Search

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 × 10−18 (odds ratio = 1.19, 95% confidence interval = 1.14–1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.

MM-DCGP_Supplementary_eTable_1_and_2 for The development of multimorbidity during 16 years after diagnosis of type 2 diabetes by Sandra Pouplier, Maria Åhlander Olsen, Tora Grauers Willadsen, Håkon Sandholdt, Volkert Siersma, Christen Lykkegaard Andersen, and Niels de Fine Olivarius in Journal of Comorbidity

Disc-related sciatica has a prevalence of about 2% in adults, but is rare in adolescents. If conservative treatment is unsuccessful, surgery is an option.The aim of this study was to compare the outcomes of surgery for lumbar disc herniation in adolescents with adults in the Swedish Spine Register.This is a prospective observational study: National Quality Register.This study included 151 patients, 18 years or younger, 4,386 patients, 19-39 years, and 6,078 patients, 40 years or older, followed for 1-2 years after surgery.The primary outcomes were patient satisfaction and global assessment of leg and back pain. Secondary outcomes were Visual Analog Scale (VAS) leg pain, VAS back pain, Oswestry disability index (ODI), and EuroQol-5 dimensions (EQ-5D).Statistical analyses were performed with the Welch F test, the chi-square test, and the Wilcoxon signed-rank test.At follow-up, 86% of the adolescents were satisfied compared with 78% in the younger adults and 76% in the older adults group (p.001). According to the global assessment, significantly decreased leg pain was experienced by 87% of the adolescents, 78% of the younger adults, and 71% of the older adults (p.001). Corresponding figures for back pain were 88%, 73%, and 70%, respectively (p.001). All groups experienced significant postoperative improvement of VAS leg pain, VAS back pain, ODI, and EQ-5D (all p.001).The adolescent age group was more satisfied with the treatment than the adult groups. There was a significant improvement in all age groups after surgery.

Objective. To explore views and attitudes among general practitioners (GPs) and researchers in the field of general practice towards problems and challenges related to treatment of patients with multimorbidity. Setting. A workshop entitled Patients with multimorbidity in general practice held during the Nordic Congress of General Practice in Tampere, Finland, 2013. Subjects. A total of 180 GPs and researchers. Design. Data for this summary report originate from audio-recorded, transcribed verbatim plenary discussions as well as 76 short questionnaires answered by attendees during the workshop. The data were analysed using framework analysis. Results. (i) Complex care pathways and clinical guidelines developed for single diseases were identified as very challenging when handling patients with multimorbidity; (ii) insufficient cooperation between the professionals involved in the care of multimorbid patients underlined the GPs’ impression of a fragmented health care system; (iii) GPs found it challenging to establish a good dialogue and prioritize problems with patients within the timeframe of a normal consultation; (iv) the future role of the GP was discussed in relation to diminishing health inequality, and current payment systems were criticized for not matching the treatment patterns of patients with multimorbidity. Conclusion. The participants supported the development of a future research strategy to improve the treatment of patients with multimorbidity. Four main areas were identified, which need to be investigated further to improve care for this steadily growing patient group. OBJECTIVE: To explore views and attitudes among general practitioners (GPs) and researchers in the field of general practice towards problems and challenges related to treatment of patients with multimorbidity.SETTING: A workshop entitled Patients with multimorbidity in general practice held during the Nordic Congress of General Practice in Tampere, Finland, 2013.SUBJECTS: A total of 180 GPs and researchers.DESIGN: Data for this summary report originate from audio-recorded, transcribed verbatim plenary discussions as well as 76 short questionnaires answered by attendees during the workshop. The data were analysed using framework analysis.RESULTS: (i) Complex care pathways and clinical guidelines developed for single diseases were identified as very challenging when handling patients with multimorbidity; (ii) insufficient cooperation between the professionals involved in the care of multimorbid patients underlined the GPs' impression of a fragmented health care system; (iii) GPs found it challenging to establish a good dialogue and prioritize problems with patients within the timeframe of a normal consultation; (iv) the future role of the GP was discussed in relation to diminishing health inequality, and current payment systems were criticized for not matching the treatment patterns of patients with multimorbidity.CONCLUSION: The participants supported the development of a future research strategy to improve the treatment of patients with multimorbidity. Four main areas were identified, which need to be investigated further to improve care for this steadily growing patient group.

