The personal impact of living with a myeloproliferative neoplasm.

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

The impact of temperature on vascular function in connection with vascular laser treatment.

Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which biological processes underlie its favorable outcome. Pulsed dye laser treatment at 585-595 nm targets hemoglobin in the blood, inducing local hyperthermia in surrounding blood vessels and adjacent tissues. While the impact of destructive temperatures on blood vessels has been well studied, the effects of lower temperatures on the function of several cell types within the blood vessel wall and its periphery are not known. The aim of our study is to assess the functionality of isolated blood vessels after exposure to moderate hyperthermia (45 to 60°C) by evaluating the function of endothelial cells, smooth muscle cells, and vascular nerves. We measured blood vessel functionality of rat mesenteric arteries (n=19) by measuring vascular contraction and relaxation before and after heating vessels in a wire myograph. To this end, we elicited vascular contraction by addition of either high potassium solution or the thromboxane analogue U46619 to stimulate smooth muscle cells, and electrical field stimulation (EFS) to stimulate nerves. For measurement of endothelium-dependent relaxation, we used methacholine. Each vessel was exposed to one temperature in the range of 45-60°C for 30 seconds and a relative change in functional response after hyperthermia was determined by comparison with the response per stimulus before heating. Non-linear regression was used to fit our dataset to obtain the temperature needed to reduce blood vessel function by 50% (Half maximal effective temperature, ET50). Our findings demonstrate a substantial decrease in relative functional response for all three cell types following exposure to 55°C-60°C. There was no significant difference between the ET50 values of the different cell types, which was between 55.9°C and 56.9°C (P>0.05). Our data show that blood vessel functionality decreases significantly when exposed to temperatures between 55°C-60°C for 30 seconds. The results show functionality of endothelial cells, smooth muscle cells, and vascular nerves is similarly impaired. These results help to understand the biological effects of hyperthermia and may aid in tailoring laser and light strategies for selective photothermolysis that contribute to disease modification of psoriasis after pulsed dye laser treatment.

Effectiveness of an intervention to reduce sedentary behaviour as a personalised secondary prevention strategy for patients with coronary artery disease: main outcomes of the SIT LESS randomised clinical trial.

BACKGROUND: A high sedentary time is associated with increased mortality risk. Previous studies indicate that replacement of sedentary time with light- and moderate-to-vigorous physical activity attenuates the risk for adverse outcomes and improves cardiovascular risk factors. Patients with cardiovascular disease are more sedentary compared to the general population, while daily time spent sedentary remains high following contemporary cardiac rehabilitation programmes. This clinical trial investigated the effectiveness of a sedentary behaviour intervention as a personalised secondary prevention strategy (SIT LESS) on changes in sedentary time among patients with coronary artery disease participating in cardiac rehabilitation. METHODS: Patients were randomised to usual care (n = 104) or SIT LESS (n = 108). Both groups received a comprehensive 12-week centre-based cardiac rehabilitation programme with face-to-face consultations and supervised exercise sessions, whereas SIT LESS participants additionally received a 12-week, nurse-delivered, hybrid behaviour change intervention in combination with a pocket-worn activity tracker connected to a smartphone application to continuously monitor sedentary time. Primary outcome was the change in device-based sedentary time between pre- to post-rehabilitation. Changes in sedentary time characteristics (prevalence of prolonged sedentary bouts and proportion of patients with sedentary time ≥ 9.5 h/day); time spent in light-intensity and moderate-to-vigorous physical activity; step count; quality of life; competencies for self-management; and cardiovascular risk score were assessed as secondary outcomes. RESULTS: Patients (77% male) were 63 ± 10 years and primarily diagnosed with myocardial infarction (78%). Sedentary time decreased in SIT LESS (- 1.6 [- 2.1 to - 1.1] hours/day) and controls (- 1.2 [ ─1.7 to - 0.8]), but between group differences did not reach statistical significance (─0.4 [─1.0 to 0.3]) hours/day). The post-rehabilitation proportion of patients with a sedentary time above the upper limit of normal (≥ 9.5 h/day) was significantly lower in SIT LESS versus controls (48% versus 72%, baseline-adjusted odds-ratio 0.4 (0.2-0.8)). No differences were observed in the other predefined secondary outcomes. CONCLUSIONS: Among patients with coronary artery disease participating in cardiac rehabilitation, SIT LESS did not induce significantly greater reductions in sedentary time compared to controls, but delivery was feasible and a reduced odds of a sedentary time ≥ 9.5 h/day was observed. TRIAL REGISTRATION: Netherlands Trial Register: NL9263. Outcomes of the SIT LESS trial: changes in device-based sedentary time from pre-to post-cardiac rehabilitation (control group) and cardiac rehabilitation + SIT LESS (intervention group). SIT LESS reduced the odds of patients having a sedentary time >9.5 hours/day (upper limit of normal), although the absolute decrease in sedentary time did not significantly differ from controls. SIT LESS appears to be feasible, acceptable and potentially beneficial, but a larger cluster randomised trial is warranted to provide a more accurate estimate of its effects on sedentary time and clinical outcomes. CR: cardiac rehabilitation.

