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Showing papers by "Karolinska Institutet published in 2003"


Journal ArticleDOI
TL;DR: Considering the diverse samples in this study, IPAQ has reasonable measurement properties for monitoring population levels of physical activity among 18- to 65-yr-old adults in diverse settings.
Abstract: CRAIG, C. L., A. L. MARSHALL, M. SJOSTROM, A. E. BAUMAN, M. L. BOOTH, B. E. AINSWORTH, M. PRATT, U. EKELUND, A. YNGVE, J. F. SALLIS, and P. OJA. International Physical Activity Questionnaire: 12-Country Reliability and Validity. Med. Sci. Sports Exerc., Vol. 35, No. 8, pp. 1381-1395, 2003. Background: Physical inactivity is a global concern, but diverse physical activity measures in use prevent international comparisons. The International Physical Activity Questionnaire (IPAQ) was developed as an instrument for cross-national monitoring of physical activity and inactivity. Methods: Between 1997 and 1998, an International Consensus Group developed four long and four short forms of the IPAQ instruments (administered by telephone interview or self-administration, with two alternate reference periods, either the "last 7 d" or a "usual week" of recalled physical activity). During 2000, 14 centers from 12 countries collected reliability and/or validity data on at least two of the eight IPAQ instruments. Test-retest repeatability was assessed within the same week. Concurrent (inter-method) validity was assessed at the same administration, and criterion IPAQ validity was assessed against the CSA (now MTI) accelerometer. Spearman's correlation coefficients are reported, based on the total reported physical activity. Results: Overall, the IPAQ questionnaires produced repeatable data (Spearman's clustered around 0.8), with comparable data from short and long forms. Criterion validity had a median of about 0.30, which was comparable to most other self-report validation studies. The "usual week" and "last 7 d" reference periods performed similarly, and the reliability of telephone administration was similar to the self-administered mode. Conclusions: The IPAQ instruments have acceptable measurement properties, at least as good as other established self-reports. Considering the diverse samples in this study, IPAQ has reasonable measurement properties for monitoring population levels of physical activity among 18- to 65-yr-old adults in diverse settings. The short IPAQ form "last 7 d recall" is recommended for national monitoring and the long form for research requiring more detailed assessment. Key Words: MEASUREMENT, SURVEILLANCE, EPIDEMIOLOGY

15,345 citations


Journal ArticleDOI
25 Sep 2003-Nature
TL;DR: The two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.
Abstract: Hundreds of small RNAs of approximately 22 nucleotides, collectively named microRNAs (miRNAs), have been discovered recently in animals and plants. Although their functions are being unravelled, their mechanism of biogenesis remains poorly understood. miRNAs are transcribed as long primary transcripts (pri-miRNAs) whose maturation occurs through sequential processing events: the nuclear processing of the pri-miRNAs into stem-loop precursors of approximately 70 nucleotides (pre-miRNAs), and the cytoplasmic processing of pre-miRNAs into mature miRNAs. Dicer, a member of the RNase III superfamily of bidentate nucleases, mediates the latter step, whereas the processing enzyme for the former step is unknown. Here we identify another RNase III, human Drosha, as the core nuclease that executes the initiation step of miRNA processing in the nucleus. Immunopurified Drosha cleaved pri-miRNA to release pre-miRNA in vitro. Furthermore, RNA interference of Drosha resulted in the strong accumulation of pri-miRNA and the reduction of pre-miRNA and mature miRNA in vivo. Thus, the two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.

5,191 citations


Journal ArticleDOI
01 Jan 2003-Diabetes
TL;DR: Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation andβ-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 Diabetes.
Abstract: Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.

3,710 citations


Journal ArticleDOI
TL;DR: The term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future and a quantitative method for cumulative risk assessment of vulnerable patients needs to be developed.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

2,719 citations


Journal ArticleDOI
TL;DR: The dual role of Ca2+ in living organisms is discussed in this paper, where it has been shown that cellular Ca 2+ overload, or perturbation of intracellular Ca2 + compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.
Abstract: To live or to die? This crucial question eloquently reflects the dual role of Ca2+ in living organisms--survival factor or ruthless killer. It has long been known that Ca2+ signals govern a host of vital cell functions and so are necessary for cell survival. However, more recently it has become clear that cellular Ca2+ overload, or perturbation of intracellular Ca2+ compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.

