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Joanna C Robson,1,2 Jill Dawson,3 Peter F Cronholm,4 Nataliya Milman,5 Katherine S Kellom,6 Susan Ashdown,7 Ebony Easley,8 John T Farrar,9 Don Gebhart,10,11 Georgia Lanier,10,11 Carol A McAlear,12 Jacqueline Peck,7 Raashid A Luqmani,7 Judy A Shea,13 Gunnar Tomasson,14 Peter A Merkel10,11 1Department of Rheumatology, Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK; 2School of Clinical Sciences, University of Bristol, Bristol, UK; 3Department of Population Health (HSRU), University of Oxford, Oxford, UK; 4Department of Family Medicine and Community Health, University of Pennsylvania, Philadelphia, PA, USA; 5Division of Rheumatology, Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada; 6PolicyLab, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 7Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 8Department of Family Medicine and Community Health, Mixed Methods Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA; 9Biostatistics and Epidemiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; 10Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 11Department of Biostatistics and Clinical Epidemiology, University of Pennsylvania, Philadelphia, PA, USA; 12Vasculitis Research, University of Pennsylvania, Philadelphia, PA, USA; 13School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 14Department of Public Health Sciences, University of Iceland, Reykjavik, Iceland Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are multisystem diseases of the small blood vessels. Patients experience irreversible damage and psychological effects from AAV and its treatment. An international collaboration was created to investigate the impact of AAV on health-related quality of life (HRQoL), and develop a disease-specific patient-reported outcome measure to assess outcomes of importance to patients.Methods: Patients with AAV from the UK, USA, and Canada were interviewed to identify salient aspects of HRQoL affected by AAV. The study was overseen by a steering committee including four patient research partners. Purposive sampling of interviewees ensured representation of a range of disease manifestations and demographics. Inductive analysis was used to identify themes of importance to patients; these were further confirmed by a free-listing exercise in the US. Individual themes were recast into candidate items, which were scrutinized by patients, piloted through cognitive interviews and received a linguistic and translatability evaluation.Results: Fifty interviews, conducted to saturation, with patients from the UK, USA, and Canada, identified 55 individual themes of interest within seven broad domains: general health perceptions, impact on function, psychological perceptions, social perceptions, social contact, social role, and symptoms. Individual themes were constructed into >100 candidate questionnaire items, which were then reduced and refined to 35 candidate items.Conclusion: This is the largest international qualitative analysis of HRQoL in AAV to date, and the results have underpinned the development of 35 candidate items for a disease-specific, patient-reported outcome questionnaire. Keywords: ANCA-associated vasculitis, quality of life, patient-reported outcomes, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis

Lillian Barra,1 Patrick Liang,2 Susanne M Benseler,3 David A Cabral,4 Aurore Fifi-Mah,5 Yueyang Li,1 Nataliya Milman,6 Marinka Twilt,3 Elaine Yacyshyn,7 Christian Pagnoux8 1Division of Rheumatology, The University of Western Ontario, St Joseph’s Health Care, London, Ontario, 2Division of Rheumatology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, 3Division of Rheumatology, Department of Paediatrics, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, 4Division of Rheumatology, BC Children’s Hospital, Vancouver, British Columbia, 5Division of Rheumatology, South Health Campus, University of Calgary, Calgary, Alberta, 6Division of Rheumatology, Department of Medicine, University of Ottawa, Ottawa, 7Division of Rheumatology, University of Alberta, Edmonton, Alberta, 8Department of Rheumatology, Mount Sinai Hospital, Toronto, University of Toronto, Ontario, Canada Objective: Takayasu arteritis (TAK) is a large vessel vasculitis that predominately affects young women and can cause severe ischemic complications. Given the rarity of TAK, the management of this condition is challenging. We aim to describe current rheumatologist practices for the management of TAK and identify discrepancies and gaps in knowledge. Methods: An online survey (developed by the Canadian Vasculitis Network and approved by the Canadian Rheumatology Association) containing 48 questions with regard to the diagnosis, monitoring and treatment of TAK was distributed to 495 Canadian adult and pediatric rheumatologists by email. Results: Sixty-six rheumatologists completed the survey (13% response rate): the majority (73%) were from academic centers and ≤25% reported managing more than ten patients in their career. For establishing the diagnosis of TAK, they relied on a combination of signs and symptoms of ischemia, elevations of inflammatory markers and vascular imaging (typically computed tomography and magnetic resonance angiography). The frequency of monitoring for disease activity and the methods employed (clinical, laboratory or imaging) were variable. All physicians used corticosteroids for the treatment of TAK, but 42% would treat for at least 6–12 months, 26% for 12–24 months and 23% would never stop corticosteroids. Fifty-three percent would always use an immunosuppressant (most commonly methotrexate or azathioprine) in addition to corticosteroids and the remainder would only start an immunosuppressant in patients with refractory or relapsing disease. Conclusion: Physician practices for the management of TAK are variable, suggesting that there are knowledge gaps, which may impact outcomes in patients with TAK. Keywords: Takayasu arteritis, physician practice patterns, practice guidelines, large vessel vasculitis, aortitis