Estuarine dissolved speciation and partitioning of trace metals: a novel approach to study biogeochemical processes.

Estuaries are complex systems involving numerous biogeochemical gradients and processes that influence the behavior of trace metals. Lead (Pb), cadmium (Cd), and copper (Cu) speciation and partitioning were studied in the Gironde Estuary (SW France), using a multi-method approach in which data from innovative sensors and laboratory-based techniques were combined. For the first time in this system, the so-called dynamic fractions of the target metals (dissolved forms that are potentially bioavailable) were recorded on-board through voltammetry using unique antifouling gel-integrated microelectrode arrays (GIME) incorporated in a submersible sensing probe (TracMetal). Trace metals in the operationally defined dissolved <0.2 µm and <0.02 µm fractions, as well as complexed with suspended particles (collected after centrifugation) were quantified through sampling/laboratory-based techniques. High spatial resolution trace metal concentrations were monitored along the salinity gradient (S = 0.10 to S = 34.0) together with master bio-physicochemical parameters providing robust cruise-specific information on how well-known abiotic and biotic processes control the Gironde estuarine trace element partitioning, (i.e. conservative behavior, addition/removal). Combining conventional methods with GIME measurements showed: (i) the dominance of Cd dynamic species in the intra-estuarine total dissolved fraction (up to 90%), (ii) the importance of small colloids as trace metal carrier phases, desorbing and complexing dynamic fractions of Pb and Cu, and (iii) the potential influence of photo-redox processes remobilizing Pb under their dynamic forms (up to 80%). Data also suggest trace metal release/sorption by phytoplankton with an increase of dissolved Cu concentrations in the riverine branch, as well as Cu and Cd particulate concentrations showing higher levels towards productive coastal waters. This complete approach allowed to monitor key estuarine biogeochemical processes and highlighted the valuable use of the TracMetal to record subtle variations of potentially bioavailable dissolved metal fractions.

Effectiveness of the "Living with Cancer" peer self-management support program for persons with advanced cancer and their relatives: study protocol of a non-randomized stepped wedge study.

BACKGROUND: Persons with advanced cancer and their relatives experience physical, emotional, and psychosocial consequences of the illness. Most of the time, they must deal with these themselves. While peer self-management support programs may be helpful, there is little evidence on their value for this population. We present the research protocol of our SMART study that will evaluate the effectiveness of the "Living with Cancer" peer self-management support program, aimed at improving self-management behaviors, self-efficacy, and health-related quality of life of persons with advanced cancer and their relatives. METHODS: We will conduct a non-randomized stepped wedge study in the Netherlands. We will include 130 persons with advanced cancer and 32 relatives. Participants can choose to either start the program within 4 weeks after inclusion or after eight to 10 weeks. The "Living with Cancer" is a peer self-management support program, based on the Chronic Disease Self-Management Program. It consists of six 1,5 hours video-conferencing group meetings with eight to 12 participants, preceded by two or three preparatory audio clips with supportive text per session. The program has the following core components: the learning of self-management skills (action-planning, problem-solving, effective communication, and decision-making), discussing relevant themes (e.g. dealing with pain and fatigue, living with uncertainty, and future planning), and sharing experiences, knowledge, and best practices. The primary outcome for both persons with advanced cancer and relatives is self-management behavior assessed by the subscale "constructive attitudes and approaches" of the Health Education Impact Questionnaire. Secondary outcomes are other self-management behaviors, self-efficacy, health-related quality of life, symptoms, depression and anxiety, and loneliness. Participants complete an online questionnaire at baseline, and after eight and 16 weeks. After each session, they complete a logbook about their experiences. Group meetings will be video recorded. DISCUSSION: SMART aims to evaluate an innovative program building on an evidence-based self-management program. New features are its use for persons with advanced cancer, the inclusion of relatives, and the video-conferencing format for this population. The use of both quantitative and qualitative analyses will provide valuable insight into the effectiveness and value of this program. TRIAL REGISTRATION: This study was registered in the Dutch Trial Register on October 2021, identifier NL9806 .

Impact of COVID-19 lockdown on physical activity and sedentary behaviour in Dutch cardiovascular disease patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) lockdown restrictions may impact lifestyle and therefore also physical (in)activity patterns in patients with cardiovascular disease (CVD). This study aimed to evaluate the effect of lockdown on physical activity and sedentary behaviour. METHODS: A total of 1565 Dutch CVD patients participated in this prospective cohort study, in which we compared physical activity and sedentary behaviour before and during the COVID-19 lockdown period. Baseline measures were assessed in 2018 and data on follow-up measures were collected between 17 and 24 April 2020 (5 weeks after the introduction of COVID-19 lockdown restrictions). Validated questionnaires were used to assess physical activity and sedentary behaviour. RESULTS: Moderate-to-vigorous physical activities increased from 1.6 (0.9, 2.8) to 2.0 (1.0, 3.5) h/day [median (interquartile range)] (p < 0.001) during the COVID-19 lockdown, mainly due to an increase in time spent walking and doing odd jobs. In contrast, time spent exercising significantly declined [1.0 (0.0, 2.3) to 0.0 (0.0, 0.6) h/week], whereas sedentary time increased from 7.8 (6.1, 10.4) to 8.9 (6.8, 11.4) h/day (p < 0.001). The absolute increase in physical activity was 13 (-36, 81) min/day, whereas sedentary behaviour increased by 55 (-72, 186) min/day. CONCLUSION: Despite a small increase in physical activities, the larger increase in sedentary time induced a net reduction in habitual physical activity levels in Dutch CVD patients during the first-wave COVID-19 lockdown. Since a more inactive lifestyle is strongly associated with disease progression and mortality, we encourage CVD patients and their caregivers to explore novel solutions to increase physical activity levels and reduce sedentary time during (and beyond) the COVID-19 pandemic.

Structure and function of resistance arteries from BB-creatine kinase and ubiquitous Mt-creatine kinase double knockout mice.

Increasing evidence indicates that the enzyme creatine kinase (CK) is intimately involved in microvascular contractility. The mitochondrial isoenzyme catalyses phosphocreatine synthesis from ATP, while cytoplasmic CK, predominantly the BB isoenzyme in vascular tissue, is tightly bound near myosin ATPase, where it favours ATP production from phosphocreatine to metabolically support vascular contractility. However, the effect of CK gene inactivation on microvascular function is hitherto unknown. We studied functional and structural parameters of mesenteric resistance arteries isolated from 5 adult male mice lacking cytoplasmic BB-CK and ubiquitous mitochondrial CK (CK-/-) vs 6 sex/age-matched controls. Using a Mulvany Halpern myograph, we assessed the acute maximum contractile force with 125 mM K+ and 10-5 M norepinephrine, and the effect of two inhibitors, dinitrofluorobenzene, which inhibits phosphotransfer enzymes (0.1 µM), and the specific adenylate kinase inhibitor P1, P5-di(adenosine 5') pentaphosphate (10-6 to 10-5 M). WT and CK-/- did not significantly differ in media thickness, vascular elasticity parameters, or acute maximum contractile force. CK-/- arteries displayed greater reduction in contractility after dinitrofluorobenzene 38%; vs 14% in WT; and after AK inhibition, 14% vs 5.5% in WT, and displayed abnormal mitochondria, with a partial loss of the inner membrane. Thus, CK-/- mice display a surprisingly mild phenotype in vascular dysfunction. However, the mitochondrial abnormalities and greater effect of inhibitors on contractility may reflect a compromised energy metabolism. In CK-/- mice, compensatory mechanisms salvage energy metabolism, as described for other CK knock-out models.

