Showing papers by "Karolinska Institutet published in 2008"
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TL;DR: An in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments yielding a digital inventory of gene and mRNA isoform expression suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.
Abstract: Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.
4,711 citations
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Federal University of Bahia1, McMaster University2, University of Amsterdam3, National Institutes of Health4, Charité5, Catholic University of Cordoba6, University of Genoa7, Radboud University Nijmegen8, Transilvania University of Brașov9, Ghent University10, University of Tennessee Health Science Center11, University of Naples Federico II12, Laval University13, Universidade Federal de Minas Gerais14, University of Oslo15, University of Manchester16, Aarhus University17, Imperial College London18, Erasmus University Rotterdam19, George Washington University20, Seoul National University21, Medical University of Łódź22, Hai phong University Of Medicine and Pharmacy23, Université de Montréal24, Guangzhou Medical University25, University of South Florida26, University of California, San Diego27, University of California28, University of Chicago29, Monash University30, Teikyo University31, National and Kapodistrian University of Athens32, Nippon Medical School33, Sofia Medical University34, Leiden University35, Leiden University Medical Center36, University College London37, University of Manitoba38, University of Helsinki39, Finnish Institute of Occupational Health40, National University of Singapore41, Karolinska Institutet42, University of Minnesota43, Celal Bayar University44, University of Cape Town45, Pierre-and-Marie-Curie University46, Tunis University47, University of Ghana48, University of Wisconsin-Madison49, University of British Columbia50, Georgia Regents University51, Vilnius University52, University of Washington53, University of Dundee54, University of Poitiers55, University of Mississippi56, Federal University of São Paulo57, German Red Cross58, Jagiellonian University Medical College59, Chiba University60, American Pharmacists Association61, University of Aberdeen62, University of Nevada, Reno63, University of North Carolina at Chapel Hill64
TL;DR: The ARIA guidelines for the management of allergic rhinitis and asthma are similar in both the 1999 ARIA workshop report and the 2008 Update as discussed by the authors, but the GRADE approach is not yet available.
Abstract: Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations.
In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease.
This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work.
The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available.
Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed.
The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.
3,769 citations
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TL;DR: A grading system of definite, probable, and possible neuropathic pain is proposed, which includes the grade possible, which can only be regarded as a working hypothesis, and the grades probable and definite, which require confirmatory evidence from a neurologic examination.
Abstract: Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes.
2,342 citations
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TL;DR: This Review discusses the emerging important biological functions of the nitrate–nitrite–NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration.
Abstract: The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration
2,228 citations
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TL;DR: It is shown that adipocyte number is a major determinant for the fat mass in adults, however, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that thenumber of adipocytes is set during childhood and adolescence.
Abstract: Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.
2,098 citations
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TL;DR: Basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts are reviewed.
Abstract: Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-alpha signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-beta signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.
2,074 citations
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TL;DR: In this paper, a review of the latest developments with regard to physical fitness and several health outcomes in young people is presented, and the authors suggest that health promotion policies and physical activity programs should be designed to improve cardiorespiratory fitness, but also two other physical fitness components such us muscular fitness and speed/agility.
Abstract: This review aims to summarize the latest developments with regard to physical fitness and several health outcomes in young people. The literature reviewed suggests that (1) cardiorespiratory fitness levels are associated with total and abdominal adiposity; (2) both cardiorespiratory and muscular fitness are shown to be associated with established and emerging cardiovascular disease risk factors; (3) improvements in muscular fitness and speed/agility, rather than cardiorespiratory fitness, seem to have a positive effect on skeletal health; (4) both cardiorespiratory and muscular fitness enhancements are recommended in pediatric cancer patients/survivors in order to attenuate fatigue and improve their quality of life; and (5) improvements in cardiorespiratory fitness have positive effects on depression, anxiety, mood status and self-esteem, and seem also to be associated with a higher academic performance. In conclusion, health promotion policies and physical activity programs should be designed to improve cardiorespiratory fitness, but also two other physical fitness components such us muscular fitness and speed/agility. Schools may play an important role by identifying children with low physical fitness and by promoting positive health behaviors such as encouraging children to be active, with special emphasis on the intensity of the activity.
2,048 citations
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Haukeland University Hospital1, Uppsala University2, Karolinska Institutet3, University of Liverpool4, Humboldt University of Berlin5, Goethe University Frankfurt6, Southampton General Hospital7, Princess Alexandra Hospital8, Bristol Royal Infirmary9, University of Birmingham10, European Organisation for Research and Treatment of Cancer11, Katholieke Universiteit Leuven12
TL;DR: In this article, the authors compared the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer.
1,741 citations
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University of Lyon1, Los Angeles Biomedical Research Institute2, Federal University of São Paulo3, Emory University4, University of Trieste5, Vanderbilt University Medical Center6, University of California, Davis7, Karolinska Institutet8, French Institute of Health and Medical Research9, Baylor College of Medicine10, National Autonomous University of Mexico11, University of Würzburg12
TL;DR: An expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI recommends the term 'protein-energy wasting' for loss of body protein mass and fuel reserves.
1,584 citations
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Broad Institute1, Harvard University2, Massachusetts Institute of Technology3, Cardiff University4, University College London5, University of Edinburgh6, Trinity College, Dublin7, Karolinska Institutet8, Uppsala University9, University of Southern California10, University of Aberdeen11, University of North Carolina at Chapel Hill12, QIMR Berghofer Medical Research Institute13, Royal College of Surgeons in Ireland14, National Health Service15, University of Oxford16, Queen Mary University of London17, State University of New York System18, University of Coimbra19
TL;DR: A genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls provides strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.
Abstract: Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.
1,465 citations
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TL;DR: CuO nanoparticles were most potent regarding cytotoxicity and DNA damage, and carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested.
Abstract: Since the manufacture and use of nanoparticles are increasing, humans are more likely to be exposed occupationally or via consumer products and the environment. However, so far toxicity data for most manufactured nanoparticles are limited. The aim of this study was to investigate and compare different nanoparticles and nanotubes regarding cytotoxicity and ability to cause DNA damage and oxidative stress. The study was focused on different metal oxide particles (CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, Fe2O3), and the toxicity was compared to that of carbon nanoparticles and multiwalled carbon nanotubes (MWCNT). The human lung epithelial cell line A549 was exposed to the particles, and cytotoxicity was analyzed using trypan blue staining. DNA damage and oxidative lesions were determined using the comet assay, and intracellular production of reactive oxygen species (ROS) was measured using the oxidation-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate (DCFH-DA). The results showed that there was a high variation among different nanoparticles concerning their ability to cause toxic effects. CuO nanoparticles were most potent regarding cytotoxicity and DNA damage. The toxicity was likely not explained by Cu ions released to the cell medium. These particles also caused oxidative lesions and were the only particles that induced an almost significant increase (p = 0.058) in intracellular ROS. ZnO showed effects on cell viability as well as DNA damage, whereas the TiO2 particles (a mix of rutile and anatase) only caused DNA damage. For iron oxide particles (Fe3O4, Fe2O3), no or low toxicity was observed, but CuZnFe2O4 particles were rather potent in inducing DNA lesions. Finally, the carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested. The effects were not explained by soluble metal impurities. In conclusion, this study highlights the in vitro toxicity of CuO nanoparticles.
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TL;DR: It is reported that a long noncoding RNA is directly implicated in the increased abundance of Aβ 1–42 in Alzheimer's disease.
Abstract: BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amyloid-β generation and possibly disease progression.
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Austrian Academy of Sciences1, Tokyo Medical and Dental University2, Medical University of Vienna3, European Bioinformatics Institute4, University of Cologne5, University of Western Ontario6, University of Hong Kong7, Peking Union Medical College8, École Polytechnique Fédérale de Lausanne9, United States Department of the Army10, University of Toronto11, Osaka University12, Karolinska Institutet13
TL;DR: It is reported that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI), and it is shown that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI.
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TL;DR: The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly.
Abstract: Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown. A cross-sectional design of 13 601 subjects (age 20–79.9 years; 49% men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25% in men and>35% in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race. BMI-defined obesity (⩾30 kg m−2) was present in 19.1% of men and 24.7% of women, while BF%-defined obesity was present in 43.9% of men and 52.3% of women. A BMI⩾30 had a high specificity (men=95%, 95% confidence interval (CI), 94–96 and women=99%, 95% CI, 98–100), but a poor sensitivity (men=36%, 95% CI, 35–37 and women=49%, 95% CI, 48–50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25–29.9 kg m−2), BMI failed to discriminate between BF% and lean mass in both sexes. The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of⩾30 kg m−2 has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.
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TL;DR: This study assessed functional connectivity within the default mode network during both rest and a continuous working memory task on a region-by-region basis using partial correlation analysis, a data-driven method that provides insight into effective connectivity within neuronal networks.
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TL;DR: This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year, but it cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.
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Columbia University1, University of Zulia2, University of Buenos Aires3, Case Western Reserve University4, University of California, San Diego5, Indiana University6, University College Hospital, Ibadan7, Stellenbosch University8, King's College London9, Karolinska Institutet10, Peking Union Medical College Hospital11, Medical College of Wisconsin12
TL;DR: Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions, and use of traditional diets and medicinal plant extracts might aid prevention and treatment.
