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Purpose: We determine the effects of bevacizumab on collagen production in a mouse model of conjunctival scarring., Methods: Experimental surgery was performed as described for the mouse model of conjunctival scarring, and bevacizumab was introduced by conjunctival injection. The capacity of bevacizumab to recognize conjunctival VEGF-A was determined by ELISA. Col1a1 was measured by real-time PCR and immunoblotting. T cells and collagen were visualized by immunofluorescence and picrosirius red staining of bleb cryosections. Conjunctival CD4+ or CD8a+ T cells were counted by flow cytometry. Mouse splenic T cells were cultured with bevacizumab/IgG and their numbers, cell cycle, and collagen production were measured using a cell counter, flow cytometry, and sircol soluble collagen assay, respectively. Reconstitution experiments in severe combined immunodeficiency (SCID) mice were performed by injection of freshly isolated T cells on day 2 postoperatively., Results: Bevacizumab recognized approximately 20% of endogenous murine VEGF-A. Injection of bevacizumab raised Col1a1 expression in the blebs at mRNA and protein levels. Bevacizumab did not induce collagen in conjunctival fibroblasts, but increased CD4+ and CD8a+ cell numbers as well as collagen production by these cells. Collagen appeared to accumulate in the vicinity of T cells in the bevacizumab-treated blebs. While SCID blebs did not show elevated collagen levels, reconstitution with CD4+ or CD8a+ cells resulted in increased Col1a1 expression at mRNA and protein levels., Conclusions: Bevacizumab increased collagen production in the mouse model of conjunctival scarring. This collagen induction was mediated by T cells that were also stimulated by bevacizumab to increase in numbers.

The unparalleled velocity achieved by overhead throwers subjects the shoulder to extreme forces, resulting in both adaptive changes and pathologic findings that can be detected at imaging. A key biomechanical principle of throwing is achieving maximum external rotation, which initially leads to adaptive changes that may result in a pathologic cascade of injuries. In addition to the well-established concepts of glenohumeral internal rotation deficit and internal impingement, osseous and soft-tissue injuries of the shoulder unique to overhead athletes are illustrated. The epidemiology and biomechanics of throwing injuries are reviewed, and examples from the authors' institutional experience with competitive, collegiate, and professional baseball players are provided to demonstrate the constellation of unique imaging findings seen in overhead throwing athletes. Given the widespread popularity of baseball, and other sports relying on overhead throwing motions at all playing levels from recreational to professional, it is important for radiologists in various practice settings to be familiar with the special mechanisms, locations, and types of shoulder injuries seen in the overhead throwing population. © RSNA, 2018.

Purpose: To investigate the drug release profiles of a tacrolimus-loaded poly(D,L-lactide-co-ε-caprolactone) (PLC) microfilm, and to evaluate its efficacy on the treatment of allergic conjunctivitis using a mouse model., Methods: The in vitro and in vivo drug release profiles were first characterized. Balb/c mice were immunized with short ragweed (SRW) injection followed by re-challenges with topical SRW solution. The mice were divided into six groups (n = 12 in each): negative control (NC); positive control (PC); tacrolimus eye drops (Te); subconjunctival tacrolimus microfilm (Tm); dexamethasone eye drops (De); and tacrolimus + dexamethasone eye drops (Te+De). The mice were evaluated for 28 days by a scoring system for allergic conjunctivitis. Histopathologic and immunohistochemical staining with CD11c, CD4, and IL-4 were performed., Results: The microfilms were biocompatible and delivered clinically sufficient dose in a sustained manner, with a steady rate of 0.212 to 0.243 μg/day in vivo. Compared to the PC groups, the Te, Tm, De, and Te+De groups significantly reduced the allergic clinical scores throughout the study period (all P < 0.01; 0.0 ± 0.0, 5.6 ± 0.9, 3.3 ± 0.9, 3.2 ± 0.9, 1.9 ± 0.4 and 1.7 ± 0.8 for the NC, PC, Tm, Te, De, and Te+De groups, respectively, at 4 weeks after treatment). The suppressed eosinophils, CD11c, CD4, and IL-4 expression were also observed in all treatment groups, with more reduction in the Te+De group., Conclusions: Tacrolimus-loaded microfilms display good biocompatibility and desirable sustained drug release. It was as effective as conventional tacrolimus eye drops on the treatment of allergic conjunctivitis, providing a promising clinically applicable alternative for controlling allergic disease activity, or other immune-mediated ocular diseases.

Due to the limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for ependymoma treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy. Understanding the mechanism of therapeutic failure caused by radio-resistance is, therefore, crucial in ependymoma treatment. Here we retrospectively analyze clinic-pathological factors in 82 cases of ependymoma less than 20 years old and identify radio-resistant genes through gene expression microarray followed by qRT-PCR validation and immunohistochemistry staining. Thirty-one out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross-total resection is the single significant prognostic factor for longer 10 years PFS and OS in the multivariant analysis ( p<0.05 ). According to the microarray analysis, CCND1 is up-regulated in supratentorial and infratentorial ependymomas and is associated with DNA repair. We demonstrated that 24 primary and 16 recurrent ependymomas were up-regulated, and 5 out of 7 paired samples exhibited higher CCND1 expression in recurrent tumors. We also found RAD51, another DNA repair gene, was up-regulated in supratentorial and infratentorial ependymomas. Knocking down CCND1 reduced cell proliferation and repressed several genes associated with S-phase and DNA repair. Homologous recombination activities of DNA repair were significantly decreased in CCND1-deficient cells while the level of γH2AX was increased after irradiation. In summary, these observations suggest a robust role of CCND1 in regulating cell proliferation and radio-resistance in ependymomas, providing a potential therapeutic target for pediatric ependymomas., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial or nonfinancial interest.

Polymers have the obvious advantages of flexibility in design and cost effectiveness to fabricate a lab-on-a-chip (LOC) device. Polyether ether ketone (PEEK) in particular is very attractive choice as it adds biocompatibility in addition to the possibility of hematic sealing in a 3D design. Hereby, we extend our previous successful technology of autohesive hermetic bonding of medical implants into lab-on-a-chip devices. We explore a conceptual 3D micro channels design with hermetic potential using PEEK and PS sheets. A hermetic and mechanically strong (through tensile test) 3D multilayer device was obtained using plasma treatment with oxygen and methane as precursors followed by pressing at temperature near of T g  + 20 of the polymer with the lowest T g (PS). This nanotexturing technique is also used to facilitate thermal and mechanical stability of the microchannels for microfluidic applications. X-ray tomography measurements showed that 3D polymer made chips, at certain plasma and press bonding conditions, have structural integrity and no deformation were detected in channels shape post thermal pressing process. The dimension stability of channels and reservoirs and the rigid interfacial region at PEEK-PS make this chip design attractive and feasible for advanced lab-on-a-chip applications.

Age-related macular degeneration (AMD) is a leading cause of blindness in the modern world. The standard treatment regimen for neovascular AMD is the monthly/bimonthly intravitreal injection of anti-VEGF agents such as ranibizumab or aflibercept. However, these repeated invasive injections can lead to sight-threatening complications. Sustained delivery by encapsulation of the drug in carriers is a way to reduce the frequency of these injections. Liposomes are biocompatible, non-toxic vesicular nanocarriers, which can be used to encapsulate therapeutic agents to provide sustained release. The protein encapsulation was performed by a modified dehydration-rehydration (DRV) method. The liposomes formed were characterized for size, zeta potential, encapsulation efficiency, stability, in vitro release, and ex vivo release profiles. In addition, the localization of the liposomes themselves was studied ex vivo. Entrapment-efficiency of ranibizumab into 100-nm liposomes varied from 14.7 to 57.0%. Negatively-charged liposomes prepared from DPPC-DPPG were found to have the slowest release with a low initial burst release compared to the rest of liposomal formulations. The ex vivo protein release was found to slower than the in vitro protein release for all samples. In conclusion, the DPPC-DPPG liposomes significantly improved the encapsulation and release profile of ranibizumab.

The current study examined the unique and shared contributions of arithmetic operation understanding and numerical magnitude representation to children's mathematics achievement. A sample of 124 fourth graders was tested on their arithmetic operation understanding (as reflected by their understanding of arithmetic principles and the knowledge about the application of arithmetic operations) and their precision of rational number magnitude representation. They were also tested on their mathematics achievement and arithmetic computation performance as well as the potential confounding factors. The findings suggested that both arithmetic operation understanding and numerical magnitude representation uniquely predicted children's mathematics achievement. The findings highlight the significance of arithmetic operation understanding in mathematics learning., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Soft-tissue augmentation and implants are increasingly seen by the radiologist as more techniques emerge for a variety of indications and locations. Some surgical and implant procedures are performed for purely cosmetic reasons in otherwise healthy patients seeking to improve their body image, and some are performed for reconstruction after cancer or other chronic illnesses. Abdominoplasty, liposuction, and autologous fat grafting can be performed for abdominal and gluteal contouring. Injection of liquid injectable silicone has historically been fraught with legal issues, although it continues to be used for augmentation in a variety of anatomic locations. Newer solid silicone implants have revolutionized cosmetic and reconstructive muscular contouring. Subdermal implants placed by nonmedical professionals are relatively new and unrecognized within the medical establishment, although such implants have been described in the popular culture. Perhaps the most rapidly increasing segment of cosmetic procedures, however, is minimally invasive cosmesis in the form of soft-tissue fillers in the hands and face. Finally, the major principles of breast augmentation and penile implants are also reviewed. Regardless of the location and the type of implant, complications of plastic surgery and soft-tissue implants can generally be classified into the following categories: seroma, hematoma, infection, migration, vascular or nerve compression, fibrosis, foreign-body reaction, and rupture or breakdown. Key concepts include knowing the appropriate anatomic location and the normal postoperative appearance so that complications can be properly detected. A broad range of approved, off-label, and illicit plastic surgical and implant procedures are described and their complications illustrated with cases with classic imaging findings. © RSNA, 2017.

Purpose: We evaluate the toxicity and plasma toxicokinetic (TK) profile of a biodegradable subconjunctival microrod for sustained prednisolone acetate (PA) release over 12 weeks in a non-human primate model., Methods: The biodegradable copolymer poly(l-lactide-co-ε-caprolactone) (PLC) and 40-wt% PA microrods were used and fashioned into 8 and 16 mm lengths. Twelve monkeys were divided into two treatment groups of PA-loaded and blank microrods, with six monkeys each receiving either 8- or 16-mm microrods subconjunctively implanted into both eyes. TK and hematology parameters were analyzed. Ophthalmic clinical evaluation, including slit-lamp and ophthalmoscopy examinations, was performed., Results: Over the study period of 12 weeks, the mean area under the plasma concentration-time curve was 45.7% higher, and the maximum plasma concentration was 17.2% lower for the animals treated with 40-wt% PA 16-mm microrods compared to 8-mm microrods (251.44 versus 172.54 hours × nanograms per milliliter and 8.53 versus 10.30 ng/mL, respectively). The PA release was significantly below the levels of assumed toxicity. There was no significant difference in the time to reach maximum concentration between the 8- and 16-mm microrod groups (7.33 and 8 hours; P = 0.421). Findings from clinical evaluation, hematology, and histopathology showed no ocular side effects and no significant adverse systemic effects., Conclusion: The PA biodegradable microrods demonstrated safe toxicokinetics even with the larger size implant containing a higher amount of drug. The PA implant may be considered as a safe alternative to the application of topical PA eyedrops., Translational Relevance: The results provide the evidence of the safety of implanting a steroid delivery system subconjunctively, offering an alternative to topical PA eyedrops.

Purpose: We previously identified three distinct subgroups of patients with primary angle closure glaucoma (PACG) based on anterior segment optical coherence tomography (ASOCT) imaging. Group 1 was characterized by a large iris area with deepest anterior chambers, group 2 by a large lens vault (LV) and shallow anterior chamber depth (ACD), and group 3 displayed intermediate values across iris area, LV, and ACD. The purpose of the present study was to determine the distribution of plateau iris in these subgroups using ultrasound biomicroscopy (UBM) features., Methods: UBM images of the 210 subjects who were previously enrolled for the ASOCT subgrouping analysis and had undergone laser peripheral iridotomy were assessed and graded by a single glaucoma fellowship trained clinician. Plateau iris was defined as the presence of all the following UBM criteria in at least two quadrants: anteriorly directed ciliary body, absent ciliary sulcus, iris angulation, flat iris plane, and iridoangle touch., Results: Of 210 subjects, 23 were excluded due to poor-quality images. Based on standardized UBM criteria, the overall prevalence of plateau iris was 36.9% (n = 187). The proportion of plateau iris was similar across the three groups (subgroup 1:35.4% (n = 29); subgroup 2:39.0% (n = 32); subgroup 3:34.8% (n = 8), P = 0.87). On multiple logistic regression analysis, iris thickness at 750 μm from the scleral spur (IT750) was the only variable associated with plateau iris (odds ratio: 1.5/100 μm increase in iris thickness [IT], P = 0.04)., Conclusions: The proportion of plateau iris was similar across the three ASOCT-based PACG subgroups and more than one-third of subjects with PACG were diagnosed with plateau iris based on standardized UBM criteria. In addition, we noted that eyes with increased peripheral IT have an increased likelihood of plateau iris.

Objective: The purpose of this article is to discuss common elbow injuries found in pediatric athletes who participate in sports that entail overhead movements with focus on mechanism, clinical features, imaging appearance, and treatment options., Conclusion: Elbow injuries are commonly seen in pediatric overhead athletes and have been on the rise owing to the increased participation in and demand of youth sports. Imaging plays a critical role in identifying the type and severity of injury, which helps to determine appropriate treatment options.