2,685 citations


Journal ArticleDOI
29 May 2003-Nature
TL;DR: In this article, the authors identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4) as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes.
Abstract: Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1?kb 3′ region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

2,173 citations


Journal ArticleDOI
TL;DR: Undifferentiated and differentiated MSC do not elicit alloreactive lymphocyte proliferative responses and modulate immune responses, and the findings support that MSC can be transplantable between HLA-incompatible individuals.

1,650 citations


Journal ArticleDOI
TL;DR: MSC added to PBL cultures had various effects, ranging from slight inhibition to stimulation of DNA synthesis, which was not affected by the MSC dose or by the addition of allogeneic or autologous MSCs to the lymphocytes.
Abstract: We aimed to study the effects of mesenchymal stem cells (MSCs) on alloreactivity and effects of T-cell activation on human peripheral blood lymphocytes (PBLs) in vitro. MSCs were expanded from the bone marrow of healthy subjects. MSCs isolated from second to third passage were positive for CD166, CD105, CD44, CD29, SH-3 and SH-4, but negative for CD34 and CD45. MSCs cultured in osteogenic, adipogenic or chondrogenic media differentiated, respectively, into osteocytes, adipocytes or chondrocytes. MSC added to PBL cultures had various effects, ranging from slight inhibition to stimulation of DNA synthesis. The stimulation index (SI = (PBL + MSC)/PBL) varied between 0.2 and 7.3. The SI was not affected by the MSC dose or by the addition of allogeneic or autologous MSCs to the lymphocytes. Suppression of proliferative activity was observed in all experiments after the addition of 10,000-40,000 MSCs to mixed lymphocyte cultures (MLCs). Lymphocyte proliferation was 10-90%, compared with a control MLC run in parallel without MSCs. In contrast, the addition of fewer MSCs (10-1000 cells) led to a less consistent suppression or a marked lymphocyte proliferation in several experiments, ranging from 40 to 190% of the maximal lymphocyte proliferation in control MLCs. The ability to inhibit or stimulate T-cell alloresponses appeared to be independent of the major histocompatibility complex, as results were similar using 'third party' MSCs or MSCs that were autologous to the responder or stimulating PBLs. The strongest inhibitory effect was seen if MSCs were added at the beginning of the 6 day culture, and the effect declined if MSCs were added on day 3 or 5. Marked inhibitory effects of allogeneic and autologous MSCs (15,000) were also noted after mitogenic lymphocyte stimulation by phytohaemagglutinin (median lymphocyte proliferation of 30% of controls), Concanavalin A (56%) and protein A (65%). Little, if any, inhibition occurred after stimulation with pokeweed mitogen. Low numbers of MSCs (150 cells) were unable to inhibit mitogen-induced T-cell responses. MSCs have significant immune modulatory effects on MLCs and after mitogenic stimulation of PBL. High numbers of MSCs suppress alloreactive T cells, whereas very low numbers clearly stimulated lymphocyte proliferation in some experiments. The effect of a larger number of MSCs on MLCs seems more dependent on cell dose than histocompatibility and could result from an 'overload' of a stimulatory mechanism.

1,379 citations


Journal ArticleDOI
TL;DR: Antibacterial peptides: basic facts and emerging concepts (Review).
Abstract: Antibacterial peptides are the effector molecules of innate immunity. Generally they contain 15-45 amino acid residues and the net charge is positive. The cecropin type of linear peptides without cysteine were found first in insects, whilst the defensin type with three disulphide bridges were found in rabbit granulocytes. Now a database stores more than 800 sequences of antibacterial peptides and proteins from the animal and plant kingdoms. Generally, each species has 15-40 peptides made from genes, which code for only one precursor. The dominating targets are bacterial membranes and the killing reaction must be faster than the growth rate of the bacteria. Some antibacterial peptides are clearly multifunctional and an attempt to predict this property from the hydrophobicity of all amino acid side chains are given. Gene structures and biosynthesis are known both in the fruit fly Drosophila and several mammals. Humans need two classes of defensins and the cathelicidin-derived linear peptide LL-37. Clinical cases show that deficiencies in these peptides give severe symptoms. Examples given are morbus Kostmann and atopic allergy. Several antibacterial peptides are being developed as drugs.

