Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.     

Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides

Anti‐neutrophilic cytoplasmic antibody (ANCA) positivity is seen in some systemic necrotizing vasculitides. Wegener's granulomatosis and microscopic polyangiitis are among the ANCA‐associated systemic vasculitides (AASV) and mortality is very high when renal failure occurs together with alveolar hemorrhage. The role of plasmapheresis in the treatment of these diseases has been studied retrospectively. Twelve patients with AASV who had plasmapheresis together with immunosuppressive medications have been involved. Primary diseases, immunosuppressive protocols, the number of plasmapheresis sessions, the amount of plasma that has been exchanged, urea and creatinine levels before and after treatment, pulmonary findings, the need for hemodialysis, and the outcome of patients were recorded. The mean age of patients was 52.9 ± 18.2 years. Wegener's granulomatosis was diagnosed in seven (58.3%) and microscopic polyangiitis in five (41.7%) patients. All patients had pulse cyclophosphamide and methylprednisolone followed by maintenance doses and plasmapheresis. Seven patients had hemodialysis at the beginning, and hemodialysis needed to be continued in three patients. Partial and complete remission was seen in 6 (50%) and 3 (25%) patients, respectively, and pulmonary findings regressed in all patients. End‐stage renal disease develops generally in AASV due to rapidly progressive glomerulonephritis causing severe irreversible glomerular damage. The mortality rate rises to 50% in cases of renal failure with diffuse alveolar hemorrhage; therefore, pulse immunosuppressive treatment with plasmapheresis may be life‐saving, as shown in our study.     

Shoulder pain in hemiplegia: results from a national rehabilitation hospital in Turkey

OBJECTIVE: Shoulder pain is a common complication after stroke that can limit the patients' ability to reach their maximum functional potential and impede rehabilitation. The aim of our study was to examine the occurrence of hemiplegic shoulder pain in a group of Turkish patients and clarify contributing factors such as glenohumeral subluxation, reflex sympathetic dystrophy, tonus changes, motor functional level, limitation in shoulder range of motion, thalamic pain, neglect, and time since onset of hemiplegia. The effect of shoulder pain on the duration of rehabilitation stay was also identified. DESIGN: A total of 85 consecutive patients with hemiplegia admitted to a national rehabilitation center were evaluated for the presence of shoulder pain. A brief history of pain was taken for each patient, and each patient was evaluated by radiographic and ultrasonographic examination. The subjects with shoulder pain were compared with those without pain in regard to certain of the above variables. RESULTS: Of the 85 patients with stroke, 54 patients (54/85, 63.5%) were found to have shoulder pain. Shoulder pain was significantly more frequent in subjects with reflex sympathetic dystrophy, lower motor functional level of shoulder and hand (P < 0001), subluxation, and limitation of external rotation and flexion of shoulder (P < 0,05). Age was also a significant factor in the development of shoulder pain. We were unable to demonstrate a significant relationship between shoulder pain and sex, time since onset of disease, hemiplegic side, pathogenesis, spasticity, neglect, and thalamic pain. There was no prolongation of rehabilitation stay in patients with shoulder pain. CONCLUSION: These results indicate that shoulder pain is a frequent complication after stroke and that it may develop from a variety of factors. To prevent and alleviate shoulder pain, efforts should be directed toward proper positioning of the shoulder, range of motion activities, and the avoidance of immobilization.     

Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1–expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1’s receptor, deleted in colorectal carcinoma; and therapeutic α₁ adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1⁺ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α₁ adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1–driven adrenergic processes and introduced α₁ blockers as a potentially new fibrotic therapy.     

From the Cover: Childhood self-control forecasts the pace of midlife aging and preparedness for old age

The ability to control one’s own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children’s self-control across their first decade of life using a multi-occasion/multi-informant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children’s self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals’ self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.

