CI, 8.5-22.7) post-reduction, 15.1° (90% CI, 10.1-20.1) at 2 to 14 days post-reduction, and 16.5° (90% CI, 10.4-22.6) at 21 to 35 days post-reduction. Conclusions Closed reduction of pediatric fifth metacarpal neck fractures with initial fracture angulation less than 50° may not meaningfully improve sagittal alignment. For fractures with initial angulation greater than or equal to 50°, closed reduction resulted in clinically important, statistically significant, and lasting improvements of 16.5°.

Uncovering the sanctuaries of the long-lived HIV-1 reservoir is crucial to develop cure strategies. Pediatric immunity is distinct from that of adults, which may alter where the reservoir is established in infancy. Thus, it is important to utilize pediatric models to inform cure-directed approaches for HIV-1-infected children. We used an infant rhesus macaque model of HIV-1 infection via breastfeeding to identify key sites of viral persistence under antiretroviral therapy (ART). The gastrointestinal tract was found to be a site for low-level viral transcription during ART. We also show that naive CD4+ T cells harbored intact provirus and were a major contributor to blood and lymphoid reservoir size. This is particularly striking, as memory CD4+ T cells are generally regarded as the main source of latent HIV/simian immunodeficiency virus (SIV) infection of adult humans and rhesus macaques. Our findings highlight unique features of reservoir composition in pediatric infection that should be considered for eradication efforts., Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) continues to cause new pediatric cases of infection through breastfeeding, a setting where it is not always possible to initiate early antiretroviral therapy (ART). Without novel interventions that do not rely on daily ART, HIV-1-infected children face lifelong medications to control infection. A detailed analysis of virus persistence following breast milk transmission of HIV-1 and ART has not been performed. Here, we used infant rhesus macaques orally infected with simian/human immunodeficiency virus (SHIV) (SHIV.C.CH505) to identify cellular and anatomical sites of virus persistence under ART. Viral DNA was detected at similar levels in blood and tissue CD4+ T cells after a year on ART, with virus in blood and lymphoid organs confirmed to be replication competent. Viral RNA/DNA ratios were elevated in rectal CD4+ T cells compared to those of other sites (P ≤ 0.0001), suggesting that the gastrointestinal tract is an active site of virus transcription during ART-mediated suppression of viremia. SHIV.C.CH505 DNA was detected in multiple CD4+ T cell subsets, including cells with a naive phenotype (CD45RA+ CCR7+ CD95–). While the frequency of naive cells harboring intact provirus was lower than in memory cells, the high abundance of naive cells in the infant CD4+ T cell pool made them a substantial source of persistent viral DNA (approximately 50% of the total CD4+ T cell reservoir), with an estimated 1:2 ratio of intact provirus to total viral DNA. This viral reservoir profile broadens our understanding of virus persistence in a relevant infant macaque model and provides insight into targets for cure-directed approaches in the pediatric population. IMPORTANCE Uncovering the sanctuaries of the long-lived HIV-1 reservoir is crucial to develop cure strategies. Pediatric immunity is distinct from that of adults, which may alter where the reservoir is established in infancy. Thus, it is important to utilize pediatric models to inform cure-directed approaches for HIV-1-infected children. We used an infant rhesus macaque model of HIV-1 infection via breastfeeding to identify key sites of viral persistence under antiretroviral therapy (ART). The gastrointestinal tract was found to be a site for low-level viral transcription during ART. We also show that naive CD4+ T cells harbored intact provirus and were a major contributor to blood and lymphoid reservoir size. This is particularly striking, as memory CD4+ T cells are generally regarded as the main source of latent HIV/simian immunodeficiency virus (SIV) infection of adult humans and rhesus macaques. Our findings highlight unique features of reservoir composition in pediatric infection that should be considered for eradication efforts.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

Highlights • Less IFG activation and more fronto-limbic connectivity was found in OCD. • IFG hypoactivation and fronto-limbic hyperconnectivity persisted after exposure therapy. • Activation and connectivity before treatment did not predict treatment outcome., Response inhibition has previously been suggested as an endophenotype for obsessive–compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it’s unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.

Background Few population-based studies assess both invasive and in situ melanoma. We document all patients with a first biopsied melanoma in a general population in New Zealand (NZ). Methods All residents in a defined area of New Zealand with a biopsy showing a new primary invasive or in situ melanoma from 2010 to 2012 were identified, 974 patients; analysis used multivariate methods. Results Age-standardised incidence rates were 34.3 in females (F) and 41.4 in males (M) for invasive, 20.9 F and 27.6 M for in situ, and 55.2 F and 69.0 M for total melanoma. More in situ melanoma occurred in older patients and on the head and neck. Geometric mean Breslow thickness for invasive was 0.78 mm F and 0.85 mm M, with thicker lesions at ages over 60 and on the lower limb; there was no significant relationship with sex, distance from care or social deprivation assessed from residential address. Nodular melanomas (15%) were more frequent in older and male patients, and on the limbs, and were thicker. The estimated cumulative risk for melanoma is 4.4% F and 4.6% M by age 70. The body site distribution and sex differences were consistent with sun exposure patterns. Estimated incidence of melanoma in New Zealand in 2018 is 2500 invasive and 1700 in situ cases. Conclusions Assessing both in situ and invasive melanoma expands the clinical picture, better estimating health care demand and costs. Results suggest that in situ disease is a more slowly growing lesion than the early phase of invasive disease. The features of thicker or nodular melanoma show priorities for prevention and early detection.

Aim: To describe the clinical features, treatment and outcomes in Australian adults with focal segmental glomerulosclerosis and identify predictors of disease progression and all-cause mortality. Methods: The study included all patients with biopsy confirmed focal segmental glomerulosclerosis between January 1997 and June 2014 at participating hospitals. Clinical factors, histopathological findings, biochemical markers and treatments were analysed and potential predictors of doubling serum creatinine, end stage kidney disease or death identified. Results: 98 patients were included with a median follow-up of 4.3 years. 34 (35%) patients were Aboriginal or Torres Strait Islander. Focal segmental glomerulosclerosis not otherwise specified was the most common variant. 17 (59%) patients initially treated with immunosuppression experienced an improvement in renal function. At the end of follow-up 43 (44%) patients had progressed to the composite outcome. Baseline tubulointerstitial scarring and lower haemoglobin predicted shorter time to doubling serum creatinine. Dual diagnosis, higher serum creatinine, lower estimated glomerular filtration rate and doubling creatinine were associated with shorter time to end stage kidney disease with remission the only protective factor. Age was the only variable associated with all-cause mortality. Conclusion: Focal segmental glomerulosclerosis holds serious implications for patients. Concomitant diabetic nephropathy, higher serum creatinine and lower estimated glomerular filtration rate at renal biopsy were associated with poorer renal prognosis. Indigenous people had a female predominance and are over-represented in relation to their population size, however were not associated with poorer prognosis. Remission was the only modifiable variable and thus should be at the forefront of patient management goals and future studies.

Adhesive shoulder capsulitis, or arthrofibrosis, describes a pathological process in which the body forms excessive scar tissue or adhesions across the glenohumeral joint, leading to pain, stiffness and dysfunction. It is a debilitating condition that can occur spontaneously (primary or idiopathic adhesive capsulitis) or following shoulder surgery or trauma (secondary adhesive capsulitis). Here, we review the pathophysiology of adhesive shoulder capsulitis, highlighting its clinical presentation, natural history, risk factors, pathoanatomy and pathogenesis. Both current non-operative and operative treatments for adhesive capsulitis are described, and evidence-based studies are presented in support for or against each corresponding treatment. Finally, the review also provides an update on the gene expression profile of adhesive capsulitis and how this new understanding can help facilitate development of novel pharmacological therapies.

Most organisms have an endogenous circadian clock with a period length of approximately 24 h that enables adaptation, synchronization and anticipation to environmental cycles. The circadian system (circa = about or around, diem = a day) may provide evolutionary benefits when entrained to the 24-h light-dark cycle. The more the internal circadian period (τ) deviates from the external light-dark cycle, the larger the daily phase shifts need to be to synchronize to the environment. In some species, large daily phase shifts reduce survival rate. Here we tested this 'resonance fitness hypothesis' on the diurnal wasp Nasonia vitripennis, which exhibits a large latitudinal cline in free-running period with longer circadian period lengths in the north than in the south. Longevity was measured in northern and southern wasps placed into light-dark cycles (T-cycles) with periods ranging from 20 h to 28 h. Further, locomotor activity was recorded to estimate range and phase angle of entrainment under these various T-cycles. A light pulse induced phase response curve (PRC) was measured in both lines to understand entrainment results. We expected a concave survival curve with highest longevity at T = τ and a reduction in longevity the further τ deviates from T (τ/T<>1). Our results do not support this resonance fitness hypothesis. We did not observe a reduction in longevity when τ deviates from T. Our results may be understood by the strong circadian light resetting mechanism (type 0 PRC) to single light pulses that we measured in Nasonia, resulting in: (1) the broad range of entrainment, (2) the wide natural variation in circadian free-running period, and (3) the lack of reduced survival when τ/T ratio's deviates from 1. Together this indicates that circadian adaption to latitude may lead to changes in circadian period and light response, without negative influences on survival.

Contains fulltext : 207095.pdf (Publisher’s version ) (Open Access) BACKGROUND: Social exclusion (SE), or the inability to participate fully in society, is considered one of the driving forces of health inequalities. Systematic evidence on this subject is pertinent but scarce. This review aims to systematically summarise peer reviewed studies examining the association between the multidimensional concepts of SE and social inclusion (SI) and health among adults in EU and OECD countries. METHODS: The protocol was registered on Prospero (CRD42017052718). Three major medical databases were searched to identify studies published before January 2018, supplemented by reference and citation tracking. Articles were included if they investigated SE or SI as a multidimensional concept with at least two out of the four dimensions of SE/SI, i.e. economic, social, political and cultural. A qualitative synthesis was conducted. RESULTS: Twenty-two observational studies were included. In the general population, high SE/low SI was associated with adverse mental and general health. For physical health, the evidence was inconclusive. In groups at high risk of SE, support was found for the association between high SE/low SI and adverse mental health but no conclusions could be drawn for physical and general health. CONCLUSIONS: This review found evidence for the association between high SE/low SI and adverse health outcomes, particularly mental health outcomes. The evidence is mainly based on cross-sectional studies using simple and often ad hoc indicators of SE/SI. The development and use of validated measures of SE/SI and more longitudinal research is needed to further substantiate the evidence base and gain better understanding of the causal pathways.