1,041 citations


Journal ArticleDOI
TL;DR: The effects of shift work is reviewed and finds strong, acute effects on sleep and alertness in relation to night and morning work, similar to that seen in clinical insomnia.
Abstract: Of the many health-related effects of shift work, disturbed sleep is the most common. This review describes the main observed effects of the three principal shifts (night, morning and afternoon) on patterns of sleep and wakefulness. The mechanism of sleep disruption in relation to circadian rhythms and the specific impact of aspects of shift organization (speed and direction of rotation) are discussed. The most troublesome acute symptoms are difficulty getting to sleep, shortened sleep and somnolence during working hours that continues into successive days off. These are only partially amenable to amelioration by manipulating shift patterns. However, there is no clear indication that chronic sleep problems result from long-term shift work.

1,000 citations


Journal ArticleDOI
TL;DR: In this article, the authors have shown that mutations in genes corresponding to the building blocks of type IV collagen cause Alport's syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture's syndrome.
Abstract: Defects in type IV collagen, a collagenous protein involved in the formation of basement membranes, have been implicated in hereditary Alport's syndrome and acquired Goodpasture's syndrome. Mutations in genes corresponding to the building blocks of type IV collagen cause Alport's syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture's syndrome.

Journal ArticleDOI
TL;DR: The expression profile identified alterations in numerous virulence and SOS response genes and revealed unexpected findings concerning the biology of the Salmonella–macrophage interaction, suggesting that intracellular growth involves novel macrophage‐associated functions.
Abstract: For intracellular pathogens such as Salmonellae, Mycobacteriae and Brucellae, infection requires adaptation to the intracellular environment of the phagocytic cell. The transition from extracellular to intravacuolar environment has been expected to involve a global modulation of bacterial gene expression, but the precise events have been difficult to determine. We now report the complete transcriptional profile of intracellular Salmonella enterica sv. Typhimurium following macrophage infection. During replication in murine macrophage-like J774-A.1 cells, 919 of 4451 S. Typhimurium genes showed significant changes in transcription. The expression profile identified alterations in numerous virulence and SOS response genes and revealed unexpected findings concerning the biology of the Salmonella-macrophage interaction. We observed that intracellular Salmonella are not starved for amino acids or iron (Fe2+), and that the intravacuolar environment is low in phosphate and magnesium but high in potassium. S. Typhimurium appears to be using the Entner-Douderoff pathway to use gluconate and related sugars as a carbon source within macrophages. Almost half the in vivo-regulated genes were of unknown function, suggesting that intracellular growth involves novel macrophage-associated functions. This is the first report that identifies the whole set of in vivo-regulated genes for any bacterial pathogen during infection of mammalian cells.

Journal ArticleDOI
TL;DR: This work has shown that in one vertebrate model system, the lamprey, it has been possible to make the connection between different subtypes of ion channels and transmitters and their roles at the cellular and network levels, and it is therefore possible to link the role of certain genes or molecules to motor behaviour in this system.
Abstract: The vertebrate motor system is equipped with a number of neuronal networks that underlie different patterns of behaviour, from simple protective reflexes to complex movements. The current challenge is to understand the intrinsic function of these networks: that is, the cellular basis of motor behaviour. In one vertebrate model system, the lamprey, it has been possible to make the connection between different subtypes of ion channels and transmitters and their roles at the cellular and network levels. It is therefore possible to link the role of certain genes or molecules to motor behaviour in this system.

