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Showing papers by "Karolinska Institutet published in 2002"


Journal ArticleDOI
Yasushi Okazaki, Masaaki Furuno, Takeya Kasukawa1, Jun Adachi, Hidemasa Bono, S. Kondo, Itoshi Nikaido2, Naoki Osato, Rintaro Saito3, Harukazu Suzuki, Itaru Yamanaka, H. Kiyosawa2, Ken Yagi, Yasuhiro Tomaru4, Yuki Hasegawa2, A. Nogami2, Christian Schönbach, Takashi Gojobori, Richard M. Baldarelli, David P. Hill, Carol J. Bult, David A. Hume5, John Quackenbush6, Lynn M. Schriml7, Alexander Kanapin, Hideo Matsuda8, Serge Batalov9, Kirk W. Beisel10, Judith A. Blake, Dirck W. Bradt, Vladimir Brusic, Cyrus Chothia11, Lori E. Corbani, S. Cousins, Emiliano Dalla, Tommaso A. Dragani, Colin F. Fletcher9, Colin F. Fletcher12, Alistair R. R. Forrest5, K. S. Frazer13, Terry Gaasterland14, Manuela Gariboldi, Carmela Gissi15, Adam Godzik16, Julian Gough11, Sean M. Grimmond5, Stefano Gustincich17, Nobutaka Hirokawa18, Ian J. Jackson19, Erich D. Jarvis20, Akio Kanai3, Hideya Kawaji8, Hideya Kawaji1, Yuka Imamura Kawasawa21, Rafal M. Kedzierski21, Benjamin L. King, Akihiko Konagaya, Igor V. Kurochkin, Yong-Hwan Lee6, Boris Lenhard22, Paul A. Lyons23, Donna Maglott7, Lois J. Maltais, Luigi Marchionni, Louise M. McKenzie, Harukata Miki18, Takeshi Nagashima, Koji Numata3, Toshihisa Okido, William J. Pavan7, Geo Pertea6, Graziano Pesole15, Nikolai Petrovsky24, Ramesh S. Pillai, Joan Pontius7, D. Qi, Sridhar Ramachandran, Timothy Ravasi5, Jonathan C. Reed16, Deborah J Reed, Jeffrey G. Reid, Brian Z. Ring, M. Ringwald, Albin Sandelin22, Claudio Schneider, Colin A. Semple19, Mitsutoshi Setou18, K. Shimada25, Razvan Sultana6, Yoichi Takenaka8, Martin S. Taylor19, Rohan D. Teasdale5, Masaru Tomita3, Roberto Verardo, Lukas Wagner7, Claes Wahlestedt22, Y. Wang6, Yoshiki Watanabe25, Christine A. Wells5, Laurens G. Wilming26, Anthony Wynshaw-Boris27, Masashi Yanagisawa21, Ivana V. Yang6, L. Yang, Zheng Yuan5, Mihaela Zavolan14, Yunhui Zhu, Anne M. Zimmer28, Piero Carninci, N. Hayatsu, Tomoko Hirozane-Kishikawa, Hideaki Konno, M. Nakamura, Naoko Sakazume, K. Sato4, Toshiyuki Shiraki, Kazunori Waki, Jun Kawai, Katsunori Aizawa, Takahiro Arakawa, S. Fukuda, A. Hara, W. Hashizume, K. Imotani, Y. Ishii, Masayoshi Itoh, Ikuko Kagawa, A. Miyazaki, K. Sakai, D. Sasaki, K. Shibata, Akira Shinagawa, Ayako Yasunishi, Masayasu Yoshino, Robert H. Waterston29, Eric S. Lander30, Jane Rogers26, Ewan Birney, Yoshihide Hayashizaki 
05 Dec 2002-Nature
TL;DR: The present work, completely supported by physical clones, provides the most comprehensive survey of a mammalian transcriptome so far, and is a valuable resource for functional genomics.
Abstract: Only a small proportion of the mouse genome is transcribed into mature messenger RNA transcripts There is an international collaborative effort to identify all full-length mRNA transcripts from the mouse, and to ensure that each is represented in a physical collection of clones Here we report the manual annotation of 60,770 full-length mouse complementary DNA sequences These are clustered into 33,409 'transcriptional units', contributing 901% of a newly established mouse transcriptome database Of these transcriptional units, 4,258 are new protein-coding and 11,665 are new non-coding messages, indicating that non-coding RNA is a major component of the transcriptome 41% of all transcriptional units showed evidence of alternative splicing In protein-coding transcripts, 79% of splice variations altered the protein product Whole-transcriptome analyses resulted in the identification of 2,431 sense-antisense pairs The present work, completely supported by physical clones, provides the most comprehensive survey of a mammalian transcriptome so far, and is a valuable resource for functional genomics