More salt, please: global patterns, responses and impacts of foliar sodium in grasslands.

Sodium is unique among abundant elemental nutrients, because most plant species do not require it for growth or development, whereas animals physiologically require sodium. Foliar sodium influences consumption rates by animals and can structure herbivores across landscapes. We quantified foliar sodium in 201 locally abundant, herbaceous species representing 32 families and, at 26 sites on four continents, experimentally manipulated vertebrate herbivores and elemental nutrients to determine their effect on foliar sodium. Foliar sodium varied taxonomically and geographically, spanning five orders of magnitude. Site-level foliar sodium increased most strongly with site aridity and soil sodium; nutrient addition weakened the relationship between aridity and mean foliar sodium. Within sites, high sodium plants declined in abundance with fertilisation, whereas low sodium plants increased. Herbivory provided an explanation: herbivores selectively reduced high nutrient, high sodium plants. Thus, interactions among climate, nutrients and the resulting nutritional value for herbivores determine foliar sodium biogeography in herbaceous-dominated systems.

[An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and non-pharmacological management of female pelvic floor dysfunction]. / Traduction française de la terminologie commune de l'International Urogynecological Association (IUGA) et de l'International Continence Society (ICS) relative à la prise en charge conservatrice et non pharmacologique des troubles pelvi-périnéaux de la femme.

INTRODUCTION: There has been an increasing need for the terminology for the conservative management of female pelvic floor dysfunction to be collated in a clinically-based consensus report. METHODS: This report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology and nursing were invited to comment on the paper. RESULTS: A terminology report for the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically-based with the most common symptoms, signs, assessments, diagnoses and treatments defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for the conservative management of female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Undocumented children in the Amsterdam region: an analysis of health, school, and living circumstances.

Undocumented migrants are people who do not have a valid residence permit. There are only estimates about how many undocumented migrants are living in the European Union; the number of children among them is unclear. Studies about undocumented children are scarce and little is known about their living situation and their access to health care. Therefore, we aimed to estimate the number of undocumented children in the population of visitors of our primary care clinic for undocumented patients. Moreover, we explored whether these children's rights with respect to health care, education, and living circumstances were met. All undocumented adult patients visiting the clinic between September 1, 2016 and December 31, 2016 received a questionnaire. In total, 267 undocumented adults responded; 30% of them had children, and 15% had one or more undocumented children living in the Netherlands. Eleven percent of those undocumented children did not attend school, 17% was not vaccinated, 83% did not have a general practitioner, and 30% did not have a permanent place of residence. CONCLUSION: There are probably a considerable number of undocumented children in the Netherlands; our study estimated a percentage of 17% of the undocumented population. Not all their basic human rights are met; more awareness among people involved with child and health policies is needed. What is Known: • There are only estimates of the number of undocumented migrants in the European Union, the number of children among them is not clear. • Studies about undocumented children are scarce and little is known about their living circumstances and access to health care. What is New: • A substantial number of undocumented children do not go to school, are not vaccinated, and do not have a general practitioner. • The hidden group of undocumented children, whose basic human rights are not met, need special attention when they or their caregivers present at a health care facility.

Medial tibial stress syndrome can be diagnosed reliably using history and physical examination.