Journal ArticleDOI
TL;DR: The HOOS 2.0 appears to be useful for the evaluation of patient-relevant outcome after THR and is more responsive than the WOMAC LK 3.0.
Abstract: Background: The aim of the study was to evaluate if physical functions usually associated with a younger population were of importance for an older population, and to construct an outcome measure for hip osteoarthritis with improved responsiveness compared to the Western Ontario McMaster osteoarthritis score (WOMAC LK 3.0). Methods: A 40 item questionnaire (hip disability and osteoarthritis outcome score, HOOS) was constructed to assess patient-relevant outcomes in five separate subscales (pain, symptoms, activity of daily living, sport and recreation function and hip related quality of life). The HOOS contains all WOMAC LK 3.0 questions in unchanged form. The HOOS was distributed to 90 patients with primary hip osteoarthritis (mean age 71.5, range 49–85, 41 females) assigned for total hip replacement for osteoarthritis preoperatively and at six months follow-up. Results: The HOOS met set criteria of validity and responsiveness. It was more responsive than WOMAC regarding the subscales pain (SRM 2.11 vs. 1.83) and other symptoms (SRM 1.83 vs. 1.28). The responsiveness (SRM) for the two added subscales sport and recreation and quality of life were 1.29 and 1.65, respectively. Patients ≤ 66 years of age (range 49–66) reported higher responsiveness in all five subscales than patients >66 years of age (range 67–85) (Pain SRM 2.60 vs. 1.97, other symptoms SRM 3.0 vs. 1.60, activity of daily living SRM 2.51 vs. 1.52, sport and recreation function SRM 1.53 vs. 1.21 and hip related quality of life SRM 1.95 vs. 1.57). Conclusion: The HOOS 2.0 appears to be useful for the evaluation of patient-relevant outcome after THR and is more responsive than the WOMAC LK 3.0. The added subscales sport and recreation function and hip related quality of life were highly responsive for this group of patients, with the responsiveness being highest for those younger than 66.

Journal ArticleDOI
TL;DR: The characterization of mice lacking ERalpha, or ERbeta, or both has revealed that both receptor subtypes have overlapping but also unique roles in estrogen-dependent action in vivo, and how ERalpha and ERbeta directly or indirectly affect each other's function are paramount to understanding the cellular and biological events of estrogen-mediated gene regulation in normal and diseased tissues.
Abstract: The biological actions of estrogens are mediated by estrogen binding to one of two specific estrogen receptors (ERs) ERalpha and ERbeta, which belong to the nuclear receptor superfamily, a family of ligand-regulated transcription factors. ERalpha and ERbeta are products of different genes and exhibit tissue- and cell-type specific expression. The characterization of mice lacking ERalpha, or ERbeta, or both has revealed that both receptor subtypes have overlapping but also unique roles in estrogen-dependent action in vivo. Additionally, ERalpha and ERbeta have different transcriptional activities in certain ligand, cell-type, and promoter contexts. Both receptors, however, are coexpressed in a number of tissues and form functional heterodimers. The biological roles of ERalpha /beta heterodimers in the presence of each respective homodimer are unknown. When coexpressed, ERbeta exhibits an inhibitory action on ERalpha -mediated gene expression and in many instances opposes the actions of ERalpha. A number of ERalpha and ERbeta isoforms have also been described, many of which alter estrogen-mediated gene expression. Uncovering the molecular mechanisms regulating the expression of both ERs, and how ERalpha and ERbeta directly or indirectly affect each other's function are paramount to understanding the cellular and biological events of estrogen-mediated gene regulation in normal and diseased tissues.

Journal ArticleDOI
TL;DR: It is reported that expression of the transcription factors Sox1, Sox2 and Sox3 (Sox1–3) is a critical determinant of neurogenesis and the generation of neurons from stem cells depends on the inhibition of Sox1-3 expression by proneural proteins.
Abstract: The generation of neurons from stem cells involves the activity of proneural basic helix-loop-helix (bHLH) proteins, but the mechanism by which these proteins irreversibly commit stem cells to neuronal differentiation is not known. Here we report that expression of the transcription factors Sox1, Sox2 and Sox3 (Sox1-3) is a critical determinant of neurogenesis. Using chick in ovo electroporation, we found that Sox1-3 transcription factors keep neural cells undifferentiated by counteracting the activity of proneural proteins. Conversely, the capacity of proneural bHLH proteins to direct neuronal differentiation critically depends on their ability to suppress Sox1-3 expression in CNS progenitors. These data suggest that the generation of neurons from stem cells depends on the inhibition of Sox1-3 expression by proneural proteins.