1,663 citations


Journal ArticleDOI
TL;DR: This paper showed that Bacteroides thetaiotaomicron, a prominent and genetically manipulatable component of the normal human and mouse gut, modifies many aspects of intestinal cellular differentiation/gene expression to benefit both host and microbe.
Abstract: Humans and other mammals are colonized by a vast, complex, and dynamic consortium of microorganisms. One evolutionary driving force for maintaining this metabolically active microbial society is to salvage energy from nutrients, particularly carbohydrates, that are otherwise nondigestible by the host. Much of our understanding of the molecular mechanisms by which members of the intestinal microbiota degrade complex polysaccharides comes from studies of Bacteroides thetaiotaomicron, a prominent and genetically manipulatable component of the normal human and mouse gut. Colonization of germ-free mice with B. thetaiotaomicron has shown how this anaerobe modifies many aspects of intestinal cellular differentiation/gene expression to benefit both host and microbe. These and other studies underscore the importance of understanding precisely how nutrient metabolism serves to establish and sustain symbiotic relationships between mammals and their bacterial partners.

1,569 citations


Journal ArticleDOI
01 Mar 2002-Science
TL;DR: Using positron emission tomography, it is confirmed that both opioid and placebo analgesia are associated with increased activity in the rostral anterior cingulate cortex and the brainstem, indicating a related neural mechanism in placebo and opioid analgesia.
Abstract: It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomography, we confirmed that both opioid and placebo analgesia are associated with increased activity in the rACC. We also observed a covariation between the activity in the rACC and the brainstem during both opioid and placebo analgesia, but not during the pain-only condition. These findings indicate a related neural mechanism in placebo and opioid analgesia.

1,397 citations


Journal ArticleDOI
TL;DR: It is shown that transplanting low doses of undifferentiated mouse embryonic stem cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons that can restore cerebral function and behavior in an animal model of Parkinson's disease.
Abstract: Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease.

1,231 citations


Journal ArticleDOI
TL;DR: This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.
Abstract: Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality among transplant recipients. For the purpose of developing consistent reporting of CMV in clinical trials, definitions of CMV infection and disease were developed and published. This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.

1,206 citations


Journal ArticleDOI
TL;DR: In this article, the authors used a new training paradigm with intensive and adaptive training of WM tasks and evaluated the effect of training with a double blind, placebo controlled design and found that the training significantly improved performance on a nontrained visuo-spatial WM task and on Raven's Progressive Matrices.
Abstract: Working memory (WM) capacity is the ability to retain and manipulate information during a short period of time. This ability underlies complex reasoning and has generally been regarded as a fixed trait of the individual. Children with attention deficit hyperactivity disorder (ADHD) represent one group of subjects with a WM deficit, attributed to an impairment of the frontal lobe. In the present study, we used a new training paradigm with intensive and adaptive training of WM tasks and evaluated the effect of training with a double blind, placebo controlled design. Training significantly enhanced performance on the trained WM tasks. More importantly, the training significantly improved performance on a nontrained visuo-spatial WM task and on Raven’s Progressive Matrices, which is a nonverbal complex reasoning task. In addition, motor activity ‐ as measured by the number of head movements during a computerized test ‐ was significantly reduced in the treatment group. A second experiment showed that similar training-induced improvements on cognitive tasks are also possible in young adults without ADHD. These results demonstrate that performance on WM tasks can be significantly improved by training, and that the training effect also generalizes to nontrained tasks requiring WM. Training improved performance on tasks related to prefrontal functioning and had also a significant effect on motor activity in children with ADHD. The results thus suggest that WM training potentially could be of clinical use for ameliorating the symptoms in ADHD.

1,158 citations


Journal ArticleDOI
TL;DR: In this article, the authors investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding interleukin-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-six replacement.
Abstract: The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents.