BACKGROUND: The majority of sporting injuries are clinically diagnosed using history and physical examination as the cornerstone. There are no studies supporting the reliability of making a clinical diagnosis of medial tibial stress syndrome (MTSS). AIM: Our aim was to assess if MTSS can be diagnosed reliably, using history and physical examination. We also investigated if clinicians were able to reliably identify concurrent lower leg injuries. METHODS: A clinical reliability study was performed at multiple sports medicine sites in The Netherlands. Athletes with non-traumatic lower leg pain were assessed for having MTSS by two clinicians, who were blinded to each others' diagnoses. We calculated the prevalence, percentage of agreement, observed percentage of positive agreement (Ppos), observed percentage of negative agreement (Pneg) and Kappa-statistic with 95%CI. RESULTS: Forty-nine athletes participated in this study, of whom 46 completed both assessments. The prevalence of MTSS was 74%. The percentage of agreement was 96%, with Ppos and Pneg of 97% and 92%, respectively. The inter-rater reliability was almost perfect; k=0.89 (95% CI 0.74 to 1.00), p<0.000001. Of the 34 athletes with MTSS, 11 (32%) had a concurrent lower leg injury, which was reliably noted by our clinicians, k=0.73, 95% CI 0.48 to 0.98, p<0.0001. CONCLUSION: Our findings show that MTSS can be reliably diagnosed clinically using history and physical examination, in clinical practice and research settings. We also found that concurrent lower leg injuries are common in athletes with MTSS.

The Histological Composition of Capsular Contracture Focussed on the Inner Layer of the Capsule: An Intra-Donor Baker-I Versus Baker-IV Comparison.

BACKGROUND: Capsular contracture remains one of the major complications after breast implantation surgery. The extent of capsular contraction is scored using the Baker scale. The aim of this study was to compare intra-individual Baker-I with Baker-IV capsules, and in particular the prevalence and histological properties of the inner capsule layer. METHODS: Twenty capsules from ten patients were included after bilateral explantation surgery due to unilateral capsular contracture (Baker-IV) after cosmetic augmentation with textured implants. All capsules underwent (immune-)histochemical analysis: haematoxylin-eosin (morphology), CD68 (macrophages), cytokeratin (epithelial cells) and vimentin (fibroblasts), and were visually scored for cell density and the presence of an inner layer and measured for thickness. RESULTS: Baker-IV (n = 10) capsules were significantly thicker compared to Baker-I (n = 10) capsules (P = 0.004). An inner layer was present in 8 Baker-I capsules. All Baker-I capsules were vimentin and CD68-positive and cytokeratin-negative. Positive vimentin was seen throughout the inner layer, and CD-68 staining was observed adjacent to the intermediate capsule layer. In contrast, only 2 Baker-IV capsules had an inner layer, of which only 1 showed the same profile as Baker-I capsules (P = 0.016). No cytokeratin positivity was seen in any capsule. In Baker-IV capsules, outer layers showed more positivity for both vimentin and CD68. CONCLUSION: The inner layer is morphologically consistent with synovial metaplasia and is more prevalent in healthy, uncontracted Baker-I capsules. This inverse relation between the presence of the inner layer and higher Baker classification or pathological contracture could indicate a protective role of the inner layer against capsular contracture formation. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Quantitative agreement between [(15)O]H2O PET and model free QUASAR MRI-derived cerebral blood flow and arterial blood volume.

The purpose of this study was to assess whether there was an agreement between quantitative cerebral blood flow (CBF) and arterial cerebral blood volume (CBVA) measurements by [(15)O]H2O positron emission tomography (PET) and model-free QUASAR MRI. Twelve healthy subjects were scanned within a week in separate MRI and PET imaging sessions, after which quantitative and qualitative agreement between both modalities was assessed for gray matter, white matter and whole brain region of interests (ROI). The correlation between CBF measurements obtained with both modalities was moderate to high (r(2): 0.28-0.60, P < 0.05), although QUASAR significantly underestimated CBF by 30% (P < 0.001). CBVA was moderately correlated (r(2): 0.28-0.43, P < 0.05), with QUASAR yielding values that were only 27% of the [(15)O]H2O-derived values (P < 0.001). Group-wise voxel statistics identified minor areas with significant contrast differences between [(15)O]H2O PET and QUASAR MRI, indicating similar qualitative CBVA and CBF information by both modalities. In conclusion, the results of this study demonstrate that QUASAR MRI and [(15)O]H2O PET provide similar CBF and CBVA information, but with systematic quantitative discrepancies.