Journal ArticleDOI
TL;DR: Results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA–induced dyskinesia.
Abstract: Long-term treatment with the dopamine precursor levodopa (L-DOPA) induces dyskinesia in Parkinson's disease (PD) patients We divided hemiparkinsonian rats treated chronically with L-DOPA into two groups: one showed motor improvement without dyskinesia, and the other developed debilitating dyskinesias in response to the treatment We then compared the plasticity of corticostriatal synapses between the two groups High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in both groups of animals Control and non-dyskinetic rats showed synaptic depotentiation in response to subsequent low-frequency synaptic stimulation, but dyskinetic rats did not The depotentiation seen in both L-DOPA-treated non-dyskinetic rats and intact controls was prevented by activation of the D1 subclass of dopamine receptors or inhibition of protein phosphatases The striata of dyskinetic rats contained abnormally high levels of phospho[Thr34]-DARPP-32, an inhibitor of protein phosphatase 1 These results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA-induced dyskinesia

Journal ArticleDOI
TL;DR: The data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs.
Abstract: Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF+/−) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3+/− mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.

Journal ArticleDOI
TL;DR: It is reported that a combination of two angiogenic factors, platelet-derived growth factor (PDGF)-BB and fibroblast growth factors (FGF)-2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenesis factors.
Abstract: The establishment of functional and stable vascular networks is essential for angiogenic therapy. Here we report that a combination of two angiogenic factors, platelet-derived growth factor (PDGF)-BB and fibroblast growth factor (FGF)-2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenic factors. In both rat and rabbit ischemic hind limb models, PDGF-BB and FGF-2 together markedly stimulated collateral arteriogenesis after ligation of the femoral artery, with a significant increase in vascularization and improvement in paw blood flow. A possible mechanism of angiogenic synergism between PDGF-BB and FGF-2 involves upregulation of the expression of PDGF receptor (PDGFR)-alpha and PDGFR-beta by FGF-2 in newly formed blood vessels. Our data show that a specific combination of angiogenic factors establishes functional and stable vascular networks, and provides guidance for the ongoing clinical trials of angiogenic factors for the treatment of ischemic diseases.

Journal ArticleDOI
TL;DR: The results indicate that addition of specific preseason strength training for the hamstrings – including eccentric overloading – would be beneficial for elite soccer players, both from an injury prevention and from performance enhancement point of view.
Abstract: The primary purpose of this study was to evaluate whether a preseason strength training programme for the hamstring muscle group - emphasising eccentric overloading - could affect the occurrence and severity of hamstring injuries during the subsequent competition season in elite male soccer players. Thirty players from two of the best premier-league division teams in Sweden were divided into two groups; one group received additional specific hamstring training, whereas the other did not. The extra training was performed 1-2 times a week for 10 weeks by using a special device aiming at specific eccentric overloading of the hamstrings. Isokinetic hamstring strength and maximal running speed were measured in both groups before and after the training period and all hamstring injuries were registered during the total observational period of 10 months. The results showed that the occurrence of hamstring strain injuries was clearly lower in the training group (3/15) than in the control group (10/15). In addition, there were significant increases in strength and speed in the training group. However, there were no obvious coupling between performance parameters and injury occurrence. These results indicate that addition of specific preseason strength training for the hamstrings - including eccentric overloading - would be beneficial for elite soccer players, both from an injury prevention and from performance enhancement point of view.

Journal ArticleDOI
TL;DR: The results indicate that, in general, there are only minor differences in the genetic architecture of height between affluent Caucasian populations, especially among men.
Abstract: A major component of variation in body height is due to genetic differences, but environmental factors have a substantial contributory effect. In this study we aimed to analyse whether the genetic architecture of body height varies between affluent western societies. We analysed twin data from eight countries comprising 30,111 complete twin pairs by using the univariate genetic model of the Mx statistical package. Body height and zygosity were self-reported in seven populations and measured directly in one population. We found that there was substantial variation in mean body height between countries; body height was least in Italy (177 cm in men and 163 cm in women) and greatest in the Netherlands (184 cm and 171 cm, respectively). In men there was no corresponding variation in heritability of body height, heritability estimates ranging from 0.87 to 0.93 in populations under an additive genes/unique environment (AE) model. Among women the heritability estimates were generally lower than among men with greater variation between countries, ranging from 0.68 to 0.84 when an additive genes/shared environment/unique environment (ACE) model was used. In four populations where an AE model fit equally well or better, heritability ranged from 0.89 to 0.93. This difference between the sexes was mainly due to the effect of the shared environmental component of variance, which appears to be more important among women than among men in our study populations. Our results indicate that, in general, there are only minor differences in the genetic architecture of height between affluent Caucasian populations, especially among men.