1,088 citations


Journal ArticleDOI
TL;DR: This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis.
Abstract: This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive immunity, with its T cells, antibodies, and immunoregulatory cytokines, powerfully modulates disease activity and progression. Atherogenesis involves cross talk between and shared pathways involved in adaptive and innate immunity. Immune processes can influence the balance between cell proliferation and death, between synthetic and degradative processes, and between pro- and antithrombotic processes. Various established and emerging risk factors for atherosclerosis modulate aspects of immune responses, including lipoproteins and their modified products, vasoactive peptides, and infectious agents. As we fill in the molecular details, new potential targets for therapies will doubtless emerge.

1,021 citations


Journal ArticleDOI
TL;DR: This work found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53, named PRIMA-1, which rescued both DNA contact and structural p53 mutants in vitro and in living cells.
Abstract: The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.

1,004 citations


Journal ArticleDOI
TL;DR: Marrow stromal cells constitute an easily accessible, easily expandable source of cells that may prove useful in the establishment of spinal cord repair protocols and possibly effects on functional outcome in animals rendered paraplegic.
Abstract: Marrow stromal cells (MSC) can be expanded rapidly in vitro and differentiated into multiple mesodermal cell types. In addition, differentiation into neuron-like cells expressing markers typical for mature neurons has been reported. To analyze whether such cells, exposed to differentiation media, could develop electrophysiological properties characteristic of neurons, we performed whole-cell recordings. Neuron-like MSC, however, lacked voltage-gated ion channels necessary for generation of action potentials. We then delivered MSC into the injured spinal cord to study the fate of transplanted MSC and possible effects on functional outcome in animals rendered paraplegic. MSC given 1 week after injury led to significantly larger numbers of surviving cells than immediate treatment and significant improvements of gait. Histology 5 weeks after spinal cord injury revealed that MSC were tightly associated with longitudinally arranged immature astrocytes and formed bundles bridging the epicenter of the injury. Robust bundles of neurofilament-positive fibers and some 5-hydroxytryptamine-positive fibers were found mainly at the interface between graft and scar tissue. MSC constitute an easily accessible, easily expandable source of cells that may prove useful in the establishment of spinal cord repair protocols.

991 citations


Journal ArticleDOI
TL;DR: Implant loss was most frequently described (reported in about 100% of studies), while biological complications were considered in only 40-60% and technical complications in only 60-80% of the studies, indicating that data on the incidence of biological andTechnical complications may be underestimated and should be interpreted with caution.
Abstract: Objective: To systematically review the incidence of biological and technical complications in implant therapy reported in prospective longitudinal studies of at least 5 years. Methods: A MEDLINE search was conducted for prospective longitudinal studies with follow-up periods of at least 5 years. Screening and data abstraction were performed independently by multiple reviewers. The types of complications assessed were as follows: implant loss, sensory disturbance, soft tissue complications, peri-implantitis, bone loss ≥2.5 mm, implant fracture and technical complications related to implant components and suprastructures. Results: The search provided 1310 titles and abstracts, out of which 159 were selected for full-text analysis. Finally, 51 studies were included. Meta analysis of these studies indicated that implant loss prior to functional loading is to be expected to occur in about 2.5% of all implants placed in implant therapy including more than one implant and when routine procedures are used. Implant loss during function occurs in about 2–3% of implants supporting fixed reconstructions, while in overdenture therapy >5% of the implants can be expected to be lost during a 5-year period. Few studies (41% of those included) reported data on the incidence of persisting sensory disturbance >1 year following implant surgery. Most of the studies that provided such data reported on the absence or a low incidence (1–2%) of this complication beyond this interval. A higher incidence of soft tissue complications was reported for patients treated with implants supporting overdentures. There is limited information regarding the occurrence of peri-implantitis and implants exhibiting bone loss ≥2.5 mm. Implant fracture is a rare complication and occurs in <1% of all implants during a 5-year period. The incidence of technical complications related to implant components and suprastructures was higher in overdentures than in fixed reconstructions. Conclusion: Implant loss was most frequently described (reported in about 100% of studies), while biological complications were considered in only 40–60% and technical complications in only 60–80% of the studies. This observation indicates that data on the incidence of biological and technical complications may be underestimated and should be interpreted with caution.

