Region-Aware Color Smudging.

Color smudge operations from digital painting software enable users to create natural shading effects in high-fidelity paintings by interactively mixing colors. To precisely control results in traditional painting software, users tend to organize flat-filled color regions in multiple layers and smudge them to generate different color gradients. However, the requirement to carefully deal with regions makes the smudging process time-consuming and laborious, especially for non-professional users. This motivates us to investigate how to infer user-desired smudging effects when users smudge over regions in a single layer. To investigate improving color smudge performance, we first conduct a formative study. Following the findings of this study, we design SmartSmudge, a novel smudge tool that offers users dynamical smudge brushes and real-time region selection for easily generating natural and efficient shading effects. We demonstrate the efficiency and effectiveness of the proposed tool via a user study and quantitative analysis.

Effect of digital ocular massage on intraocular pressure and Schlemm's canal dimensions.

Digital ocular massage has been reported to temporarily lower intraocular pressure (IOP). This could be related to an enhanced aqueous humor outflow; however, the mechanism is not clearly understood. Using anterior segment optical coherence tomography, the Schlemm's canal (SC) and trabecular meshwork (TM) can be imaged and measured. Here, 66 healthy adults underwent digital ocular massage for 10 min in their right eyes. The IOP and dimensions of the SC and TM were measured before and after ocular massage. All subjects demonstrated IOP reduction from 15.7 ± 2.5 mmHg at baseline to 9.6 ± 2.2 mmHg immediately after, and median of 11.6 mmHg 5-min after ocular massage (Friedman's test, p < 0.001). There was significant change in SC area (median 10,063.5 µm2 at baseline to median 10,151.0 µm2 after ocular massage, Wilcoxon test, p = 0.02), and TM thickness (median 149.8 µm at baseline to 144.6 ± 25.3 µm after ocular massage, Wilcoxon test, p = 0.036). One-third of the subjects demonstrated collapse of the SC area (-2 to -52%), while two-thirds showed expansion of the SC area (2 to 168%). There were no significant changes in SC diameter (270.4 ± 84.1 µm vs. 276.5 ± 68.7 µm, paired t-test, p = 0.499), and TM width (733.3 ± 110.1 µm vs. 733.5 ± 111.6 µm, paired t-test, p = 0.988). Eyes with a higher baseline IOP demonstrated a greater IOP reduction (Pearson correlation coefficient r = -0.521, p < 0.001). Eyes with smaller SC area at baseline showed greater SC area expansion (Pearson correlation coefficient = -0.389, p < 0.001). Greater IOP reduction appeared in eyes with greater SC area expansion (Pearson correlation coefficient r = -0.306, p = 0.01). Association between change in IOP and change in TM thickness was not significant (Spearman's ρ = 0.015, p = 0.902). Simple digital ocular massage is an effective method to lower IOP values, and change in the SC area was significantly associated with IOP changes.

Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine.

BACKGROUND: Sickle cell disease (SCD) is caused by an inherited structural abnormality of adult hemoglobin causing polymerization. Fetal hemoglobin interferes with polymerization but is epigenetically silenced by DNA methyltransferase 1 (DNMT1) in adult erythropoiesis. Decitabine depletes DNMT1 and increases fetal and total hemoglobin in SCD patients, but is rapidly catabolized by cytidine deaminase (CDA) in vivo. Tetrahydrouridine (THU) inhibits CDA, safeguarding decitabine. METHODS: The pharmacokinetics and pharmacodynamics of three oral combination formulations of THU and decitabine, with different coatings producing different delays in decitabine release, were investigated in healthy participants. RESULTS: Tetrahydrouridine and decitabine were rapidly absorbed into the systemic circulation after a single combination oral dose, with relative bioavailability of decitabine ≥74% in fasted males compared with separate oral administration of THU followed by decitabine 1 h later. THU and decitabine Cmax and area under the plasma concentration versus time curve were higher in females versus males, and fasted versus fed states. Despite sex and food effect on pharmacokinetics, the pharmacodynamic effect of DNMT1 downregulation was comparable in males and females and fasted and fed states. Treatments were well tolerated. CONCLUSION: Combination oral formulations of THU with decitabine produced pharmacokinetics and pharmacodynamics suitable for oral DNMT1-targeted therapy.

Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses.

BACKGROUND & AIMS: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the only two classes of FDA-approved drugs for individuals with advanced hepatocellular carcinoma (HCC). While TKIs confer only modest survival benefits, ICIs have been associated with remarkable outcomes but only in the minority of patients who respond. Understanding the mechanisms that determine the efficacy of ICIs in HCC will help to stratify patients likely to respond to ICIs. This study aims to elucidate how genetic composition and specific oncogenic pathways regulate the immune composition of HCC, which directly affects response to ICIs. METHODS: A collection of mouse HCCs with genotypes that closely simulate the genetic composition found in human HCCs were established using genome-editing approaches involving the delivery of transposon and CRISPR-Cas9 systems by hydrodynamic tail vein injection. Mouse HCC tumors were analyzed by RNA-sequencing while tumor-infiltrating T cells were analyzed by flow cytometry and single-cell RNA-sequencing. RESULTS: Based on the CD8+ T cell-infiltration level, we characterized tumors with different genotypes into cold and hot tumors. Anti-PD-1 treatment had no effect in cold tumors but was greatly effective in hot tumors. As proof-of-concept, a cold tumor (Trp53KO/MYCOE) and a hot tumor (Keap1KO/MYCOE) were further characterized. Tumor-infiltrating CD8+ T cells from Keap1KO/MYCOE HCCs expressed higher levels of proinflammatory chemokines and exhibited enrichment of a progenitor exhausted CD8+ T-cell phenotype compared to those in Trp53KO/MYCOE HCCs. The TKI sorafenib sensitized Trp53KO/MYCOE HCCs to anti-PD-1 treatment. CONCLUSION: Single anti-PD-1 treatment appears to be effective in HCCs with genetic mutations driving hot tumors, while combined anti-PD-1 and sorafenib treatment may be more appropriate in HCCs with genetic mutations driving cold tumors. IMPACT AND IMPLICATIONS: Genetic alterations of different driver genes in mouse liver cancers are associated with tumor-infiltrating CD8+ T cells and anti-PD-1 response. Mouse HCCs with different genetic compositions can be grouped into hot and cold tumors based on the level of tumor-infiltrating CD8+ T cells. This study provides proof-of-concept evidence to show that hot tumors are responsive to anti-PD-1 treatment while cold tumors are more suitable for combined treatment with anti-PD-1 and sorafenib. Our study might help to guide the design of patient stratification systems for single or combined treatments involving anti-PD-1.

Complex abdominal wall reconstruction combined with bladder closure in OEIS complex.

PURPOSE: Due to the large abdominal defect from the omphalocele and extreme pubic diastasis in cloacal exstrophy (CE), bioprosthetic material may be used to bridge this gap during abdominal closure in CE. This study examined presurgical factors associated with the use of bioprosthetic materials in CE closure and complications in these patients. METHODS: An institutional database of exstrophy-epispadias complex patients was reviewed for CE. Inclusion criteria included CE and primary closure performed at the host institution from 1998 to 2018. Data collection included demographics, presurgical factors, use of bioprosthetic material, complications, and outcomes. RESULTS: All 32 patients had a staged closure and pelvic osteotomy prior to bladder closure. Ten of the 32 patients incorporated a bioprosthetic material during abdominal wall closure. There is at least 3 months follow up for all patients, all had successful bladder closure without any postoperative hernias. Those who underwent closure without bioprosthetic material were younger at the time of closure (565 vs 693 days, p = 0.043). The differences in complication rates and mean pubic diastasis was not statistically significant, p = 0.079 and p = 0.457 respectively. CONCLUSIONS: The use of bioprosthetic material is associated with older age at abdominal wall and bladder closure. The use of bioprosthetic material is a useful adjunct for secure abdominal wall closure in the reconstruction of CE. TYPE OF STUDY: Prognostic. LEVEL OF EVIDENCE: III.

In Silico Serotyping Based on Whole-Genome Sequencing Improves the Accuracy of Shigella Identification.

Bacteria of the genus Shigella, consisting of 4 species and >50 serotypes, cause shigellosis, a foodborne disease of significant morbidity, mortality, and economic loss worldwide. Classical Shigella identification based on selective media and serology is tedious, time-consuming, expensive, and not always accurate. A molecular diagnostic assay does not distinguish Shigella at the species level or from enteroinvasive Escherichia coli (EIEC). We inspected genomic sequences from 221 Shigella isolates and observed low concordance rates between conventional designation and molecular serotyping: 86.4% and 80.5% at the species and serotype levels, respectively. Serotype determinants for 6 additional serotypes were identified. Examination of differentiation gene markers commonly perceived as characteristic hallmarks in Shigella showed high variability among different serotypes. Using this information, we developed ShigaTyper, an automated workflow that utilizes limited computational resources to accurately and rapidly determine 59 Shigella serotypes using Illumina paired-end whole-genome sequencing (WGS) reads. Shigella serotype determinants and species-specific diagnostic markers were first identified through read alignment to an in-house curated reference sequence database. Relying on sequence hits that passed a threshold level of coverage and accuracy, serotype could be unambiguously predicted within 1 min for an average-size WGS sample of ∼500 MB. Validation with WGS data from 380 isolates showed an accuracy rate of 98.2%. This pipeline is the first step toward building a comprehensive WGS-based analysis pipeline of Shigella spp. in a field laboratory setting, where speed is essential and resources need to be more cost-effectively dedicated.IMPORTANCEShigella causes diarrheal disease with serious public health implications. However, conventional Shigella identification methods are laborious and time-consuming and can be erroneous due to the high similarity between Shigella and enteroinvasive Escherichia coli (EIEC) and cross-reactivity between serotyping antisera. Further, serotype interpretation is complicated for inexperienced users. To develop an easier method with higher accuracy based on whole-genome sequencing (WGS) for Shigella serotyping, we systematically examined genomic information of Shigella isolates from 53 serotypes to define rules for differentiation and serotyping. We created ShigaTyper, an automated pipeline that accurately and rapidly excludes non-Shigella isolates and identifies 59 Shigella serotypes using Illumina paired-end WGS reads. A serotype can be unambiguously predicted at a data processing speed of 538 MB/min with 98.2% accuracy from a regular laptop. Once it is installed, training in bioinformatics analysis and Shigella genetics is not required. This pipeline is particularly useful to general microbiologists in field laboratories.

Trends in the incidence of retinopathy of prematurity over a 10-year period.

AIM: To describe and evaluate the trends in the incidence of retinopathy of prematurity over a 10-year period in a tertiary hospital in Hong Kong. METHODS: A retrospective review was performed on all preterm infants screened and/or treated for retinopathy of prematurity from January 2006 to December 2015 at Prince of Wales Hospital, Hong Kong. Preterm infants with incomplete records or transferred-in from other hospitals/region solely for treatment of ROP were excluded. The incidence of any ROP or Type 1 ROP was analysed with gestational age and birth weight over a 10-year period with consecutive 2-year intervals to evaluate the trends. RESULTS: Of all 754 infants included in the study, 234 (31.0%) patients had any ROP and 34 (4.5%) infants developed Type 1 ROP. The incidence of any ROP demonstrated a statistically significant decreasing trend over the five consecutive 2-year intervals (p = 0.016), but the incidence trend of Type 1 ROP is not statistically significant. No infants weighing more than 1250 g developed Type 1 ROP. CONCLUSION: We observed a decreasing trend in the incidence of any ROP across the 10-year period in a tertiary hospital in Hong Kong, while the incidence of Type 1 ROP remained stable at 4.5%. The factors leading to the trend were unclear. Improved prenatal care, changing proportion of cases with different birth weight and gestational age, oxygenation level practice in neonatal unit may all contribute to the decreasing trend. Revision of screening criteria may be made according to local experience to maximise cost-effectiveness.

Visual outcome and refractive status in first 3 years of age in preterm infants suffered from laser-treated Type 1 retinopathy of prematurity (ROP): a 6-year retrospective review in a tertiary centre in Hong Kong.

