An N-ethyl-n-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess

Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, maybe due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumors, respectively. ACTH secretion is stimulated by CRH, and we report a mouse model for Cushing's syndrome due to an N-ethyl-N-nitrosourea (ENU) induced Crh mutation at -120 bp of the promoter region, which significantly increased luciferase reporter activity and was thus a gain-of-function mutation. Crh -120/+ mice, when compared with wild-type littermates, had obesity, muscle wasting, thin skin, hair loss, and elevated plasma and urinary concentrations of corticosterone. In addition, Crh-120/+ mice had hyperglycemia, hyperfructosaminemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia but normal adiponectin. Crh -120/+ mice also had low bone mineral density, hypercalcemia, hypercalciuria, and decreased concentrations of plasma PTH and osteocalcin. Bone histomorphometry revealed Crh-120/+ mice to have significant reductions in mineralizing surface area, mineral apposition, bone formation rates, osteoblast number, and the percentage of corticoendosteal bone covered by osteoblasts, which was accompanied by an increase in adipocytes in the bone marrow. Thus, a mouse model for Cushing's syndrome has been established, and this will help in further elucidating the pathophysiological effects of glucocorticoid excess and in evaluating treatments for corticosteroid-induced osteoporosis.

The genetic basis of spondyloarthritis: SPARTAN/IGAS 2009

A joint meeting was held in July 2009 in Houston, Texas, of members of the Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), and members of International Genetics of AS (IGAS), founded in 2003 to encourage and coordinate studies internationally in the genetics of AS. The general topic was the genetic basis of SpA, with presentations on the future of human genetic studies; microbes, SpA, and innate immunity; susceptibility of AS to the major histocompatibility complex (MHC) and non-MHC; and individual discussions of the genetics of psoriasis and psoriatic arthritis, uveitis, inflammatory bowel disease, and enteropathic arthritis. Summaries of those discussions are presented.

Biceps femoris architecture and strength in athletes with a prior ACL reconstruction

Purpose To determine if limbs with a history of anterior cruciate ligament (ACL) injury reconstructed from the semitendinosus (ST) display different biceps femoris long head (BFlh) architecture and eccentric strength, assessed during the Nordic hamstring exercise, compared to the contralateral uninjured limb. Methods The architectural characteristics of the BFlh were assessed at rest and at 25% of a maximal voluntary isometric contraction (MVIC) in the control (n=52) and previous ACL injury group (n=15) using two-dimensional ultrasonography. Eccentric knee-flexor strength was assessed during the Nordic hamstring exercise. Results Fascicle length was shorter (p=0.001; d range: 0.90 to 1.31) and pennation angle (p range: 0.001 to 0.006: d range: 0.87 to 0.93) was greater in the BFlh of the ACL injured limb when compared to the contralateral uninjured limb at rest and during 25% of MVIC. Eccentric strength was significantly lower in the ACL injured limb than the contralateral uninjured limb (-13.7%; -42.9N; 95% CI = -78.7 to -7.2; p=0.021; d=0.51). Fascicle length, MVIC and eccentric strength were not different between the left and right limb in the control group. Conclusions Limbs with a history of ACL injury reconstructed from the ST have shorter fascicles and greater pennation angles in the BFlh compared to the contralateral uninjured side. Eccentric strength during the Nordic hamstring exercise of the ACL injured limb is significantly lower than the contralateral side. These findings have implications for ACL rehabilitation and hamstring injury prevention practices which should consider altered architectural characteristics.