Journal ArticleDOI
TL;DR: The results indicate that the release of cytochrome c involves a distinct two-step process that is undermined when either step is compromised, and this mechanism also extends to conditions of mitochondrial permeability transition insofar as cy tochrome c release is significantly depressed when the electrostatic interaction between cyto Chrome c and cardiolipin remains intact.
Abstract: Cytochrome c is often released from mitochondria during the early stages of apoptosis, although the precise mechanisms regulating this event remain unclear. In this study, with isolated liver mitochondria, we demonstrate that cytochrome c release requires a two-step process. Because cytochrome c is present as loosely and tightly bound pools attached to the inner membrane by its association with cardiolipin, this interaction must first be disrupted to generate a soluble pool of this protein. Specifically, solubilization of cytochrome c involves a breaching of the electrostatic and/or hydrophobic affiliations that this protein usually maintains with cardiolipin. Once cytochrome c is solubilized, permeabilization of the outer mitochondrial membrane by Bax is sufficient to allow the extrusion of this protein into the extramitochondrial environment. Neither disrupting the interaction of cytochrome c with cardiolipin, nor permeabilizing the outer membrane with Bax, alone, is sufficient to trigger this protein's release. This mechanism also extends to conditions of mitochondrial permeability transition insofar as cytochrome c release is significantly depressed when the electrostatic interaction between cytochrome c and cardiolipin remains intact. Our results indicate that the release of cytochrome c involves a distinct two-step process that is undermined when either step is compromised.

Journal ArticleDOI
TL;DR: Results suggest that stimulating activity, either mentally or socially oriented, may protect against dementia, indicating that both social interaction and intellectual stimulation may be relevant to preserving mental functioning in the elderly.
Abstract: Recent findings suggest that a rich social network may decrease the risk of developing dementia. The authors hypothesized that such a protective effect may be due to social interaction and intellectual stimulation. To test this hypothesis, data from the 1987-1996 Kungsholmen Project, a longitudinal population-based study carried out in a central area of Stockholm, Sweden, were used to examine whether engagement in different activities 6.4 years before dementia diagnosis was related to a decreased incidence of dementia. Dementia cases were diagnosed by specialists according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria. After adjustment for age, sex, education, cognitive functioning, comorbidity, depressive symptoms, and physical functioning at the first examination, frequent (daily-weekly) engagement in mental, social, or productive activities was inversely related to dementia incidence. Adjusted relative risks for mental, social, and productive activities were 0.54 (95% confidence interval (CI): 0.34, 0.87), 0.58 (95% CI: 0.37, 0.91), and 0.58 (95% CI: 0.38, 0.91), respectively. Similar results were found when these three factors were analyzed together in the same model. Results suggest that stimulating activity, either mentally or socially oriented, may protect against dementia, indicating that both social interaction and intellectual stimulation may be relevant to preserving mental functioning in the elderly.

Journal ArticleDOI
TL;DR: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic Acid might be an effective treatment for postmenopausal osteoporosis.
Abstract: Background Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. Methods We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. Results There were similar increases in bone ...

Journal ArticleDOI
TL;DR: The expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions is characterized to illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerosis, and they encourage further exploration of innate immunity in the pathogenesis of Atherosclerosis.
Abstract: Background— Innate immune reactions against bacteria and viruses have been implicated in the pathogenesis of atherosclerosis. To explore the molecular mechanism by which microbe recognition occurs in the artery wall, we characterized the expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions. Methods and Results— Semiquantitative polymerase chain reaction and immunohistochemical analysis demonstrated that of 9 TLRs, the expression of TLR1, TLR2, and TLR4 was markedly enhanced in human atherosclerotic plaques. A considerable proportion of TLR-expressing cells were also activated, as shown by the nuclear translocation of nuclear factor-κB. Conclusion— Our findings illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerotic lesions, and they encourage further exploration of innate immunity in the pathogenesis of atherosclerosis.