Background/Objectives: The content of [sup.13]C and [sup.15]N isotopes is higher in marine than in terrestrial food. [sup.13]C and [sup.15]N in human tissue therefore reflects the relative proportions of marine and terrestrial food consumed by the individual. The objective of this study was to measure [sup.13]C and [sup.15]N in liver tissue from Greenlandic Inuit and Danes. Subjects/Methods: Normal liver tissue was obtained at autopsy in 1992-1994 from 60 Inuit with a median age of 61 years (range 25-83) and in 1986 from 15 ethnic Danes with a median age of 84 years (range 66-93). By sieving, liver tissue was separated in a 'cellular fraction' and a 'connective tissue fraction'. [sup.13]C and [sup.15]N in dry liver tissue was measured on a mass spectrometer. [δ.sup.13]C indicates the [sup.13]C content relative to the IAEA-CH-6 reference standard. [δ.sup.15]N indicates [sup.15]N content relative to the atmospheric nitrogen reference standard. Results: Inuit: median [δ.sup.13]C was -21.2% in cellular and -20.0% in connective tissue fractions (P = 0.001). Median [δ.sup.15]N was 10.6% in both cellular and connective tissue fractions. Body mass index was negatively correlated with [δ.sup.13]C in the connective tissue fraction ([r.sub.s] = -0.42, P = 0.057). Danes: median [δ.sup.13]C was -27.0% in cellular and -24.3% in connective tissue fractions (P = 0.11). Median [δ.sup.15]N was 9.5% in cellular and 8.9% in connective tissue fractions (P = 0.5). Inuit had higher [δ.sup.13]C than Danes in both cellular and connective tissue fractions (P< 0.001) as well as higher [δ.sup.15]N in the cellular fraction (P = 0.01). Conclusions: Inuit showed considerable variation in the ratio between marine and terrestrial food consumption, reflecting a vanishing hunter culture where elderly Inuit still adhere to the traditional hunters food with a high content of marine food, whereas the younger urbanized Inuit population consume food with a lower content of marine food and a higher content of terrestrial food. Danes consumed food of almost exclusively terrestrial origin. The present [sup.13]C and [sup.15]N analyses are in accordance with the dietary patterns obtained by dietary surveys. European Journal of Clinical Nutrition (2010) 64, 739-744; doi: 10.1038/ejcn.2010.67; published online 2 June 2010 Keywords: [sup.13]carbon; Denmark; Eskimos; Greenland; Inuit; liver; mass spectrometry; [sup.15]nitrogen, Introduction You are what you eat! This slogan indicates that the composition of body tissues reflects the dietary intake of the individual. All atoms in human tissues, except hydrogen and [...]

OBJECTIVE: To assess effects of iron supplementation, 66 mg elemental iron daily as ferrous fumarate, on iron status markers during normal pregnancies. METHODS: Randomized, double-blind, placebo-controlled study of 119 women (62 iron-, 57 placebo -treated) and their newborns. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage (TSAT) and S-erythropoietin (S-EPO) were measured at 14–18, 24–27 weeks of gestation, prepartum, 1 and 8 weeks postpartum. RESULT: From 24–27 weeks gestation to 8 weeks postpartum, the iron group had higher Hb, S-ferritin and TSAT than the placebo group; prepartum, 11% had iron deficiency (ID) and 0% iron deficiency anemia (IDA) in the iron group, vs 60% and 18% in the placebo group; 8 weeks postpartum 1.6% in the iron group had ID and 1.6% IDA vs 14% and 7% in the placebo group. S-EPO levels in the iron group were lower than in the placebo group (p < 0.001). Mothers prepartum S-EPO values were correlated to newborns cord S-EPO values (p < 0.001). Newborns to iron treated mothers had higher cord S-ferritin levels than those to placebo treated mothers (p = 0.02). Newborn girls had higher cord S-ferritin levels than boys (p < 0.01). There was no impact of iron supplementation on the length of gestation, placental weight, or newborns birth weight. Birth weight was correlated only with mothers' body weight, length of gestation and placental weight. CONCLUSION: Iron supplementation had a "positive" impact on iron status and Hb both during pregnancy and postpartum, with a low frequency of ID/IDA and also a "positive" influence on newborns iron status. [ABSTRACT FROM AUTHOR]

