A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

High-dose calcineurin inhibitor-free everolimus as a maintenance regimen for heart transplantation may be a risk factor for Pneumocystis pneumonia.

BACKGROUND: Everolimus reduces the incidence of cardiac-allograft vasculopathy (CAV) and is less renally toxic than are calcineurin inhibitors (CNIs). We evaluated the safety of CNI-free everolimus for post-heart transplant (HTx) patients. METHODS: We retrospectively reviewed the records of 36 consecutive patients who had undergone an HTx between January 2006 and December 2013 in National Cheng Kung University Hospital. All patients initially had been treated with the standard tacrolimus regimen. The Study group-12 patients with CAV, renal impairment, or a history of malignancy-were switched from tacrolimus to everolimus. The Control group consisted of 19 patients who remained on the standard regimen. The target everolimus trough concentration was 8-14 ng/mL. The primary outcome was survival, and the secondary outcomes were bacterial, viral, fungal, and other infections; Pneumocystis jirovecii pneumonia (PJP); and rejection (≥2R). RESULTS: During a 53.3±25.6-month follow-up, the survival rate, rejection rate, and number of infections, except for PJP, were not significantly different between the two groups. In the Study group, 6 patients were diagnosed with PJP 33±18.2 months after switching. None of the Control group patients were diagnosed with PJP during follow-up. CONCLUSIONS: A high-dose CNI-free everolimus maintenance regimen might yield a higher incidence of post-transplantation PJP.

A Coral-Derived Compound Improves Functional Recovery after Spinal Cord Injury through Its Antiapoptotic and Anti-Inflammatory Effects.

BACKGROUND: Our previous in vitro results demonstrated that 11-dehydrosinulariolide significantly reduced 6-hydroxydopamine-induced cytotoxicity and apoptosis in a human neuroblastoma cell line, SH-SY5Y, and suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 in lipopolysaccharide-stimulated macrophage cells. The neuroprotective and anti-inflammatory effects of 11-dehydrosinulariolide may be suitable for treating spinal cord injury (SCI). METHODS: In the present study, Wistar rats were pretreated with 11-dehydrosinulariolide or saline through intrathecal injection after a thoracic spinal cord contusion injury induced using a New York University (NYU) impactor. The apoptotic cells were assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression and localization of proinflammatory, apoptosis-associated and cell survival-related pathway proteins were examined through immunoblotting and immunohistochemistry. RESULTS: 11-Dehydrosinulariolide attenuated SCI-induced cell apoptosis by upregulating the antiapoptotic protein Bcl-2 and cell survival-related pathway proteins p-Akt and p-ERK, 8 h after SCI. Furthermore, the transcription factor p-CREB, which regulates Bcl-2 expression, was upregulated after 11-dehydrosinulariolide treatment. On day 7 after SCI, 11-dehydrosinulariolide exhibited an anti-inflammatory effect, attenuating SCI-induced upregulation of the inflammatory proteins iNOS and tumor necrosis factor-α. 11-Dehydrosinulariolide also induced an increase in the expression of arginase-1 and CD206, markers of M2 microglia, in the injured spinal cord on day 7 after SCI. Thus, the anti-inflammatory effect of 11-dehydrosinulariolide may be related to the promotion of an alternative pathway of microglia activation. CONCLUSION: The results show that 11-dehydrosinulariolide exerts antiapoptotic effects at 8 h after SCI and anti-inflammatory effects at 7 days after SCI. We consider that this compound may be a promising therapeutic agent for SCI.

Bioactive Isoprenoid-Derived Natural Products from a Dongsha Atoll Soft Coral Sinularia erecta.

Four new isoprenoids, including two norcembranoids sinulerectols A and B (1 and 2), a cembranoid sinulerectol C (3), and a degraded cembranoid sinulerectadione (4), along with three known isoprenoids, an unnamed norcembrene (5), sinularectin (6), and ineleganolide (7), and a known nitrogen-containing compound (Z)-N-[2-(4-hydroxyphenyl)ethyl]-3-methyldodec-2-enamide (8), were isolated from an extract of the marine soft coral Sinularia erecta. The structure of sinularectin (6) was revised, too. Compounds 3, 4, and 8 exhibited inhibitory activity against the proliferation of a limited panel of cancer cell lines, whereas 1, 2, and 8 displayed potent anti-inflammatory activity in fMLP/CB-stimulated human neutrophils.

Lens Position Parameters as Predictors of Intraocular Pressure Reduction After Cataract Surgery in Glaucomatous Versus Nonglaucomatous Eyes.

