Atmospheric Peroxy Radical Chemistry Studied by Infrared Kinetic Spectroscopy

Peroxy radical (RO2) chemistry plays a central role in atmospheric science. RO2 radicals control the oxidative capacity of the atmosphere and are key intermediates in the cycling of ozone in the troposphere in regions where levels of nitrogen oxides (NOx &#8801; NO + NO2) are high. In more remote regions of the Earth where NOx concentrations are low, RO2 loss is dominated by reaction with hydroperoxy (HO2) and other peroxy radicals, leading to removal of reactive radicals from the troposphere. However, for certain species of RO2, reaction with HO2 can also propagate radical chemistry by recycling hydroxyl (OH) radicals, a primary oxidant in the atmosphere. Both HO2 and OH radicals play important roles in atmospheric oxidation reactions. Accurate characterization of various RO2 reactions that contribute to consuming and recycling HOx (HOx &#8801; HO2 + OH) are instrumental for understanding the effects of atmospheric composition on climate forcing, air quality, and the global ozone budget. My thesis work used laboratory studies to characterize gas phase organic peroxy radical (RO2) reactions that are relevant to atmospheric chemistry. The main body of my work focused on studying the self reactions of HO2 and RO2 as well as their cross reactions (HO2 + RO2) using a time-resolved experimental technique called Infrared Kinetic Spectroscopy (IRKS), which combines infrared (IR) and ultraviolet (UV) absorption spectroscopy. Perfect isolation of one specific reaction is generally difficult or impossible due to radical recycling and secondary chemistry, which leads to numerous reactions occurring simultaneously. Thus, although laboratory studies provide controlled environments to study these reactions, the accuracy of the results are highly dependent on the experiment's selectivity and sensitivity to specific transient species. In this work, a new mid-IR (MIR) laser was implemented into the existing apparatus for measuring OH radicals. In addition to UV absorption spectroscopy, the IRKS apparatus was equipped for selective detection of HO2 and OH radicals in the near-IR (NIR) and MIR, respectively. The kinetics and product yields of a reaction are two important factors for assessing the impact of these reactions on the atmosphere. IRKS was used to study the kinetics of the self reactions of acetylperoxy (CH3C(O)O2) and acetonylperoxy (CH3C(O)CH2O2), as well as their reactions with HO2. The OH and O3 yields from the reaction of HO2 + CH3C(O)O2 were also measured, providing the first parametrization of the temperature dependence of the OH product channel. The temperature dependence of the HO2 self reaction kinetics was re-investigated to resolve discrepancies in the results previously reported in the literature. Furthermore, this work identified and characterized rate enhancement effects on the HO2 self reaction by the adducts of HO2 formed from the reaction of HO2 with methanol (CH3OH), acetaldehyde (CH3CHO), and acetone (CH3C(O)CH3), which were used as radical precursors for HO2, CH3C(O)O2, and CH3C(O)CH2O2, respectively. Finally, the improved sensitivity of the IRKS apparatus enabled the investigation of fast reaction kinetics. The rate constants of Cl atoms with CH3OH and CH3CHO were measured over a wide range of temperatures. The results were consistent with previously reported values in the literature and additionally validated assumptions that had been made regarding the temperature independence of these reactions. The temperature and pressure dependences of the OH yield from the reaction of CH3CO with O2 were also studied to resolve current discrepancies in the literature. The yield of HO2 from this reaction was also directly measured for the first time. </p

Variability of Response Time as a Predictor of Methylphenidate Treatment Response in Korean Children with Attention Deficit Hyperactivity Disorder

PURPOSE: Methylphenidate (MPH) is an effective medication for the treatment of attention deficit hyperactivity disorder (ADHD). However, about 30% of patients do not respond to or are unable to tolerate MPH. Based on previous findings, we hypothesized that great variability in response time (RT) among Korean children with ADHD on a computerized continuous performance attention test would be related to poor MPH treatment response. MATERIALS AND METHODS: Children (ages 6-18 years) with ADHD were recruited for a prospective 12-week, open-labeled, multicenter study to examine optimal dosage of OROS methylphenidate. Of the 144 subjects selected, 28 dropped out due to adverse events, medication noncompliance, or follow-up loss, and an additional 26 subjects with comorbid disorders were excluded from statistical analyses. We defined 'responders' as subjects who received a score of less than 18 on the attention deficit hyperactivity disorder rating scale (ARS; Korean version, K-ARS) and a score of 1 or 2 on the Clinical Global Impression-Improvement scale (CGI-I). RT variability was assessed with the ADHD diagnostic system (ADS). RESULTS: Fifty-nine (67%) subjects responded to MPH treatment. The non-responders showed greater RT variability at baseline (Mann Whitney U = 577.0, p < 0.01). Baseline RT variability was a significant predictor of MPH response (Nagelkerke R(2) = 0.136, p < 0.01). It predicted 94.9% of responder, 17.2% of non-responder and 69.3% of overall group. CONCLUSION: High RT variability may predict poor response to MPH treatment in children with ADHDope

Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud \ud PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud \ud RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud \ud CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud \u

CD160 serves as a negative regulator of NKT cells in acute hepatic injury

[EN] CD160 and BTLA both bind to herpes virus entry mediator. Although a negative regulatory function of BTLA in natural killer T (NKT) cell activation has been reported, whether CD160 is also involved is unclear. By analyzing CD160−/− mice and mixed bone marrow chimeras, we show that CD160 is not essential for NKT cell development. However, CD160−/− mice exhibit severe liver injury after in vivo challenge with α-galactosylceramide (α-GalCer). Moreover, CD160−/− mice are more susceptible to Concanavalin A challenge, and display elevated serum AST and ALT levels, hyperactivation of NKT cells, and enhanced IFN-γ, TNF, and IL-4 production. Lastly, inhibition of BTLA by anti-BTLA mAb aggravates α-GalCer-induced hepatic injury in CD160−/− mice, suggesting that both CD160 and BTLA serve as non-overlapping negative regulators of NKT cells. Our data thus implicate CD160 as a co-inhibitory receptor that delivers antigen-dependent signals in NKT cells to dampen cytokine production during early innate immune activationSIWe thank the NIH Tetramer Core Facility for providing PBS 57 ligand loaded CD1d Tetramers. Further, we thank the staffs of Gyerim Experimental Animal Resource Center for animal care and technical assistance. K.-M. Lee was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future planning (NRF-2016M3A9B6948342, NRF- 2017R1A2B3004828, and NRF-2018M3A9D3079288). S.-J. Kim was supported by the Korea Health Industry Development Institute (KHIDI-HI14C2640) grant funded by Korea Government. S.-J. Ha was supported by a grant from the NRF (NRF- 2018R1A2A1A05076997). T.-J. Kim was additionally supported by a grant from the NRF (NRF-2016R1A6A3A04009698

Function after spinal treatment, exercise and rehabilitation (FASTER): improving the functional outcome of spinal surgery

Background: The life-time incidence of low back pain is high and diagnoses of spinal stenosis and disc prolapse are increasing. Consequently, there is a steady rise in surgical interventions for these conditions. Current evidence suggests that while the success of surgery is incomplete, it is superior to conservative interventions. A recent survey indicates that there are large differences in the type and intensity of rehabilitation, if any, provided after spinal surgery as well as in the restrictions and advice given to patients in the post-operative period. This trial will test the hypothesis that functional outcome following two common spinal operations can be improved by a programme of post-operative rehabilitation that combines professional support and advice with graded active exercise and/or an educational booklet based on evidence-based messages and advice.Methods/Design: The study design is a multi-centre, factorial, randomised controlled trial with patients stratified by surgeon and operative procedure. The trial will compare the effectiveness and cost-effectiveness of a rehabilitation programme and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression, each compared with "usual care" using a 2 x 2 factorial design. The trial will create 4 sub-groups; rehabilitation-only, booklet-only, rehabilitation-plus-booklet, and usual care only. The trial aims to recruit 344 patients, which equates to 86 patients in each of the four sub-groups. All patients will be assessed for functional ability (through the Oswestry Disability Index - a disease specific functional questionnaire), pain (using visual analogue scales), and satisfaction pre-operatively and then at 6 weeks, 3, 6 and 9 months and 1 year post-operatively. This will be complemented by a formal analysis of cost-effectiveness.Discussion: This trial will determine whether the outcome of spinal surgery can be enhanced by either a postoperative rehabilitation programme or an evidence-based advice booklet or a combination of the two and as such will contribute to our knowledge on how to manage spinal surgery patients in the post-operative period

Orlistat after initial dietary/behavioural treatment: changes in body weight and dietary maintenance in subjects with sleep related breathing disorders