Brain oscillations underlie the function of our brains, dictating how we both think and react to the world around us. The synchronous activity of neurons generates these rhythms, which allow different parts of the brain to communicate and orchestrate responses to internal and external stimuli. Perturbations of cognitive rhythms and the underlying oscillator neurons that synchronize different parts of the brain contribute to the pathophysiology of diseases including Alzheimer's disease, (AD), Parkinson's disease (PD), epilepsy and other diseases of rhythm that have been studied extensively by Gyorgy Buzsaki. In this review, we discuss how neurologists manipulate brain oscillations with neuromodulation to treat diseases and how this can be leveraged to improve cognition and pathology underlying AD. While multiple modalities of neuromodulation are currently clinically indicated for some disorders, nothing is yet approved for improving memory in AD. Recent investigations into novel methods of neuromodulation show potential for improving cognition in memory disorders. Here, we demonstrate that neuronal stimulation using audiovisual sensory stimulation that generated 40‐HZ gamma waves reduced AD‐specific pathology and improved performance in behavioural tests in mouse models of AD, making this new mode of neuromodulation a promising new avenue for developing a new therapeutic intervention for the treatment of dementia. [ABSTRACT FROM AUTHOR]

Objectives: The existing set of outcomes for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) needs to incorporate views of outcome measure stakeholders to meet the current standards of outcome measurement proposed by the Outcome Measures in Rheumatology (OMERACT) initiative. This study identifies domains that clinical experts (one group of stakeholders) consider to be important to determining the impact of AAV using the International Classification of Functioning, Disability and Health (ICF), a framework that describes health along four components: body functions, body structures, activities and participation, and contextual factors.Method: An international group of clinicians with expertise in the clinical care of patients with vasculitis were identified through consultation with three major vasculitis societies. The relevant domains were determined using a three-round e-mail-based Delphi questionnaire.Results: Eighty-two clinicians were invited to participate in this study and 41 responded. Nineteen domains were identified as important by > 80% of participants: six body functions (energy, seeing, hearing, pain, respiratory, and renal function), seven body structures (peripheral nerves, eye, ear, nose, sinuses, lungs (and airways), and kidneys), three activities and participation (carrying out daily routine, remunerative employment, and recreation and leisure), and three environmental factors (medications, support and relationships, and health services, systems, and policies).Conclusions: Clinical experts focus on the physiological effects of AAV with less importance given to the effect of AAV on patients' activities and participation in life situations and the role of contextual factors. This study represents a step towards incorporating views of a range of stakeholders into disease assessment in AAV. [ABSTRACT FROM AUTHOR]

Background/Objectives:The content of 13C and 15N isotopes is higher in marine than in terrestrial food. 13C and 15N in human tissue therefore reflects the relative proportions of marine and terrestrial food consumed by the individual. The objective of this study was to measure 13C and 15N in liver tissue from Greenlandic Inuit and Danes.Subjects/Methods:Normal liver tissue was obtained at autopsy in 1992–1994 from 60 Inuit with a median age of 61 years (range 25–83) and in 1986 from 15 ethnic Danes with a median age of 84 years (range 66–93). By sieving, liver tissue was separated in a ‘cellular fraction’ and a ‘connective tissue fraction’. 13C and 15N in dry liver tissue was measured on a mass spectrometer. δ13C indicates the 13C content relative to the IAEA-CH-6 reference standard. δ15N indicates 15N content relative to the atmospheric nitrogen reference standard.Results:Inuit: median δ13C was −21.2‰ in cellular and −20.0‰ in connective tissue fractions (P=0.001). Median δ15N was 10.6‰ in both cellular and connective tissue fractions. Body mass index was negatively correlated with δ13C in the connective tissue fraction (rs=−0.42, P=0.057). Danes: median δ13C was −27.0‰ in cellular and −24.3‰ in connective tissue fractions (P=0.11). Median δ15N was 9.5‰ in cellular and 8.9‰ in connective tissue fractions (P=0.5). Inuit had higher δ13C than Danes in both cellular and connective tissue fractions (P<0.001) as well as higher δ15N in the cellular fraction (P=0.01).Conclusions:Inuit showed considerable variation in the ratio between marine and terrestrial food consumption, reflecting a vanishing hunter culture where elderly Inuit still adhere to the traditional hunters food with a high content of marine food, whereas the younger urbanized Inuit population consume food with a lower content of marine food and a higher content of terrestrial food. Danes consumed food of almost exclusively terrestrial origin. The present 13C and 15N analyses are in accordance with the dietary patterns obtained by dietary surveys. [ABSTRACT FROM AUTHOR]