PURPOSE: To evaluate the relationship between lens position parameters and intraocular pressure (IOP) reduction after cataract surgery in patients with primary open-angle glaucoma (POAG) and in nonglaucomatous patients. METHODS: The main outcomes of this prospective study were percent and absolute IOP change, which were calculated using the preoperative IOP and the IOP 4 months after cataract surgery in POAG and nonglaucomatous eyes. Lens position (LP), defined as anterior chamber depth (ACD) + one-half lens thickness (LT), was assessed preoperatively using parameters from optical biometry. Preoperative IOP, axial length (AL), ACD, LT, relative lens position (RLP), and the ratio of preoperative IOP to ACD (PD ratio) were also evaluated as potential predictors of IOP change. RESULTS: Four months postoperatively, the average IOP reduction was 2.80 ± 3.83 mm Hg (15.79%) from the preoperative mean of 14.73 ± 2.89 mm Hg for nonglaucomatous eyes. The average IOP reduction was 2.66 ± 2.07 mm Hg (16.98%) from the preoperative mean of 14.86 ± 2.97 mm Hg for POAG eyes. Preoperative IOP, sex, AL, ACD, PD ratio, and LP predicted IOP change in nonglaucomatous eyes. Preoperative IOP and PD ratio predicted IOP change in POAG eyes. CONCLUSIONS: Intraocular pressure reduction after phacoemulsification cataract surgery in nonglaucomatous eyes is significantly greater in more anteriorly positioned lenses. Though it did not reach statistical significance in patients with glaucoma, the association of LP with IOP reduction is in the same direction as in nonglaucomatous patients where smaller LP appears to predict greater IOP reduction. Lens position is a simple, easily calculable, accurate, and widely available parameter, which clinicians can potentially utilize in managing glaucoma.

Complete mitochondrial genome of Junceella fragilis (Gorgonacea, Ellisellidae).

In this article, the complete mitogenome of the Octocorallia, zooxanthellate, Junceella fragilis has been amplified and sequenced. This mitochondrial genome consists of 18,724 bp, with 14 protein-coding genes, 2 ribosomal RNA genes, 1 transfer RNA genes, no intron was observed. It has been observed that a mitochondrial mismatch repair (mtMutS) gene was present in all octocorals. The overall base composition of the heavy strand was A, 29.1%; G, 20.4%; C, 33.0%; and T, 17.5%, with a slight AT bias of 62.1%. The complete mitogenomic data may provide more informative for phylogenetic approach for soft corals phylogeny especially for octocorallian species.

Lens Position Parameters as Predictors of Intraocular Pressure Reduction After Cataract Surgery in Nonglaucomatous Patients With Open Angles.

PURPOSE: To evaluate the relationship between lens position parameters and intraocular pressure (IOP) reduction after cataract surgery in nonglaucomatous eyes with open angles. METHODS: The main outcome of the prospective study was percentage of IOP change, which was calculated using the preoperative IOP and the IOP 4 months after cataract surgery in nonglaucomatous eyes with open angles. Lens position (LP), defined as anterior chamber depth (ACD) + 1/2 lens thickness (LT), was assessed preoperatively using parameters from optical biometry. Preoperative IOP, central corneal thickness, ACD, LT, axial length (AXL), and the ratio of preoperative IOP to ACD (PD ratio) were also evaluated as potential predictors of percentage of IOP change. The predictive values of the parameters we found to be associated with the primary outcome were compared. RESULTS: Four months after cataract surgery, the average IOP reduction was 2.03 ± 2.42 mm Hg, a 12.74% reduction from the preoperative mean of 14.5 ± 3.05 mm Hg. Lens position was correlated with IOP reduction percentage after adjusting for confounders (P = 0.002). Higher preoperative IOP, shallower ACD, shorter AXL, and thicker LT were significantly associated with percentage of IOP decrease. Although not statistically significant, LP was a better predictor of percentage of IOP change compared to PD ratio, preoperative IOP, and ACD. CONCLUSIONS: The percentage of IOP reduction after cataract surgery in nonglaucomatous eyes with open angles is greater in more anteriorly positioned lenses. Lens position, which is convenient to compute by basic ocular biometric data, is an accessible predictor with considerable predictive value for postoperative IOP change.

Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp. QWI-06 using mass-spectrometry-based metabolomics approach.

A robust and convenient research strategy integrating state-of-the-art analytical techniques is needed to efficiently discover novel compounds from marine microbial resources. In this study, we identified a series of amino-polyketide derivatives, vitroprocines A-J, from the marine bacterium Vibrio sp. QWI-06 by an integrated approach using imaging mass spectroscopy and molecular networking, as well as conventional bioactivity-guided fractionation and isolation. The structure-activity relationship of vitroprocines against Acinetobacter baumannii is proposed. In addition, feeding experiments with (13)C-labeled precursors indicated that a pyridoxal 5'-phosphate-dependent mechanism is involved in the biosynthesis of vitroprocines. Elucidation of amino-polyketide derivatives from a species of marine bacteria for the first time demonstrates the potential of this integrated metabolomics approach to uncover marine bacterial biodiversity.