The ability to control one’s own emotions, thoughts, and behaviors in early life sets the stage for many positive outcomes in later life. These include educational attainment, career success, healthy lifestyles (1–4), and, in particular, longevity (5–8). Prospective studies of children, adolescents, and adults have shown that individuals with better self-control—often measured as higher conscientiousness or lower impulsivity—live longer lives (5–8). But, do they also exhibit better midlife aging? Answering this question could reveal opportunities to extend not only life span (how long we live) but also health span [how long we live free of disease and disability (9)]. Here, we used data collected across five decades to connect children’s self-control to their pace of aging in midlife. We also linked children’s self-control with their midlife aging preparedness: the health, financial, and social reserves that may help prepare individuals for longer life span and better health span.Midlife represents a useful window during which to measure individual differences in aging and their relation to childhood self-control. Meaningful variation between individuals in the speed of both physiological and cognitive aging can be detected already at this life stage (10, 11), and prior work has established that individual differences in midlife health are linked to early-life factors (12–14). Furthermore, midlife is a critical period for preparing for the demands of older age (15). Now past their healthy young adult years, individuals must devote greater attention to preventing age-related diseases, increasing their financial reserves for retirement, and building the social networks that will provide practical and emotional supports in old age. Signs of one’s own aging emerge at this life stage, reminding us that multiple health, financial, and social demands are approaching: menopause and presbyopia set in, we start paying attention to our savings accounts, and we see our own futures in our parents’ decline.If outcomes of self-control extend as far as midlife, then it could be a key intervention target. It would also suggest the hypothesis that there may be opportunities to build aging preparedness while individuals are still in their robust forties (15, 16). Much emphasis has been placed on the importance of intervening early in development, and there is vigorous debate over the optimal timing for implementing early-years programs (17–19). Midlife, however, remains a largely unexplored potential window of opportunity for self-control intervention.We tested associations between childhood self-control and midlife aging using data from the Dunedin Longitudinal Study, a prospective study of a complete birth cohort of 1,037 individuals followed from birth to age 45 with 94% retention. As previously reported in this journal, we measured study members’ self-control across their first decade of life using a multi-occasion/multi-informant strategy (2, 20). We measured their pace of aging as well as their aging preparedness in midlife using a range of prespecified measures known to be associated with life span and/or health span (Fig. 1 and SI Appendix, Table S1), which were derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. We used these data to test two hypotheses. First, we tested the hypothesis that individuals with better self-control in childhood exhibit slower aging of the body and fewer signs of brain aging in midlife. Second, we tested the hypothesis that individuals with better self-control in childhood exhibit better preparedness for the health, financial, and social demands that emerge in later life. Research has shown that self-control predicts health behaviors such as diet, smoking, alcohol consumption, and exercise (4, 21–24). Here, we extend the reach of this research by testing whether self-control predicts outcomes beyond health behaviors, including individuals’ practical health knowledge, their attitudes toward and expectancies about aging, their practical financial knowledge and financial behavior, their social integration, and their satisfaction with life.Open in a separate windowFig. 1.Aging domains and measures assessed in the current study. Column three indicates reference numbers for prior studies documenting associations between the given measure and life span and/or health span. The complete reference list is included in SI Appendix, Table S1.Children’s self-control is correlated with their socioeconomic circumstances (25, 26) and their intelligence (27, 28). Both social class and intelligence have been implicated in life span and health span (29, 30); in fact, both social class and intelligence have been called “fundamental causes” of later-life health (31–33). Social class has been proposed as a fundamental cause because it influences multiple disease outcomes through multiple mechanisms, it embodies access to important resources, and its associations with health outcomes are maintained even when intervening mechanisms change (31). Intelligence has been conceptualized as a fundamental cause for similar reasons (32). For childhood self-control to be implicated as an active ingredient in healthy aging, it is important to show that its effects are independent of these two fundamental influences on children’s futures. We therefore tested whether associations between self-control and aging survived after accounting for children’s social class and intelligence quotient (IQ) [assessing each, like self-control, using repeated measurements across childhood (Methods)].     

Tensor total variation approach to optical coherence tomography reconstruction for improved visualization of retinal microvasculature

A novel optical coherence tomography (OCT) reconstruction approach is introduced for improved visualization of inner-retina capillaries in retinal OCT tomograms. The proposed method utilizes a minimization framework based on a tensor total variation (TTV) energy functional, to enforce capillary structural characteristics in the spatial domain. By accounting for structure tensor characteristics, the TTV reconstruction method allows for contrast enhancement of capillary structural characteristics. The novel TTV method was tested on high resolution OCT images acquired in-vivo from the foveal region of the retina of a healthy human subject. Experimental results demonstrate significant contrast and visibility enhancement of the inner retina capillaries in the retinal OCT tomograms, achieved by use of the TTV reconstruction method. Therefore, the TTV method has a strong potential for improved disease progression analysis based on the study of disease-induced changes in the inner retina vasculature.     

Neural correlates of facial affect processing in children and adolescents with autism spectrum disorder

OBJECTIVE: To examine the neural basis of impairments in interpreting facial emotions in children and adolescents with autism spectrum disorders (ASD). METHOD: Twelve children and adolescents with ASD and 12 typically developing (TD) controls matched faces by emotion and assigned a label to facial expressions while undergoing functional magnetic resonance imaging. RESULTS: Both groups engaged similar neural networks during facial emotion processing, including activity in the fusiform gyrus (FG) and prefrontal cortex. However, between-group analyses in regions of interest revealed that when matching facial expressions, the ASD group showed significantly less activity than the TD group in the FG, but reliably greater activity in the precuneus. During the labeling of facial emotions, no between-group differences were observed at the behavioral or neural level. Furthermore, activity in the amygdala was moderated by task demands in the TD group but not in the ASD group. CONCLUSIONS: These findings suggest that children and adolescents with ASD in part recruit different neural networks and rely on different strategies when processing facial emotions. High-functioning individuals with ASD may be relatively unimpaired in the cognitive assessment of basic emotions, yet still show differences in the automatic processing of facial expressions.     

Dramatic response of aneurysmal bone cyst to denosumab: Case report and literature review

Denosumab, a monoclonal antibody that specifically targets cytokine receptor activator of nuclear factor‐kappa B ligand (RANKL), is a potentially viable option in resistant aneurysmal bone cysts.