Abstract: Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa Illiteracy remains a risk factor for dementia The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia Use of traditional diets and medicinal plant extracts might aid prevention and treatment Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions
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TL;DR: This work has employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing, and demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level.
Abstract: Humans host complex microbial communities believed to contribute to health maintenance and, when in imbalance, to the development of diseases. Determining the microbial composition in patients and healthy controls may thus provide novel therapeutic targets. For this purpose, high-throughput, cost-effective methods for microbiota characterization are needed. We have employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing. In silico modeling demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level. Here we applied the technique to analyze microbial communities in throat, stomach and fecal samples. Our results demonstrate the applicability of barcoded pyrosequencing as a high-throughput method for comparative microbial ecology.
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TL;DR: Findings reveal a mechanism by which frontal and basal ganglia activity exerts attentional control over access to working memory storage in the parietal cortex in humans, and makes an important contribution to inter-individual differences in working memory capacity.
Abstract: Our capacity to store information in working memory might be determined by the degree to which only relevant information is remembered. The question remains as to how this selection of relevant items to be remembered is accomplished. Here we show that activity in the prefrontal cortex and basal ganglia preceded the filtering of irrelevant information and that activity, particularly in the globus pallidus, predicted the extent to which only relevant information is stored. The preceding frontal and basal ganglia activity were also associated with inter-individual differences in working memory capacity. These findings reveal a mechanism by which frontal and basal ganglia activity exerts attentional control over access to working memory storage in the parietal cortex in humans, and makes an important contribution to inter-individual differences in working memory capacity.
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TL;DR: It is demonstrated that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway, and the identified pathway reveals promising targets for future therapies.
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St George's, University of London1, University of Sydney2, University of California, San Diego3, University of Iceland4, Karolinska Institutet5, University of Amsterdam6, University of Saskatchewan7, National Institute for Health and Welfare8, University of Helsinki9, Thomas Jefferson University10, University of Southampton11, Norwegian University of Science and Technology12, Crozer-Keystone Health System13, University College London14, University of Bristol15, University of London16, Dokkyo Medical University17, Harvard University18, University of Eastern Finland19, Providence Sacred Heart Medical Center and Children's Hospital20
TL;DR: In most populations studied, birth weight was inversely related to type 2 diabetes risk, and the shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less.
Abstract: Context Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. Objective To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. Data Sources and Study Selection Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. Data Extraction Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. Data Synthesis Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight–type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I 2 = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight–type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. Conclusion In most populations studied, birth weight was inversely related to type 2 diabetes risk.
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TL;DR: It is shown that Lgr5+ cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time.
Abstract: In mouse hair follicles, a group of quiescent cells in the bulge is believed to have stem cell activity. Lgr5, a marker of intestinal stem cells, is expressed in actively cycling cells in the bulge and secondary germ of telogen hair follicles and in the lower outer root sheath of anagen hair follicles. Here we show that Lgr5(+) cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time. Lgr5(+) progeny repopulate other stem cell compartments in the hair follicle, supporting the existence of a stem or progenitor cell hierarchy. By marking Lgr5(+) cells during trafficking through the lower outer root sheath, we show that these cells retain stem cell properties and contribute to hair follicle growth during the next anagen. Expression analysis suggests involvement of autocrine Hedgehog signaling in maintaining the Lgr5(+) stem cell population.
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TL;DR: The authors identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.
Abstract: Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci Methods We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent Genotypes from 1557 additional control subjects were obtained from public data repositories We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden Results Genetic variation in the region upstream from the transcription initiation site of the gene encod
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TL;DR: The potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population is emphasized and the need for more studies in this area is emphasized.
Abstract: End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.
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TL;DR: Findings confirm the link between maternal glucose and neonatal adiposity and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biological relationship influencing fetal growth.
Abstract: Objective: To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity.
Research Design and Methods: Eligible pregnant women underwent a standard 75 gm OGTT between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skinfolds > 90th percentile or percent body fat > 90th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the baby's gender.
Results: Among 23,316 HAPO study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-hour, and 2-hour plasma glucose higher by one standard deviation.
Conclusions: These findings confirm the link between maternal glucose and neonatal adiposity, and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biologic relationship influencing fetal growth.
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TL;DR: The use of sporting gear to prevent other types of injury was not associated with increased neck injuries in bicycling, hockey, or skiing, and future research should concentrate on longitudinal designs exploring preventive strategies and modifiable risk factors for neck pain.