PURPOSE: To report the visual outcome and refractive status in first 3 years of age in preterm infants suffered from laser-treated Type 1 retinopathy of prematurity (ROP): a 6-year review in Hong Kong DESIGN: Retrospective case series METHODOLOGY: Clinical records of all infants suffered from Type 1 ROP who had undergone laser therapy between 2007 and 2012 were retrospectively reviewed. Basic demographic data, serial changes of refractive error, visual acuity, severity of ROP and laser were analyzed. Correlation with myopia and astigmatism progression, body weight, height, growth and gestational age were also analyzed. RESULT: Among 494 babies screened, 14 Chinese babies (26 eyes) recruited with 1:1 male-to-female ratio in this study. All eyes showed gradual progression of myopia in first 3 years of age but no significant change of astigmatism. Further correlation analysis showed no correlation with laser energy consumed, birth weight (p = 0.14), head circumference growth (p = 0.57) and body weight growth (p = 0.71). However, severity of myopia was related to the post-conceptual age when receiving laser therapy (p < 0.005), gestation age (p = 0.02) and possibly body height growth with age (p = 0.05). CONCLUSION: Myopia in early life is one of the most common ocular sequelae in Type 1 ROP survivors. Early detection of refractive error is important for prompt correction and visual rehabilitation to prevent amblyopia.

Retinopathy of prematurity: applicability and compliance of guidelines in Hong Kong.

OBJECTIVE: To analyse the incidence, application and compliance to Royal College of Ophthalmologists retinopathy of prematurity (ROP) screening recommendations and subsequent treatment of ROP in a neonatal intensive care unit of a large tertiary referral centre in Hong Kong. DESIGN: A retrospective review was performed for all eligible premature neonates screened for ROP over a 7-year period from June 2008 to December 2015 in our local tertiary neonatal intensive care unit in Prince of Wales Hospital, Hong Kong, using the Royal College of Ophthalmologists ROP screening guideline (2008). Comparison between established UK and American screening guidelines were analysed for their applicability in our locality. RESULTS: A total of 602 infants were screened, with the incidence of ROP in 28.2% and type 1 ROP in 3.8%, and indirect diode laser performed in all type 1 ROP cases. Overall, adherence for screening criteria was 99.7%, with the average time to commence first screening at 4 weeks postnatal age. Of the 602 cases, 94 (15.6%) were early and 35 (5.8%) were later than the guidelines, of which only 5 (0.8%) of late-screened cases developed ROP requiring treatment. Subsequent treatment of ROP for all the late-screened cases was not delayed. CONCLUSIONS: Current ROP screening using the UK guidelines (2008) is applicable, effective and safe to our predominantly Asian population in Hong Kong, with a low rate of delayed screening.

Data-driven methods towards learning the highly nonlinear inverse kinematics of tendon-driven surgical manipulators.

BACKGROUND: Accurate motion control of flexible surgical manipulators is crucial in tissue manipulation tasks. The tendon-driven serpentine manipulator (TSM) is one of the most widely adopted flexible mechanisms in minimally invasive surgery because of its enhanced maneuverability in torturous environments. TSM, however, exhibits high nonlinearities and conventional analytical kinematics model is insufficient to achieve high accuracy. METHODS: To account for the system nonlinearities, we applied a data driven approach to encode the system inverse kinematics. Three regression methods: extreme learning machine (ELM), Gaussian mixture regression (GMR) and K-nearest neighbors regression (KNNR) were implemented to learn a nonlinear mapping from the robot 3D position states to the control inputs. RESULTS: The performance of the three algorithms was evaluated both in simulation and physical trajectory tracking experiments. KNNR performed the best in the tracking experiments, with the lowest RMSE of 2.1275 mm. CONCLUSIONS: The proposed inverse kinematics learning methods provide an alternative and efficient way to accurately model the tendon driven flexible manipulator.

Refractive Errors and Concomitant Strabismus: A Systematic Review and Meta-analysis.

