TGFß-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism.

The optic fissure is a transient gap in the developing vertebrate eye, which must be closed as development proceeds. A persisting optic fissure, coloboma, is a major cause for blindness in children. Although many genes have been linked to coloboma, the process of optic fissure fusion is still little appreciated, especially on a molecular level. We identified a coloboma in mice with a targeted inactivation of transforming growth factor ß2 (TGFß2). Notably, here the optic fissure margins must have touched, however failed to fuse. Transcriptomic analyses indicated an effect on remodelling of the extracellular matrix (ECM) as an underlying mechanism. TGFß signalling is well known for its effect on ECM remodelling, but it is at the same time often inhibited by bone morphogenetic protein (BMP) signalling. Notably, we also identified two BMP antagonists among the downregulated genes. For further functional analyses we made use of zebrafish, in which we found TGFß ligands expressed in the developing eye, and the ligand binding receptor in the optic fissure margins where we also found active TGFß signalling and, notably, also gremlin 2b (grem2b) and follistatin a (fsta), homologues of the regulated BMP antagonists. We hypothesized that TGFß is locally inducing expression of BMP antagonists within the margins to relieve the inhibition from its regulatory capacity regarding ECM remodelling. We tested our hypothesis and found that induced BMP expression is sufficient to inhibit optic fissure fusion, resulting in coloboma. Our findings can likely be applied also to other fusion processes, especially when TGFß signalling or BMP antagonism is involved, as in fusion processes during orofacial development.

The triad of pruritus, xanthomas, and cholestasis: Two cases and a brief review of the literature.

When encountered in children, xanthomas are most commonly associated with a group of disorders known as familial hyperlipidemias. Aside from cosmetic concerns, these xanthomas are typically asymptomatic, but when generalized pruritus is a prominent associated symptom, clinicians should consider a different set of diagnoses that includes cholestasis of the liver. In this article we present two illustrative cases of children with cholestatic disease, pruritus, and xanthomas and discuss other disorders that may include this triad.

Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.

COACH syndrome is an autosomal recessive developmental disorder, a subtype of Joubert syndrome and related disorders, characterized by cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Although mutations in TMEM67 (transmembrane protein 67)/MKS3 (Meckel-Gruber syndrome, type 3) were reported to cause COACH syndrome, this causality has not verified by functional studies. In a 20-year-old Korean man, we found cerebellar ataxia, isolated elevation in serum γ-glutamyl transpeptidase (γ-GTP) activity, oligophrenia, the molar tooth sign (MTS) in the brain MR images and congenital hepatic fibrosis (CHF). Two novel compound heterozygous mutations were found in TMEM67 in the patient: i) missense mutation (c.395 G > C and p.Gly132Ala) in exon 3, and ii) deletion in exon 26 (c.2758delT and p.Tyr920ThrfsX40). Western blotting showed that the p.Tyr920ThrfsX40 mutation accelerates turnover of the TMEM67 protein. Although wild-type human TMEM67 RNA rescued phenotypes of zebrafish embryos injected with anti-sense oligonucleotide morpholinos against tmem67, the two human TMEM67 RNAs individually harboring the two mutations did not. Finally, Wnt signaling, but not Hedgehog signaling, was suppressed in tmem67 morphants. To the best of our knowledge, this is the first report verifying the causality between COACH syndrome and TMEM67, which will further our understanding of molecular pathogenesis of the syndrome.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

Intravitreal anti-vascular endothelial growth factor therapy for choroidal neovascularization due to Sorsby macular dystrophy.