Infants with an immobile arm may be easily overlooked in primary care settings. Differential diagnoses include injuries, infections, neuropathies, ischemia and rarely, neoplasms. We report the case of a one-year-old boy with weakness in his left arm after minor trauma with a diagnosis of brachial plexus palsy initially. After rehabilitation for 2months, his weakness progressed to unsteady gait and quadriparesis. MRI revealed a huge solid tumor in the left supraclavicular fossa, which also involved the left brachial plexus, upper thoracic cavity, and left paravertebral space with invasion into the spinal canal. Microscopically, the medium-large polygonal tumor cells had an eccentric eosinophilic cytoplasm and immunostaining showed a loss of nuclear INI1 expression. Array comparative genomic hybridization of the tumor tissue confirmed a segmental deletion at chromosome region 22q11.23 involving the SMARCB1 gene. The final diagnosis was cervical paravertebral malignant rhabdoid tumor with intraspinal epidural and intradural invasion, a rare case of extrarenal extracranial rhabdoid tumor (ERRT). The intraspinal part of the tumor was resected followed by interval-compressed chemotherapy with vincristine-doxorubicin-cyclophosphamide alternating with ifosfamide-etoposide (VDC/IE). The tumor showed very good partial response to four cycles of chemotherapy with gradual recovery of neurological symptoms. ERRT is a very rare and aggressive tumor that mainly occurs in infants and children and may manifest with vague neurological symptoms when it involves the spinal cord and/or peripheral nerves. A neoplasm such as ERRT originating from or involving the brachial plexus should be considered in the differential diagnosis of an immobile arm in infancy., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

While ASCII art is a worldwide popular art form, automatic generating structure-based ASCII art from natural photographs remains challenging. The major challenge lies on extracting the perception-sensitive structure from the natural photographs so that a more concise ASCII art reproduction can be produced based on the structure. However, due to excessive amount of texture in natural photos, extracting perception-sensitive structure is not easy, especially when the structure may be weak and within the texture region. Besides, to fit different target text resolutions, the amount of the extracted structure should also be controllable. To tackle these challenges, we introduce a visual perception mechanism of non-classical receptive field modulation (non-CRF modulation) from physiological findings to this ASCII art application, and propose a new model of non-CRF modulation which can better separate the weak structure from the crowded texture, and also better control the scale of texture suppression. Thanks to our non-CRF model, more sensible ASCII art reproduction can be obtained. In addition, to produce more visually appealing ASCII arts, we propose a novel optimization scheme to obtain the optimal placement of proportional-font characters. We apply our method on a rich variety of images, and visually appealing ASCII art can be obtained in all cases.

Intracranial germ cell tumors differ in histology and location, and require different clinical management strategies. We characterized the imaging features that may aid pre-operative differentiation of intracranial germinomas and non-germinomatous germ cell tumors (NGGCTs). This retrospective study analyzed 85 patients with intracranial germ cell tumors and adequate preoperative or pretreatment MRIs between 2000 and 2013 at our institution. Pretreatment MRI characteristics, apparent diffusion coefficient (ADC) values, tumor histopathology, and patient outcomes were compared. NGGCTs occurred in the pineal region and cerebral hemispheres more often than germinomas; all bifocal lesions were germinomas. NGGCTs (36.6 ± 17.0 mm) were significantly larger than germinomas (25.7 ± 11.6 mm; P = 0.002). The presence of pure solid tumor (45.5 vs. 20.0%, P = 0.033) and an infiltrative margin (20.0 vs. 3.3%, P = 0.035) were significantly more common in germinomas than NGGCTs. The presence of intratumoral T1 hyperintense foci (66.7 vs. 10.9%, P < 0.001) and moderate/marked enhancement (86.7 vs. 50.9%, P < 0.001) were significantly more common in NGGCTs than in germinomas. Mean ADC mean values (×10 -3  mm 2 /s) were significantly lower in germinomas (1.113 ± 0.415) than in NGGCTs (2.011 ± 0.694, P = 0.001). Combined a lack of T1 hyperintense foci and an ADC mean threshold value (1.143 × 10 -3 mm 2 /s) had the highest specificity (91.3%) and positive predictive value (92.3%), while the combination of lack of a T1 hyperintensense foci, no/mild enhancement, and an ADC mean threshold value had 100% sensitivity and 100% negative-predictive value for discriminating germinomas from NGGCTs. Pre-operative conventional MRI characteristics and diffusion-weighted MRI help clinicians to assess patients with intracranial germ cell tumors. Tumor size, location, T1 hyperintense foci, intratumoral cystic components, tumor margin and enhancing patterns demonstrate contrast between germinomas and NGGCTs. Serum tumor markers and adjunctive combination with T1 hyperintensity and/or enhancing pattern with ADC offer potential in preoperative differentiating intracranial germinomas and NGGCTs.

Purpose: Medulloblastoma (MB) is the most commonly occurring malignant pediatric brain tumor worldwide. However, a recent study found that the treatment outcomes in those with high-risk disease receiving conventional treatment were suboptimal. This study aimed to assess outcomes and treatment strategies for specific histologic subtypes of pediatric MB., Methods: A total of 114 pediatric patients (age < 20 years) diagnosed with MB between March 1998 and August 2011 were retrospectively reviewed; 52 that were treated with surgery followed by adjuvant radiotherapy (RT) and chemotherapy (CHT) were included., Results: The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 73 and 69%, respectively. Median time to relapse was 17 months with a median survival time of 6 months after relapse. Patients of average risk had a better 5-year OS rate compared with high-risk patients (p = 0.027). The 5-year RFS of high-risk patients was lower compared with average risk (p = 0.038). A greater proportion of patients with large cell/anaplastic (LC/A) MB had recurrence than classic MB with 5-year RFS rate of 34 and 76%, respectively (p = 0.001), and OS rate of 56 and 76%, respectively (p = 0.04)., Conclusion: High-risk group and histology of LC/A were the most significant factors associated with worse OS and RFS. Patients with LC/A-MB had higher relapse rates and worse survival than those with classic MB. LC/A-MB carries a high risk for recurrence and should be treated with the more aggressive strategies.

Background: Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB)., Methods: We divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain., Results: Transcranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme., Conclusions: Transcranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy.

Purpose: To evaluate the intraocular pressure (IOP) change and associated factors 6 months after phacoemulsification in eyes with primary angle-closure suspect (PACS) and eyes with primary angle closure (PAC) that had no medical therapy., Setting: Singapore National Eye Center, Singapore, Singapore., Design: Retrospective case series., Methods: Patients with PACS or PAC (with corrected distance visual acuity <20/40) who had uneventful phacoemulsification were recruited. Patients were excluded if they were on IOP-lowering medications within 6 months preoperatively and postoperatively. Preoperative gonioscopy, A-scan biometry, anterior segment optical coherence tomography, and automated refraction were reviewed. Factors related to the percentage of and absolute IOP change were assessed using multiple linear regression analyses after adjusting for age, sex, and diagnosis., Results: The study evaluated 85 patients (85 eyes; 52 PACS, 33 PAC) after 7 eyes (1 PACS, 6 PAC) were excluded because of poor quality imaging. Overall, IOP decreased by 19.9% from the preoperative mean of 16.1 mm Hg ± 3.1 (SD) to 12.9 ± 2.7 mm Hg. The IOP change between the PACS group (-3.3 ± 2.8 mm Hg; -20.6%) and the PAC group (-3.2 ± 4.7 mm Hg; -19.6%) was similar (P > .05). In multiple linear regression analyses, a higher preoperative IOP (β = 0.68, P < .001) and fewer clock hours of peripheral anterior synechiae (PAS) (β = -0.30, P = .03) predicted a greater absolute change in and percentage of reduction in IOP, respectively., Conclusions: The mean IOP reduction 6 months after phacoemulsification was 20%. Less IOP reduction was observed in the presence of lower preoperative IOP and more extensive PAS., (Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Excessive accumulation of collagen is often used to assess the development of fibrosis. This study aims to identify collagen genes that define fibrosis in the conjunctiva following glaucoma filtration surgery (GFS). Using the mouse model of GFS, we have identified collagen transcripts that were upregulated in the fibrotic phase of wound healing via RNA-seq. The collagen transcripts that were increased the most were encoded by Col8a1 , Col11a1 and Col8a2 Further analysis of the Col8a1 , Col11a1 and Col8a2 transcripts revealed their increase by 67-, 54- and 18-fold, respectively, in the fibrotic phase, compared with 12-fold for Col1a1 , the most commonly evaluated collagen gene for fibrosis. However, only type I collagen was significantly upregulated at the protein level in the fibrotic phase. Type VIII and type I collagens colocalized in fibrous structures and in ACTA2-positive pericytes, and appeared to compensate for each other in expression levels. Type XI collagen showed low colocalization with both type VIII and type I collagens but can be found in association with macrophages. Furthermore, we show that both mouse and human conjunctival fibroblasts expressed elevated levels of the most highly expressed collagen genes in response to TGFβ2 treatment. Importantly, conjunctival tissues from individuals whose GF surgeries have failed due to scarring showed 3.60- and 2.78-fold increases in type VIII and I collagen transcripts, respectively, compared with those from individuals with no prior surgeries. These data demonstrate that distinct collagen transcripts are expressed at high levels in the conjunctiva after surgery and their unique expression profiles may imply differential influences on the fibrotic outcome., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Arginine vasotocin is a hormone produced in the hypothalamus of teleost fish that has been shown to regulate gonad development and sexual behavior. To study the role of arginine vasotocin in the gonadal cycle of the hermaphrodite gilthead seabream, Sparus aurata, we cloned the seabream arginine vasotocin (avt) complementary DNA (cDNA). We investigated the expression of brain avt throughout the gonad cycle using real-time quantitative PCR and compared its expression levels to the expression levels of two key gonadal steroidogenic enzymes, cyp19a1a and cyp11b2. In July, when the process of sex reversal is thought to begin, avt expression was elevated over the previous 2 months. Avt in the brain remained at or above the level of July until November then peaked again in December. There was no difference between males and females in the expression levels of brain avt throughout the year. However, only in ambisexual fish was the expression of the cyp19a1a gonadal aromatase correlated to the expression of avt in the brain. Cyp11b2 did not show any correlation to brain avt expression. We also found that females had more intense body coloration than males and that this intensity peaked prior to spawning. Avt expression and female coloration were positively correlated. The fact that brain avt expression was lowest during gonad quiescence, together with the observation of a correlation between brain avt with gonadal cyp19a1a and body coloration during that time suggests that avt may play a role during the process of sex reversal and spawning of the gilthead seabream.

