Glycosaminoglycans and collagen fibril organization in corneal tissue

Hypothesis: The hypothesis of this research is that changes in the sulphation patterns of the glycosaminoglycans are directly related to changes in ultrastructure, and hence transparency of the cornea. Aims: The aims of this research were to investigate glycosaminoglycan sulphation patterns and collagen fibril ultrastructure from central to peripheral regions of the cornea, and to gain a greater understanding in the effects of keratan sulphate and its reliance on oxygen supply. Methods: The bovine corneal extracellular matrix composition and collagen fibril parameters (fibril diameter and interfibrillar spacing) were biochemically and biophysically evaluated. This involved taking measurements of corneal thickness and hydration, as well as the amount of hydroxyproline and sulphated glycosaminoglycan. Immunolocalization of proteoglycan protein cores (lumican and keratocan) and specific glycosaminoglycans, particularly their sulphation distribution were studied using specific antibodies. Sulphation patterns of keratan sulphate were also quantified using specific antibodies. Transmission electron microscopy coupled with synchrotron small angle x-ray fibre diffraction was also employed to gain a greater understanding of the corneas' collagen fibril architecture and its interaction with glycosaminoglycans across the depths of the cornea. Results: The bovine cornea is thicker in the outer peripheral regions of the cornea and accordingly an increased amount of hydroxyproline is found at this region of the tissue. Keratan sulphate is predominantly found in the bovine cornea and is particularly heavily sulphated across the cornea. The degree of sulphation of keratan sulphate decreases at the outer peripheral regions of the cornea, which, interestingly, is where a transition of collagen fibrils occurs in that fibrils become less uniformly arranged, changes in fibril diameter are seen, and interfibrillar spacing values alter. Depth- profiled synchrotron microbeam analyses show that at different radial positions, from the corneal centre outwards, fibril diameter is greater superficially than in deep stromal regions. This does not include Bowman's layer which is below the spatial resolution of the analysis. The mid-depth stroma has higher interfibrillar spacing than is seen in posterior regions of the stroma, where fibril spacing appeared more compact. Previous work has pointed to a link between glycosaminoglycan content and oxygen availability. Work presented here indicates that in rabbit corneas, after 24 hr in 2% atmospheric O2, the glycosaminoglycan sulphation pattern changes significantly, with a significant increase of the high sulphated epitope of keratan sulphate. Conclusion: My data reveal that collagen fibrils in the central regions of the cornea are more closely packed and uniform in diameter than those in the outer peripheral cornea, and this may have potential implications for the transparency of the tissue. Stromal architecture is likely governed by sulphated proteoglycans, and changes in the types and sulphation patterns of corneal glycosaminoglycans from the corneal centre to periphery might be linked to differences in collagen ultrastructure. Moreover, the findings of differences in collagen fibril ultrastructure with depth through the cornea are possibly linked to biochemical alterations in proteoglycans. Finally, it is hypothesised that detrimental conditions, such as hypoxia after contact lens wear, might have an effect on the type and sulphation status of glycosaminoglycan synthesized and in vitro evidence for this is presented and discussed. (Abstract shortened by UMI.

crs: A package for nonparametric spline estimation in R

crs is a library for R written by Jeffrey S. Racine (Maintainer) and Zhenghua Nie. This add-on package provides a collection of functions for spline-based nonparametric estimation of regression functions with both continuous and categorical regressors. Currently, the crs package integrates data-driven methods for selecting the spline degree, the number of knots and the necessary bandwidths for nonparametric conditional mean, IV and quantile regression. A function for multivariate density spline estimation with mixed data is also currently in the works. As a bonus, the authors have also provided the first simple R interface to the NOMAD (‘nonsmooth mesh adaptive direct search’) optimization solver which can be applied to solve other mixed integer optimization problems that future users might find useful in other settings. Although the crs package shares some of the same functionalities as its kernel-based counterpart—the np package by the same author—it currently lacks some of the features the np package provides, such as hypothesis testing and semiparametric estimation. However, what it lacks in breadth, crs makes up in speed. A Monte Carlo experiment in this review uncovers sizable speed gains compared to its np counterpart, with a marginal loss in terms of goodness of fit. Therefore, the package will be extremely useful for applied econometricians interested in employing nonparametric techniques using large amounts of data with a small number of discrete covariates

Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain

Background: Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3) in both carrageenan- and complete Freund's adjuvant (CFA)-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation. Methods: Here we used mechanical stimuli to assess behavioral responses in paw and muscle inflammation induced by carrageenan or CFA. We also used immunohistochemistry staining and western blot methodology to evaluate the expression of ASIC3 in dorsal root ganglion (DRG) neurons. Results: In comparison with the control, the inflammation group showed significant mechanical hyperalgesia with both intraplantar carrageenan and CFA-induced inflammation. Interestingly, both carrageenan- and CFA-induced hyperalgesia were accompanied by ASIC3 up-regulation in DRG neurons. Furthermore, electroacupuncture (EA) at the ST36 rescued mechanical hyperalgesia through down-regulation of ASIC3 overexpression in both carrageenan- and CFA-induced inflammation. Conclusions: In addition, electrical stimulation at the ST36 acupoint can relieve mechanical hyperalgesia by attenuating ASIC3 overexpression

Change in angina symptom status after acute myocardial infarction and its association with readmission risk: An analysis of the translational research investigating underlying disparities in acute myocardial infarction patients' health status (TRIUMPH) registry