This systematic review and meta-analysis is to evaluate the risk of development of concomitant strabismus due to refractive errors. Eligible studies published from 1946 to April 1, 2016 were identified from MEDLINE and EMBASE that evaluated any kinds of refractive errors (myopia, hyperopia, astigmatism and anisometropia) as an independent factor for concomitant exotropia and concomitant esotropia. Totally 5065 published records were retrieved for screening, 157 of them eligible for detailed evaluation. Finally 7 population-based studies involving 23,541 study subjects met our criteria for meta-analysis. The combined OR showed that myopia was a risk factor for exotropia (OR: 5.23, P = 0.0001). We found hyperopia had a dose-related effect for esotropia (OR for a spherical equivalent [SE] of 2-3 diopters [D]: 10.16, P = 0.01; OR for an SE of 3-4D: 17.83, P < 0.0001; OR for an SE of 4-5D: 41.01, P < 0.0001; OR for an SE of ≥5D: 162.68, P < 0.0001). Sensitivity analysis indicated our results were robust. Results of this study confirmed myopia as a risk for concomitant exotropia and identified a dose-related effect for hyperopia as a risk of concomitant esotropia.

Mucous fistula refeeding decreases parenteral nutrition exposure in postsurgical premature neonates.

BACKGROUND/PURPOSE: Premature neonates can develop intraabdominal conditions requiring emergent bowel resection and enterostomy. Parenteral nutrition (PN) is often required, but results in cholestasis. Mucous fistula refeeding allows for functional restoration of continuity. We sought to determine the effect of refeeding on nutrition intake, PN dependence, and PN associated hepatotoxicity while evaluating the safety of this practice. METHODS: A retrospective review of neonates who underwent bowel resection and small bowel enterostomy with or without mucous fistula over 2years was undertaken. Patients who underwent mucous fistula refeeding (RF) were compared to those who did not (OST). Primary outcomes included days from surgery to discontinuation of PN and goal enteral feeds, and total days on PN. Secondary outcomes were related to PN hepatotoxicity. RESULTS: Thirteen RF and eleven OST were identified. There were no significant differences among markers of critical illness (p>0.20). In the interoperative period, RF patients reached goal enteral feeds earlier than OST patients (median 28 versus 43days; p=0.03) and were able to have PN discontinued earlier (median 25 versus 41days; p=0.04). Following anastomosis, the magnitude of effect was more pronounced, with RF patients reaching goal enteral feeds earlier than OST patients (median 7.5 versus 20days; p≤0.001) and having PN discontinued sooner (30.5 versus 48days; p=0.001). CONCLUSIONS: RF neonates reached goal feeds and were able to be weaned from PN sooner than OST patients. A prospective multicenter trial of refeeding is needed to define the benefits and potential side effects of refeeding in a larger patient population in varied care environments.

Association of Gestational Hypertensive Disorders with Retinopathy of prematurity: A Systematic Review and Meta-analysis.

The role of gestational hypertensive disorders, which includes both pre-eclampsia and gestational hypertension, in the development of retinopathy of prematurity (ROP) has been controversial. Therefore, this systematic review and meta-analysis is to evaluate the association between gestational hypertensive disoders and ROP. Eligible studies published up to June 5, 2016 were identified from MEDLINE and EMBASE that evaluated the association between the two conditions. Totally 1142 published records were retrieved for screening, 925 of them eligible for detailed evaluation. Finally 19 studies involving 45281 infants with 5388 cases of ROP met our criteria for meta-analysis. Gestational hypertensive disorders were not associated with ROP (unadjusted OR: 0.89; P = 0.38; adjusted OR: 1.35; P = 0.18). Subgroup analyses also revealed no significant association between ROP with pre-eclampsia (unadjusted OR: 0.85; P = 0.29; adjusted OR:1.29; P = 0.28) or with gestational hypertension (unadjusted OR: 1.10; P = 0.39; adjusted OR: 1.25; P = 0.60) separately. Sensitivity analysis indicated our results were robust. We concluded no significant association between gestational hypertensive disorders and ROP. More large scale well-conducted prospective cohorts on the topic are needed.

Topical Therapy with Mesenchymal Stem Cells Following an Acute Experimental Head Injury Has Benefits in Motor-Behavioral Tests for Rodents.