Journal ArticleDOI
TL;DR: In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk, and the complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.
Abstract: A substantial excess risk of lymphomas and nonmelanoma skin cancer has been demonstrated following organ transplantation. Large sample size and long follow-up time may, however, allow more accurate risk estimates and detailed understanding of long-term cancer risk. The objective of the study was to assess the risk of cancer following organ transplantation. A nationwide cohort study comprising 5931 patients who underwent transplantation of kidney, liver or other organs during 1970-1997 in Sweden was conducted. Complete follow-up was accomplished through linkage to nationwide databases. We used comparisons with the entire Swedish population to calculate standardised incidence ratios (SIRs), and Poisson regression for multivariate internal analyses of relative risks (RRs) with 95% confidence intervals (CI). Overall, we observed 692 incident first cancers vs 171 expected (SIR 4.0; 95% CI 3.7-4.4). We confirmed marked excesses of nonmelanoma skin cancer (SIR 56.2; 95% CI 49.8-63.2), lip cancer (SIR 53.3; 95% CI 38.0-72.5) and of non-Hodgkin's lymphoma (NHL) (SIR 6.0; 95% CI 4.4-8.0). Compared with patients who underwent kidney transplantation, those who received other organs were at substantially higher risk of NHL (RR 8.4; 95% CI 4.3-16). Besides, we found, significantly, about 20-fold excess risk of cancer of the vulva and vagina, 10-fold of anal cancer, and five-fold of oral cavity and kidney cancer, as well as two- to four-fold excesses of cancer in the oesophagus, stomach, large bowel, urinary bladder, lung and thyroid gland. In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk. The complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.

Journal ArticleDOI
TL;DR: The large majority of subjectsHaving COPD were symptomatic, while the proportion of those diagnosed as having COPD or similar diagnoses was small, and the absolutely dominating risk factors were increasing age and smoking.

Journal ArticleDOI
TL;DR: The findings indicate that MSCs escape recognition by CTLs and alloreactive NK cells, and inhibit the formation of cytotoxic T cells by secreting a soluble factor, but that they do not interfere with C TLs and NK cell lysis.
Abstract: Background Mesenchymal stem cells (MSCs) can reduce the incidence of graft-versus-host disease because of their ability to inhibit T-lymphocyte proliferation. There are no publications on the effect that MSCs have on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, effector cells vital for the graft-versus-leukemia effect. Methods Cytotoxic T cells were primed in mixed lymphocyte culture (MLC) against irradiated stimulator lymphocytes, and irradiated third-party MSCs were added at different time points. The CTLs were collected, and their cytotoxic potential was analyzed in a chromium-release assay against the same stimulator cells as in the MLC. Purified NK cells were mixed with irradiated MSCs, and the lysis was measured in chromium-release assay against K562 target cells. Results We found that MSCs inhibited CTL-mediated lysis by 70% if added at the beginning of the 6-day MLC. The lysis was not affected on day 3 or in the cytotoxic phase. Furthermore, MSCs inhibited the formation of cytotoxic lymphocytes when the cells were separated in a transwell system, which indicates that the effect is mediated by a soluble factor. NK cell-mediated lysis of K562 cells was not inhibited by MSCs. MSCs did not induce proliferation of allogeneic lymphocytes, and they were not lysed by allogeneic CTLs or NK cells. Conclusion Our findings indicate that MSCs escape recognition by CTLs and alloreactive NK cells, and inhibit the formation of cytotoxic T cells by secreting a soluble factor, but that they do not interfere with CTLs and NK cell lysis.

Journal ArticleDOI
28 Nov 2003
TL;DR: The current review summarizes the recent advances with regard to hormone-sensitive lipase structure and molecular mechanisms involved in regulating its activity and lipolysis in general.
Abstract: Hormone-sensitive lipase, the rate-limiting enzyme of intracellular TG hydrolysis, is a major determinant of fatty acid mobilization in adipose tissue as well as other tissues. It plays a pivotal role in lipid metabolism, overall energy homeostasis, and, presumably, cellular events involving fatty acid signaling. Detailed knowledge about its structure and regulation may provide information regarding the pathogenesis of such human diseases as obesity and diabetes and may generate concepts for new treatments of these diseases. The current review summarizes the recent advances with regard to hormone-sensitive lipase structure and molecular mechanisms involved in regulating its activity and lipolysis in general. A summary of the current knowledge regarding regulation of expression, potential involvement in lipid disorders, and role in tissues other than adipose tissue is also provided.

