The electroretinographic diagnosis of the incomplete form of congenital stationary night blindness

AbstractFifteen patients with the incomplete form of congenital stationary night blindness (iCSNB) were reviewed to better characterize their electroretinographic (ERG) findings in view of differential diagnosis with other retinal conditions also presenting with negative bright-flash ERG responses. In all 15 patients, in dark-adapted conditions, the bright-flash ERG response had a normal a-wave followed by a subnormal b-wave. Oscillatory potentials (OPs) observed on the ascending limb of the b-wave, although delayed in implicit time, were of large amplitude. The response to a long-wavelength stimulus showed cone-related components and some well-delineated OPs. On the other hand, the photopically elicited cone responses were strongly abnormal, with a subnormal a-wave followed by a barely recordable b-wave. No OPs could be elicited under photopic conditions. The cone related components and the OP characteristics clearly distinguish iCSNB from the complete form of CSNB and other retinal conditions presenting with minimal fundus abnormalities but with negative bright-flash ERG responses, such as found in Duchenne muscular dystrophy and Åland Island eye disease. The severely abnormal post-synaptic components in the photopic recordings contrast with the well-differentiated cone activity evoked in scotopic conditions. We propose a cone system that does not respond optimally under the normal operating range (photopic) but rather under mesopic or scotopic conditions. In spite of the severe cone-ERG deficits, visual acuity was only slightly reduced. We propose that the defect, which interferes marginally with the neuronal flow of information, lies in the structures responsible for the building of the b-wave

MMP-3 deficiency alleviates endotoxin-induced acute inflammation in the posterior eye segment

Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood-central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood-retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor alpha (Tnf alpha), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation

The ICC Compression Questionnaire: A Comprehensive Tool to Evaluate Compression Materials or Devices Applied in Subjects with Lymphedema or Chronic Venous Disease

Background: Compression therapy is an important part of the treatment of patients with lymphedema or chronic venous disease. However, there is no validated questionnaire evaluating the effect of compression and its acceptance by the patient. Therefore, the aims of this study were to construct a questionnaire evaluating the effect of compression and its acceptance by the patient, that is, the Dutch ICC Compression Questionnaire (ICC-CQ), to investigate its reliability and validity, and to translate it into English. Methods and Results: Eleven experts in applying compression and 51 Dutch patients with experience of using compression were involved in the construction process. One part of the ICC-CQ has to be completed by the patient and evaluates seven domains. The other part has to be completed by the health care provider and comprises three domains. Reliability and validity of the final version was investigated in a new group of 79 Dutch-speaking patients with lymphedema or chronic venous disease, wearing compression garments (N = 52) or bandages (N = 27). Except for one domain, the Intraclass Correlation Coefficients for test-rest/interrater reliability ranged from 0.55 to 0.93. Cronbach's alpha for internal consistency ranged from 0.71 to 0.97. Eighty-nine percent of the patients fully understood the questionnaire indicating good face validity, and 87% found it complete indicating good content validity. Construct validity was considered good since 10 out of 11 hypotheses were accepted. Conclusion: The ICC-CQ is the first reliable and valid questionnaire evaluating different kinds of compression and the experience by patients with lymphedema or chronic venous disease

Dual role of Mic10 in mitochondrial cristae organization and ATP synthase-linked metabolic adaptation and respiratory growth

Invaginations of the mitochondrial inner membrane, termed cristae, are hubs for oxidative phosphorylation. The mitochondrial contact site and cristae organizing system (MICOS) and the dimeric F(1)F(o)-ATP synthase play important roles in controlling cristae architecture. A fraction of the MICOS core subunit Mic10 is found in association with the ATP synthase, yet it is unknown whether this interaction is of relevance for mitochondrial or cellular functions. Here, we established conditions to selectively study the role of Mic10 at the ATP synthase. Mic10 variants impaired in MICOS functions stimulate ATP synthase oligomerization like wild-type Mic10 and promote efficient inner membrane energization, adaptation to non-fermentable carbon sources, and respiratory growth. Mic10's functions in respiratory growth largely depend on Mic10(ATPsynthase), not on Mic10(MICOS). We conclude that Mic10 plays a dual role as core subunit of MICOS and as partner of the F(1)F(o)-ATP synthase, serving distinct functions in cristae shaping and respiratory adaptation and growth

New insights into the kinetics and variability of egg excretion in controlled human hookworm infections

Four healthy volunteers were infected with 50 Necator americanus infective larvae (L3) in a controlled human hookworm infection trial and followed for 52 weeks. The kinetics of fecal egg counts in volunteers was assessed with Bayesian multilevel analysis, which revealed an increase between weeks 7 and 13, followed by an egg density plateau of about 1000 eggs/g of feces. Variation in egg counts was minimal between same-day measurements but varied considerably between days, particularly during the plateau phase. These analyses pave the way for the controlled human hookworm model to accelerate drug and vaccine efficacy studies

Transcriptional control of microglia phenotypes in health and disease

Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals. We then describe functions of specific transcription factors in normal and pathological contexts and conclude with a consideration of open questions to be addressed in the future

Beyond the ‘East-West’ dichotomy: global variation in cultural models of selfhood

Markus and Kitayama’s (1991) theory of independent and interdependent self-construals had a major influence on social, personality, and developmental psychology by highlighting the role of culture in psychological processes. However, research has relied excessively on contrasts between North American and East Asian samples, and commonly used self-report measures of independence and interdependence frequently fail to show predicted cultural differences. We revisited the conceptualization and measurement of independent and interdependent self-construals in 2 large-scale multinational surveys, using improved methods for cross-cultural research. We developed (Study 1: N = 2924 students in 16 nations) and validated across cultures (Study 2: N = 7279 adults from 55 cultural groups in 33 nations) a new 7-dimensional model of self-reported ways of being independent or interdependent. Patterns of global variation support some of Markus and Kitayama’s predictions, but a simple contrast between independence and interdependence does not adequately capture the diverse models of selfhood that prevail in different world regions. Cultural groups emphasize different ways of being both independent and interdependent, depending on individualism-collectivism, national socioeconomic development, and religious heritage. Our 7-dimensional model will allow future researchers to test more accurately the implications of cultural models of selfhood for psychological processes in diverse ecocultural contexts

Promotion, prevention and protection: interventions at the population- and community-levels for mental, neurological and substance use disorders in low- and middle-income countries

Background In addition to services within the health system, interventions at the population and community levels are also important for the promotion of mental health, primary prevention of mental, neurological and substance use (MNS) disorders, identification and case detection of MNS disorders; and to a lesser degree treatment, care and rehabilitation. This study aims to identify “best practice” and “good practice” interventions that can feasibly be delivered at these population- and community-levels in low- and middle-income countries (LMICs), to aid the identification of resource efficiencies and allocation in LMICs. Methods A narrative review was conducted given the wide range of relevant interventions. Expert consensus was used to identify “best practice” at the population-level on the basis of existing quasi-experimental natural experiments and cost effectiveness, with small scale emerging and promising evidence comprising “good practice”. At the community-level, using expert consensus, the ACE (Assessing Cost-Effectiveness in Prevention Project) grading system was used to differentiate “best practice” interventions with sufficient evidence from “good practice” interventions with limited but promising evidence. ResultsAt the population-level, laws and regulations to control alcohol demand and restrict access to lethal means of suicide were considered “best practice”. Child protection laws, improved control of neurocysticercosis and mass awareness campaigns were identified as “good practice”. At the community level, socio-emotional learning programmes in schools and parenting programmes during infancy were identified as “best practice”. The following were all identified as “good practice”: Integrating mental health promotion strategies into workplace occupational health and safety policies; mental health information and awareness programmes as well as detection of MNS disorders in schools; early child enrichment/preschool educational programs and parenting programs for children aged 2–14 years; gender equity and/or economic empowerment programs for vulnerable groups; training of gatekeepers to identify people with MNS disorders in the community; and training non-specialist community members at a neighbourhood level to assist with community-based support and rehabilitation of people with mental disorders. Conclusion Interventions provided at the population- and community-levels have an important role to play in promoting mental health, preventing the onset, and protecting those with MNS disorders. The importance of inter-sectoral enga

Cancer treatment: the combination of vaccination with other therapies

Harnessing of the immune system by the development of ‘therapeutic’ vaccines, for the battle against cancer has been the focus of tremendous research efforts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed on the surface of cancer cells, have been characterized. To this end, recent years research has focussed on characterization of antigens that play an important role for the growth and survival of cancer cells. Anti-apoptotic molecules like survivin that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of different proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new approach to fight cancer, the combination with additional therapy could create a number of synergistic effects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending on the specific chemotherapeutics. Also, chemotherapy represents one of several options available for clearance of CD4+ Foxp3+ regulatory T cells. Moreover, therapies based on monoclonal antibodies may have synergistic potential in combination with vaccination, both when used for targeting of tumor cells and endothelial cells. The efficacy of therapeutic vaccination against cancer will over the next few years be studied in settings taking advantage of strategies in which vaccination is combined with other treatment modalities. These combinations should be based on current knowledge not only regarding the biology of the cancer cell per se, but also considering how treatment may influence the malignant cell population as well as the immune system

Impact of nonoptimal intakes of saturated, polyunsaturated, and trans fat on global burdens of coronary heart disease

Background: Saturated fat (SFA), ω‐6 (n‐6) polyunsaturated fat (PUFA), and trans fat (TFA) influence risk of coronary heart disease (CHD), but attributable CHD mortalities by country, age, sex, and time are unclear. Methods and Results: National intakes of SFA, n‐6 PUFA, and TFA were estimated using a Bayesian hierarchical model based on country‐specific dietary surveys; food availability data; and, for TFA, industry reports on fats/oils and packaged foods. Etiologic effects of dietary fats on CHD mortality were derived from meta‐analyses of prospective cohorts and CHD mortality rates from the 2010 Global Burden of Diseases study. Absolute and proportional attributable CHD mortality were computed using a comparative risk assessment framework. In 2010, nonoptimal intakes of n‐6 PUFA, SFA, and TFA were estimated to result in 711 800 (95% uncertainty interval [UI] 680 700–745 000), 250 900 (95% UI 236 900–265 800), and 537 200 (95% UI 517 600–557 000) CHD deaths per year worldwide, accounting for 10.3% (95% UI 9.9%–10.6%), 3.6%, (95% UI 3.5%–3.6%) and 7.7% (95% UI 7.6%–7.9%) of global CHD mortality. Tropical oil–consuming countries were estimated to have the highest proportional n‐6 PUFA– and SFA‐attributable CHD mortality, whereas Egypt, Pakistan, and Canada were estimated to have the highest proportional TFA‐attributable CHD mortality. From 1990 to 2010 globally, the estimated proportional CHD mortality decreased by 9% for insufficient n‐6 PUFA and by 21% for higher SFA, whereas it increased by 4% for higher TFA, with the latter driven by increases in low‐ and middle‐income countries. Conclusions: Nonoptimal intakes of n‐6 PUFA, TFA, and SFA each contribute to significant estimated CHD mortality, with important heterogeneity across countries that informs nation‐specific clinical, public health, and policy priorities.peer-reviewe