Background: Blau syndrome is a chronic granulomatous disease with an autosomal dominant trait characterized by the triad granulomatous dermatitis, arthritis, and uveitis. It is caused by mutations in the NOD2 gene, also termed the CARD15 gene. Objective: To report a novel mutation in the NOD2 gene associated with Blau syndrome. Methods and results: The proband was a 68-year-old ethnic Norwegian male who had uveitis and arthritis since 10 years of age followed by lifelong recurrent arthritis and chronic eye involvement. Genetic analysis showed a heterozygous c.1814 C>A, T605N mutation in NOD2 that has not previously been described. All of his three children had Blau syndrome and had inherited the NOD2 mutation. The proband's first son had exanthema, arthritis, and uveitis from 10 years of age and later presented with granulomatous lymphadenopathy, granulomatous parotitis, and granulomatous intestinal inflammation. The proband's daughter had arthritis, uveitis, and exanthema from 3 years of age. The proband's second son had uveitis, exanthema, and arthritis from 1.5 years of age. None of the cases had any involvement of the heart or lungs. Conclusion: We report a novel Blau syndrome-associated mutation with an autosomal dominant heritage. Most likely the mutation has arisen de novo in the proband. Genetic counselling and antenatal diagnostics should be available to the involved families. [ABSTRACT FROM AUTHOR]

Objective. Trefoil factors (TFF1-3) are 7-12 kDa peptides secreted by mucosal surfaces, with changing levels of expression reflected in serum concentrations. The genes for the peptides are located on chromosome 21, the chromosome duplicated in trisomy 21. We studied the levels of circulating TFFs in pregnant women carrying trisomy 21 foetuses and in women with normal pregnancies, throughout pregnancy and postpartum. Material and methods. Employing ELISA methods, serum collected at gestational weeks (GW) 18, 32, 39 and 8 weeks postpartum from women carrying normal foetuses (n = 141) was analysed for TFFs. In addition, serum collected at GW 6-14 (median = 10) from women carrying trisomy 21 foetuses (n = 48) or healthy foetuses (n = 46) was analysed. Results. Peaking at 39 GW, concentrations of TFF2 and TFF3 were 3.5 and 47 times higher, respectively, than postpartum. Postpartum levels were comparable to concentrations previously measured in non-pregnant women. TFF1 concentrations rose throughout pregnancy and postpartum, being 1.5 times higher postpartum compared to 18 GW. No differences in the levels of TFFs were observed between women carrying trisomy 21 and those with healthy foetuses. To our knowledge, circulating TFF3 has never been reported to reach the levels observed here. Also, the pattern of increase is unusual, as previous reports have shown parallel increases in TFF1 and TFF3 with no alterations in TFF2. Conclusions. Our results demonstrate that circulating TFFs are not candidate markers of trisomy 21 in first-trimester pregnancies, but raise intriguing questions concerning the origin of TFFs produced during pregnancy and their physiological function. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: In elderly Danes, reference intervals for hemoglobin (Hb) concentrations are derived from younger population groups. The aim was to examine reference intervals for Hb and cut-off limits for anemia by application of criteria for normality to a representative population of 80-year-olds. METHODS: Participants in this epidemiological health survey cohort were 358 subjects (171 men) 80 years of age. A dietary survey was performed in 232 subjects. Blood samples included Hb, red cell indices, serum ferritin, serum C-reactive protein, renal and hepatic function tests. Normality criteria for Hb were: 1) values in all participants; 2) values in apparently healthy subjects; 3) values in 10-year survivors. Hb was compared with muscle strength, physical performance and diet. RESULTS: In the entire series, median Hb was 140 g/L, 5-95 percentile 116-160 g/L in men, and 131 g/L, 5-95 percentile 114-147 g/L in women (p<0.001). The prevalence of anemia, as defined by World Health Organization (WHO) criteria, was 18% in men and 17% in women. Apparently healthy iron-replete men (n=129) and women (n=141) had median Hb of 141 g/L and 131 g/L. Median Hb levels were higher in 10-year surviving men (143 g/L) than in deceased men (139 g/L), whereas surviving and deceased women had similar median Hb (131 g/L). Hb and muscle strength were significantly correlated. Subjects with physical performance score >/=20 had a lower frequency of anemia. There was no correlation between Hb and dietary or supplemental iron intake. In men, Hb was correlated to meat consumption. CONCLUSIONS: WHO decision limits for anemia should not be lowered in 80-year-old subjects. 'Optimal' Hb concentrations with respect to survival appear to be at least 140 g/L in men and 131 g/L in women. Further research should evaluate whether not only treating anemia, but also increasing Hb by using erythropoietin and hematinics, may improve functional status and survival in the elderly. [ABSTRACT FROM AUTHOR]