PURPOSE: To report the first case of intravitreal bevacizumab and ranibizumab to treat choroidal neovascularization secondary to Sorsby macular dystrophy. CASE: A 57-year-old male with metamorphopsia, color vision deficits, and ocular family history of Sorsby macular dystrophy was found to have a choroidal neovascular membrane (CNVM) in his left eye. He was initially treated with intravitreal bevacizumab and had visual acuity improvement and resolution of the subretinal fluid on OCT. After 8 injections, he developed presumed mild inflammation secondary to intravitreal bevacizumab and was switched to combination intravitreal bevacizumab/dexamethasone in his left eye, which consistently demonstrated efficacy in stabilizing his vision and the CNVM without producing intraocular inflammation. The right eye later developed the CNVM and he was started on intravitreal bevacizumab in this eye as well. After 8 injections in the right eye, he experienced a similar inflammatory reaction following intravitreal bevacizumab injections and was switched to combination intravitreal bevacizumab/dexamethasone in the right eye as well. Subsequently, he was switched to intravitreal ranibizumab in the left eye alone, which continued to stabilize his vision and OCT and did not cause an inflammatory reaction as he previously experienced with bevacizumab. After 5 ranibizumab injections, he experienced no inflammatory response that he appeared to have with bevacizumab, but chose to switch back to combination intravitreal bevacizumab and dexamethasone due to financial reasons. Initially, in his clinical course, he experienced consistent visual acuity improvements with intravitreal antivascular endothelial growth factor therapy and continues to enjoy functional vision nearly 7 years after his initial symptoms. CONCLUSIONS: Intravitreal bevacizumab and ranibizumab demonstrated efficacy in this case in the treatment of CNVM associated with Sorsby macular dystrophy.

The development of recurrent choroidal neovascularization in a patient with choroidal coloboma.

We report a case of recurrent choroidal neovascularization (CNV) in an eye with chorioretinal coloboma. A 36-year-old woman presented complaining of decreased visual acuity (VA) in her left eye. Best corrected visual acuity (BCVA) was 20/200 and iris coloboma was observed. Funduscopy and fluorescein angiography (FA) showed CNV in the superior extrafoveal region with chorioretinal coloboma reaching just inferior to the optic disc. No other cause for CNV was observed except for the chorioretinal coloboma. BCVA improved to 20/30 after laser photocoagulation. She revisited our clinic for deteriorating VA (20/400) in the same eye 3 years after treatment. Funduscopy and FA demonstrated recurrent CNV with subfoveal hemorrhage. Photodynamic therapy (PDT) was followed by three consecutive intravitreal bevacizumab injections (IVB) for the subfoveally-located CNV. However, the CNV persisted with the appearance of a fresh subretinal hemorrhage. Additional PDT was combined with IVB on the same day 6 months after the initial PDT. The CNV regressed 3 months after treatment and has not recurred as of 8 months after the last treatment. The patient's BCVA improved to 20/60. This case suggests that PDT combined with IVB can be an alternative treatment for the management of recurrent CNV after laser photocoagulation in eyes with chorioretinal coloboma.

Treacher Collins syndrome: an undescribed characteristic of the condition and its management with botulinum toxin and surgery.

Mandibulofacial dysostosis (Treacher Collins syndrome) is associated with clinical abnormalities of structures derived from the first and second branchial arches, including antimongoloid slant of palpebral fissures, colobomas of the lower eyelid, eyelash malformations, and malar and mandibular defects. We describe an unusual clinical feature associated with colobomas of the lower eyelids, in a patient with mandibulofacial dysostosis, successfully treated with botulinum toxin and subsequent surgery.

Suppressor cell activity in a male infant with T-and B-lymphocyte dysfunction treated with thymosin.

A male infant with bilateral iris coloboma who had had repeated infections and malabsorption was studied. The levels of total lymphocytes and of T and B cells were normal or high, but IgA became undectable and IgG low, whereas IgM was normal. His lymphocytes did not respond to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen (PWM) or in mixed lymphocyte reactions (MLR), nor did they respond in vitro when thymosin was included in the test systems. He was skin-test-negative, even to dinitrochlorobenzene. His crudely isolated T lymphocytes and the supernatant of his PHA-stimulated lymphocytes inhibit the response of normal lymphocytes to PHA, PWM, and in MLR. During thymosin treatment skin test and lymphocyte reactivity to mitogen remained negative. He became faintly positive in MLR, and the suppressor activity in the supernatant of his PHA-stimulated lymphocytes no longer inhibited the response of normal lymphocytes to PHA, PWM, or in MLR. In parallel with thymosin treatment he showed quite marked clinical improvement.