<p>Abstract</p> <p>Background</p> <p>Sleep related breathing disorders (SRBD) are associated with increased morbidity and mortality and weight loss is recommended to overweight or obese patients with SRBD. However, maintenance of weight loss is difficult to achieve and strategies for weight loss maintenance is needed. Orlistat is a pharmacological agent that reduces the intestinal absorption of fat and may favour long-term weight maintenance.</p> <p>Objective</p> <p>To examine the change in body weight and dietary intake during a 1-year treatment with orlistat after an initial weight loss in obese subjects with SRBD. Furthermore, to explore the dietary determinants of weight maintenance during treatment with orlistat.</p> <p>Methods</p> <p>Men and women with SRBD aged 32-62 years (n = 63) participated in a 3-month dietary intervention to increase intake of vegetables and fruit. After an initial weight loss of 3.4 kg they achieved a mean body mass index of 34.3 ± 4.7 kg/m2. Subsequently they were treated with orlistat for 1 year. During this year, dietary and behavioural interventions to attain weight loss were provided in the course of 14 group sessions. Dietary intake, energy density and food choices were assessed with a food frequency questionnaire before and after orlistat treatment.</p> <p>Results</p> <p>With orlistat, body weight decreased by a mean of 3.5 kg (95% CI 1.5, 5.5). The dietary E% from saturated fat, intake of fatty dairy products and energy density increased after 1 year while intakes of oils, fish and vegetables decreased (all P < 0.05). After multivariate adjustments, weight loss was associated with E% protein (R2_adj= 0.19 [95% CI 0.10, 0.46]), and inversely associated with E% saturated fat (R2_adj= 0.20 [95% CI 0.12, 0.47]) and fatty dairy products (R2_adj= 0.23 [95% CI 0.12, 0.49]).</p> <p>Conclusions</p> <p>Orlistat induced further weight loss, but dietary compliance declined with time. Increasing dietary protein and restricting saturated fat and fatty dairy products may facilitate weight loss with orlistat.</p

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Evaluating Electronic Referrals for Specialty Care at a Public Hospital

Poor communication between referring clinicians and specialists may lead to inefficient use of specialist services. San Francisco General Hospital implemented an electronic referral system (eReferral) that facilitates iterative pre-visit communication between referring and specialty clinicians to improve the referral process. The purpose of the study was to determine the impact of eReferral (compared with paper-based referrals) on specialty referrals. The study was based on a visit-based questionnaire appended to new patient charts at randomly selected specialist clinic sessions before and after the implementation of eReferral. Specialty clinicians. The questionnaire focused on the self-reported difficulty in identifying referral question, referral appropriateness, need for and avoidability of follow-up visits. We collected 505 questionnaires from speciality clinicians. It was difficult to identify the reason for referral in 19.8% of medical and 38.0% of surgical visits using paper-based methods vs. 11.0% and 9.5% of those using eReferral (p-value 0.03 and &lt;0.001). Of those using eReferral, 6.4% and 9.8% of medical and surgical referrals using paper methods vs. 2.6% and 2.1% were deemed not completely appropriate (p-value 0.21 and 0.03). Follow-up was requested for 82.4% and 76.2% of medical and surgical patients with paper-based referrals vs. 90.1% and 58.1% of eReferrals (p-value 0.06 and 0.01). Follow-up was considered avoidable for 32.4% and 44.7% of medical and surgical follow-ups with paper-based methods vs. 27.5% and 13.5% with eReferral (0.41 and &lt;0.001). Use of technology to promote standardized referral processes and iterative communication between referring clinicians and specialists has the potential to improve communication between primary care providers and specialists and to increase the effectiveness of specialty referrals

Race and Inflammatory Bowel Disease in an Urban Healthcare System

Inflammatory bowel disease (IBD) is increasingly common among non-Caucasian populations, but interracial differences in disease characteristics and management are not well-characterized. We tested the hypothesis that disease characteristics and management vary by race among IBD patients in an ethnically diverse healthcare system. A retrospective study of the safety net healthcare system of San Francisco, CA, from 1996 to 2009 was undertaken. Patient records with International Classification of Diseases, 9th Revision (ICD9) codes 555.xx, 556.xx, and 558.xx were reviewed. Adult patients with confirmed IBD diagnoses were included. Interracial variations in disease characteristics and management were assessed broadly; focused between-race comparisons identified specific differences. The 228 subjects included 77 (33.4%) with Crohn’s disease (CD), 150 (65.8%) with ulcerative colitis, and 1 (0.4%) with IBD, type unclassified. The race distribution included 105 (46.1%) white, 34 (14.9%) black, 35 (15.4%) Hispanic, and 51 (22.4%) Asian subjects. Asians and Hispanics were diagnosed at older ages (41.0 and 37.1 years, respectively) and had shorter disease durations (5.4 and 5.2 years, respectively) than whites (30.5 years at diagnosis and 8.6 years duration, P &lt; 0.05) and blacks (31.7 years at diagnosis and 12.1 years duration, P &lt; 0.05). CD was more common among blacks (50% of subjects) than Asians (25.5% of subjects, P = 0.015). The Montreal classification of IBD was similar among races. Hispanics were less likely than others to be treated with 5-aminosalicylates (5-ASA), immunomodulators, and steroids. Medical and surgical management was otherwise similar among races. Modest race-based differences in IBD characteristics exist in this racially diverse healthcare system, but the management of IBD is similar among race groups