Gonadotropin-inhibitory hormone (GNIH) was discovered in quail with the ability to reduce gonadotropin expression/secretion in the pituitary. There have been few studies on GNIH orthologs in teleosts (LPXRFamide (Lpxrfa) peptides), which have provided inconsistent results. Therefore, the goal of this study was to determine the roles and modes of action by which Lpxrfa exerts its functions in the brain-pituitary axis of zebrafish (Danio rerio). We localized Lpxrfa soma to the ventral hypothalamus, with fibers extending throughout the brain and to the pituitary. In the preoptic area, Lpxrfa fibers interact with gonadotropin-releasing hormone 3 (Gnrh3) soma. In pituitary explants, zebrafish peptide Lpxrfa-3 downregulated luteinizing hormone beta subunit and common alpha subunit expression. In addition, Lpxrfa-3 reduced gnrh3 expression in brain slices, offering another pathway for Lpxrfa to exert its effects on reproduction. Receptor activation studies, in a heterologous cell-based system, revealed that all three zebrafish Lpxrfa peptides activate Lpxrf-R2 and Lpxrf-R3 via the PKA/cAMP pathway. Receptor activation studies demonstrated that, in addition to activating Lpxrf receptors, zebrafish Lpxrfa-2 and Lpxrfa-3 antagonize Kisspeptin-2 (Kiss2) activation of Kisspeptin receptor-1a (Kiss1ra). The fact that kiss1ra-expressing neurons in the preoptic area are innervated by Lpxrfa-ir fibers suggests an additional pathway for Lpxrfa action. Therefore, our results suggest that Lpxrfa may act as a reproductive inhibitory neuropeptide in the zebrafish that interacts with Gnrh3 neurons in the brain and with gonadotropes in the pituitary, while also potentially utilizing the Kiss2/Kiss1ra pathway., (© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Kisspeptin and neurokinin B (NKB) are neuropeptides co-expressed in the mammalian hypothalamus and coordinately control GnRH signaling. We have found that Nkb and kisspeptin neurons are distinct in the teleost, striped bass (STB) and capitalized on this phenomenon to study the mode of action of Nkb and its related neuropeptide-F (Nkf), both of which are encoded by the tac3 gene. In vitro brain slices and in vivo administration studies revealed that Nkb/f consistently downregulated kiss2 , whereas antagonist (AntD) administration restored this effect. Overall, a minor effect was noted on gnrh1 expression, whereas Gnrh1 content in the pituitaries was reduced after Nkb/f treatment and increased with AntD. Concomitantly, immunostaining demonstrated that hypothalamic Nkb neurons border and densely innervate the largest kiss2 neuronal population in the hypothalamus, which also coexpresses Nkb receptor. No expression of Nkb receptor or Nkb neuronal projections was detected near/in Gnrh1 soma in the preoptic area. At the level of the pituitary, however, the picture was more complex: both Nkb/f and AntD upregulated lhb and fshb expression and Lh secretion in vivo Together with the stimulatory effect of Nkb/f on Lh/Fsh secretion from pituitary cells, in vitro , this may indicate an additional independent action of Nkb/f within the pituitary, in which the hypothalamic pathway is more dominant. The current study demonstrates that Nkb/f utilizes multiple pathways to regulate reproduction in the STB and that in the brain, Nkb mainly acts as a negative modulator of kiss2 to regulate the release of Gnrh1., (© 2017 Society for Endocrinology.)

While lasers have been commonly used as illumination sources in photoacoustic (PA) imaging, their high purchase and maintenance costs, as well as their bulkiness, have hindered the rapid clinical dissemination of PA imaging. With this in mind, we explore an alternative illumination source for PA tomography—a xenon flash lamp with high pulse energy and a microsecond pulse width. We demonstrate that, by using a single xenon flash lamp, we can image both a black latex cord placed in chicken breast tissue at a depth of up to 3.5 cm ex vivo and an entire mouse body in vivo. Our findings indicate that the xenon flash lamp, producing optical illumination that is safe for humans, can be potentially applied to human tissue imaging.

Sustained-release drug delivery systems that replace the need for daily glaucoma medications will improve outcomes for those who are nonadherent and reduce the inconvenience of having to take medications on a recurring basis.The objective is to estimate uptake (i.e., demand) for a new technology that delivers sustained-release glaucoma medication and to investigate how uptake varies by product attributes, physician recommendations, peer adoption (i.e., percentage of patients seen in a clinic using the new technology), and patient characteristics.In a web-enabled discrete-choice experiment survey, glaucoma patients in the United States were asked to choose between continuing eye drop use or purchasing the new delivery system. In a cross-sectional web-enabled survey, ophthalmologists were asked their likelihood of recommending the new technology based on product and patient characteristics.Study participants were 500 glaucoma patients who were on topical administration of daily eye drops and 155 ophthalmologists who practice in the US.Main outcomes were predicted uptake for patients and likelihood of recommending a new drug delivery system for ophthalmologists. Logistic models were used to analyze the choice data.Uptake was estimated to be 18% at an annual cost of $1000 and to be 24% when the cost was $500. A physician's recommendation increased uptake by 6% to 12%, whereas an increase in peer adoption from 5% to 50% increased uptake by 3% to 7%. Patients aged ≥ 65 and those with lower income were more likely to remain on eye drops. Physicians were more likely to recommend a product if the interval between administrations is 6 months or longer and when long-term safety and efficacy data are available. They were less likely to recommend it to patients with lower income and no adherence problems.Results suggest a significant interest in an injectable solution or other sustained-release alternatives to daily eye drops. However, in this survey, patient uptake was greatly influenced by out-of-pocket cost and the interval between treatment administrations. Few physicians were willing to recommend sustained-release technology if the treatment interval was less than 3 months.