BACKGROUND: The neuroprotective effects of mesenchymal stem cells (MSCs) have been reported in rodent and in preliminary clinical studies. MSCs are usually transplanted to patients by systemic infusion. However, only a few of the infused MSCs are delivered to the brain because of pulmonary trapping and the blood-brain barrier. In this study, MSCs were topically applied to the site of traumatic brain injury (TBI) and the neuroprotective effects were assessed. MATERIALS AND METHODS: TBI was induced in Sprague-Dawley (SD) rats with an electromagnetically controlled cortical impact device after craniotomy was performed between the bregma and lambda, 1 mm lateral to the midline. We applied 1.5 million MSCs, derived from the adipose tissue of transgenic green fluorescent protein (GFP)-SD rats, to the exposed cerebral cortex at the injured site. The MSCs were held in position by a thin layer of fibrin. Neurological function in the test (n = 10) and control (n = 10) animals was evaluated using the rotarod test, the water maze test, and gait analysis at different time points. RESULTS: Within 5 days following topical application, GFP-positive cells were found in the brain parenchyma. These cells co-expressed with markers of Glial fibrillary acidic protein (GFAP), nestin, and NeuN. There was less neuronal death in CA1 and CA3 of the hippocampus in the test animals. Neurological functional recovery was significantly improved. CONCLUSION: Topically applied MSCs can migrate to the injured brain parenchyma and offer neuroprotective effects.

Surgical outcome of medial rectus resection in recurrent exotropia: a novel surgical formula.

Purpose. To evaluate the surgical outcomes of unilateral or bilateral medial rectus (MR) muscle resection for recurrent exotropia after bilateral lateral rectus (BLR) muscle recession based on a novel surgical formula. Methods. Forty-one consecutive patients with unilateral or bilateral MR muscle resection for recurrent exotropia after BLR muscle recession were included in this retrospective study. All surgeries were performed according to the formula: 1.0 mm MR muscle resection for every 5 prism dioptres (PD) of exotropia, with an addition of 0.5 mm to each MR muscle operated on. Results. The mean recurrent exotropia distant deviation was 28 PD ± 11.2 (range 14 to 55 PD). Overall at postoperative 1 month, 36 (88%) achieved successful outcomes, 4 (10%) had undercorrection, and 1 (2%) had overcorrection. At postoperative 6 months, 29 (71%) achieved successful outcomes, 12 (29%) had undercorrection, and none had overcorrection. Subgroup analysis showed no statistically significant difference in success rates between unilateral and bilateral MR groups. Conclusion. Unilateral or bilateral MR muscle resection using our surgical formula is a safe and effective method for calculating the amount of MR resection in moderate to large angle recurrent exotropia, with a low overcorrection rate.

A nipple-valve technique for ureteroneocystostomy in pediatric kidney transplantation.

The ureteroneocystostomy in kidney transplantation can be performed with a variety of techniques. Over a 20-yr period, we utilized a technique of nipple-valve ureteroneocystostomy for the pediatric kidney transplants performed at our institution. The distal ureter is everted upon itself and anchored in place with four interrupted sutures to create a nipple valve, which is then inserted into the bladder and sewn mucosa-to-mucosa with the same sutures. The muscularis layer is closed around the ureter without tunneling and without routine ureteral stenting. After 109 transplants, patient survival was 97.2, 97.2, and 86.9% at one, five, and 10 yr, respectively. Graft survival was 91.7, 71.7, and 53.9% at one, five, and 10 yr, respectively. The most common cause of graft loss was acute or chronic rejection, seen in 75% of those experiencing graft loss. Two patients (1.8%) developed pyelonephritis in the transplanted kidney. Nipple-valve ureteroneocystostomy in pediatric kidney transplantation is a safe and simple method for performing the ureterovesical anastomosis with a low rate of pyelonephritis after transplantation.

Three different ophthalmic presentations of juvenile xanthogranuloma.

Three cases of juvenile xanthogranuloma from two ophthalmology departments were reviewed. Clinical histories, ophthalmic examination, physical examination, investigations, and treatment of these cases are described. A 4-month-old boy presented with spontaneous hyphema and secondary glaucoma. He was treated with intensive topical steroid and anti-glaucomatous eye drops. The hyphema gradually resolved and the intra-ocular pressure reverted to 11 mm Hg without any other medication. Biopsy of his scalp mass confirmed the diagnosis of juvenile xanthogranuloma. A 31-month-old boy presented with a limbal mass. Excisional biopsy of the mass was performed and confirmed it was a juvenile xanthogranuloma. A 20-month-old boy was regularly followed up for epiblepharon and astigmatism. He presented to a paediatrician with a skin nodule over his back. Skin biopsy confirmed juvenile xanthogranuloma. He had no other ocular signs. Presentation of juvenile xanthogranuloma can be very different, about which ophthalmologists should be aware of. Biopsy of the suspected lesion is essential to confirm the diagnosis.

The pharmacokinetic effect of coadministration of apremilast and methotrexate in individuals with rheumatoid arthritis and psoriatic arthritis.

Apremilast is a novel agent for the treatment of inflammatory based autoimmune disorders. The objective of this study was to assess the pharmacokinetic effects of co administration of apremilast and methotrexate on both agents. This was an open-label, multi-center, 3-treatment period, sequential study conducted in otherwise healthy subjects with psoriatic arthritis or rheumatoid arthritis who were receiving a stable oral dose of methotrexate between 7.5 to 20 mg once weekly. Subjects received their dose of methotrexate on Days 1 and 8 of the study in addition to Apremilast 30 mg oral every 12 hours on Days 3-8. Pharmacokinectic profiles of methotrexate and 7-OH methotrexate were characterized after methotrexate alone (Day 1) and after co-administration of methotrexate and Apremilast (on Day 8). The pharmacokinetic profile of Apremilast was characterized after Apremilast alone (on Day 7) and after co-administration of methotrexate and Apremilast (on Day 8). The 90% confidence interval of the ratio of the geometric means for the Cmax and AUC parameters for methotrexate, 7-OH methotrexate, and Apremilast alone and after co-adminstration are all within the FDA acceptance range for equivalency (80-125%). This study showed that methotrexate and apremilast can be co-administered without any effect on the pharmacokinetic exposure of either agent.

Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome.

PURPOSE: To determine the underlying genetic cause of Duane retraction syndrome (DRS) in a non-consanguineous Chinese Han family. METHODS: Detailed ophthalmic and physical examinations were performed on all members from a pedigree with DRS. All exons and their adjacent splicing junctions of the sal-like 4 (SALL4) gene were amplified with polymerase chain reaction and analyzed with direct sequencing in all the recruited family members and 200 unrelated control subjects. RESULTS: Clinical examination revealed a broad spectrum of phenotypes in the DRS family. Mutation analysis of SALL4 identified a novel heterozygous duplication mutation, c.1919dupT, which was completely cosegregated with the disease in the family and absent in controls. This mutation was predicted to cause a frameshift, introducing a premature stop codon, when translated, resulting in a truncated SALL4 protein, i.e., p.Met640IlefsX25. Bioinformatics analysis showed that the affected region of SALL4 shared a highly conserved sequence across different species. Diversified clinical manifestations were observed in the c.1919dupT carriers of the family. CONCLUSIONS: We identified a novel truncating mutation in the SALL4 gene that leads to diversified clinical features of DRS in a Chinese family. This mutation is predicted to result in a truncated SALL4 protein affecting two functional domains and cause disease development due to haploinsufficiency through nonsense-mediated mRNA decay.

Transplantation of mesenchymal stem cells to the brain by topical application in an experimental traumatic brain injury model.

Mesenchymal stem cells (MSCs) have been shown in various animal models to be capable of neurorepair and neuroprotection. To carry out a therapeutic function, MSCs must be delivered to the target organ. MSCs are administered to patients via systemic infusion, which has many drawbacks, including a low engraftment rate and the migration of MSCs to non-target organs. However, other approaches such as direct intracerebral injection of MSCs might cause cerebral bleeding. In this study, a traumatic brain injury (TBI) was induced over the right parietal cerebral cortex in Sprague Dawley rats, and green fluorescent protein (GFP)-expressing MSCs (GFP-MSCs), together with a thin layer of fibrin, were applied to the external surface of the contralateral side 2 days later. Within 5 days of topical application, the GFP-MSCs had migrated from the site of application on the cortical surface, through the white matter, and had emerged at the cortical surface of the TBI site on the contralateral cerebral hemisphere, apparently following axons along the corpus callosum. In sham-injured control animals, the topically applied GFP-MSCs proliferated superficially on the cortex at the site of application, and no GFP-MSCs were found at the contralateral cortical surface. In all instances, GFP-MSCs were not detected in other organs of either the test or the control animals. Our study demonstrated that MSCs topically applied to the brain surface can migrate to a TBI site.