BACKGROUND: Many register studies make use of information about permanent nursing home residents. Statistics Denmark (StatD) identifies nursing home residents by two different indirect methods, one based on reports from the municipalities regarding home care in taken place in a nursing home, and the other based on an algorithm created by StatD. The aim of the present study was to validate StatD's nursing home register using dedicated administrative municipality records on individual nursing home residents as gold standard.METHODS: In total, ten Danish municipalities were selected. Within each Danish Region, we randomly selected one municipality reporting to Stat D (Method 1) and one not reporting where instead an algorithm created by StatD was used to discover nursing home residents (Method 2). Method 1 means that municipalities reported to Stat D whether home care has taken place in a nursing home or in a private home. Method 2 is based on an algorithm created by Stat D for the municipalities where Method 1 is not applicable. Our gold standard was the information from the local administrative system in all ten selected municipalities. Each municipality provided a list with all individuals > 65 years living in a nursing home on January 1st, 2013 as well as the central personal number. This was compared to the list of individuals >65 living in nursing home facilities in the same ten municipalities on January 1st, 2013 retrieved from StatD.RESULTS: According to the data received directly from the municipalities, which was used as our gold Standard 3821 individuals were identified as nursing home residents. The StatD register identified 6,141 individuals as residents. Additionally, 556 of the individuals identified by the municipalities were not identified in the StatD register. Overall sensitivity for the ten municipalities in the StatD nursing home register was 0.85 (95% CI 0.84-0.87) and the PPV was 0.53 (95% CI 0.52-0.54). The municipalities for which nursing home status was based on the StatD algorithm (method 2) had a sensitivity of 0.84 (95% CI 0.82-0.86) and PPV of 0.48 (95% CI 0.46-0.50). Both slightly lower than the reporting municipalities (method 1) where the sensitivity was 0.87(95% CI 0.85-0.88) and the PPV was 0.57 (95% CI 0.56-0.59). Additionally, the sensitivity and PPV of the Stat D register varied heavily among the ten municipalities from 0.51 (95% CI 0.43-0.59) to 0.96 (95% CI 0.95-0.98) and PPV correspondingly, from 0.14 (95% CI: 0.11-0.17) to 0.73 (95% CI 0.69-0.77).CONCLUSIONS: The overall PPV of StatD nursing home register was low and differences between municipalities existed. Even in countries with extensive nation-wide registers, validating studies should be conducted for outcomes based on these registers.

BACKGROUND: Prospective data on health-related quality of life in patients with idiopathic scoliosis treated surgically as adults is needed. We compared preoperative and 1- and 2-year follow-up data in surgically treated adults with idiopathic scoliosis with juvenile or adolescent onset. Results were compared to untreated adults with scoliosis and population normative data. METHODS: A comparison of preoperative and 1- and 2-year follow-up data of 75 adults surgically treated for idiopathic scoliosis at a mean age of 28 years (range 18 to 69) from a prospective national register study, as well as a comparison with age- and sex-matched data from 75 untreated adults with less severe scoliosis and 75 adults without scoliosis, was made. Outcome measures were EuroQol-5 dimensions (EQ-5D) and Scoliosis Research Society (SRS)-22r questionnaire. RESULTS: In the surgically treated, EQ-5D and SRS-22r scores had statistically significant improvements at both 1- and 2-year follow-ups (all p

A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p. V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.

The role of EVs can range from that of passive loads with no difference compared to the traditional ones to active components highly beneficial to the modern power system. An essential part in changing EV storages from passive to active components is the contractual framework. Therefore, we present several different agreements that can be formed between a power supplier and an EV owner. These agreements establish the terms for utilization of storages when an EV is parked and connected to a household charger. We show that these benefits are significant and present a valuable economic opportunity for both EV owners and power suppliers.

To develop reliable and physically based models for the crash behaviour of composite laminates, a thorough understanding of the failure mechanisms is crucial. Compression tests of corrugated Non-Crimp Fabric (NCF) laminates, made of carbon fibre unidirectional (UD) fabric with a [0/90](3S) stacking sequence and epoxy, have been performed to study the energy absorbing damage mechanisms. Samples from the specimens have been studied with optical microscopy and Scanning Electron Microscopy (SEM) to identify the mechanisms involved in the crushing process. The specimens tested fail partly in bending and partly in pure compression with a mode I delamination separating these two regions. In the region failing in pure compression, the main damage mechanisms are kink band formation and matrix cracking of transverse bundles, whereas in the part failing in bending mixed mode delaminations, intralaminar shear fracture of axial bundles and kink band formation through parts of bundles are identified.

This paper proposes a time-efficient method for sub-optimal design of a plug-in hybrid electric vehicle with a parallel powertrain topology. The method finds the optimal design of the vehicle by iteratively using dynamic programming (DP) and convex optimization to minimize sum of operational and component costs over a given driving cycle. In particular, DP is used to optimize energy management, gear shifting and engine on-off for given component sizes, and convex optimization is used to optimize energy management and component sizes using the gear shifting and engine on-off strategies obtained by DP. Next, DP is re-optimized with the component sizes obtained by convex optimization, and the procedure is repeated until the component sizes converge. The result of this iterative method is compared by using DP on a grid of possible component sizes. It is shown that the iterative method gives a result very close to the global optimum in a comparably short time.

Idiopathic scoliosis (IS), the most common spinal deformity, affects otherwise healthy children and adolescents during growth. The aetiology is still unknown, although genetic factors are believed to be important. The present review corroborates the understanding of IS as a complex disease with a polygenic background. Presumably IS can be due to a spectrum of genetic risk variants, ranging from very rare or even private to very common. The most promising candidate genes are highlighted.

This paper introduces a novel method for the simultaneous optimization of energy management and powertrain component sizing of a parallel plug-in hybrid electric vehicle (PHEV). The problem is formulated as a convex optimization problem to minimize an objective function, which is a weighted sum of operational and component costs. The operational cost includes the consumed fossil fuel and electrical energy, whereas the component cost includes the cost of the battery, electric motor (EM), and internal combustion engine (ICE). The powertrain model includes quadratic losses for the powertrain components. Moreover, the combustion engine and the electric motor losses are assumed to linearly scale with respect to the size and the losses of baseline components. The result of the optimization is the variables of the global optimal energy management for every time instant and optimal component sizes. Due to the dependency of the result on the driving cycle, a long real-life cycle with its charging times is chosen to represent a general driving pattern. The method allows the study of the effect of some performance requirements, i.e., acceleration, top speed, and all-electric range, on the component sizes and total cost.

In the past decade, it has been demonstrated that Plug-in Hybrid Electric Vehicles (PHEVs) can significantly reduce petroleum consumptions. However, the extend to which these vehicles can reduce the petroleum consumption highly depends on components size and driving patterns. In other words, PHEVs show the best benefits if the components are dimensioned to match the driver’s driving behavior. In this paper, the effect of different driving patterns on the optimal sizing of three major components of series PHEVs, i.e., battery, electric motor, and engine generator unit is studied. Different driving cycles are generated stochastically from real driving data using Markov chains, to represent life-time driving patterns of different drivers. To find the optimal size of the components, the problem is formulated as a convex optimization problem. The optimization variables (the variables of component size and energy management) are obtained by minimizing a cost function which is the sum of the operational and component costs.

High-throughput sequencing using pooled DNA samples can facilitate genome-wide studies on rare and low-frequency variants in a large population. Some major questions concerning the pooling sequencing strategy are whether rare and low-frequency variants can be detected reliably, and whether estimated minor allele frequencies (MAFs) can represent the actual values obtained from individually genotyped samples. In this study, we evaluated MAF estimates using three variant detection tools with two sets of pooled whole exome sequencing (WES) and one set of pooled whole genome sequencing (WGS) data. Both GATK and Freebayes displayed high sensitivity, specificity and accuracy when detecting rare or low-frequency variants. For the WGS study, 56% of the low-frequency variants in Illumina array have identical MAFs and 26% have one allele difference between sequencing and individual genotyping data. The MAF estimates from WGS correlated well (r = 0.94) with those from Illumina arrays. The MAFs from the pooled WES data also showed high concordance (r = 0.88) with those from the individual genotyping data. In conclusion, the MAFs estimated from pooled DNA sequencing data reflect the MAFs in individually genotyped samples well. The pooling strategy can thus be a rapid and cost-effective approach for the initial screening in large-scale association studies.

