Lateral mobility of FcγRIIa is reduced by protein kinase C activation

AbstractThe lateral mobility of membrane proteins can reflect the extent of various protein-protein interactions. Using the fluorescence recovery after photobleaching technique, we have studied the lateral mobility of human FcγRIIa and some FcγRIIa mutants expressed in either P388D1 cells, a mouse macrophagelike cell line, or in Chinese hamster ovary (CHO) cells [1]. After treatment with phorbol myristate acetate (PMA), only the FcγRIIa molecules capable of mediating rapid endocytosis of immune complexes exhibited a reduced lateral diffusion coefficient with respect to untreated controls. Wild type FcγRIIa expressed in CHO cells, and nonfunctional FcγRIIa mutants expressed in P388D1 cells did not show any differences upon PMA treatment. This finding suggests that protein kinase C activation evokes additional protein-protein interactions with the cytoplasmic domain of functional FcγRIIa, which reduced receptor lateral mobility. The identity of these putative interacting proteins and the nature of the interactions remain to be elucidated

Isotopic ratios of H, C, N, O, and S in comets C/2012 F6 (Lemmon) and C/2014 Q2 (Lovejoy)

The apparition of bright comets C/2012 F6 (Lemmon) and C/2014 Q2 (Lovejoy) in March-April 2013 and January 2015, combined with the improved observational capabilities of submillimeter facilities, offered an opportunity to carry out sensitive compositional and isotopic studies of the volatiles in their coma. We observed comet Lovejoy with the IRAM 30m telescope between 13 and 26 January 2015, and with the Odin submillimeter space observatory on 29 January - 3 February 2015. We detected 22 molecules and several isotopologues. The H$_2^{16}$O and H$_2^{18}$O production rates measured with Odin follow a periodic pattern with a period of 0.94 days and an amplitude of ~25%. The inferred isotope ratios in comet Lovejoy are $^{16}$O/$^{18}$O = 499 $\pm$ 24 and D/H = 1.4 $\pm$ 0.4 $\times 10^{-4}$ in water, $^{32}$S/$^{34}$S = 24.7 $\pm$ 3.5 in CS, all compatible with terrestrial values. The ratio $^{12}$C/$^{13}$C = 109 $\pm$ 14 in HCN is marginally higher than terrestrial and $^{14}$N/$^{15}$N = 145 $\pm$ 12 in HCN is half the Earth ratio. Several upper limits for D/H or 12C/13C in other molecules are reported. From our observation of HDO in comet C/2014 Q2 (Lovejoy), we report the first D/H ratio in an Oort Cloud comet that is not larger than the terrestrial value. On the other hand, the observation of the same HDO line in the other Oort-cloud comet, C/2012 F6 (Lemmon), suggests a D/H value four times higher. Given the previous measurements of D/H in cometary water, this illustrates that a diversity in the D/H ratio and in the chemical composition, is present even within the same dynamical group of comets, suggesting that current dynamical groups contain comets formed at very different places or times in the early solar system.Comment: Accepted for publication in Astronomy and Astrophysic

Pore Shape Modification of a Microporous Metal-Organic Framework Using High Pressure:Accessing a New Phase with Oversized Guest Molecules

The authors thank the Royal Society of Edinburgh and the Scottish Government for a fellowship to S.A.M. The authors thank EPSRC (EP/J02077X/1) and Leverhulme Trust for a research project grant (RPG-209) for financial support. They also thank the UK Carr Parinello consortium for allocation of computing time on the EPSRC high performance computing resource ARCHER (managed by the Edinburgh Parallel Computing Centre, the EaSTCHEM Research Computing Facility and the University of Edinburgh ECDF facility).Pressures up to 0.8 GPa have been used to squeeze a range of sterically "oversized" C5-C8 alkane guest molecules into the cavities of a small-pore Sc-based metal?organic framework. Guest inclusion causes a pronounced reorientation of the aromatic rings of one-third of the terephthalate linkers, which act as "torsion springs", resulting in a fully reversible change in the local pore structure. The study demonstrates how pressure-induced guest uptake can be used to investigate framework flexibility relevant to "breathing" behavior and to understand the uptake of guest molecules in MOFs relevant to hydrocarbon separation.PostprintPeer reviewe

King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation

Pain is a key unmet need and a major aspect of non‐motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross‐sectional, open, multicenter, one‐point‐in‐time evaluation with retest study of the first PD‐specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0‐3) multiplied by frequency (0‐4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy‐eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29‐85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non‐PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser‐Mayer‐Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item‐total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD‐Motor, Non‐Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD. © 2015 International Parkinson and Movement Disorder Societ