Ethnic differences in trabecular meshwork height by optical coherence tomography.

IMPORTANCE: Differences in ocular anatomy may contribute to ethnic differences in glaucoma risk. Because the trabecular meshwork (TM) plays an important role in aqueous outflow, its anatomy in relation to at-risk populations may provide insight into a potential contributor to elevated intraocular pressure and thus to probability of glaucoma development. OBJECTIVE: To investigate whether differences exist in TM height between ethnic groups. DESIGN, SETTING, AND PARTICIPANTS: This prospective study took place from January 1, 2012, to December 31, 2013. Adult patients who self-reported as being of white, Asian, Hispanic, or African American ethnicity were recruited from ophthalmology clinics at the University of California, San Francisco. The TM height was assessed using spectral-domain anterior segment optical coherence tomography. MAIN OUTCOMES AND MEASURES: Trabecular meshwork height was measured from the scleral spur to the Schwalbe line. We hypothesized that ethnicities with a higher prevalence of glaucoma would tend to have shorter TM heights. RESULTS: We collected data from 460 eyes of 291 participants after excluding 34 optical coherence tomographic scans owing to poor image quality. The final sample was 32.2% white, 45.1% Asian, 10.5% African American, and 12.1% Hispanic. There were 64.2% women, and the mean age was 68.1 years. The mean (SD) TM height among all eyes included in the study was 836 (131) µm. The mean (SD) TM height was characterized among white (851 [131] µm), Asian (843 [126] µm), Hispanic (822 [147] µm), and African American (771 [118] µm) persons. Ethnicity was not associated with TM height overall (P = .23, linear mixed regression model). However, the TM heights of African American participants (771 µm) were shorter than those of white (851 µm; adjusted difference 95% CI, -119.8 to -8.1; P = .02) and Asian (843 µm; adjusted difference 95% CI, -117.4 to -10.8; P = .02) participants. CONCLUSIONS AND RELEVANCE: Although TM height is not associated with ethnicity overall, African American individuals have shorter TM heights compared with Asian and white persons. Trabecular meshwork size may play a role in ethnic differences of glaucoma risk and be a new risk factor to consider in primary open-angle glaucoma.

Myopia and glaucoma: sorting out the difference.

PURPOSE OF REVIEW: The aim of the present review was to summarize the evidence implicating the association between myopia and glaucoma, the possible underlying mechanisms for this relation, and the controversies surrounding detection of glaucomatous changes in coexisting myopia. RECENT FINDINGS: Numerous studies have shown that increasing categories of myopia are associated with a higher risk for optic neuropathy and glaucoma-like visual field defects. Recently, some high-resolution imaging modalities have been developed that aid further detection of the microanatomical changes of the optic nerve head and thus may provide a new insight to explain the association between myopia and glaucoma. Although the highly myopic eye usually shows many structural and functional defects that are difficult to distinguish from those caused by glaucoma, some new methods have been introduced to better differentiate between these changes. SUMMARY: The interaction of myopia with glaucoma risk remains complex, largely because of the retinal and nerve fiber layer damage that occurs in myopia alone. Whether to treat for glaucoma relies on the suspicion level of the clinician who must consider other risk factors for vision loss. Ultimately, it is the progression of glaucoma-like findings that determines whether a myopic patient has glaucoma.

Ophthalmic plastic and orbital surgery in Taiwan.

We describe in this paper the current status of ophthalmic plastic and orbital surgery in Taiwan. Data were collected from the Bureau of National Health Insurance of Taiwan, the Bulletin of the Taiwan Ophthalmic Plastic and Reconstructive Society, and the Statistics Yearbook of Practicing Physicians and Health Care Organizations in Taiwan by the Taiwan Medical Association. We ascertained that 94 ophthalmologists were oculoplastic surgeons and accounted for 5.8% of 1621 ophthalmologists in Taiwan. They had their fellowship training abroad (most ophthalmologists trained in the United States of America) or in Taiwan. All ophthalmologists were well trained and capable of performing major oculoplastic surgeries. The payment rates by our National Health Insurance for oculoplastic and orbital surgeries are relatively low, compared to Medicare payments in the United States. Ophthalmologists should promote the concept that oculoplastic surgeons specialize in periorbital plastic and aesthetic surgeries. However, general ophthalmologists should receive more educational courses on oculoplastic and cosmetic surgery.

Orbital hemangiopericytoma in an Asian population.

BACKGROUND/PURPOSE: Hemangiopericytoma is a very rare orbital tumor. The purpose of this study was to report the clinical and histopathological features of six cases of orbital hemangiopericytoma in an Asian population. METHODS: Clinical and histopathological features were reviewed in six patients who were histopathologically confirmed as having primary orbital hemangiopericytoma in National Taiwan University Hospital between May 2001 and December 2010. RESULTS: Among the six cases who were diagnosed as having primary orbital hemangiopericytoma, all lesions were reported as vascular tumors and featured branching "staghorn appearance" vessels. All patients, including one male and five females, presented with progressive proptosis and some associated symptoms such as extraocular motility limitation with diplopia, displacement of the globe, afferent pupillary defect, congested vessels of conjunctiva, or decreased visual acuity. On computed tomography, the orbital tumors tended to manifest as circumscribed masses with homogeneous medium-to-high enhancement with contrast studies. All six patients received surgical treatments, and four of them had additional radiotherapy. Three patients had recurrence after surgeries, and one of them had multiple metastases to lung and liver. All patients were still alive after a follow-up period of 5-10 years. CONCLUSION: Orbital hemangiopericytoma has malignant potential, which may lead to local recurrence and/or metastasis. Histopathological findings alone are insufficient to predict the behavior of this tumor. Therefore, both clinical and histopathological findings are important to evaluate the treatment outcomes. Total excision accompanied with radiotherapy is suggested and long-term follow-up is required.

Cytotoxic and anti-inflammatory metabolites from the soft coral Scleronephthya gracillimum.

Five new pregnane-type steroids, sclerosteroids J-N (1-5), and a diterpenoid with a new chemotype 3-methyl-5-(10'-acetoxy-2',6',10'-trimethylundecyl)-2-penten-5-olide (6), have been isolated from a soft coral Scleronephthya gracillimum. The structures of the metabolites were determined by extensive spectroscopic analysis. Compound 4 exhibited cytotoxicity against HepG2, A549, and MDA-MB-231 cancer cell lines. Furthermore, steroids 2 and 4 were found to significantly inhibit the accumulation of the pro-inflammatory iNOS protein, and 1, 2, 4 and 5 could effectively reduce the accumulation of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.

Steroids from the soft coral Sinularia crassa.

One new sterol, crassarosterol A (1), and four new steroidal glycosides, crassarosterosides A-D (2-5) were isolated from the Formosan soft coral Sinularia crassa. The absolute configuration of 1 was determined using the Mosher's method. The absolute configurations for the sugar moieties of 2-5 were determined by HPLC analysis on the o-tolylthiocarbamates derived from the liberated sugar after acid hydrolysis. Compounds 2 and 4 could significantly inhibit the expression of pro-inflammatory iNOS protein at 10 µM. In contrast, 1-3 were found to stimulate the expression of COX-2 protein at this concentration. Steroids 1 and 4 also showed cytotoxicity toward the selected human liver cancer cells.

nardosinane-type sesquiterpenoids from the formosan soft coral Paralemnalia thyrsoides.

Five new nardosinane-type sesquiterpenoids, paralemnolins Q-U (1-5), along with three known compounds (6-8), were isolated from the Formosan soft coral Paralemnalia thyrsoides. The structures of new metabolites were elucidated on the basis of extensive spectroscopic methods, and the absolute configuration of 1 was determined by the application of Mosher's method on 1. Among these metabolites, 1 and 3 are rarely found nardosinane-type sesquiterpenoids, possessing novel polycyclic structures. Compounds 1, 3, 6 and 7 were found to possess neuroprotective activity.

Bioactive cembranoids from the soft coral Sinularia crassa.

Eight new cembranoids, crassarines A-H (1-8) were isolated from the Formosan soft coral Sinularia crassa. Compounds 1-3 represent the rare cembranoids with a 1,12-oxa-bridged tetrahydrofuran ring, while 4 and 5 are the firstly discovered 1,11-oxa-bridged tetrahydropyranocembranoids. The absolute configuration of 6 was determined using the Mosher's method. Compounds 6 and 8 were found to significantly inhibit the expression of both pro-inflammatory iNOS and COX-2 proteins at 10 µM, respectively, while compounds 4-8 were found to be non-cytotoxic toward the selected human liver cancer cells.

Crassocolides N-P, three cembranoids from the Formosan soft coral Sarcophyton crassocaule.

Three new cembranoids crassocolides N-P (1-3), was isolated from the organic extract of a Formosan soft coral Sarcophyton crassocaule. These structures were elucidated on the basis of spectroscopic analyses and by comparison with those previously reported in literature. The cytotoxicity of these compounds toward various cancer cell lines has also been determined.

Nardosinane sesquiterpenoids from the Formosan soft coral Lemnalia flava.

Four new nardosinane-type sesquiterpenoids, flavalins A-D (1-4), have been isolated from the Formosan soft coral Lemnalia flava. The structures of the new metabolites were determined by extensive spectroscopic analysis, and the structure of 2 was confirmed by X-ray diffraction analysis. A plausible biosynthetic pathway to 1 and 2 is proposed. Compound 1 was found to display dose-dependent inhibition of iNOS protein expression, and 1 and 2 were shown to possess significant neuroprotective activity.