Every year approximately 90,500 people die in Sweden, about 19 000 of these die suddenly. A large portion dies in the hospital and many times the death comes unexpected. It is the health professionals task to find and support the relatives. Nurses working with emergency care, almost daily come in contact with relatives who have lost a loved one and they are expected to manage the related parties grief in a professional manner. Some of the people have undergone a preparation time, while others may experience a more unexpected and sudden death of their relatives. The aim of this literature overview was to examine nurses' experiences to meet and take care of the relatives after a sudden death in emergency care. The method has been implemented as a literature review with descriptive design that is to say that the result is based on an already published research, which the author has compiled into an elaborated text in the results section. The literature review is based on fourteen scientific articles. Articles were searched in approved scientific databases and all the articles included was of good quality according to the guidelines from Sophiahemmets quality control and all the included articles were relevant to the literature review purpose. The result is based on three main categories that were developed during the data analysis. The main categories were the nurse's perspective, factors influencing the meeting with the relatives and the effect of care relationship when meeting with the relatives. The nurse's obvious task was to support and see and meet the needs of the related parties. To do so required a good care relationship. The articles gave examples of what the nurses were considered to be part of and the difficulty in the meeting with the relatives who have suddenly lost a loved one. Articles highlights the nurses own feelings and experiences, but also the organization behind the nurses, both the good and bad sides. The nurses also noticed a deficiency in their education and that they lacked the knowledge and guidance of activities in the area. The discussion shows that in situations where relatives lose their loved one suddenly and unexpectedly, often perceived as a difficulty by nurses. In some cases nurses are experiencing emotional difficulties and discomfort that causes that they feel that they are not enough for the family and their needs and expectations. Which means that the nurses are unsure whether they satisfy the related enough in these situations. From previous studies it is seen that nurses' experiences is that the training and knowledge of the subject is, and inadequate grounds. In order to prevent their negative thought patterns and their uncertainty in the care of relatives who unexpectedly lost a loved one, it will need more knowledge and theoretical knowledge given space in practice. Conclusion of the literature is that emergency nurse would strengthen their working profession in the care of relatives who have suddenly lost a loved one through more knowledge and then with both theoretical and practical teaching, better structure and clearer guidelines. Keywords: Sudden death, relatives, emergency care, nurse and experiences. Varje år dör det cirka 90 500 människor i Sverige, cirka 19 000 av dessa dör plötsligt. En stor del avlider på sjukhuset och många gånger mycket oväntat. Det är vårdpersonalens uppgift att finnas och stötta de närstående. Sjuksköterskor som arbetar inom akutsjukvård kommer nästan dagligen i kontakt med närstående som förlorat en anhörig och förväntas kunna hantera de närståendes sorg på ett professionellt sätt. En del närstående har genomgått en förberedelse tid medan andra får uppleva en mer oväntad och plötsligt bortgång av sina anhöriga. Syftet med litteraturöversikten var att belysa sjuksköterskors upplevelser av att möta och ta hand om de närstående efter ett plötsligt dödsfall inom akutsjukvård. Metoden har genomförts som en litteraturöversikt med deskriptiv design det vill säga att resultatet bygger på ett redan publicerat forskningsresultat som författaren har sammanställt till en genomarbetad text i resultatdelen. Litteraturöversikten bygger på 14 vetenskapliga artiklar. Artiklarna söktes i vetenskapliga godkända databaser och alla artiklar som inkluderades höll god kvalitet enligt riktlinjer från Sophiahemmets kvalitetsgranskning och alla inkluderade artiklar var relevanta till litteraturöversiktens syfte. Resultatet grundar sig på tre huvudkategorier som arbetades fram under dataanalysen. Huvudkategorierna var sjuksköterskans perspektiv, faktorer som påverkar möte med närstående och vårdrelationens betydelse i mötet med närstående. Sjuksköterskans tydligaste arbetsuppgift var att stödja och se och tillmötesgå de närståendes behov. För att kunna göra det krävdes en god vårdrelation. Artiklarna gav exempel på vad sjuksköterskorna ansågs vara en del av svårigheten i att möta närstående som förlorat en anhörig plötsligt. Artiklarna lyfter framförallt fram sjuksköterskornas egna känslor och erfarenheter men även verksamheterna och då både bra respektive dåliga orsaker. Sjuksköterskorna upplevde även en bristfällighet i deras grundutbildning och att de saknade kunskap och riktlinjer från verksamheten inom området. Diskussionen visar att i situationer där närstående förlora sin anhörig plötsligt och oväntat många gånger upplevs som en svårighet av sjuksköterskorna. I vissa fall upplever sjuksköterskorna känslomässiga svårigheter och obehag som leder till att de upplever en känsla av att de inte räcker till för de närstående och deras behov och förväntningar. Det leder till att sjuksköterskorna är osäkra på om de tillgodoser de närstående tillräckligt i dessa situationer. Tidigare studier visar att sjuksköterskor upplever att grundutbildningen är bristfällig, utbildningen erbjuder inte tillräckligt med kunskap om vården av närstående. För att förhindra deras negativa tankemönster och osäkerhet vid omvårdnaden av närstående som plötsligt har förlorat en anhörig, behövs mer kunskap och att den teoretiska kunskapen får utrymme i praktiken. Slutsatsen är att akutsjuksköterskan skulle stärka sin yrkesprofession i omhändertagandet av närstående som plötsligt har förlorat en anhörig genom mer kunskap och då med både teoretiskt och praktiskt undervisning, bättre struktur och tydligare riktlinjer ute i verksamheten.

Sedan 1990-talet har uttrycket ”det svenska musikundret” använts för att beskriva Sverige som en stor musikexportör i världen. Detta begrepp är dock mångfacetterat och inte helt oproblematiskt. I denna uppsats har jag genom en kritisk diskursanalys studerat hur det svenska musikundret framställs inom kulturjournalistiken. Mitt syfte har varit att ta reda på vilka diskurser av det svenska musikundret som dominerar i medieframställningen, hur dikotomin kultur och ekonomi synliggörs i framställningen av dessa diskurser samt vilken roll journalisten har i reproducerandet. Uppsatsen har Bourdieus teorier om kapital och fält som grund, vilka är essentiella för förstå de regler som förekommer inom populärmusikens produktionsfält. Vidare har jag utgått från kritisk teori, forskning kring kulturjournalistik samt relationen mellan ekonomi och kultur. I min analys har jag kommit fram till fyra dominerande diskurser – den postmoderna, den marknadsliberala, den kollektivistiska och den anti- nationalistiska diskursen. Utifrån dessa diskurser har jag kommit fram till några olika sätt som dikotomin kultur och ekonomi synliggörs på. Det har skett en de-differentiering och placeringen på produktionsfältet kan idag tillåtas vara närmare den kommersiella polen. Musikundret är en del av ”varumärket Sverige”, där Sverige som musikland lyfts fram, och fungerar som en populärmusikalisk kanon eftersom uttrycket pekar på någon slag enhet. Journalisterna är representanter i ett åsiktsmaskineri som handlar om det svenska musik- undret, vilka till stor del består av vita män. De bidrar till formandet och reproducerandet av synen på det svenska musikundret som baseras på subjektiva åsikter. Synen på populärmusik verkar från journalisthåll ha förändrats mot en större öppenhet även för mer kommersiella akter inom musikundret. Det visar på att journalisternas texter präglas av den samhälleliga kontexten, samtidigt som deras texter är med och formar samhällskontexten.