A 3D numerical study of the collateral capacity of the circle of Willis with anatomical variation in the posterior circulation

Background The Circle of Willis (CoW) is the most important collateral pathway of the cerebral artery. The present study aims to investigate the collateral capacity of CoW with anatomical variation when unilateral internalcarotid artery (ICA) is occluded. Methods Basing on MRI data, we have reconstructed eight 3D models with variations in the posterior circulation of the CoW and set four different degrees of stenosis in the right ICA, namely 24%, 43%, 64% and 79%, respectively. Finally, a total of 40 models are performed with computational fluid dynamics simulations. All of the simulations share the same boundary condition with static pressure and the volume flow rate (VFR) are obtained to evaluate their collateral capacity. Results As for the middle cerebral artery (MCA) and the anterior cerebral artery (ACA), the transitional-type model possesses the best collateral capacity. But for the posterior cerebral artery (PCA), unilateral stenosis of ICA has the weakest influence on the unilateral posterior communicating artery (PCoA) absent model. We also find that the full fetal-type posterior circle of Willis is an utmost dangerous variation which must be paid more attention. Conclusion The results demonstrate that different models have different collateral capacities in coping stenosis of unilateral ICA and these differences can be reflected by different outlets. The study could be used as a reference for neurosurgeon in choosing the best treatment strategy.

Study of Pinna nobilis growth from inner record: How biased are posterior adductor muscle scars estimates?

Previous studies have shown that the external growth records of the posterior adductor muscle scar (PAMS) of the bivalve Pinna nobilis are incomplete and do not produce accurate age estimations. We have developed a new methodology to study age and growth using the inner record of the PAMS, which avoids the necessity of costly in situ shell measurements or isotopic studies. Using the inner record we identified the positions of PAMS previously obscured by nacre and estimated the number of missing records in adult specimens with strong abrasion of the calcite layer in the anterior portion of the shell. The study of the PAMS and inner record of two shells that were 6 years old when collected showed that only 2 and 3 PAMS were observed, while 6 inner records could be counted, thus confirming our working methodology. Growth parameters of a P. nobilis population located in Moraira, Spain (western Mediterranean) were estimated with the new methodology and compared to those obtained using PAMS data and in situ measurements. For the comparisons, we applied different models considering the data alternatively as length-at-age (LA) and tag-recapture (TR). Among every method we tested to fit the Von Bertalanffy growth model, we observed that LA data from inner record fitted to the model using non-linear mixed effects and the estimation of missing records using the calcite width was the most appropriate. The equation obtained with this method, L = 573*(1 - e(-0.16(t-0.02))), is very similar to that calculated previously from in situ measurements for the same population.

Muscular activity and fatigue in lower-limb and trunk muscles during different sit-to-stand tests

Sit-to-stand (STS) tests measure the ability to get up from a chair, reproducing an important component of daily living activity. As this functional task is essential for human independence, STS performance has been studied in the past decades using several methods, including electromyography. The aim of this study was to measure muscular activity and fatigue during different repetitions and speeds of STS tasks using surface electromyography in lower-limb and trunk muscles. This cross-sectional study recruited 30 healthy young adults. Average muscle activation, percentage of maximum voluntary contraction, muscle involvement in motion and fatigue were measured using surface electrodes placed on the medial gastrocnemius (MG), biceps femoris (BF), vastus medialis of the quadriceps (QM), the abdominal rectus (AR), erector spinae (ES), rectus femoris (RF), soleus (SO) and the tibialis anterior (TA). Five-repetition STS, 10-repetition STS and 30-second STS variants were performed. MG, BF, QM, ES and RF muscles showed differences in muscle activation, while QM, AR and ES muscles showed significant differences in MVC percentage. Also, significant differences in fatigue were found in QM muscle between different STS tests. There was no statistically significant fatigue in the BF, MG and SO muscles of the leg although there appeared to be a trend of increasing fatigue. These results could be useful in describing the functional movements of the STS test used in rehabilitation programs, notwithstanding that they were measured in healthy young subjects.

CBCT image guidance in head and neck irradiation: The impact of daily and weekly imaging protocols

Purpose This study evaluated the impact of a daily and weekly image-guided radiotherapy protocols in reducing setup errors and setting of appropriate margins in head and neck cancer patients. Materials and methods Interfraction and systematic shifts for the hypothetical day 1–3 plus weekly imaging were extrapolated from daily imaging data from 31 patients (964 cone beam computed tomography (CBCT) scans). In addition, residual setup errors were calculated by taking the average shifts in each direction for each patient based on the first three shifts and were presumed to represent systematic setup error. The clinical target volume (CTV) to planning target volume (PTV) margins were calculated using van Herk formula and analysed for each protocol. Results The mean interfraction shifts for daily imaging were 0·8, 0·3 and 0·5 mm in the S-I (superior-inferior), L-R (left-right) and A-P (anterior-posterior) direction, respectively. On the other hand the mean shifts for day 1–3 plus weekly imaging were 0·9, 1·8 and 0·5 mm in the S-I, L-R and A-P direction, respectively. The mean day 1–3 residual shifts were 1·5, 2·1 and 0·7 mm in the S-I, L-R and A-P direction, respectively. No significant difference was found in the mean setup error for the daily and hypothetical day 1–3 plus weekly protocol. However, the calculated CTV to PTV margins for the daily interfraction imaging data were 1·6, 3·8 and 1·4 mm in the S-I, L-R and A-P directions, respectively. Hypothetical day 1–3 plus weekly resulted in CTV–PTV margins of 5, 4·2 and 5 mm in the S-I, L-R and A-P direction. Conclusions The results of this study show that a daily CBCT protocol reduces setup errors and allows setup margin reduction in head and neck radiotherapy compared to a weekly imaging protocol.

Miniscleral lens wear influences corneal curvature and optics

Purpose Transient changes in corneal topography associated with soft and conventional or reverse geometry rigid contact lens wear have been well documented; however, only a few studies have examined the influence of scleral contact lens wear upon the cornea. Therefore, in this study, we examined the influence of modern miniscleral contact lenses, which land entirely on the sclera and overlying tissues, upon anterior corneal curvature and optics. Methods Anterior corneal topography and elevation data were acquired using Scheimpflug imaging (Pentacam HR, Oculus) immediately prior to and following 8 hours of miniscleral contact lens wear in 15 young healthy adults (mean age 22 ± 3 years, 8 East Asian, 7 Caucasian) with normal corneae. Corneal diurnal variations were accounted for using data collected on a dedicated measurement day without contact lens wear. Corneal clearance was quantified using an optical coherence tomographer (RS-3000, Nidek) following lens insertion and after 8 hours of lens wear. Results Although corneal clearance was maintained throughout the 8 hour lens wear period, significant corneal flattening (up to 0.08 ± 0.04 mm) was observed, primarily in the superior mid-peripheral cornea, which resulted in a slight increase in against-the-rule corneal astigmatism (mean +0.02/-0.15 x 94 for an 8 mm diameter). Higher order aberration terms of horizontal coma, vertical coma and spherical aberration all underwent significant changes for an 8 mm corneal diameter (p ≤ 0.01), which typically resulted in a decrease in RMS error values (mean change in total higher order RMS -0.035 ± 0.046 µm for an 8 mm diameter). There was no association between the magnitude of change in central or mid-peripheral corneal clearance during lens wear and the observed changes in corneal curvature (p > 0.05). However, Asian participants displayed a significantly greater reduction in corneal clearance (p = 0.04) and greater superior-nasal corneal flattening compared to Caucasians (p = 0.048). Conclusions Miniscleral contact lenses that vault the cornea induce significant changes in anterior corneal surface topography and higher order aberrations following 8 hours of lens wear. The region of greatest corneal flattening was observed in the superior-nasal mid-periphery, more so in Asian participants. Practitioners should be aware that corneal measurements obtained following miniscleral lens removal may mask underlying corneal steepening.

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) approximately 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximately 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Biometry of eyes in type 1 diabetes

This is a comprehensive study of a large range of biometric and optical parameters in people with type 1 diabetes. The parameters of 74 people with type 1 diabetes and an age matched control group were assessed. Most of the people with diabetes had low levels of neuropathy, retinopathy and nephropathy. Marginal or no significant differences were found between groups for corneal shape, corneal thickness, pupil size, and pupil decentrations. Relative to the control group, the diabetes group demonstrated smaller anterior chamber depths, more curved lenses, greater lens thickness and lower lens equivalent refractive index. While the optics of diabetic eyes make them appear as older eyes than those of people of the same age without diabetes, the differences did not increase significantly with age. Age-related changes in the optics of the eyes of people with diabetes need not be accelerated if the diabetes is well controlled.