Journal ArticleDOI
23 Nov 2002-BMJ
TL;DR: Self reported cannabis use is associated with an increased risk of subsequently developing schizophrenia, consistent with a causal relation This association is not explained by sociability personality traits, or by use of amphetamines or other drugs Self medication with cannabis is an unlikely explanation for the association observed.
Abstract: Objectives: An association between use of cannabis in adolescence and subsequent risk of schizophrenia was previously reported in a follow up of Swedish conscripts. Arguments were raised that this association may be due to use of drugs other than cannabis and that personality traits may have confounded results. We performed a further analysis of this cohort to address these uncertainties while extending the follow up period to identify additional cases. Design: Historical cohort study. Setting: 1969-70 survey of Swedish conscripts (>97% of the country's male population aged 18-20). Participants: 50 087 subjects: data were available on self reported use of cannabis and other drugs, and on several social and psychological characteristics. Main outcome measures: Admissions to hospital for ICD-8/9 schizophrenia and other psychoses, as determined by record linkage. Results: Cannabis was associated with an increased risk of developing schizophrenia in a dose dependent fashion both for subjects who had ever used cannabis (adjusted odds ratio for linear trend of increasing frequency 1.2, 95% confidence interval 1.1 to 1.4, P 50 times was 6.7 (2.1 to 21.7) in the cannabis only group. Similar results were obtained when analysis was restricted to subjects developing schizophrenia after five years after conscription, to exclude prodromal cases. Conclusions: Cannabis use is associated with an increased risk of developing schizophrenia, consistent with a causal relation. This association is not explained by use of other psychoactive drugs or personality traits relating to social integration. #### What is already known about this topic What is already known about this topic Use of cannabis has been associated with an increased risk of developing schizophrenia Alternative explanations for this association include confounding by personality or by use of other drugs such as amphetamines, and use of cannabis as a form of self medication secondary to the disorder #### What this study adds What this study adds Self reported cannabis use is associated with an increased risk of subsequently developing schizophrenia, consistent with a causal relation This association is not explained by sociability personality traits, or by use of amphetamines or other drugs Self medication with cannabis is an unlikely explanation for the association observed

Journal ArticleDOI
01 Jul 2002-Diabetes
TL;DR: The findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2, which is implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis.
Abstract: Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.

Journal ArticleDOI
26 Jul 2002-Science
TL;DR: The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might contribute to virulence and the extraordinary chronicity ofH.pylori infection.
Abstract: Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.

Journal ArticleDOI
TL;DR: It is shown that one intronic SNP in PDCD1 is associated with development of SLE in Europeans, and this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development ofSLE in humans.
Abstract: Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

Journal ArticleDOI
TL;DR: Findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease, and are associated with autosomal-recessive hypomagnesemia with secondary hypocalcemia.
Abstract: Magnesium is an essential ion involved in many biochemical and physiological processes. Homeostasis of magnesium levels is tightly regulated and depends on the balance between intestinal absorption and renal excretion. However, little is known about specific proteins mediating transepithelial magnesium transport. Using a positional candidate gene approach, we identified mutations in TRPM6 (also known as CHAK2), encoding TRPM6, in autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH, OMIM 602014), previously mapped to chromosome 9q22 (ref. 3). The TRPM6 protein is a new member of the long transient receptor potential channel (TRPM) family and is highly similar to TRPM7 (also known as TRP-PLIK), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity. TRPM6 is expressed in intestinal epithelia and kidney tubules. These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease.

Journal ArticleDOI
TL;DR: There are indications that subjects with low MMA in urine have faster elimination of ingested arsenic, compared to those with more MMA in pee, and to what extent MMA( III) and DMA(III) contribute to the observed toxicity following exposure to inorganic arsenic remains to be elucidated.

Journal ArticleDOI
TL;DR: The assignment of patients to watchful waiting or radical prostatectomy entails different risks of erectile dysfunction, urinary leakage, and urinary obstruction, but on average, the choice has little if any influence on well-being or the subjective quality of life after a mean follow-up of four years.
Abstract: Background We evaluated symptoms and self-assessments of quality of life in men with localized prostate cancer who participated in a randomized comparison between radical prostatectomy and watchful waiting Methods Between 1989 and 1999, a group of Swedish urologists randomly assigned men with localized prostate cancer to radical prostatectomy or watchful waiting In this follow-up study, we obtained information from 326 of 376 eligible men (87 percent) concerning certain symptoms, symptom-induced distress, well-being, and the subjective assessment of quality of life by means of a mailed questionnaire Results Erectile dysfunction (80 percent vs 45 percent) and urinary leakage (49 percent vs 21 percent) were more common after radical prostatectomy, whereas urinary obstruction (eg, 28 percent vs 44 percent for weak urinary stream) was less common Bowel function, the prevalence of anxiety, the prevalence of depression, well-being, and the subjective quality of life were similar in the two groups Conc

Journal ArticleDOI
TL;DR: The Swedish Twin Registry is a unique resource for clinical, epidemiological and genetic studies (Review) and should be considered for further study.
Abstract: . Lichtenstein P, de Faire U, Floderus B, Svartengren M, Svedberg P, Pedersen NL (Karolinska Institutet; Karolinska Hospital; Institute of Environmental Medicine, Karolinska Institutet, National Institute for Working life, Stockholm, Sweden; and University of Southern California, CA, USA) The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies (Review). J Intern Med 2002; 252: 184–205. The Swedish Twin Registry (STR), which today hasdeveloped into a unique resource, was first established in the late 1950s to study the importance of smoking and alcohol consumption on cancer and cardiovascular diseases whilst controlling for genetic propensity to disease. Since that time, the Registry has been expanded and updated on several occasions, and the focus has similarly broadened to most common complex diseases. In the following, we will summarize the content of the database, describe for the first time recent data collection efforts and review some of the principal findings that have come from the Registry.