0 0 1 300 1716 University of Gothenburg 14 4 2012 14.0 Normal 0 false false false SV JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0cm; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-ansi-language:SV;} Mutations leading to Ras gene activation are important contributors to myeloid leukemogenesis. Kras is one of three homologues of the Ras family, and oncogenic Kras is frequently found in monocytic forms of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myeloproliferative diseases (MPD). Earlier studies show that excessive amounts of reactive oxygen species (ROS) are produced in Kras-mutated myeloid malignancies. Myeloid cells, including Kras-mutated leukemic cells, express the ROS-generating enzyme NOX2. Relatively little is known about the impact of ROS formation, in particular NOX2-derived ROS formation, on leukemogenesis. Mice where oncogenic Kras was induced in hematopoietic cells of LSL-KrasG12D and Mx1-Cre double transgenic mice with ensuing myeloproliferation were treated with a histamine H2-receptor selective NOX2 inhibitor, Nα -methyl histamine (NMH) to assess whether NOX2 is a feasible therapeutic target in Kras-driven leukemia. Spleens of diseased Kras mice were infiltrated with mature CD11b+Gr1+ myeloid cells that expressed NOX2 and produced ROS. The NOX2-dependent formation of ROS in CD11b+Gr1+ cells was inhibited by NMH. In vivo administration of NMH delayed the development of myeloproliferative disease and significantly prolonged survival of Kras mice (p=0.003). In contrast, treatment with NMH did not alter the survival of mice when Kras expression was induced in hematopoietic cells of NOX2-deficient mice that did not produce ROS (Nox2-/-, LSL-KrasG12D and Mx1-Cre triple transgenic mice). In Kras-mutated Nox+/+ mice, but not in Kras-mutated Nox-/- mice, the in vivo administration of NMH entailed diminished ROS levels and reduced oxidative stress as reflected by reduced DCFDA and anti-8 Hydroxyguanosine staining. We propose that NOX2-derived ROS in Kras-mutated hematopoetic cells mediate genomic instability that may contribute to the progression of leukemia. Strategies to target NOX2 should be further evaluated in Ras-mutated hematopoietic cancer. Citation Format: Ebru Aydin, Alexander Hallner, Hanna Grauers Wiktorin, Anna Staffas, Kristoffer Hellstrand, Anna Martner. NOX2 inhibition reduces oxidative stress and prolongs survival of mice with Kras induced myeloproliferative disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 441.

The NOX2 enzyme is highly expressed in normal myeloid cells, as well as in subpopulations of malignant myeloid cells, where it contributes to the generation of reactive oxygen species (ROS). We have utilized mice and leukemic cells genetically depleted of NOX2 and the NOX2-specific inhibitor histamine dihydrochloride (HDC) to further elucidate the role of NOX2-derived ROS in hematopoietic cancer. HDC was found to promote the maturation of human DCs from monocytes and to enhance T cell priming. In addition, treatment of mice with HDC reduced the growth of murine EL-4 lymphomas in parallel with an increment of tumor-infiltrating DCs in NOX2-sufficient mice but not in Nox2-/- mice. HDC was also found to facilitated the maturation and inhibit the proliferation of NOX2-expressing human acute myeloid leukemia (AML) cells. These effects were absent in NOX2-/- AML cells. In microarray analysis, HDC was found to regulate the expression of genes involved in cell differentiation and cell cycle progression in NOX2+ but not in NOX2-/- AML cells. In a xenograft mouse model, systemic treatment with HDC reduced the expansion of engrafted monocytic AML cells in bone marrow but did not exert anti-leukemic activity against engrafted NOX2-/- AML cells.

Background: Knowledge about prevalent and deadly combinations of multimorbidity is needed. Objective: To determine the nationwide prevalence of multimorbidity and estimate mortality for the most prevalent combinations of one to five diagnosis groups. Furthermore, to assess the excess mortality of the combination of two groups compared to the product of mortality associated with the single groups. Design: A prospective cohort study using Danish registries and including 3.986.209 people aged ≥18 years on 1 January, 2000. Multimorbidity was defined as having diagnoses from at least 2 of 10 diagnosis groups: lung, musculoskeletal, endocrine, mental, cancer, neurological, gastrointestinal, cardiovascular, kidney, and sensory organs. Logistic regression (odds ratios, ORs) and ratio of ORs (ROR) were used to study mortality and excess mortality. Results: Prevalence of multimorbidity was 7.1% in the Danish population. The most prevalent combination was the musculoskeletal–cardiovascular (0.4%), which had double the mortality (OR, 2.03) compared to persons not belonging to any of the diagnosis groups but showed no excess mortality (ROR, 0.97). The neurological–cancer combination had the highest mortality (OR, 6.35), was less prevalent (0.07%), and had no excess mortality (ROR, 0.94). Cardiovascular–lung was moderately prevalent (0.2%), had high mortality (OR, 5.75), and had excess mortality (ROR, 1.18). Endocrine–kidney had high excess mortality (ROR, 1.81) and cancer–mental had low excess mortality (ROR, 0.66). Mortality increased with the number of groups. Conclusions: All combinations had increased mortality risk with some of them having up to a six-fold increased risk. Mortality increased with the number of diagnosis groups. Most combinations did not increase mortality above that expected, that is, were additive rather than synergistic.