Objective: The purpose of this article is to review common elbow injuries found in overhead athletes with focus on mechanism, clinical features, imaging appearance, and treatment options., Conclusion: The overhead throwing motion subjects the elbow to a variety of complex forces, which places both osseous and soft-tissue structures at high risk for injury.

Developmental dyscalculia (DD) is a specific learning disability in mathematics that affects around 6% of the population. Currently, the core deficit of DD remains unknown. While the number sense deficit hypothesis suggests that the core deficit of DD lies in the inability to represent nonsymbolic numerosity, the access deficit hypothesis suggests that the origin of this disability lies in the inability to associate numbers with the underlying magnitude representation. The present study compared the performance of DDs with their low-achieving (LA) and normally achieving peers in nonsymbolic numerosity processing and number-magnitude mapping over 1 year (from kindergarten to 1st grade). The results demonstrated differential impairments in different subgroups of children with mathematics difficulties. While DDs showed deficits in both nonsymbolic numerosity processing and number-magnitude mapping, LAs showed deficit only in the number-magnitude mapping. Furthermore, the deficit in number-magnitude mapping among the DD group was partially explained by their number sense deficit. The number sense deficit hypothesis is supported. Theoretical and practical implications are discussed., (© Hammill Institute on Disabilities 2015.)

Purpose: Secreted protein acidic and rich in cysteine (SPARC) and Hevin are structurally related matricellular proteins involved in extracellular matrix assembly. In this study, we compared the anterior chamber biometric parameters and iris collagen properties in SPARC-, Hevin- and SPARC-/Hevin-null with wild-type (WT) mice., Methods: The right eyes of 53 WT, 35 SPARC-, 56 Hevin-, and 63 SPARC-/Hevin-null mice were imaged using the RTVue-100 Fourier-domain optical coherence tomography system. The parameters measured were anterior chamber depth (ACD), trabecular-iris space area (TISA), angle opening distance (AOD), and pupil diameter. Biometric data were analyzed using analysis of covariance and adjusted for age, sex, and pupil diameter. Expression of Col1a1, Col8a1, and Col8a2 transcripts in the irises was measured by quantitative polymerase chain reaction. Collagen fibril thickness was evaluated by transmission electron microscopy., Results: Mice that were SPARC- and SPARC-/Hevin-null had 1.28- and 1.25-fold deeper ACD, 1.45- and 1.53-fold larger TISA, as well as 1.42- and 1.51-fold wider AOD than WT, respectively. These measurements were not significantly different between SPARC- and SPARC-/Hevin-null mice. The SPARC-null iris expressed lower Col1a1, but higher Col8a1 and Col8a2 transcripts compared with WT. Collagen fibrils in the SPARC- and SPARC-/Hevin-null irises were 1.5- and 1.7-fold thinner than WT, respectively. The Hevin-null iris did not differ from WT in these collagen properties., Conclusions: SPARC-null mice have deeper anterior chamber as well as wider drainage angles compared with WT. Therefore, SPARC plays a key role in influencing the spatial organization of the anterior segment, potentially via modulation of collagen properties, while Hevin is not likely to be involved.

Background: This study aimed to evaluate differences in iris gene expression profiles between primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) and their interaction with biometric characteristics., Design: Prospective study., Participants: Thirty-five subjects with PACG and thirty-three subjects with POAG who required trabeculectomy were enrolled at the Singapore National Eye Centre, Singapore., Methods: Iris specimens, obtained by iridectomy, were analysed by real-time polymerase chain reaction for expression of type I collagen, vascular endothelial growth factor (VEGF)-A, -B and -C, as well as VEGF receptors (VEGFRs) 1 and 2. Anterior segment optical coherence tomography (ASOCT) imaging for biometric parameters, including anterior chamber depth (ACD), anterior chamber volume (ACV) and lens vault (LV), was also performed pre-operatively., Main Outcome Measures: Relative mRNA levels between PACG and POAG irises, biometric measurements, discriminant analyses using genes and biometric parameters., Results: COL1A1, VEGFB, VEGFC and VEGFR2 mRNA expression was higher in PACG compared to POAG irises. LV, ACD and ACV were significantly different between the two subgroups. Discriminant analyses based on gene expression, biometric parameters or a combination of both gene expression and biometrics (LV and ACV), correctly classified 94.1%, 85.3% and 94.1% of the original PACG and POAG cases, respectively. The discriminant function combining genes and biometrics demonstrated the highest accuracy in cross-validated classification of the two glaucoma subtypes., Conclusions: Distinct iris gene expression supports the pathophysiological differences that exist between PACG and POAG. Biometric parameters can combine with iris gene expression to more accurately define PACG from POAG., (© 2016 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Currently, infections following cataract surgery are not as effectively managed with antibiotic eye drops, which suffer from poor bioavailability of drug and low patient compliance. The ideal solution, which can help to overcome the issue of drug wastage and poor bioavailabilty, as well as the need for frequent applications (patient inconvenience), is a drug-eluting intraocular lens (IOL). We describe a novel approach to such a drug-eluting lens by using a peripheral IOL attachment as a drug depot to deliver antibiotics, Levofloxacin (LFX) or Moxifloxacin (MFX). In this work, drug was entrapped within a fully-degradable polymer, poly(L-lactide-co-ɛ-caprolactone) (PLC). The effects of drug loading and solvent type on drug release and film morphology were investigated using cast films. The study clearly demonstrated that a slower-evaporating solvent tetrahydrofuran (THF) resulted in a better surface morphology, as well as lower initial burst compared to dichloromethane (DCM), and hence, was better suited to developing a drug-eluting attachment with sustained release of drug. When attachments were fabricated with drugs at high loading percentages (20% and 25% in polymer), significant burst was observed compared to films: this is attributed to the higher surface-to-volume ratio of the attachments. When the levofloxacin (LFX) loading percentage was decreased to 3% and 5%, the attachments presented lower burst and sustained release with therapeutic efficacy. This work has demonstrated the potential of using an IOL attachment as a more efficacious anti-infective option compared to daily eye drops., Competing Interests: The authors have declared that no competing interests exist.