Distribution of ocular biometry in 7- and 14-year-old Chinese children

Purpose: To describe distributions of ocular biometry and their associations with refraction in 7- and 14-year-old children in urban areas of Anyang, central China. Methods: A total of 2271 grade 1 students aged 7.1 ± 0.4 years and 1786 grade 8 students aged 13.7 ± 0.5 years were measured with ocular biometry and cycloplegic refraction. A parental myopia questionnaire was administered to parents. Results: Mean axial length, anterior chamber depth, lens thickness, central corneal thickness, corneal diameter, corneal radius of curvature, axial length/corneal radius of curvature ratio, and spherical equivalent refraction were 22.72 ± 0.76 mm, 2.89 ± 0.24 mm, 3.61 ± 0.19 mm, 540.5 ± 31 μm, 12.06 ± 0.44 mm, 7.80 ± 0.25 mm, 2.91 ± 0.08, and +0.95 ± 1.05 diopters (D), respectively, in 7-year-old children. They were 24.39 ± 1.13 mm, 3.42 ± 0.41 mm, 3.18 ± 0.24 mm, 548.9 ± 33 μm, 12.03 ± 0.43 mm, 7.80 ± 0.26 mm, 3.13 ± 0.14, and −2.06 ± 2.20 D, respectively, in 14-year-old children. Compared with 7-year-old children, the older group had significantly more myopia (−3.0 D), longer axial length (1.7 mm), deeper anterior chamber depth (0.3 mm), thinner lens thickness (−0.2 mm), thicker central corneal thickness (10 μm), and greater axial length/corneal radius of curvature ratio (0.22) (all p < 0.001), as well as smaller corneal diameter (−0.03 mm, p = 0.02) and similar corneal radius of curvature. Sex differences were similar in both age groups, with boys having longer axial length (0.5 mm), deeper anterior chamber depth (0.1 mm), shorter lens thickness (0.03 mm), greater central corneal thickness (5 μm), greater corneal diameter (0.15 mm), and greater corneal radius of curvature (0.14 mm) than girls (all p < 0.01). The most important variables related to spherical equivalent refraction were vitreous length, corneal radius of curvature, and lens thickness. Conclusions: The 14-year-old group had larger parameter dimensions than the 7-year-old group except for corneal radius of curvature (unchanged) and lens thickness and corneal diameter (both smaller). Boys had large parameter dimensions than girls except for lens thickness (smaller). Axial length, corneal radius of curvature, and lens thickness were the most important determinants of refraction.

Paraxial schematic eye models for 7- and 14-year-old Chinese children

Purpose.: To develop three-surface paraxial schematic eyes with different ages and sexes based on data for 7- and 14-year-old Chinese children from the Anyang Childhood Eye Study. Methods.: Six sets of paraxial schematic eyes, including 7-year-old eyes, 7-year-old male eyes, 7-year-old female eyes, 14-year-old eyes, 14-year-old male eyes, and 14-year-old female eyes, were developed. Both refraction-dependent and emmetropic eye models were developed, with the former using linear dependence of ocular parameters on refraction. Results.: A total of 2059 grade 1 children (boys 58%) and 1536 grade 8 children (boys 49%) were included, with mean age of 7.1 ± 0.4 and 13.7 ± 0.5 years, respectively. Changes in these schematic eyes with aging are increased anterior chamber depth, decreased lens thickness, increased vitreous chamber depth, increased axial length, and decreased lens equivalent power. Male schematic eyes have deeper anterior chamber depth, longer vitreous chamber depth, longer axial length, and lower lens equivalent power than female schematic eyes. Changes in the schematic eyes with positive increase in refraction are decreased anterior chamber depth, increased lens thickness, decreased vitreous chamber depth, decreased axial length, increased corneal radius of curvature, and increased lens power. In general, the emmetropic schematic eyes have biometric parameters similar to those arising from regression fits for the refraction-dependent schematic eyes. Conclusions.: The paraxial schematic eyes of Chinese children may be useful for myopia research and for facilitating comparison with other children with the same or different racial backgrounds and living in different places.

Morphological changes in the conjunctiva, episclera and sclera following short-term miniscleral contact lens wear in rigid lens neophytes

PURPOSE To quantify the influence of short-term wear of miniscleral contact lenses on the morphology of the corneo-scleral limbus, the conjunctiva, episclera and sclera. METHODS OCT images of the anterior eye were captured before, immediately following 3h of wear and then 3h after removal of a miniscleral contact lens for 10 young (27±5 years) healthy participants (neophyte rigid lens wearers). The region of analysis encompassed 1mm anterior, to 3.5mm posterior to the scleral spur. Natural diurnal variations in thickness were measured on a separate day and compensated for in subsequent analyses. RESULTS Following 3h of lens wear, statistically significant tissue thinning was observed across all quadrants, with a mean decrease in thickness of -24.1±3.6μm (p<0.001), which diminished, but did not return to baseline 3h after lens removal (-16.9±1.9μm, p<0.001). The largest tissue compression was observed in the superior quadrant (-49.9±8.5μm, p<0.01) and in the annular zone 1.5mm from the scleral spur (-48.2±5.7μm), corresponding to the approximate edge of the lens landing zone. Compression of the conjunctiva/episclera accounted for about 70% of the changes. CONCLUSIONS Optimal fitting miniscleral contact lenses worn for three hours resulted in significant tissue compression in young healthy eyes, with the greatest thinning observed superiorly, potentially due to the additional force of the eyelid, with a partial recovery of compression 3h after lens removal. Most of the morphological changes occur in the conjunctiva/episclera layers.

Assessment of conjunctival goblet cell density using laser scanning confocal microscopy versus impression cytology

Purpose To determine the association between conjunctival goblet cell density (GCD) assessed using in vivo laser scanning confocal microscopy and conjunctival impression cytology in a healthy population. Methods Ninety (90) healthy participants undertook a validated 5-item dry eye questionnaire, non-invasive tear film break-up time measurement, ocular surface fluorescein staining and phenol red thread test. These tests where undertaken to diagnose and exclude participants with dry eye. The nasal bulbar conjunctiva was imaged using laser scanning confocal microscopy (LSCM). Conjunctival impression cytology (CIC) was performed in the same region a few minutes later. Conjunctival goblet cell density was calculated as cells/mm2. Results There was a strong positive correlation of conjunctival GCD between LSCM and CIC (ρ = 0.66). Conjunctival goblet cell density was 475 ± 41 cells/mm2 and 466 ± 51 cells/mm2 measured by LSCM and CIC, respectively. Conclusions The strong association between in vivo and in vitro cellular analysis for measuring conjunctival GCD suggests that the more invasive CIC can be replaced by the less invasive LSCM in research and clinical practice.

In response: UV–vis light transmittance through tinted contact lenses and the effect of color on values

In the study, we used the Agilent 8453 spectrophotometer (which is equipped with a limiting aperture that restricts the light beam to the central 5 mm of the contact lens), to measure the transmittance of various coloured contact lenses including the one Day Acuvue define manufactured by Johnson and Johnson which the authors represent. We measured the instrument baseline before the transmittance spectra of lenses were tested. The values of lens transmittances were thus the difference between baseline and lens measurement at each time. The transmittance measurements were obtained at 0.5 nm intervals, from 200 to 700 nm after a soak in saline to remove the influence of any surface active agents within the packaging products. The technique used in our study was not very different from how other research studies [2], [3], [4], [5] and [6] have measured the spectra transmittances of contact lenses...