Background The incidence, presentation and outcomes of lupus nephritis (LN) vary with geography, ethnicity, socioeconomic status and gender. There are relatively few data on LN in the non-Caucasian populations in Australia. Aims To describe the clinical presentation, histological features, natural history, and outcomes of a historical cohort of Aboriginal and Torres Strait Islanders people in Far North Queensland with biopsy-proven LN. Methods This is a retrospective observational study, and the study was conducted in Cairns and Hinterland Hospital and Health Service, Queensland, Australia. The study included Aboriginal and Torres Strait Islander patients with biopsy-proven LN treated between 1990 and 2013. The main outcome measures were renal replacement therapy and overall patient survival. Results Aboriginal and Torres Strait Islander people represented a substantial proportion (n = 16/40, 40%) of all patients diagnosed with LN during the observation period. The frequency of nephrotic range proteinuria (n = 11/14, 78.5%), estimated glomerular filtration rate

Until a few years ago, lymphatic vessels and lymphatic endothelial cells (LEC) were viewed as part of a passive conduit for lymph and immune cells to reach lymph nodes (LN). However, recent work has shown that LEC are active immunological players whose interaction with dendritic cells and T cells is of important immunomodulatory relevance. While the immunological interaction between LEC and other immune cells has taken a center stage, molecular analysis of LEC antigen processing and presentation machinery is still lagging. Herein we review the current knowledge of LEC MHC I and MHC II antigen processing and presentation pathways, Including the role of LEC in antigen phagocytosis, classical, and non-classical MHC II presentation, proteasome processing and MHC I presentation, and cross-presentation. The ultimate goal is to provide an overview of the LEC antigen processing and presentation machinery that constitutes the molecular basis for their role in MHC I and MHC II-restricted immune responses.

Impaired cognitive–motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive–motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

BackgroundError processing and inhibitory control enable the adjustment of behaviors to meet task demands. Functional magnetic resonance imaging studies report brain activation abnormalities in patients with obsessive-compulsive disorder (OCD) during both processes. However, conclusions are limited by inconsistencies in the literature and small sample sizes. Therefore, the aim here was to perform a meta-analysis of the existing literature using unthresholded statistical maps from previous studies.MethodsA voxelwise seed-based d mapping meta-analysis was performed using t-maps from studies comparing patients with OCD and healthy control subjects (HCs) during error processing and inhibitory control. For the error processing analysis, 239 patients with OCD (120 male; 79 medicated) and 229 HCs (129 male) were included, while the inhibitory control analysis included 245 patients with OCD (120 male; 91 medicated) and 239 HCs (135 male).ResultsPatients with OCD, relative to HCs, showed longer inhibitory control reaction time (standardized mean difference= 0.20, p= .03, 95% confidence interval= 0.016, 0.393) and more inhibitory control errors (standardized mean difference= 0.22, p= .02, 95% confidence interval= 0.039, 0.399). In the brain, patients showed hyperactivation in the bilateral dorsal anterior cingulate cortex, supplementary motor area, and pre-supplementary motor area as well as right anterior insula/frontal operculum and anterior lateral prefrontal cortex during error processing but showed hypoactivation during inhibitory control in the rostral and ventral anterior cingulate cortices and bilateral thalamus/caudate, as well as the right anterior insula/frontal operculum, supramarginal gyrus, and medial orbitofrontal cortex (all seed-based d mapping z value >2, p < .001).ConclusionsA hyperactive error processing mechanism in conjunction with impairments in implementing inhibitory control may underlie deficits in stopping unwanted compulsive behaviors in the disorder.

Alcohol dependence has long been related to impaired emotion regulation-including reappraisal-but little is known about the performance and associated neural activity of alcohol-dependent patients (ADPs) on an emotion reappraisal task. This study, therefore, compares reappraisal of negative, positive, neutral, and alcohol-related images at a behavioral and neural level between ADPs and healthy controls (HCs). Thirty-nine ADPs and 39 age-, gender-, and education-matched HCs performed an emotion reappraisal task during functional magnetic resonance imaging (fMRI), and craving was measured before and after the reappraisal task. During the emotion reappraisal task, participants were instructed to either attend or reappraise positive, negative, neutral, or alcohol-related images, and to indicate their experienced emotion on a visual analogue scale (VAS). Both ADPs and HCs completed the emotion reappraisal task successfully, showing significant differences in self-reported experienced emotion after attending versus reappraising visual stimuli and in brain activity in emotion processing/reappraisal relevant areas. ADPs were not impaired in cognitive reappraisal at a behavioral or neural level relative to HCs, nor did ADPs indicate any difference in self-reported emotion while attending emotional images. However, ADPs were different from HC in emotion processing: ADPs revealed a blunted response in the (posterior) insula, precuneus, operculum, and superior temporal gyrus while attending emotional images compared neutral images compared to HCs, and in ADPs, higher baseline craving levels were associated with a less blunted response to alcohol-related images than in HCs. These results reveal that ADPs do not show impaired reappraisal abilities when instructed, although future studies should assess voluntary reappraisal abilities in alcohol-dependent patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

Contains fulltext : 215791.pdf (Publisher’s version ) (Open Access) BACKGROUND: The recently developed Social Exclusion Index for Health Surveys (SEI-HS) revealed particularly strong social exclusion in non-Western immigrant groups compared to the native Dutch population. To qualify such results, cross-cultural validation of the SEI-HS in non-Western immigrant groups is called for. METHODS: A sequential explanatory mixed methods design was used, employing quantitative data from the Netherlands Public Health Monitor along with qualitative interviews. Data from 1,803 adults aged 19 years or older of Surinamese, 1,009 of Moroccan and 1,164 of Turkish background and 19,318 native Dutch living in the four largest cities in the Netherlands were used to test the factorial structure of the SEI-HS and differential item functioning across immigrant groups. Additionally, 52 respondents with a high score on the SEI-HS and from different background were interviewed on the item content of the SEI-HS and subjective feelings of exclusion. For each SEI-HS item the semantic, conceptual and contextual connotations were coded and compared between the immigrant groups and native Dutch. RESULTS: High levels of social exclusion were found in 20.0% of the urban population of Surinamese origin, 20.9% of Moroccan, 28.7% of Turkish and 4.2% of native Dutch origin. The 4-factor structure of the SEI-HS was confirmed in all three immigrant groups. None of the items demonstrated substantial differential item functioning in relation to immigration background. The interviews uncovered some methodological shortcomings, but these did not substantially impact the observed excess of social exclusion in immigrant groups. CONCLUSIONS: The present study provides evidence in support of the validity of the SEI-HS in adults of Surinamese, Moroccan and Turkish background and confirms the major social exclusion of these immigrant groups in the main cities in the Netherlands. Policy measures to enhance social inclusion and reduce exclusion are urgently needed.

Lymphatic and blood vessels are formed by specialized lymphatic endothelial cells (LEC) and blood endothelial cells (BEC), respectively. These endothelial populations not only form peripheral tissue vessels, but also critical supporting structures in secondary lymphoid organs, particularly the lymph node (LN). Lymph node LEC (LN-LEC) also have been shown to have important immunological functions that are not observed in LEC from tissue lymphatics. LN-LEC can maintain peripheral tolerance through direct presentation of self-antigen via MHC-I, leading to CD8 T cell deletion; and through transfer of self-antigen to dendritic cells for presentation via MHC-II, resulting in CD4 T cell anergy. LN-LEC also can capture and archive foreign antigens, transferring them to dendritic cells for maintenance of memory CD8 T cells. The molecular basis for these functional elaborations in LN-LEC remain largely unexplored, and it is also unclear whether blood endothelial cells in LN (LN-BEC) might express similar enhanced immunologic functionality. Here, we used RNA-Seq to compare the transcriptomic profiles of freshly isolated murine LEC and BEC from LN with one another and with freshly isolated LEC from the periphery (diaphragm). We show that LN-LEC, LN-BEC, and diaphragm LEC (D-LEC) are transcriptionally distinct from one another, demonstrating both lineage and tissue-specific functional specializations. Surprisingly, tissue microenvironment differences in gene expression profiles were more numerous than those determined by endothelial cell lineage specification. In this regard, both LN-localized endothelial cell populations show a variety of functional elaborations that suggest how they may function as antigen presenting cells, and also point to as yet unexplored roles in both positive and negative regulation of innate and adaptive immune responses. The present work has defined in depth gene expression differences that point to functional specializations of endothelial cell populations in different anatomical locations, but especially the LN. Beyond the analyses provided here, these data are a resource for future work to uncover mechanisms of endothelial cell functionality.

While evaluation, diagnosis, and treatment of soft tissue masses are a daily part of the orthopaedic oncologist's practice, it is rare for a patient to present initially to the orthopaedic clinic with melanoma. More commonly, the patient presents as a referral from the medical oncologist for 1) evaluation of a long bone metastasis concerning for [impending] pathologic fracture or 2) amputation of a digit or limb to achieve wide resection for cure. We present here a rare case of metastatic melanoma presenting initially to the orthopaedic oncologist as a fungating soft tissue mass concerning for a sarcoma. Through effective collaboration with a melanoma specialist at our cancer center, an impressive local response was observed within weeks of initiating targeted therapy with encorafenib and binimetinib. The patient was thus spared a palliative amputation.

Introduction: Brain regions are anatomically and functionally interconnected in order to facilitate important functions like cognition and movement. It remains incompletely understood how brain connectivity contributes to the pathophysiology of Tourette's disorder (TD). By using resting-state functional MRI, we aimed to identify alterations in the default mode network (DMN), frontal-parietal network (FPN), sensori-motor network (SMN), and salience network (SN) in TD compared with healthy control (HC) subjects.Method: In 23 adult TD patients and 22 HC, 3T-MRI resting-state scans were obtained. Independent component analysis was performed comparing TD and HC to investigate connectivity patterns within and between resting-state networks.Results: TD patients showed higher involvement of the dorsal medial prefrontal cortex in the connectivity of the DMN and less involvement of the inferior parietal cortex in the connectivity of the FPN when compared to HC. Moreover, TD patients showed a stronger coupling between DMN and left FPN than HC. Finally, in TD patients, functional connectivity within DMN correlated negatively with tic severity.Conclusion: We tentatively interpret the increased functional connectivity within DMN in TD patients as compensatory to the lower functional connectivity within left FPN. The stronger coupling between DMN and left FPN, together with the finding that higher DMN intrinsic connectivity is associated with lower tic severity would indicate that DMN is recruited to exert motor inhibition.

Background: The role of chronotype, the individual timing of sleep/activity, has been studied in relation todepressive and anxiety disorders. A cross-sectional association between a depressive episode and evening-typehas been identified. However, until now the predicting capacity of chronotype concerning persistence of psy-chiatric disorders remains unclear. Our aim is to examine whether a later chronotype in patients with a de-pressive and/or anxiety disorder can serve as a predictor of a persistent course.Methods: A subsample of patients with a depressive and/or anxiety disorder diagnosis and chronotype data ofthe longitudinal Netherlands Study of Depression and Anxiety (NESDA) was used. Diagnosis of depressive andanxiety disorders (1-month DSM-IV based diagnosis) were determined at baseline (n = 505). From this grouppersistence was determined at 2-year (FU2) (persistent course: n = 248, non-persistent course: n = 208) and 4-year follow-up (FU4) (persistent course: n = 151, non-persistent course: n = 264). Chronotype was assessed atbaseline with the Munich Chronotype Questionnaire.Results: A later chronotype did not predict a persistent course of depressive and/or anxiety disorder at FU2 (OR(95% CI) = 0.99 (0.83–1.19), P = 0.92) or at FU4 (OR (95% CI) = 0.94 (0.77–1.15), P = 0.57).Limitations: Persistence was defined as having a diagnosis of depressive and/or anxiety disorder at the two-yearand four-year follow-up, patients may have remitted and relapsed between assessments.Conclusion: Chronotype, measured as actual sleep timing, of patients with a depressive or anxiety disorder didnot predict a persistent course which suggests it might be unsuitable as predictive tool in clinical settings.

Background and objectives Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by tics. A hallmark of GTS is the ability to voluntarily suppress tics. Our aim was to distinguish the neural circuits involved in the voluntary suppression of ocular tics in GTS patients from blink suppression in healthy subjects. Methods Fifteen GTS patients and 22 healthy control subjects were included in a multimodal study using eye-tracker recordings during functional MRI (fMRI). The ability to suppress tics/blinks was compared both on subjective (self-rating) and objective (eye-tracker) performance. For fMRI analysis we used a novel designed performance-adapted block design analysis of tic/blink suppression and release based on eye-tracker monitoring. Results We found that the subjective self-reported ability to suppress tics or blinks showed no significant correlation with objective task performance. In GTS during successful suppression of tics, the dorsal anterior cingulate cortex and associated limbic areas showed increased activation. During successful suppression of eye blinks in healthy subjects, the right ventrolateral prefrontal cortex and supplementary and cingulate motor areas showed increased activation. Conclusions These findings demonstrate that GTS patients use a characteristic limbic suppression strategy. In contrast, control subjects use the voluntary sensorimotor circuits and the classical ‘stop’ network to suppress natural urges. The employment of different neural suppression networks provides support for cognitive behavioral therapy in GTS., Highlights • Neural networks of tic suppression are specific and differ from blink suppression. • Tourette patients employ a limbic suppression strategy to suppress tics. • Controls use sensorimotor circuits and ‘stop’ networks for blink suppression. • Objective task performance is highly recommended during functional MRI of tics.

Motor axons in peripheral nerves have the capacity to regenerate after injury. However, full functional motor recovery rarely occurs clinically, and this depends on the nature and location of the injury. Recent preclinical findings suggest that there may be a time after nerve injury where, while regrowth to the muscle successfully occurs, there is nevertheless a failure to re-establish motor function, suggesting a possible critical period for synapse reformation. We have now examined the temporal and anatomical determinants for the re-establishment of motor function after prolonged neuromuscular junction (NMJ) denervation in rats and mice. Using both sciatic transection-resuture and multiple nerve crush models in rats and mice to produce prolonged delays in reinnervation, we show that regenerating fibres reach motor endplates and anatomically fully reform the NMJ even after extended periods of denervation. However, in spite of this remarkably successful anatomical regeneration, after 1 month of denervation there is a consistent failure to re-establish functional recovery, as assessed by behavioural and electrophysiological assays. We conclude that this represents a failure in re-establishment of synaptic function, and the possible mechanisms responsible are discussed, as are their clinical implications.

© 2015 Elsevier Inc. Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability. Omura et al. screened for neuronal growth on myelin and find CAST/Ei inbred mice are uniquely able to regenerate axons in the injured CNS through Activin signaling. Enhancing Activin signaling confers a CNS-regenerative capacity in normally non-regenerative mouse strains.

Objectives: Impaired response inhibition is related to neurodevelopmental disorders, such as Tourette’s disorder (TD) and obsessive-compulsive disorder (OCD). Unlike OCD, in which neural correlates of response inhibition have been extensively studied, TD literature is limited. By using a Stop-Signal task, we investigated the neural mechanisms underlying response inhibition deficits in TD compared to OCD and healthy controls (HCs). Methods: Twenty-three TD patients, 20 OCD patients and 22 HCs were scanned (3T MRI). Region-of-interest analyses were performed between TD, OCD and HCs. Results: Performance was similar across all subject groups. During inhibition TD compared with HCs showed higher right inferior parietal cortex (IPC) activation. During error processing TD compared with HCs showed hyperactivity in the left cerebellum, right mesencephalon, and right insula. Three-group comparison showed an effect of group for error-related activation in the supplementary motor area (SMA). Post-hoc analyses showed higher error-related SMA activity in TD compared with OCD and HCs. Error-related left cerebellar activity correlated positively with tic severity. Conclusions: Hyperactivation of IPC during inhibition and a widespread hyperactivated network during error processing in TD suggest compensatory inhibition- and error-related circuit recruitment to boost task performance. The lack of overlap with activation pattern in OCD suggests such compensatory mechanism is TD-specific.

Background Social exclusion (SE) refers to the inability of certain groups or individuals to fully participate in society. SE is associated with socioeconomic inequalities in health, and its measurement in routine public health monitoring is considered key to designing effective health policies. In an earlier retrospective analysis we demonstrated that in all four major Dutch cities, SE could largely be measured with existing local public health monitoring data. The current prospective study is aimed at constructing and validating an extended national measure for SE that optimally employs available items. Methods In 2012, a stratified general population sample of 258,928 Dutch adults completed a version of the Netherlands Public Health Monitor (PHM) questionnaire in which 9 items were added covering aspects of SE that were found to be missing in our previous research. Items were derived from the SCP social exclusion index, a well-constructed 15-item instrument developed by the Netherlands Institute for Social Research (SCP). The dataset was randomly divided into a development sample (N =129,464) and a validation sample (N = 129,464). Canonical correlation analysis was conducted in the development sample. The psychometric properties were studied and compared with those of the original SCP index. All analyses were then replicated in the validation sample. Results The analysis yielded a four dimensional index, the Social Exclusion Index for Health Surveys (SEI-HS), containing 8 SCP items and 9 PHM items. The four dimensions: “lack of social participation”, “material deprivation”, “lack of normative integration” and “inadequate access to basic social rights”, were each measured with 3 to 6 items. The SEI-HS showed adequate internal consistency for both the general index and for two of four dimension scales. The internal structure and construct validity of the SEI-HS were satisfactory and similar to the original SCP index. Replication of the SEI-HS in the validation sample confirmed its generalisability. Conclusion This study demonstrates that the SEI-HS offers epidemiologists and public health researchers a uniform, reliable, valid and efficient means of assessing social exclusion and its underlying dimensions. The study also provides valuable insights in how to develop embedded measures for public health surveillance. Electronic supplementary material The online version of this article (doi:10.1186/s12889-017-4175-1) contains supplementary material, which is available to authorized users.

Objectives: Executive network deficits are putative neurocognitive endophenotypes for obsessive-compulsive disorder (OCD). Yet, unlike alterations in fronto-striatal and limbic connectivity, connectivity in the fronto-parietal (FPN) and cingulo-opercular (CON) networks involved in cognitive control has received little attention. Methods: The coherence of FPN, CON and fronto-limbic networks was investigated in 39 unmedicated OCD patients, 16 of their unaffected siblings and 36 healthy controls using resting-state functional-connectivity MRI and a seed-based analysis approach. Results: FPN and CON connectivity was similar for patients and controls. Siblings showed higher connectivity than patients within the CON, and between the CON and FPN compared to patients and controls (trend level). In OCD patients, but not in siblings, fronto-limbic hyperconnectivity was present compared to controls. In contrast to our expectations, no group differences in resting-state connectivity of the cognitive control networks were observed between OCD patients and controls. Conclusions: The increased within- and between-network connectivity in siblings, but not in patients, could indicate a mechanism of increased cognitive control that may act as a protective mechanism. None of the observed network alterations can be considered an endophenotype for OCD since differences were present in either patients or siblings, but not in both groups.

According to the norm-based version of the multidimensional face space model (nMDFS, Valentine, 1991), any given face and its corresponding anti-face (which deviates from the norm in exactly opposite direction as the original face) should be equidistant to a hypothetical prototype face (norm), such that by definition face and anti-face should bear the same level of perceived typicality. However, it has been argued that familiarity affects perceived typicality and that representations of familiar faces are qualitatively different (e.g., more robust and image-independent) from those for unfamiliar faces. Here we investigated the role of face familiarity for rated typicality, using two frequently used operationalisations of typicality (deviation-based: DEV), and distinctiveness (face in the crowd: FITC) for faces of celebrities and their corresponding anti-faces. We further assessed attractiveness, likeability and trustworthiness ratings of the stimuli, which are potentially related to typicality. For unfamiliar faces and their corresponding anti-faces, in line with the predictions of the nMDFS, our results demonstrate comparable levels of perceived typicality (DEV). In contrast, familiar faces were perceived much less typical than their anti-faces. Furthermore, familiar faces were rated higher than their anti-faces in distinctiveness, attractiveness, likability and trustworthiness. These findings suggest that familiarity strongly affects the distribution of facial representations in norm-based face space. Overall, our study suggests (1) that familiarity needs to be considered in studies of mental representations of faces, and (2) that familiarity, general distance-to-norm and more specific vector directions in face space make different and interactive contributions to different types of facial evaluations.

ObjectivesReversal learning (RL) is impaired in obsessive–compulsive disorder (OCD) as well as in major depressive disorder (MDD). It is yet unknown to what extent pathophysiological mechanisms are state-dependent.MethodsNeural activation patterns during RL were measured using event-related functional magnetic resonance imaging (fMRI) reversal learning in patients with OCD (N=18) and MDD (N=15). A naturalistic follow-up design enabled investigation of the relationship between changes in clinical state, task performance and task-related neural activation over time.ResultsDuring follow-up, disease severity decreased significantly in both groups. Whereas task speed improved trend-significantly, task accuracy was unchanged. Task-related dorsal frontal-striatal activation decreased at follow-up in MDD, but increased in OCD. In both groups, symptom improvement was associated with reward-related changes in neural activation in the putamen and the orbitofrontal cortex.ConclusionsIn both OCD and MDD, symptom reduction over time was associated with partial normalization of task-related activation patterns in brain regions. Whereas in OCD this normalization was characterized by increased recruitment of previously hypoactive frontal-striatal brain regions (i.e. dorsal frontal-striatal failure), in MDD previously hyperactive brain regions (frontal-striatal inefficiency), were recruited less after recovery. These results show that in both disorders frontal-striatal dysfunction is at least partly state-dependent.

Background: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive–compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored.Methods: We performed a mega-analysis pooling structural MRI scans from the Obsessive–compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software.Results: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex.Limitations: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres.Conclusion: Our results provide evidence for structural network–level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders.

Objective: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with moderate genetic influences and white matter abnormalities in frontal-striatal and limbic regions. Inconsistencies in reported white matter results from diffusion tensor imaging (DTI) studies can be explained, at least partly, by medication use and between-group differences in disease profile and stage. We used a family design aiming to establish whether white matter abnormalities, if present in un-medicated OCD patients, also exist in their unaffected siblings.Method: Forty-four OCD patients, un-medicated for at least the past 4 weeks, 15 of their unaffected siblings, and 37 healthy controls (HC) underwent DTI using a 3-Tesla MRI-scanner. Data analysis was done using tract-based spatial statistics (TBSS). Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values were compared within seven skeletonised regions of interest (ROIs), i.e., corpus callosum, bilateral cingulum bundle, bilateral inferior longitudinal fasciculus/frontal-occipital fasciculus (ILF/FOF) and bilateral superior longitudinal fasciculus (SLF).Results: Un-medicated OCD patients, compared with HC, had significantly lower FA in the left cingulum bundle. FA was trend-significantly lower in all other ROIs, except for the corpus callosum. Significant three-group differences in FA (and in RD at trend-significant level) were observed in the left cingulum bundle, with the unaffected siblings representing an intermediate group between OCD patients and HC.Conclusions: OCD patients showed lower FA in the left cingulum bundle, partly driven by trend-significantly higher values in RD. Since the unaffected siblings were found to be an intermediate group between OCD patients and HC, this white matter alteration may be considered an endophenotype for OCD.

BackgroundThere is accumulating evidence for the role of fronto-striatal and associated circuits in obsessive–compulsive disorder (OCD) but limited and conflicting data on alterations in cortical thickness.AimsTo investigate alterations in cortical thickness and subcortical volume in OCD.MethodIn total, 412 patients with OCD and 368 healthy adults underwent magnetic resonance imaging scans. Between-group analysis of covariance of cortical thickness and subcortical volumes was performed and regression analyses undertaken.ResultsSignificantly decreased cortical thickness was found in the OCD group compared with controls in the superior and inferior frontal, precentral, posterior cingulate, middle temporal, inferior parietal and precuneus gyri. There was also a group x age interaction in the parietal cortex, with increased thinning with age in the OCD group relative to controls.ConclusionsOur findings are partially consistent with earlier work, suggesting that group differences in grey matter volume and cortical thickness could relate to the same underlying pathology of OCD. They partially support a frontostriatal model of OCD, but also suggest that limbic, temporal and parietal regions play a role in the pathophysiology of the disorder. The group x age interaction effects may be the result of altered neuroplasticity.

A method for simultaneous detection of fluorescence in situ hybridization of DNA probes and high resolution fluorescent R banding is described. Human lymphocytes were stimulated with phytohemagglutinin and synchronized using a fluorouracil block followed by exposure to bromodeoxyuridine and Hoechst 33258 prior to harvest. Metaphase preparations were treated with Hoechst 33258 and exposed to UV light. Thereafter they were incubated in sodium phosphate buffer and dried prior to in situ hybridization with a biotin-labelled centromere-specific alpha-satellite DNA probe for chromosome 1 (pUCl.77) and two digoxigenin-labelled probes, i.e., a PCR-generated chromosome 8-specific alphoid probe (#8) and a cosmid probe for FLT4 gene on 5q33-qter (class III receptor tyrosine kinase). Hybridization signals were detected by an indirect immunofluorescence method using fluorescein isothiocyanate. The chromosomes were counterstained with propidium iodide and 4',6-diamidino-2-phenylindole dihydrochloride. This simple method allows unambiguous chromosome band identification simultaneously with detection of the hybridized probes.

Introduction OCD symptoms have been associated with task-dependent alterations in brain activity implying dysregulation in limbic (e.g. the amygdala) and frontal-striatal circuits. Emerging evidence shows that there are functional neural endophenotypes in executive processing suggesting compensatory hyperactivation of fronto-parietal executive control networks and fronto-limbic dysregulation in OCD patients and first-degree relatives (de Wit et al., 2012; van Velzen et al., 2015). There are however few studies on emotional processing using a family-study design. We recently showed altered frontal-parietal and limbic functioning in OCD patients during emotion processing and emotion regulation (de Wit et al., 2015), but it remains unclear if these changes are also present in first-degree relatives. Method Forty-three unmedicated adult OCD patients, 19 of their unaffected siblings and 38 healthy controls underwent functional magnetic resonance imaging (MRI) during an emotion regulation task including neutral, fear and OCD-related visual stimuli. Stimuli were processed during natural appraisal (‘attend’ instruction) and during cognitive reappraisal (‘regulate’ instruction). Self-report distress ratings were collected from each picture. The neural correlates of emotion regulation were assessed using SPM12. Results Fear and OCD symptom provocation resulted in higher self-report distress ratings in patients compared with both siblings and healthy controls. Functional MRI analyses showed that specifically during OCD-related provocation, compared with controls, BOLD activation amplitude and timing was altered in the left hippocampus, right caudate nucleus and amygdala (for both patients and siblings), and bilateral thalamus (for siblings only). During fear regulation we previously found fronto-parietal hypoactivation in OCD patients, but fronto-parietal activation was not significantly different in siblings from patients or controls. During regulation of OCD-related stimuli siblings were more similar to patients (i.e. showing hyperactivation of the dorsomedial PFC (dmPFC) compared with controls). Compared with both patients and controls, hyperactivation in siblings was more extensive (including the supplementary motor area and parietal regions), and siblings showed increased dmPFC-connectivity with the middle cingulate, superior temporal, and superior frontal cortices during OCD-related emotion regulation. The diminished dmPFC-amygdala connectivity we previously reported in OCD patients during fear-regulation was not present in the sibling group. Discussion Unaffected siblings of OCD patients were similar to controls on the behavioral response to emotional provocation, but showed dissimilar neural responses during OCD-related emotion provocation and regulation compared to healthy controls, while there were fewer differences for general fear stimuli. During OCD-related emotion provocation we observed altered activation in limbic and striatal regions in both OCD patients and siblings. During OCD-related emotion regulation siblings showed few differences compared to patients, but showed increased activation in fronto-parietal and temporal areas compared to controls. Siblings also showed extensive dmPFC hyperconnectivity compared to the patients and controls, which suggests a compensatory response. These results extend previous findings of functional endophenotypes in OCD, and show dissociation between subjective distress and brain activity during emotion processing in unaffected siblings of people with OCD.

Kaposi’s sarcoma (KS) is an unusual neoplasia wherein the tumor consists primarily of endothelial cells infected with human herpesvirus 8 (HHV-8; Kaposi’s sarcoma-associated herpesvirus) that are not fully transformed but are instead driven to excess proliferation by inflammatory and angiogenic factors. This oncogenic process has been postulated but unproven to depend on a paracrine effect of an abnormal excess of host cytokines and chemokines produced by HHV-8-infected B lymphocytes. Using newly developed measures for intracellular detection of lytic cycle proteins and expression of cytokines and chemokines, we show that HHV-8 targets a range of naive B cell, IgM memory B cell, and plasma cell-like populations for infection and induction of interleukin-6, tumor necrosis factor alpha, macrophage inhibitory protein 1α, macrophage inhibitory protein 1β, and interleukin-8 in vitro and in the blood of HHV-8/HIV-1-coinfected subjects with KS. These B cell lineage subsets that support HHV-8 infection are highly polyfunctional, producing combinations of 2 to 5 of these cytokines and chemokines, with greater numbers in the blood of subjects with KS than in those without KS. Our study provides a new paradigm of B cell polyfunctionality and supports a key role for B cell-derived cytokines and chemokines produced during HHV-8 infection in the development of KS., IMPORTANCE Kaposi’s sarcoma (KS) is the most common cancer in HIV-1-infected persons and is caused by one of only 7 human cancer viruses, i.e., human herpesvirus 8 (HHV-8). It is unclear how this virus causes neoplastic transformation. Development and outgrowth of endothelial cell lesions characteristic of KS are hypothesized to be dependent on virus replication and multiple immune mediators produced by the KS cells and inflammatory cells, yet the roles of these viral and cell factors have not been defined. The present study advances our understanding of KS in that it supports a central role for HHV-8 infection of B cells inducing multiple cytokines and chemokines that can drive development of the cancer. Notably, HIV-1-infected individuals who developed KS had greater numbers of such HHV-8-infected, polyfunctional B cells across a range of B cell phenotypic lineages than did HHV-8-infected persons without KS. This intriguing production of polyfunctional immune mediators by B cells serves as a new paradigm for B cell function and classification.

HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4 + T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism.

The effect of persistent symptoms or compensatory processes related to cognitive dysfunction in obsessive-compulsive disorder may contribute to brain structure alterations in OCD, indicating that age is an important factor in evaluating changes in gray and white matter volumes. Objective Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables. Method A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects. Results Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age). Conclusions These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score (MLS) of 2.15 at map position 69.5 cM from pter and secondary weighted LOD-score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. Our next largest MLS is for chromosome 11 (MLS = 1.75 at 84.0 cM), followed by chromosomes 2 (MLS = 0.87 at 5.5 cM), 10 (MLS = 0.77 at 75.0 cM), and 6 (MLS = 0.61 at 112.5 cM), all under an additive model. When we condition on chromosome 2 at 8.5 cM, the MLS for chromosome 20 increases to 5.50 at 69.0 cM (P=.0014). An ordered-subsets analysis based on families with high or low diabetes-related quantitative traits yielded results that support the possible existence of disease-predisposing genes on chromosomes 6 and 10. Genomewide linkage-disequilibrium analysis using microsatellite marker data revealed strong evidence of association for D22S423 (P=.00007). Further analyses are being carried out to confirm and to refine the location of these putative diabetes-predisposing genes.

The ploidy of human bone marrow cells belonging to the megakaryocytic, granulocytic-monocytic and erythrocytic lineages was studied by in situ hybridization using the biotin-labelled Y chromosome-specific DNA probe pY431 and the chromosome 1-specific probe pUC1.77 on cells identified morphologically and immunologically by the MAC procedure. Cells of the granulocytic-monocytic and erythrocytic lineages were seen to be 2N in ploidy, whereas the ploidy of the megakaryocytic lineage ranged from 2N to 32N, with the ploidy classes 4N and 8N being predominant. The frequency of megakaryocytes with 2N chromosomes was also high., Facultad de Ciencias Naturales y Museo