Background: The Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population., Methods: Consecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured., Results: A total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations., Conclusions: The Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tumors with epicenter in the thalamus occur in about 4 % of pediatric brain tumors. The histological diagnosis is mainly gliomas. Among them, low-grade glioma (LGG) constituted of a significant entity of the tumors (Cuccia et al., Childs Nerv Syst 13:514-521, 1997; Puget et al., J Neurosurg 106:354-362, 2007; Bernstein et al., J Neurosurg 61:649-656, 1984; Bilginer et al., Childs Nerv Syst 30:1493-1498, 2014). Since Kelly's report in 1989, >90 % resection of thalamic tumors were achieved in reported series (Ozek and Ture, Childs Nerv Syst 18:450-6, 2002; Villarejo et al., Childs Nerv Syst 10:111-114, 1994; Moshel et al., Neurosurgery 61:66-75, 2007; Albright, J Neurosurg 100(5 Suppl Pediatrics): 468-472, 2004; Kelly, Neurosurgery 25:185-195, 1989; Drake et al., Neurosurgery 29: 27-33, 1991)., Materials and Methods: Sixty-nine cases of thalamic tumors in children were retrospectively reviewed. There were 25 cases of LGGs. We analyzed our experience and correlated it with reported series., Results: Summing up of 4 reported series and the present series, there were 267 cases of thalamic tumors in children. Among these tumors, 107 (40.1 %) were LGGs and 91 (34.1 %) were low-grade astrocytomas (LGAs). In the present series, all of the 25 LGGs were LGAs that consisted of 11 pilocytic astrocytomas (PAs) and 14 diffuse astrocytomas (DAs). Six cases received biopsy sampling only. The remaining 19 cases received different degrees of surgical resection via several approaches. Radical (>90 %) resection was achieved better in PAs comparing with DAs. There was no operative mortality. Two patients had increased neurological deficits. In a mean follow-up period of 11.9 years, three patients died of tumor progression and one patient died of anaplastic change. The 5- and 10-year overall survival (OS) was 87.1 and 87.1 %, respectively., Conclusion: Thalamic LGGs are mainly LGAs and are indolent. The rate of >90 % resection was relatively low in the present series. By applying contemporary diagnostic MRI studies, surgical facilities, and appropriate approaches in selective cases, we may try maximum neuroprotective radical (>90 %) resection.

Purpose: To report the incidence and risk factors of elevated IOP following deep anterior lamellar keratoplasty (DALK)., Design: A retrospective case series., Methods: A retrospective study investigating the 5-year incidence of raised IOP following DALK cases performed from 2004 to 2008 in a tertiary center. Patients with less than 6 months of follow-up were excluded. Elevated IOP was defined as IOP >21 mm Hg., Results: An episode of elevated IOP occurred in 36.1% of cases (44/122 cases), 11.4% (n = 5) occurring within the first week. The average duration of raised IOP was 48.9 (SD: 65.5) days. Causes included pupil block from air, swollen grafts, and corticosteroid response. Surgical intervention to lower IOP was required in 3 cases (6.8%). In multivariate analyses, the use of Olopatadine 0.1% or cyclosporine eye drops before DALK (OR = 14.51, 95% CI = 1.43-147.23) and use of topical prednisolone acetate 1% compared with dexamethasone 0.1% post DALK (OR = 4.79, 95% CI = 0.73-31.52) were associated with higher rates of elevated IOP post DALK. At 5 years post DALK, 3 of 71 cases (4.48%) developed de novo glaucomatous field defects, and 1 case with pre-existing glaucoma had progression of glaucomatous field defect., Conclusions: DALK was associated with a significant incidence of transiently elevated IOP postoperatively, but had a low incidence of de novo glaucoma at 5 years in our study. Risk factors for raised IOP post DALK included the use of topical prednisolone acetate 1% compared with dexamethasone 0.1%, and the use of Olopatadine 0.1% or any concentration of cyclosporine eye drops prior to DALK., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the patterns of visual field (VF) defects in primary angle-closure glaucoma (PACG) across different severity levels and to assess hemifield differences within each severity level., Design: Cross-sectional study., Participants: Three hundred four patients diagnosed with PACG were recruited from glaucoma clinics at a Singapore hospital., Methods: Point-wise total deviation values were recorded from the static automated perimetry (Swedish interactive threshold algorithm standard program 24-2; Humphrey model 750 [Carl Zeiss Meditec, Dublin, CA]) printouts. Patients were excluded if they had unreliable VFs (fixation losses >33% and false-positive responses >15%), had undergone only 10-2 VF testing, had VF defects not typical of glaucoma, or had undergone cataract extraction. Mild, moderate, and severe VF loss were defined by a mean deviation of -6.00 dB or more, -6.01 to -12.00 dB, and -12.01 dB or less, respectively. Each hemifield was divided into regions according to glaucoma hemifield test sectors. The average mean deviation (MD) of each region was obtained using total deviation values., Main Outcome Measures: Between- and within-hemifield differences of the regions across the severity levels., Results: After excluding ineligible cases, 249 patients with PACG were included in the analysis. Mean age of the patients was 65.7±8.6 years, with a 1:1 gender ratio. The number of patients who had mild, moderate, and severe VFs was 72 (28.9%), 78 (31.3%), and 99 (39.8%), respectively. For between-hemifield comparisons, all regions in the superior hemifield had worse MDs compared with their counterparts in the inferior hemifield across the severity spectrum. Likewise, for within-hemifield comparisons, MDs of the regions gradually worsened with increasing distance from the fixation point., Conclusions: In this group of clinic-based PACG patients, the superior hemifield was found to be affected more severely than the inferior hemifield, and the differences between them increased with worsening disease severity. The damage was consistently more pronounced in the nasal area., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to describe epileptic seizures in patients with primary intracranial sarcomas., Methods: We report a 17-year-old girl diagnosed with primary high-grade intracranial sarcoma with initial clinical manifestation of nonconvulsive status epilepticus. Literature reports between 2000 and 2014, relevant to primary intracranial sarcomas in children, were reviewed. The clinical presentations and neurological outcomes were analyzed., Results: Eleven of 29cases (38 %), 8 males and 3 females, who exhibited epileptic seizures as one of the initial symptoms and diagnosed with primary intracranial sarcomas were collected. The median age of disease onset was 5 years. The two most common seizure types were generalized seizures (45 %) and status epilepticus (36 %). Nine of 11 patients (82 %) had tumor growth involving the frontal lobe. Nine cases had the median duration of follow-up 1.7 years, of which 6 cases showed tumor recurrence and 3 cases died during the period of follow-up., Conclusions: Epileptic seizures as one of the clinical manifestations are uncommon. The two most common seizure types were generalized seizures and status epilepticus. The most frequent location of primary intracranial sarcoma-related seizures was the frontal lobe. The clinical outcome varied.

Purpose: The aim of this study was to investigate the incidence, clinical profiles, latency, and outcomes of radiotherapy (RT)-related intracranial aneurysms, rare but often fatal complications of cranial irradiation., Methods: We reviewed all published individual patient data regardless of language, using survival analysis to make statistical inferences., Results: We examined a total of 58 patients with RT-related intracranial aneurysms, including one unpublished case presented here, of whom 74.1 % presented with rupture. In the study, 29.3 % were younger than 18 years. The mean age at which patients received the first course of RT was 34.8 ± 22.8 years old. The mean latency between initiating RT and presenting with aneurysm was 10.4 ± 8.5 years. Rapid death ensured in 24 % shortly after presentation. The only significant predictor of death was rupture. In those with a single aneurysm, 43.1 % were located at the internal carotid artery, while 15.5 % of patients had multiple aneurysms. A male-to-female ratio of 1.87, 0.5, and 1.32 was found in patients younger than age 52, 52 years of age or older, and all 58 patients, respectively. Older age when receiving RT and presentation with ruptured aneurysm were significantly associated with shorter latency., Conclusions: RT-related intracranial aneurysms presented differently from classical ones based on age, sex, site, multiplicity, and type. Sex ratios differed with age. The younger age group showed a longer latency of occurrence of an aneurysm. Older patients and those who develop ruptured aneurysms presented earlier. Since rupture may affect outcome, early detection of aneurysms before rupture may save lives.