The Non-Motor Symptoms Scale in Parkinson's disease: validation and use

The Non‐Motor Symptoms Scale (NMSS) was developed and validated in 2007 as the first instrument for the comprehensive assessment of a range of non‐motor symptoms in Parkinson's disease (PD). Thirteen years have elapsed since its introduction and extensive international validation with good psychometric attributes has been carried out. Here, we review the validation data of the NMSS and its cross‐validity with other scales, and describe the key evidence derived from use of the NMSS in clinical studies. To date, over 100 clinical studies and trials have made use of it as an outcome measure, showing consistent and strong correlations between NMSS burden and health‐related quality of life measures. Moreover, the scale has shown to be capable of detecting longitudinal changes in non‐motor symptoms, where studies have shown differential changes over time of several of the NMSS domains. The scale has become a key outcome in several randomized clinical trials. Highlighting the prevalence and importance of non‐motor symptoms to quality of life in patients with PD, the development of NMSS has also been useful in signposting clinical and biomarker based research addressing non‐motor symptoms in PD

First comprehensive tool for screening pain in Parkinson's disease: the King's Parkinson's Disease Pain Questionnaire.

BACKGROUND AND PURPOSE: Pain is highly prevalent in Parkinson's disease (PD), impacting patients' ability, mood and quality of life. Detecting the presence of pain in its multiple modalities is necessary for adequate personalized management of PD. A 14-item, PD-specific, patient-based questionnaire (the King's Parkinson's Disease Pain Questionnaire, KPPQ) was designed corresponding to the rater-based KPP Scale (KPPS). The present multicentre study was aimed at testing the validity of this screening tool. METHODS: First, a comparison between the KPPQ scores of patients and matched controls was performed. Next, convergent validity, reproducibility (test-retest) and diagnostic performance of the questionnaire were analysed. RESULTS: Data from 300 patients and 150 controls are reported. PD patients declared significantly more pain symptoms than controls (3.96 ± 2.56 vs. 2.17 ± 1.39; P < 0.0001). The KPPQ convergent validity was high with KPPS total score (rS  = 0.80) but weak or moderate with other pain assessments. Test-retest reliability was satisfactory with kappa values ≥0.65 except for item 5, Dyskinetic pains (κ = 0.44), and the intraclass correlation coefficient (ICC) for the KPPQ total score was 0.98. After the scores of the KPPS were adapted for screening (0, no symptom; ≥1, symptom present), a good agreement was found between the KPPQ and the KPPS (ICC = 0.88). A strong correlation (rS  = 0.80) between the two instruments was found. The diagnostic parameters of the KPPQ were very satisfactory as a whole, with a global accuracy of 78.3%-98.3%. CONCLUSIONS: These results suggest that the KPPQ is a useful, reliable and valid screening instrument for pain in PD to advance patient-related outcomes

Dopamine agonist serum concentrations and impulse control disorders in Parkinson's disease

Background and purpose: Impulse control disorders (ICDs) are common among Parkinson's disease patients using dopamine agonists. We wanted to determine whether ICD patients have higher dopamine agonist serum concentrations than those without any sign of ICD. Methods: Patients who used either pramipexole or ropinirole depot once daily were screened for ICDs using the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale. Those who scored above the cut-off for one or more of the four defined ICDs (gambling, compulsive sexual behavior, compulsive shopping, and binge-eating) were compared in a case–control study to patients who scored zero points (no evidence of ICD) on the same items. They were examined clinically and evaluated using relevant scales. Three blood samples were taken on the same day: before daily dose, and then 6 and 12 h later. Results: Forty-six patients were included: 19 ICD-positive and 27 controls. Ropinirole serum concentrations 6 h after daily intake (Cmax) were higher in the case group compared to the control group, as was the daily ropinirole dosage. No differences were observed in serum concentrations, dosage or total drug exposure for pramipexole. Disease duration and length of dopamine agonist treatment was significantly longer among ICD patients for ropinirole, but not for pramipexole. Conclusions: The use of pramipexole may in itself confer high ICD risk, whereas ICDs among ropinirole users depend more on serum concentration and drug exposure. The pharmacokinetic properties of ropinirole make it challenging to predict its effects on patients, which supports the need for therapeutic drug monitoring to reduce risk of ICD

A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease

BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2-2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7-0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls