Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder.

We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.

An Exposome Perspective on Environmental Enteric Dysfunction.

BACKGROUND: Environmental exposures to chemicals have been shown to influence gastrointestinal function, yet little is known regarding whether chemical mixtures may be involved in the development of a subclinical enteric dysfunction found in infants and children born into poor hygiene and sanitation. Advances in gastrointestinal and immunotoxicology fields merit inclusion in complex discussions of environmental enteric dysfunction (EED) that severely affects children in developing countries. OBJECTIVE: We aimed to highlight exposome approaches for investigating the potential influence of environmental chemical exposures on EED development, including a role for toxicant modulation of gut immune system and microbiome function. DISCUSSION: A major focus on fecal-oral contamination in impoverished living conditions already exists for EED, and should now expand to include environmental chemicals such as pesticides and heavy metals that may be anthropogenic or dietary or from microbial sources. A comprehensive characterization of environmental chemical exposures prenatally and occurring in infants and young children will enhance our knowledge of any associated risks for EED and stunting. CONCLUSIONS: Integrating EED, chemical exposure, and stunting at various ages during childhood will enhance our apparent limited view when evaluating EED. Etiology and intervention studies should evaluate the suite of environmental chemical exposures as candidates in the composite of EED biomarkers. CITATION: Mapesa JO, Maxwell AL, Ryan EP. 2016. An exposome perspective on environmental enteric dysfunction. Environ Health Perspect 124:1121-1126; http://dx.doi.org/10.1289/ehp.1510459.

Epigenetic effects of electroconvulsive seizures.

Electroconvulsive therapy (ECT) is one of the most effective methods for managing treatment-resistant depression. Although the proposed mechanisms of action have thus far mainly been investigated at the cellular level, recent observations and developments in the field of molecular biology and genomics have provided novel insights in the actual molecular underpinnings of dynamic alterations in gene expression, particularly in response to environmental exposures, and experience-dependent plasticity, both of which are highly relevant to ECT. Here, we provided a brief background on epigenetics and we reviewed the current state of knowledge on epigenetic mediation of ECT-related therapeutic effects. We performed a systematic search on the effects of ECT on epigenetics and found only a limited number on animal studies relevant to our search. These studies, however, support the notion of a robust impact of ECT on epigenetic mechanisms and set the stage for human ECT studies on the epigenetic machinery.

Catechols in caffeic acid phenethyl ester are essential for inhibition of TNF-mediated IP-10 expression through NF-κB-dependent but HO-1- and p38-independent mechanisms in mouse intestinal epithelial cells.

SCOPE: Caffeic acid phenethyl ester (CAPE) is an active constituent of honeybee propolis inhibiting nuclear factor (NF)-κB. The aims of our study were to provide new data on the functional relevance and mechanisms underlying the role of CAPE in regulating inflammatory processes at the epithelial interface in the gut and to determine the structure/activity relationship of CAPE. METHODS AND RESULTS: CAPE significantly inhibited TNF-induced IP-10 expression in intestinal epithelial cells. Using various analogues, we demonstrated that substitution of catechol hydroxyl groups and addition of one extra hydroxyl group on ring B reversed the functional activity of CAPE to inhibit IP-10 production. The anti-inflammatory potential of CAPE was confirmed in ileal tissue explants and embryonic fibroblasts derived from TNF(ΔARE/+) mice. Interestingly, CAPE inhibited both TNF- and LPS-induced IP-10 production in a dose-dependent manner, independently of p38 MAPK, HO-1 and Nrf2 signaling pathways. We found that CAPE did not inhibit TNF-induced IκB phosphorylation/degradation or nuclear translocation of RelA/p65, but targeted downstream signaling events at the level of transcription factor recruitment to the gene promoter. CONCLUSION: This study reveals the structure-activity effects and anti-inflammatory potential of CAPE in the intestinal epithelium.

[Ophthalmological findings in microcephaly-lymphoedema-chorioretinal dysplasia syndrome]. / Okuläre Veränderungen beim Mikrozephalie-Lymphödem-Chorioretinale-Dysplasie-Syndrom.

BACKGROUND: Microcephaly-lymphoedema-chorioretinal dysplasia (MLCRD) is a rare syndrome characterized by microcephaly, chorioretinal dysplasia, lymphoedema and a characteristic facial phenotype. The exact mode of inheritance is uncertain, autosomal dominant, recessive and X-chromosomal cases have been reported. HISTORY AND SIGNS: A three-month-old boy with intrauterine growth retardation and microcephaly was referred to our clinic. The ophthalmic examination revealed a left eye with a persistent hyperplastic primary vitreous. On funduscopy of the right eye pale optic disc, chorioretinal dysplasia with pigmentary and atrophic changes and falciform folds were noted. General morphological changes and ophthalmological findings led to the diagnosis of MLCRD-syndrome. THERAPY AND OUTCOME: Eye examinations of the parents and the grandparents did not show any retinal changes, therefore an autosomal dominant inheritance was excluded. CONCLUSIONS: An ophthalmological examination in children with microcephaly and facial dysmorphies is essential. Parents and grandparents should also be considered for eye examination if a child has chorioretinal dysplasia and microcephaly.

[The eye--view into the brain]. / Das Auge--der Blick ins Hirn.

Neuro-ophthalmology is an important diagnostical tool in finding disturbances of central nervous system function. Morphological and functional testing is used to assess the proper integrity of the central visual system. Five case reports demonstrate the diagnostical power of neuro-ophthalmology.

Bilateral papilledema from a massive intracranial epidermoid cyst.

PURPOSE: To report an unusual case of bilateral papilledema from a large intracranial epidermoid cyst. METHODS: Case report. RESULTS: A 26-year-old man presented with visual loss, bilateral papilledema, and only a few neurological symptoms. Magnetic resonance imaging disclosed such a large lesion that his right cerebral hemisphere was compressed to one half its normal size. Histopathologic examination of the completely removed tumor revealed an epidermoid cyst. CONCLUSION: This unique case involved a patient with bilateral papilledema caused by a huge intracranial epidermoid cyst. Epidermoid tumors should be considered in the differential diagnosis of papilledema.

Spontaneous resolution of pituitary adenoma after apoplexy.

A patient with typical pituitary apoplexy with documented intralesional hemorrhage and spontaneous resolution is presented. There was no evidence of a tumor at a 3-month follow-up.

Manual keratometry and videokeratography after photorefractive keratectomy.

PURPOSE: To examine the relative accuracy of manual keratometry and videokeratography in eyes treated by photorefractive keratectomy (PRK). SETTING: Eye Clinic, Cantonal Hospital, Lucerne, Switzerland. METHODS: Results of manual keratometry and videokeratography were compared with those of subjective refraction in 128 eyes before and 6 months after PRK. RESULTS: Six months after PRK, the mean subjective refraction of all eyes decreased more than the mean corneal dioptric power measured with videokeratography (P <.0001). The change in the mean subjective refraction compared with the corresponding difference in the mean manual keratometry of all eyes was also significant (P <.0001). CONCLUSIONS: This study confirmed an earlier observation that there is a disparity between the change in refraction and the reduction in corneal power measured by videokeratography and with the manual keratometer. Topographical changes from PRK and the subsequent wound-healing processes are likely to falsify objective measurements. The keratometric value in the center of the cornea, since it is not measured by manual keratometry and videokeratography, may actually be lower.

Visual loss with Langerhans cell histiocytosis: multifocal central nervous system involvement.

A 42-year-old woman with a 6-year history of diabetes insipidus and progressive hypersomnolence presented with visual loss. Neuroimaging showed infiltration in the hypothalamus, the optic nerve, and the chiasm, as well as multiple lesions in other areas of the brain parenchyma. Biopsy showed Langerhans cell histiocytosis. This is an unusual presentation of Langerhans cell histiocytosis, involving the visual pathways without manifestations outside of the central nervous system. The differential diagnosis and the magnetic resonance imaging findings will be discussed.

[Differential diagnostic considerations on retrobulbar neuritis]. / Differentialdiagnostische Uberlegungen zur Retrobulbärneuritis.

Retrobulbar neuritis is a frequent diagnosis in patients (age groups 20-40 years), who complain about acute monocular loss of vision, accompanied by painful eye movements. The clinical course with recovery over about six weeks and the possibility of additional neurological dysfunction in the following years confirm the diagnosis of primarily demyelinating disease. Beside the typical retrobulbar neuritis, there is a group of vascular optic nerve disorders as well as Leber's optic neuropathy that need to be differentiated from primary demyelinating retrobulbar neuritis. Compressive optic neuropathies, unilateral chiasm disorders and infiltrative optic neuropathies will not be considered in this paper, because of their subacute presentation.

[Retrobulbar neuritis--diagnosis and differential diagnosis]. / Retrobulbärneuritis--Diagnostik und Differentialdiagnose.

The American multicenter study 'A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis' (5) showed how a retrobulbar neuritis should not be treated, Oral steroids (1 mg per kilogram of body weight per day) are not only ineffective but also associated with a higher rate of recurrences compared to high dose i.v. methylprednisolone. In the light of this study, 'low-dose' steroid therapy for retrobulbar neuritis is contraindicated. High-dose methylprednisolone speeds up recovery of the visual function and lowers the recurrence rate two years after treatment; however, this protective effect could not be demonstrated after three years. These recommendations are valid only for primary demyelinating retrobulbar neuritis. Other less common optic neuropathies, such as these of microvascular origin, respond to 'low-dose' steroids; therefore, the diagnosis of primary demyelinating retrobulbar neuritis must be made with caution as a diagnosis of exclusion. This paper discusses a number of important optic neuropathies and gives recommendations for investigations. Compressive optic neuropathies and chiasmal disease will not be covered here.

[Zygosity diagnosis in adolescent twins using questionnaires]. / Zum Problem der Zygositätsdiagnose bei jugendlichen Zwillingen mit Fragebogen.

The validity of Zazzo's questionnaire method for zygosity determination has been tested within the framework of a study on twins. 11 (20.7%) of 53 monozygotic twin pairs were classified incorrectly. For the diagnosis of zygosity in adolescent twins, a questionnaire method has been designed and implemented in the G.D.R. With the help of this new method a relatively reliable zygosity determination is possible. A correct matching for 97% was obtained.