Angina is common both before and after myocardial infarction (MI). Whether the change in angina status within the first 30 days after MI is associated with subsequent readmission and angina persistence is unknown.We studied 2915 MI patients enrolled at 24 hospitals in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) registry. Angina before and 30 days after MI was assessed with the Seattle Angina Questionnaire. Patients were divided into angina-free pre- and post-MI (-/-), resolved angina (+/-), new angina (-/+), and persistent angina (+/+) groups. Multivariable proportional hazards and hierarchical modified Poisson models were performed to assess the association of each group with all-cause readmission, readmission for MI or unplanned revascularization, and angina persistence at 1 year. Overall, 1293 patients (44%) had angina before their MI and 849 (29%) reported angina within 30 days of discharge. Patients with post-MI angina were more likely to be younger, nonwhite, and uninsured. Compared with patients who were angina-free pre- and post-MI, 1-year all-cause readmission risks were significantly higher for patients with persistent angina (hazard ratio [HR], 1.35; 95% CI 1.06-1.71) or new angina (HR, 1.40; 95% CI, 1.08-1.82). At 1 year, angina was present in 22% of patients and was more likely if angina was persistent (HR, 3.55; 95% CI, 3.05-4.13) or new (HR, 3.38; 95% CI, 2.59-4.42) at 30 days compared with patients who were angina-free pre- and post-MI.Post-MI angina, whether new or persistent, is associated with higher likelihood of readmission. Prioritizing post-MI angina management is a potential means of improving 1-year outcomes.Jacob A. Doll, Fengming Tang, Sharon Cresci, P. Michael Ho, Thomas M. Maddox, John A. Spertus and Tracy Y. Wan

Approximate k-state solutions to the Dirac-Yukawa problem based on the spin and pseudospin symmetry

Using an approximation scheme to deal with the centrifugal (pseudo-centrifugal) term, we solve the Dirac equation with the screened Coulomb (Yukawa) potential for any arbitrary spin-orbit quantum number {\kappa}. Based on the spin and pseudospin symmetry, analytic bound state energy spectrum formulas and their corresponding upper- and lower-spinor components of two Dirac particles are obtained using a shortcut of the Nikiforov-Uvarov method. We find a wide range of permissible values for the spin symmetry constant C_{s} from the valence energy spectrum of particle and also for pseudospin symmetry constant C_{ps} from the hole energy spectrum of antiparticle. Further, we show that the present potential interaction becomes less (more) attractive for a long (short) range screening parameter {\alpha}. To remove the degeneracies in energy levels we consider the spin and pseudospin solution of Dirac equation for Yukawa potential plus a centrifugal-like term. A few special cases such as the exact spin (pseudospin) symmetry Dirac-Yukawa, the Yukawa plus centrifugal-like potentials, the limit when {\alpha} becomes zero (Coulomb potential field) and the non-relativistic limit of our solution are studied. The nonrelativistic solutions are compared with those obtained by other methods.Comment: 21 pages, 6 figure

Bad influence? – an investigation into the purported negative influence of foreign domestic helpers on children's second language English acquisition

This paper explores the purported negative influence of foreign domestic helpers (FDHs) on child second language acquisition (SLA) by studying Hong Kong Cantonese children's listening ability in second language (L2) English. 31 kindergarten third graders aged 4;6 to 6, and 29 first year secondary students aged 11-14 who have had a Filipino domestic helper at home took part in the study. In addition, 34 youngsters (20 in kindergarten, 14 in secondary) who did not have a Filipino helper participated as controls. Results from two listening tasks (picture choosing task, sound discrimination task) suggest that informants do not differ from the control in their abilities to listen to American-, British-, and Hong Kong English, and that they are better at listening to Filipino-accented English than the control. These findings cast doubts on the anecdotal belief of the harmful effect FDHs have on children's language acquisition including an L2. Moreover, the additional effect of being familiar with another variety of English is arguably a desirable outcome given that English is used as a lingua franca among non-native speakers on a daily basis in this highly globalised world

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib The CheckMate 040 Randomized Clinical Trial

IMPORTANCE Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTS CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURES Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0165887

A multi-center study on the attitudes of Malaysian emergency health care staff towards allowing family presence during resuscitation of adult patients

BACKGROUND The practice of allowing family members to witness on-going active resuscitation has been gaining ground in many developed countries since it was first introduced in the early 1990s. In many Asian countries, the acceptability of this practice has not been well studied. AIM We conducted a multi-center questionnaire study to determine the attitudes of health care professionals in Malaysia towards family presence to witness ongoing medical procedures during resuscitation. METHODS Using a bilingual questionnaire (in Malay and English language), we asked our respondents about their attitudes towards allowing family presence (FP) as well as their actual experience of requests from families to be allowed to witness resuscitations. Multiple logistic regression was used to analyze the association between the many variables and a positive attitude towards FP. RESULTS Out of 300 health care professionals who received forms, 270 responded (a 90% response rate). Generally only 15.8% of our respondents agreed to allow relatives to witness resuscitations, although more than twice the number (38.5%) agreed that relatives do have a right to be around during resuscitation. Health care providers are significantly more likely to allow FP if the procedures are perceived as likely to be successful (e.g., intravenous cannulation and blood taking as compared to chest tube insertion). Doctors were more than twice as likely as paramedics to agree to FP (p-value = 0.002). This is probably due to the Malaysian work culture in our health care systems in which paramedics usually adopt a 'follow-the-leader' attitude in their daily practice. CONCLUSION The concept of allowing FP is not well accepted among our Malaysian health care providers