Journal ArticleDOI
TL;DR: Stress and the social situation at work are strongly linked to disturbed sleep and impaired awakening, that gender and, even more so, age may modify this and that the inability to stop worrying about work during free time may be an important link in the relation between stress and sleep.

Journal ArticleDOI
TL;DR: During performance of the WM task, the older children showed higher activation of cortex in the superior frontal and intraparietal cortex than the younger children did, and a second analysis found that WM capacity was significantly correlated with brain activity in the same regions.
Abstract: The aim of this study was to identify changes in brain activity associated with the increase in working memory (WM) capacity that occurs during childhood and early adulthood. Functional MRI (fMRI) was used to measure brain activity in subjects between 9 and 18 years of age while they performed a visuospatial WM task and a baseline task. During performance of the WM task, the older children showed higher activation of cortex in the superior frontal and intraparietal cortex than the younger children did. A second analysis found that WM capacity was significantly correlated with brain activity in the same regions. These frontal and parietal areas are known to be involved in the control of attention and spatial WM. The development of the functionality in these areas may play an important role in cognitive development during childhood.

Journal ArticleDOI
TL;DR: The frequency of cholangiocarcinoma is 13% and the risk of hepatobiliary carcinoma is constant after the first year after PSC diagnosis with an incidence rate of 1.5% per year, suggestive of an increased risk of pancreatic carcinoma in patients with PSC.

Journal ArticleDOI
TL;DR: The presence of two proteins that interact with mammalian POLRMT may allow flexible regulation of mtDNA gene expression in response to the complex physiological demands of mammalian metabolism.
Abstract: Characterization of the basic transcription machinery of mammalian mitochondrial DNA (mtDNA) is of fundamental biological interest and may also lead to therapeutic interventions for human diseases associated with mitochondrial dysfunction. Here we report that mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M) are necessary for basal transcription of mammalian mitochondrial DNA (mtDNA). Human TFB1M and TFB2M are expressed ubiquitously and can each support promoter-specific mtDNA transcription in a pure recombinant in vitro system containing mitochondrial RNA polymerase (POLRMT) and mitochondrial transcription factor A. Both TFB1M and TFB2M interact directly with POLRMT, but TFB2M is at least one order of magnitude more active in promoting transcription than TFB1M. Both factors are highly homologous to bacterial rRNA dimethyltransferases, which suggests that an RNA-modifying enzyme has been recruited during evolution to function as a mitochondrial transcription factor. The presence of two proteins that interact with mammalian POLRMT may allow flexible regulation of mtDNA gene expression in response to the complex physiological demands of mammalian metabolism.

Journal ArticleDOI
TL;DR: Intracellular acidosis due mainly to lactic acid accumulation has been regarded as the most important cause of skeletal muscle fatigue, but recent studies show little direct effect of acidosis on muscle function at physiological temperatures.
Abstract: Intracellular acidosis due mainly to lactic acid accumulation has been regarded as the most important cause of skeletal muscle fatigue. Recent studies on mammalian muscle, however, show little direct effect of acidosis on muscle function at physiological temperatures. Instead, inorganic phosphate, which increases during fatigue due to breakdown of creatine phosphate, appears to be a major cause of muscle fatigue.

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TL;DR: The similarities between the responses to HSPs and LPS are discussed and it is emphasized that care must be taken when working with preparations of H SPs in experimental settings and interpreting experimental data.

Journal ArticleDOI
TL;DR: Intrauterine and neonatal factors related to deviant intrauterine growth or fetal distress are important in the pathogenesis of autism, according to a study nested within a population-based cohort.
Abstract: Background. Etiologic hypotheses in infantile autism suggest a strong genetic component, as well as possible environmental risks linked to early fetal development. We evaluated the association of m ...