Abstract: STUDY DESIGN: Best evidence synthesis. OBJECTIVE: To undertake a best evidence synthesis of the published evidence on the burden and determinants of neck pain and its associated disorders in the general population. SUMMARY OF BACKGROUND DATA: The evidence on burden and determinants of neck has not previously been summarized. METHODS: The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders performed a systematic search and critical review of literature published between 1980 and 2006 to assemble the best evidence on neck pain. Studies meeting criteria for scientific validity were included in a best evidence synthesis. RESULTS: We identified 469 studies on burden and determinants of neck pain, and judged 249 to be scientifically admissible; 101 articles related to the burden and determinants of neck pain in the general population. Incidence ranged from 0.055 per 1000 person years (disc herniation with radiculopathy) to 213 per 1000 persons (self-reported neck pain). Incidence of neck injuries during competitive sports ranged from 0.02 to 21 per 1000 exposures. The 12-month prevalence of pain typically ranged between 30% and 50%; the 12-month prevalence of activity-limiting pain was 1.7% to 11.5%. Neck pain was more prevalent among women and prevalence peaked in middle age. Risk factors for neck pain included genetics, poor psychological health, and exposure to tobacco. Disc degeneration was not identified as a risk factor. The use of sporting gear (helmets, face shields) to prevent other types of injury was not associated with increased neck injuries in bicycling, hockey, or skiing. CONCLUSION: Neck pain is common. Nonmodifiable risk factors for neck pain included age, gender, and genetics. Modifiable factors included smoking, exposure to tobacco, and psychological health. Disc degeneration was not identified as a risk factor. Future research should concentrate on longitudinal designs exploring preventive strategies and modifiable risk factors for neck pain. Language: en
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TL;DR: It is demonstrated that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting or blocking of VEG FR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models, implicate VEGfr-3 as a regulator of vascular network formation.
Abstract: Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.
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Karolinska Institutet1, University of Oxford2, University of Toronto3, Centre national de la recherche scientifique4, University of California, Berkeley5, Los Alamos National Laboratory6, Tsinghua University7, University of Science and Technology of China8, Weizmann Institute of Science9, Scripps Research Institute10, Novartis11, Argonne National Laboratory12, Yeshiva University13, Brookhaven National Laboratory14, Rutgers University15, Case Western Reserve University16, University of California, San Francisco17, Columbia University18, Max Delbrück Center for Molecular Medicine19, New York University20
TL;DR: This review presents methods that could be applied at the outset of any project, a prioritized list of alternate strategies and a list of pitfalls that trip many new investigators.
Abstract: In selecting a method to produce a recombinant protein, a researcher is faced with a bewildering array of choices as to where to start. To facilitate decision-making, we describe a consensus 'what to try first' strategy based on our collective analysis of the expression and purification of over 10,000 different proteins. This review presents methods that could be applied at the outset of any project, a prioritized list of alternate strategies and a list of pitfalls that trip many new investigators.
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TL;DR: A complex integration of the hypoxia and Notch signaling pathways in regulation of EMT is demonstrated and perspectives for pharmacological intervention with hypoxiainduced EMT and cell invasiveness in tumors are opened up.
Abstract: Tumor hypoxia is linked to increased metastatic potential, but the molecular mechanisms coupling hypoxia to metastasis are poorly understood Here, we show that Notch signaling is required to convert the hypoxic stimulus into epithelial–mesenchymal transition (EMT), increased motility, and invasiveness Inhibition of Notch signaling abrogated hypoxia-induced EMT and invasion, and, conversely, an activated form of Notch could substitute for hypoxia to induce these processes Notch signaling deploys two distinct mechanisms that act in synergy to control the expression of Snail-1, a critical regulator of EMT First, Notch directly up-regulated Snail-1 expression by recruitment of the Notch intracellular domain to the Snail-1 promoter, and second, Notch potentiated hypoxia-inducible factor 1α (HIF-1α) recruitment to the lysyl oxidase (LOX) promoter and elevated the hypoxia-induced up-regulation of LOX, which stabilizes the Snail-1 protein In sum, these data demonstrate a complex integration of the hypoxia and Notch signaling pathways in regulation of EMT and open up perspectives for pharmacological intervention with hypoxiainduced EMT and cell invasiveness in tumors
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TL;DR: Manipulation of the visual perspective, in combination with the receipt of correlated multisensory information from the body was sufficient to trigger the illusion that another person's body or an artificial body was one's own.
Abstract: The concept of an individual swapping his or her body with that of another person has captured the imagination of writers and artists for decades. Although this topic has not been the subject of investigation in science, it exemplifies the fundamental question of why we have an ongoing experience of being located inside our bodies. Here we report a perceptual illusion of body-swapping that addresses directly this issue. Manipulation of the visual perspective, in combination with the receipt of correlated multisensory information from the body was sufficient to trigger the illusion that another person’s body or an artificial body was one’s own. This effect was so strong that people could experience being in another person’s body when facing their own body and shaking hands with it. Our results are of fundamental importance because they identify the perceptual processes that produce the feeling of ownership of one’s body.