We aimed to investigate the incidence and long-term outcome of moyamoya syndrome in pediatric patients with primary brain tumors after receiving cranial radiotherapy (RT) in a single institute in Taiwan. The complete medical records, medical images, and RT notes of 391 pediatric patients with primary brain tumors treated with cranial RT between January 1975 and December 2005 in Taipei Veterans General Hospital (TVGH), Taiwan, were entered into an electronic registry and reviewed. Eight (2%) cases of post-RT moyamoya syndrome were identified in the sample of 391 patients. The median latency was 3 years post-RT. Among the eight patients, three had craniopharyngioma, two had optic glioma, two had medulloblastoma, and one had a suprasellar astrocytoma. The prescribed physical doses of RT were in the range of 40-54 Gy. The incidence was highest in those with optic glioma (0.039/person-year), followed by craniopharyngioma (0.013/person-year), astrocytoma (0.003/person-year), and medulloblastoma (0.002/person-year). No patients died of vasculopathy. No difference in crude incidence was found between our results and those of other series. The incidence of moyamoya syndrome was diagnosis dependent, with the highest incidence among patients with optic glioma. No regional difference in incidence was found. Long-term, stable neurological function may be achieved following timely surgical intervention., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The purpose of this study is to statistically assess whether bi-exponential intravoxel incoherent motion (IVIM) model better characterizes diffusion weighted imaging (DWI) signal of malignant breast tumor than mono-exponential Gaussian diffusion model., Methods: 3 T DWI data of 29 malignant breast tumors were retrospectively included. Linear least-square mono-exponential fitting and segmented least-square bi-exponential fitting were used for apparent diffusion coefficient ( ADC ) and IVIM parameter quantification, respectively. F-test and Akaike Information Criterion (AIC) were used to statistically assess the preference of mono-exponential and bi-exponential model using region-of-interests (ROI)-averaged and voxel-wise analysis., Results: For ROI-averaged analysis, 15 tumors were significantly better fitted by bi-exponential function and 14 tumors exhibited mono-exponential behavior. The calculated ADC , D (true diffusion coefficient) and f (pseudo-diffusion fraction) showed no significant differences between mono-exponential and bi-exponential preferable tumors. Voxel-wise analysis revealed that 27 tumors contained more voxels exhibiting mono-exponential DWI decay while only 2 tumors presented more bi-exponential decay voxels. ADC was consistently and significantly larger than D for both ROI-averaged and voxel-wise analysis., Conclusions: Although the presence of IVIM effect in malignant breast tumors could be suggested, statistical assessment shows that bi-exponential fitting does not necessarily better represent the DWI signal decay in breast cancer under clinically typical acquisition protocol and signal-to-noise ratio (SNR). Our study indicates the importance to statistically examine the breast cancer DWI signal characteristics in practice., Competing Interests: The authors have no conflicts of interest to declare.

People map numbers onto space. The well-replicated SNARC (spatial-numerical association of response codes) effect indicates that people have a left-sided bias when responding to small numbers and a right-sided bias when responding to large numbers. This study examined whether such spatial codes were tagged to the ordinal or magnitude information of numbers among kindergarteners and whether it was related to early numerical abilities. Based on the traditional magnitude judgment task, we developed two variant tasks-namely the month judgment task and dot judgment task-to elicit ordinal and magnitude processing of numbers, respectively. Results showed that kindergarteners oriented small numbers toward the left side and large numbers toward the right side when processing the ordinal information of numbers in the month judgment task but not when processing the magnitude information in the number judgment task and dot judgment task, suggesting that the left-to-right spatial bias was probably tagged to the ordinal but not magnitude property of numbers. Moreover, the strength of the SNARC effect was not related to early numerical abilities. These findings have important implications for the early spatial representation of numbers and its role in numerical performance among kindergarteners., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Many glaucoma patients do not adhere to their medication regimens because they fail to internalize the (health) costs of non-adherence, which may not occur until years or decades later. Behavioural economic theory suggests that adherence rates can be improved by offering patients a near-term benefit. Our proposed strategy is to offer adherence-contingent rebates on medication and check-up costs. This form of value pricing (VP) ensures that rebates are granted only to those most likely to benefit. Moreover, by leveraging loss aversion, rebates are expected to generate a stronger behavioural response than equivalent financial rewards., Methods/design: The main objective of the Study on Incentives for Glaucoma Medication Adherence (SIGMA) is to test the VP approach relative to usual care (UC) in improving medication adherence. SIGMA is a randomized, controlled, open-label, single-centre superiority trial with two parallel arms. A total of 100 non-adherent (Morisky Medication Adherence Scale ≤6) glaucoma patients from the Singapore National Eye Centre are block-randomized (blocking factor: single versus multiple medications users) into the VP and UC arms in a 1:1 ratio. The treatment received by VP patients will be strictly identical to that received by UC patients, with the only exception being that VP patients can earn either a 50 % or 25 % rebate on their glaucoma-related healthcare costs conditional on being adherent on at least 90 % or 75 % of days as measured by a medication event monitoring system. Masking the arm allocation will be precluded by the behavioural nature of the intervention but blocking size will not be disclosed to protect concealment. The primary outcome is the mean change from baseline in percentage of adherent days at month 6. A day will be counted as adherent when the patients take all their medication(s) within the appropriate dosing windows., Discussion: This trial will provide evidence on whether adherence-contingent rebates can improve medication adherence among non-adherent glaucoma patients, and more generally whether this approach represents a promising strategy to cost-effectively improve chronic disease management., Trial Registration: NCT02271269 . Registered on 19 October 2014.

Gnrh is the major neuropeptide regulator of vertebrate reproduction, triggering a cascade of events in the pituitary-gonadal axis that result in reproductive competence. Previous research in mice and humans has demonstrated that Gnrh/GNRH null mutations result in hypogonadotropic hypogonadism and infertility. The goal of this study was to eliminate gnrh3 (the hypophysiotropic Gnrh form) function in zebrafish (Danio rerio) to determine how ontogeny and reproductive performance are affected, as well as factors downstream of Gnrh3 along the reproductive axis. Using the TALEN technology, we developed a gnrh3-/- zebrafish line that harbors a 62 bp deletion in the gnrh3 gene. Our gnrh3-/- zebrafish line represents the first targeted and heritable mutation of a Gnrh isoform in any organism. Using immunohistochemistry, we verified that gnrh3-/- fish do not possess Gnrh3 peptide in any regions of the brain. However, other than changes in mRNA levels of pituitary gonadotropin genes (fshb, lhb, and cga) during early development, which are corrected by adulthood, there were no changes in ontogeny and reproduction in gnrh3-/- fish. The gnrh3-/- zebrafish are fertile, displaying normal gametogenesis and reproductive performance in males and females. Together with our previous results that Gnrh3 cell ablation causes infertility, these results indicate that a compensatory mechanism is being activated, which is probably primed early on upon Gnrh3 neuron differentiation and possibly confined to Gnrh3 neurons. Potential compensation factors and sensitive windows of time for compensation during development and puberty should be explored.

Introduction: Breast cancer is the leading cause of death of Hong Kong women with increasing incidence. This study aimed to determine any prognostic differences between screen-detected and self-detected cases of breast cancer in a cohort of Hong Kong patients., Methods: This was a case series with internal comparison carried out in a private hospital in Hong Kong. Approximately 3000 cases of Chinese patients diagnosed with ductal carcinoma in situ or invasive breast cancer were reviewed., Results: The screen-detected group showed better pathological characteristics than the self-detected group. Number of lymph nodes involved, invasive tumour size, and tumour grade were more favourable in the screen-detected group. There was also a lower proportion of patients with pure invasive ductal carcinoma and mastectomy in the screen-detected group., Conclusion: This study provides indirect evidence that women in the local population may gain clinical benefit from regular breast cancer screening. The findings need to be validated in a representative population of Hong Kong women.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors affecting children, and outcomes have remained dismal, even with access to new multimodal therapies. In this study, we compared the miRNomes and transcriptomes of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p as significantly downregulated in pHGGs. miR-137 or miR-6500-3p overexpression reduced cell proliferation in two pHGG cell lines, SF188 and UW479. CENPE, KIF14 and NCAPG levels were significantly higher in pHGGs than pLGGs, and were direct targets of miR-137 or miR-6500-3p. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. In summary, our results identify novel mRNA/miRNA interactions that contribute to pediatric glioma malignancy and represent potential targets for the development of new therapeutic strategies.

Overproduction of type I collagen is associated with a wide range of fibrotic diseases as well as surgical failure such as in glaucoma filtration surgery (GFS). Its modulation is therefore of clinical importance. Valproic acid (VPA) is known to reduce collagen in a variety of tissues with unclear mechanism of action. In this report, we demonstrate that VPA inhibited collagen production in both conjunctival fibroblasts and the mouse model of GFS. In fibroblasts, VPA decreased type I collagen expression which intensified with longer drug exposure and suppressed steady-state type I collagen promoter activity. Moreover, VPA decreased Smad2, Smad3 and Smad4 but increased Smad6 expression with a similar intensity-exposure profile. Reduction of Smad3 using small hairpin RNA and/or overexpression of Smad6 resulted in decreased collagen expression which was exacerbated when VPA was simultaneously present. Furthermore, fibrogenic TGF-β2 failed to induce collagen when VPA was present, as opposed to the myofibroblast markers, beta-actin, alpha-smooth muscle actin and tenascin-C, which were elevated by TGF-β2. VPA suppressed p3TP-Lux luciferase activity and selectively rescued Smad6 expression from suppression by TGF-β2. Notably, SMAD6 overexpression reduced the effectiveness of TGF-β2 in inducing collagen expression. In corroboration, VPA inhibited type I collagen but increased Smad6 expression in the late phase of wound healing in the mouse model of GFS. Taken together, our data indicate that VPA has the capacity to effectively suppress both steady-state and fibrogenic activation of type I collagen expression by modulating Smad expression. Hence, VPA is potentially applicable as an anti-fibrotic therapeutic by targeting collagen. Key message: • VPA modulates type I collagen expression via members of the Smad family. • VPA suppresses Smad2, Smad3 and Smad4 but upregulates Smad6. • Smad3 and Smad6 are involved in VPA regulation of steady-state collagen expression. • Smad6 is involved in VPA modulation of TGF-β-stimulated collagen expression. • VPA reduces collagen and upregulates Smad6 in the mouse model of glaucoma filtration surgery.

Purpose: To determine the effectiveness of argon laser peripheral iridoplasty (ALPI) in primary angle closure (PAC) and primary angle-closure glaucoma (PACG)., Design: Randomized controlled trial., Participants: Eighty PAC or PACG subjects who underwent laser iridotomy (LI) and had at least 180° of persistent appositional angle closure and intraocular pressure (IOP) of more than 21 mmHg were enrolled., Methods: Subjects were randomized to receive either 360° ALPI (Visulas 532s; Carl Zeiss Meditec, Jena, Germany) or medical therapy (Travoprost 0.004%; Alcon-Couvreur, Puurs, Antwerp, Belgium). Repeat ALPI was performed if the IOP reduction was less than 20% from baseline along with inadequate angle widening at the month 1 or month 3 visit. Intraocular pressure was controlled with systematic addition of medications when required., Main Outcome Measures: The primary outcome measure was success rates after ALPI at 1 year. Complete success was defined as an IOP of 21 mmHg or less without medication, and qualified success was defined as an IOP of 21 mmHg or less with medication. Failure was defined as an IOP more than 21 mmHg despite additional medications or requiring glaucoma surgery., Results: Forty subjects (51 eyes) were randomized to ALPI and 40 subjects (55 eyes) were randomized to medical therapy. Complete success (IOP ≤21 mmHg without medication) was achieved in 35.0% eyes of the ALPI group compared with 85.0% of eyes in the prostaglandin analog (PGA) group (P < 0.001), and qualified success (IOP ≤21 mmHg with medication) was achieved in 35.0% and 7.5%, respectively (P = 0.003). The IOP decreased by 4.9 mmHg (95% confidence interval [CI], 3.5-6.3 mmHg) in the ALPI group (P < 0.001) and by 6.1 mmHg (95% CI, 5.1-7.1 mmHg) in the medication group (P < 0.001). A failure rate of 30.0% was noted in the ALPI group compared with 7.5% in the medication group (P = 0.01). No treatment-related complications were recorded in either group., Conclusions: After 1 year, ALPI was associated with higher failure rates and lower IOP reduction compared with PGA therapy in eyes with persistent appositional angle closure and raised IOP after LI., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The present study examines the association between various facets of generativity, that is, cultural demand for generativity, generative concern, and generative action, with the satisfaction of the needs for relatedness, competence, and autonomy in samples of elderly from Cameroon, China (Hong Kong), the Czech Republic, and Germany. Participants provided information on self-transcendence values (internalized cultural demand), generative concern and action, and need satisfaction. Results suggest, first, that internalized cultural demand affects generative action indirectly through generative concern, second, that generative concern has a positive direct effect on need satisfaction, but that, third, there is also an indirect effect of generative concern on need satisfaction through generative action, which, fourth, is positive for the needs for relatedness and competence but negative for the need for autonomy. These findings were culture-invariant in our study, suggesting generalizability to other cultures. They are discussed with respect to the role of values in generativity and a possible trade-off of generative action for the satisfaction of needs at least in the elderly., ((c) 2016 APA, all rights reserved).)

The medial part of the nucleus of Edinger-Westphal (EWM) in birds mediates light-regulated adaptive increases in choroidal blood flow (ChBF). We sought to characterize the effect of loss of EWM-mediated ChBF regulation on photoreceptor health in pigeons housed in either moderate intensity diurnal or constant light (CL). Photoreceptor abundance following complete EWM destruction was compared to that following a lesion in the pupil control circuit (as a control for spread of EWM lesions to the nearby pupil-controlling lateral EW) or following no EW damage. Birds were housed post-lesion in a 12 h 400 lux light/12 h dark light cycle for up to 16.5 months, or in constant 400 lux light for up to 3 weeks. Paraformaldehyde-glutaraldehyde fixed eyes were embedded in plastic, sectioned, slide-mounted, and stained with toluidine blue/azure II. Blinded analysis of photoreceptor outer segment abundance was performed, with outer segment types distinguished by oil droplet tint and laminar position. Brains were examined histologically to assess lesion accuracy. Disruption of pupil control had no adverse effect on photoreceptor outer segment abundance in either diurnal light or CL, but EWM destruction led to 50-60% loss of blue/violet cone outer segments in both light conditions, and a 42% loss of principal cone outer segments in CL. The findings indicate that adaptive regulation of ChBF by the EWM circuit plays a role in maintaining photoreceptor health and mitigates the harmful effect of light on photoreceptors, especially short wavelength-sensitive cone photoreceptors.