Journal ArticleDOI
TL;DR: Smokers of both sexes have an increased risk of developing seropositive, but not seronegative, RA, which occurs after a long duration, but merely a moderate intensity, of smoking and may remain for several years after smoking cessation.
Abstract: randomly selected from the study base. Self reported smoking habits among cases and controls, and rheumatoid factor status among cases were registered. The incidence of RA in current smokers, ex-smokers, and ever-smokers, respectively, was compared with that of never-smokers. Results: Current smokers, ex-smokers, and ever-smokers of both sexes had an increased risk for sero- positive RA (for ever-smokers the odds ratio was 1.7 (95% confidence interval (95% CI) 1.2 to 2.3) for women, and 1.9 (95% CI 1.0 to 3.5) for men), but not for seronegative RA. The increased risk was only apparent among subjects who had smoked >20 years, was evident at an intensity of smoking of 6-9 cigarettes/day, and remained for up to 10-19 years after smoking cessation. The risk increased with increasing cumulative dose of smoking. Conclusion: Smokers of both sexes have an increased risk of developing seropositive, but not seronegative, RA. The increased risk occurs after a long duration, but merely a moderate intensity, of smoking and may remain for several years after smoking cessation.

Journal ArticleDOI
27 Jun 2003-Cell
TL;DR: The results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling that does not require the RET receptor.

Journal ArticleDOI
TL;DR: It is suggested that computation in the local network may proceed not only by direct pyramidal‐pyramidal cell communication but also via local interneurons, ideally poised to both coordinate and expand the local pyramid cell network via pyramID‐ interneuron‐ pyramides communication.
Abstract: The extent to which neocortical pyramidal cells function as a local network is determined by the strength and probability of their connections. By mapping connections between pyramidal cells we show here that in a local network of about 600 pyramidal cells located within a cylindrical volume of 200 microm x 200 microm of neocortical layer 2/3, an individual pyramidal cell receives synaptic inputs from about 30 other pyramidal neurons, with the majority of EPSP amplitudes in the 0.2-1.0 mV range. The probability of connection decreased from 0.09 to 0.01 with intercell distance (over the range 25-200 microm). Within the same volume, local interneuron (fast-spiking non-accommodating interneuron, FS)-pyramidal cell connections were about 10 times more numerous, with the majority of connections being reciprocal. The probability of excitatory and inhibitory connections between pyramidal cells and FS interneurons decreased only slightly with distance, being in the range 0.5-0.75. Pyramidal cells in the local network received strong synaptic input during stimulation of afferent fibres in layers 1 and 6. Minimal-like stimulation of layer 1 or layer 6 inputs simultaneously induced postsynaptic potentials in connected pyramidal cells as well as in pyramidal-FS cell pairs. These inputs readily induced firing of pyramidal cells, although synaptically connected cells displayed different firing patterns. Unitary EPSPs in pyramidal-pyramidal cell pairs did not detectably alter cell firing. FS interneurons fire simultaneously with pyramidal cells. In pyramidal-FS cell pairs, both unitary EPSPs and IPSPs efficiently modulated cell firing patterns. We suggest that computation in the local network may proceed not only by direct pyramidal-pyramidal cell communication but also via local interneurons. With such a high degree of connectivity with surrounding pyramidal cells, local interneurons are ideally poised to both coordinate and expand the local pyramidal cell network via pyramidal-interneuron-pyramidal communication.

Journal ArticleDOI
TL;DR: Evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain is provided and it is shown that the rate of neurogenesis is increased after a lesion.
Abstract: New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.

Journal ArticleDOI
TL;DR: A catalytic tetrad of Asn-Ser-Tyr-Lys residues is established, which presumably form the framework for a proton relay system including the 2'-OH of the nicotinamide ribose, similar to the mechanism found in horse liver ADH.