Chlorhexidine mouthwash and sodium lauryl sulphate dentifrice: do they mix effectively or interfere?

FOCUSED QUESTION: What is the effectiveness of a chlorhexidine (CHX) mouthwash used in combination with a sodium lauryl sulphate (SLS) dentifrice on the parameters of plaque and gingivitis? MATERIAL AND METHODS: MEDLINE-PubMed, Cochrane-CENTRAL, EMBASE and other electronic databases were searched up to July 2014. The inclusion criteria were (randomized) controlled clinical trials, subjects ≥18 years of age with good general health. Papers evaluating the effect of CHX mouthwash used in combination with SLS dentifrice or a dentifrice slurry compared with CHX mouthwash as a single oral hygiene intervention or in combination with an SLS-free dentifrice were included. From the eligible studies, data were extracted, and a meta-analysis was performed when feasible. RESULTS: Independent screening of 83 unique papers resulted in four eligible publications, with nine comparisons. The meta-analysis showed that when an SLS dentifrice was used as a slurry rinse, the interference on the plaque-inhibiting effect of a CHX mouthwash was significantly decreased (MD 0.33; P ≤ 0.00001; 95% CI: <0.24; 0.42>). No significant difference was observed when SLS dentifrice was applied as a paste in combination with CHX mouthwash (MD 0.08; P = 0.42; 95% CI: <-0.26; 0.11>). Descriptive and subgroup analyses support these findings. Moreover, the observed effect for the dentifrice paste occurred regardless of the order of use. CONCLUSION: This review demonstrates that when CHX mouthwash is recommended, it can be used in combination with an SLS dentifrice without any interference regarding its inhibiting effect on dental plaque, regardless of the order of use. Consequently, the collective evidence indicates that the combined use of dentifrice and CHX mouthwash is not contraindicated. However, this recommendation has been graded as moderate taking into account a potential publication bias because three of the four included studies emerged from the same research group.

The effect of water on morning bad breath: a randomized clinical trial.

OBJECTIVES: To assess the effects of water on the parameters of 'morning bad breath' (MBB) and to evaluate whether there is a difference between rinsing with water and drinking a glass of water. MATERIALS AND METHODS: A total of 50 participants were recruited and were randomly divided into two equal groups. One group rinsed with 15 ml of water for 30 s, and another group drank 200 ml of water within 30 s. Clinical assessments were carried out during one visit between 7:30 am and 12:00 pm. Pre- and post-intervention measures were assessed organoleptically as primary outcome parameters, and a secondary outcome parameter was assessed using both the Halimeter(®) and OralChroma(™) apparatuses to evaluate volatile sulphur compounds (VSCs), hydrogen sulphide (H2 S), methyl mercaptan (CH3 SH) and dimethyl sulphide ((CH3 )2 S). In addition, the presence of tongue coating (discoloration/thickness) and tongue fissures was assessed. RESULTS: All 50 participants completed the study. In both groups, a significant reduction in the organoleptic score and the OralChroma(™) H2 S and CH3 SH readings was obtained after the intervention. Both regimens resulted in a CH3 SH reduction of approximately 60%, whereas the reduction in H2 S was between 30% and 50%. The acceptable change between pre- and post-assessments of the clinical parameters was not significantly different between the drinking and rinsing groups. CONCLUSION: Rinsing with water or drinking a glass of water had a statistically significant effect on the MBB parameters. No significant difference was obtained between the two regimens.

CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA. METHODS: A genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before. RESULTS: SNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (p<0.05), strengthening the evidence for involvement of these genes in JIA. In the majority of these replicated SNPs, effect sizes were larger when analysing a homogeneous patient cohort than when analysing all subtypes. We identified two novel associations with oligoarticular and RF-negative polyarticular JIA: CD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively). CONCLUSIONS: The CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology.

Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and α-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A. Here we describe a family with a novel late-onset neurodegenerative disorder presenting with dementia and/or parkinsonism in 12 affected individuals. The disorder is characterized by a unique neuropathological phenotype displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immunoreactivity for intermediate filaments. Combining linkage analysis, exome sequencing and proteomics analysis, we identified a heterozygous c.149T>G (p.Leu50Arg) missense mutation in the gene encoding the protein kinase A type I-beta regulatory subunit (PRKAR1B). The pathogenicity of the mutation is supported by segregation in the family, absence in variant databases, and the specific accumulation of PRKAR1B in the inclusions in our cases associated with a specific biochemical pattern of PRKAR1B. Screening of PRKAR1B in 138 patients with Parkinson's disease and 56 patients with frontotemporal dementia did not identify additional novel pathogenic mutations. Our findings link a pathogenic PRKAR1B mutation to a novel hereditary neurodegenerative disorder and suggest an altered protein kinase A function through a reduced binding of the regulatory subunit to the A-kinase anchoring protein and the catalytic subunit of protein kinase A, which might result in subcellular dislocalization of the catalytic subunit and hyperphosphorylation of intermediate filaments.

Accuracy and precision of pseudo-continuous arterial spin labeling perfusion during baseline and hypercapnia: a head-to-head comparison with ¹5O H2O positron emission tomography.

Measurements of the cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide useful information about cerebrovascular condition and regional metabolism. Pseudo-continuous arterial spin labeling (pCASL) is a promising non-invasive MRI technique to quantitatively measure the CBF, whereas additional hypercapnic pCASL measurements are currently showing great promise to quantitatively assess the CVR. However, the introduction of pCASL at a larger scale awaits further evaluation of the exact accuracy and precision compared to the gold standard. (15)O H2O positron emission tomography (PET) is currently regarded as the most accurate and precise method to quantitatively measure both CBF and CVR, though it is one of the more invasive methods as well. In this study we therefore assessed the accuracy and precision of quantitative pCASL-based CBF and CVR measurements by performing a head-to-head comparison with (15)O H2O PET, based on quantitative CBF measurements during baseline and hypercapnia. We demonstrate that pCASL CBF imaging is accurate during both baseline and hypercapnia with respect to (15)O H2O PET with a comparable precision. These results pave the way for quantitative usage of pCASL MRI in both clinical and research settings.

Molecular diagnostics of the HBB gene in an Omani cohort using bench-top DNA Ion Torrent PGM technology.

Hemoglobinopathies, such as sickle cell disease (SCD) and beta-thalassemia major (TM), are severe diseases and the most common autosomal recessive condition worldwide and in particular in Oman. Early screening and diagnosis of carriers are the key for primary prevention. Once a country-wide population screening program is mandated by law, a sequencing technology that can rapidly confirm or identify disease-causing mutations for a large number of patients in a short period of time will be necessary. While Sanger sequencing is the standard protocol for molecular diagnosis, next generation sequencing starts to become available to reference laboratories. Using the Ion Torrent PGM sequencer, we have analyzed a cohort of 297 unrelated Omani cases and reliably identified mutations in the beta-globin (HBB) gene. Our model study has shown that Ion Torrent PGM can rapidly sequence such a small gene in a large number of samples using a barcoded uni-directional or bi-directional sequence methodology, reducing cost, workload and providing accurate diagnosis. Based on our results we believe that the Ion Torrent PGM sequencing platform, able to analyze hundreds of patients simultaneously for a single disease gene can be a valid molecular screening alternative to ABI sequencing in the diagnosis of hemoglobinopathies and other genetic disorders in the near future.

Genetic variation in VTCN1 (B7-H4) is associated with course of disease in juvenile idiopathic arthritis.

OBJECTIVE: The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. METHODS: Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2 years. RESULTS: Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10(-5)) and three SNPs; VTCN1 rs10 923 223 (p=4.4*10(-5)), VTCN1 rs12 046 117 (p=0.017) and CDK6 rs42 041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10 923 223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. CONCLUSIONS: This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease.