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We performed untargeted serum metabolomic profiling of two large population-based prostate cancer populations. Molecular features have been derived and explored for association with prostate cancer status (6,138 features, 475 subjects) and prostate cancer survival (5,209 features, 534 subjects). Assessment of metabolite features revealed two features as studywide significantly associated with prostate cancer status; however, due to low observed abundance we were not able to identify the molecular identity of these features. Among features indicated in pairwise analysis molecular identification revealed Caprolactam, L-Phosphatidic acid, and Peptide (Tyr-Lys-Thr) as possibly associated with prostate cancer aetiology. Genomewide assessment of the four top associated metabolite features implicated four genes PDE7B, NRG3, ILI3RA1 and UGT3A1 of which the association between metabolite feature 174.1_53 and gene ILI3RA1 was genome-wide significant (P = 1.4 x 10-8). This finding is interesting since although IL13RA1 itself has not been associated with prostate cancer, the alpha 2 chain of the same receptor (IL13RA2) has been reported to be differentially expressed in a metastatic prostate cancer cell line, and suggested as a target for prostate cancer treatment. In summary, several metabolite features associated with prostate cancer were discovered that warrant further investigation to advance our understanding of the underlying biological processes., The original document contains color images.

Successful treatment of pathologic femur fractures can preserve a patient's independence and quality of life. The choice of implant depends on several disease and patient-specific variables; however, its durability must generally match the patient's estimated life expectancy. Failures do occur, however, it is unclear which implants are associated with greater risk of failure. We evaluated patients with femoral metastases in whom implants failed to determine (1) the rate of reoperation; (2) the timing of and most common causes for failure; and (3) incidence of perioperative complications and death., SYMPOSIUM: PAPERS PRESENTED AT THE 2011 ISOLS MEETING IN BEIJING, CHINA, Sept 15-18, 2011, Published in Clinical Orthopaedics and Related Research, Sept. 5, 2012, Government or Federal Purpose Rights License. The original document contains color images.

Our aim is to understand whether adjuvant therapy of a first primary breast cancer might predict the prognosis of a metachronous bilateral cancer. Major findings: Our findings support a selection process where adjuvant systemic treatment selectively prevents the occurrence of cancers with a favourable prognosis, allowing those with a more aggressive phenotype to surface clinically., The original document contains color images.

Purpose/scope: Our aim is to understand whether adjuvant therapy of a first primary breast cancer might predict the prognosis of a metachronous bilateral cancer. Major findings: Our findings support a selection process where adjuvant systemic treatment selectively prevents the occurrence of cancers with a favourable prognosis, allowing those with a more aggressive phenotype to surface clinically. Up-to- date report: We have requested for a no-cost extension of the project due to difficulties with collection of tissue samples., The original document contains color images.

The aim of this study is to determine whether intake of foods found to have high levels of acrylamide increase the risk of prostate cancer among men. Methods: A population-based case-control study on prostate cancer. The exposure to acrylamide was estimated by using a food frequency questionnaire (FFQ) and by hemoglobin adducts in blood. Results: The intake of acrylamide and adduct levels are in line with previous studies, but there was only a weak correlation between the two estimates. The relative risk of prostate cancer was 0.97 (95% CI 0.75-1.27) for the highest quintile of exposure compare to the lowest quintile. Conclusions: ""There was no evidence of an overall association between exposure to dietary acrylamide and prostate cancer risk in the present study., The original document contains color images.

The aim of this study is to determine whether intake of foods found to have high levels of acrylamide increase the risk of prostate cancer among men. Major findings: We have finished the data collection in a population-based case-control study on prostate cancer. The daily median intake of acrylamide was 43 microgram in the control group. Up-to-date report: The project is up and running but due to problems with the laboratory method for analysis of DNA adducts of acrylamide and the delayed payment from US army we have been granted one additional year in order to finish the tasks for months 13-29 (see "Research accomplishments"). We foresee no problems in completing them on schedule.

Background: The risk of bilateral breast cancer is substantially higher than the risk of unilateral disease and associated with early age at onset of the initial breast cancer. Of the many established risk factors for breast cancer, only family history has been consistently shown to be associated with bilateral disease. Methods: We analyzed a population-based cohort of 123,757 women with a first primary breast cancer diagnosed in Sweden from 1970 to 2000 and identified 6,550 women with a bilateral breast cancer. Results: Incidence of synchronous bilateral breast cancer mimics that of unilateral breast cancer. During 20 years from initial diagnosis, the incidence of metachronous cancer decreased from about 800 to 400 per 10(exp 5) person-years in patients first diagnosed before age 45, whilst the incidence remained stable at 500 to 600 per 10(exp 5) among those who were older at diagnosis of first cancer. Conclusions: The finding of breast cancer being simultaneously diagnosed in two breasts has an incidence far beyond the expected, but is probably not explained by genetic background rather environmental factors. The incidence pattern of metachronous bilateral cancer by age and follow-up time fits neither a model of highly penetrant genes, nor a model assuming only aggregation of environmental risk factors.

The presented implementation is a three-dimensional isotropic monodomain reaction-diffusion model with a realistic geometry coupled with the atrial ion model proposed by Nygren et al. The partial differential equations are solved by a Garlekin finite element method in space and a forward Euler approximation in time. Simulations yields the expected results and the computational performance of the model is good considering the size of the problem., Papers from the 23rd Annual International Conference of the IEEE ENgineering in Medicine and Biology Society, October 25-28, 2001, held in Istanbul, Turkey. See also ADM001351 for entire conference on cd-rom., The original document contains color images.

Purpose: To analyze to what extent women born extreme premature and women characterized as small for gestational age at birth differ with regards to breast cancer risk as adults. Scope: To identify all women within a study base of 290,000 female births during the years 1925 to 1949 in central Sweden born before the 35th gestational week and/or with a birth weight below 2,000 grams. The women in the cohort still alive in 1958 have been followed up for occurrence of breast cancer through linkage with Swedish registries. Major findings: There were 1,847 survivors January 1, 1958, of which 90 were diagnosed with breast cancer up through 1996. Preliminary analyses strongly indicate that women born extremely premature compared to those born small for gestational age have an increased risk of breast cancer. Conclusion: Our findings strongly indicate that early hormonal exposures are of importance for the risk of breast cancer later in life.

The aim of this project is to develop improved methods for the production, processing, and analysis of microarrays (gene-chips) for breast-cancer diagnostics. These methods are based upon large numbers of discrete DNA spots placed on glass microscope slides typically, and hybridized to a probe derived from a tIssue or blood sample. %or breast- cancer diagnostics, there are two likely predominant modes of use. TIssue samples from suspect lesions, e.g., can be assessed for patterns of gene expression on cDNA arrays, indicative of a specific disease type or state. Additionally, analysis of known mutations can be performed on oligonucleotide-based arrays. We are optimizing cDNA microarray methods, and have achieved excellent limits of detection, although not good enough to detect the rarest transcripts. To improve this situation, we are redesigning our novel imaging (non-scanning) fluorescence microarray reader that currently performs four times better (with respect to limit of detection) than a commercial scanner, and does so about 300 times faster. Our next goal is to implement oligonucleotide arrays by various methods including both padlock probe-based ligation assays and allele-specific hybridization tests for specific known mutations. We are also actively improving direct covalent attachment of oligonucleotides to glass, and methods for printing oligonucleotide arrays much faster and cheaper.

This limited review suggests that some traditional factors like, personality and circadian amplitude seem to have little to do with tolerance of shift work. Neither does gender, at least not if social responsibility is controlled for. Age on the other hand seems of more interest and also diurnal type, but the two seem closely related. However, the major determinants of shift work tolerance probably have more to do with states or rather ways of coping with irregular work hours. Thus, the way an individual organizes his behavior to promote sleep may be of importance, as may be the need for sleep. This may be related to commitment to night work, avoiding light after night work, etc. One should probably give priority to teaching sleep/wake optimization, rather than trying to find individuals with particular traits. One gets the feeling that the highly tolerant single night shift worker would be older, have a low need for sleep, have a high sleep quality, be in good physical shape, and plan sleep strategically (using naps). If several night shifts occur in sequence, younger individuals may have an advantage., Presented at the RTO Human Factors and Medicine Panel, Venice, Italy, 3-4 June 99. This article is from ADA388183 Individual Differences in the Adaptability to Irregular Rest-Work Rhythms/Status of the Use of Drugs in Sleep-Wakefulness Management (les Differences entre individus concernant les facultes d'adaptation aux rythmes irreguliers activite-repos/Le point sur 1'utilisation des medicaments pour la gestion des periodes veille-sommeil)

This project addresses the design and prototyping of a multiple-capillary (ultimately 96- channel) electrophoresis system that will be ideally suited for the rapid and inexpensive analysis of allele-specific and DNA-sequence-based breast-cancer diagnostic tests with high throughput. A fully- automated capillary electrophoresis system (as opposed to an electrophoresis instrument) will perform the following steps without human intervention: 1) prepare and purify DNA, ideally from blood or tissue samples, 2) mix DNA samples with PCR reagents, 3) thermally cycle and purify PCR products, 4) mix PCR samples with DNA sequencing reagents, 5) perform sequencing reactions (thermal cycling typically) and purify the fragments, 6) pre-run the capillaries and load the samples, 7) perform the electrophoresis and detect the DNA bands, 8) record and analyze the data, and 9) flush the capillaries after the previous run and fill the capillaries with fresh polymer solution. The present study will automate steps 6-9 of this process.

All the necessary approvals from the different government agencies such as the Swedish Data Inspection Board, the Swedish Cancer Registry, the Swedish Death Registry and the Swedish Emigration Registry have been procured. Two abstractors have been employed and are presently working in the different archives. They are presently retrieving information from the ledgers and also tracing the women through the population ledgers. Until now, May 1, just over 100,000 female births have been assessed yielding the expected number of those born extreme premature and/or with a birth weight less than 2,000 grams. Thus, the retrieval process is within the framework of the time plan in our proposal and the tracing will be completed in April, 2000.

The studies described herein have focused on HIV variability, in particular on biologic and antigenic variability and its relevance for pathogenesis and for development of means for immune intervention. During the third year of the grant period we have intensified studies on molecular variability of HIV-1 and attempted to molecularly map biologic and antigenic determinants. Biologic characterization involved tests for replicative capacity, cytopathic effect and monocyte tropism of virus isolates and molecular clones, whereas antigenic characterization involved virus neutralization in autologous as well as heterologous system. By use of synthetic peptides, epitopes for virus neutralization and antibody dependent cellular cytotoxicity (ADCC) have been mapped in the envelope of HIV-1 and HIV-2. Variable region 3 (V3) of the HIV-1 envelope has been studied in relation to biological and antigenic variation of HIV-1 isolates and in relation to mother-to-child transmission of HIV-1.

The results show that: (a) the replicative capacity of HIV-2, like HIV-1, correlates with the severity of immunodeficiency; (b) molecular clones of a rapid/high HIV-1 isolate may have restricted replicative capacity compared to the genetically heterogenous isolate. Transfection of the same molecular clones into different cell types may yield progeny viruses with different phenotypes; (c) monocyte tropism is a general property of HIV isolates. In some cases silent infection is established. Silently infected monocyte/macrophages harbor virus that can be recovered by cocultivation with peripheral blood mononuclear cells.

Our program during the grant period has mainly been concerned with studies on: (1) Effect of antidotes such as l-hyoscyamine and atropine, diazepam, and Hl-6, separately and in combinations, on the dynamics of acetylcholine. We found that diazepam counteracts the increased rate of synthesis and release of acetylcholine induced by l-hyoscyamine. The addition of diazepam to conventional atropine-oxime therapy is therefore more effective in cases of organophosphate intoxications. Soman-intoxicated mice pretreated with the three-drug combination show no cholinergic symptoms and have a normal turnover of acetylcholine. (2) Influence of cholinergic substances on the functional muscarinic-receptor pool. Diazepam was found to decrease the size of the active receptor pool, which may lead to the observed effect on the dynamics of acetylcholine and choline.

Our program during the last year has mainly been concerned with studies on: the effect of diazepam on 1-hyoscyamine binding in the old stock of sick and healthy mice and new stock of healthy mice, the usability of 1- hyoscyamine binding for studies of specific receptor distribution in brain, effect of different combinations of antagonists (1-hyoscyamine, diazepam, H1-6) on acetycholine turnover, and duration of the effect of diazepam on acetylcholine turnover. There is a significant difference between the old and new stock of mice as far as the influence of diazepam on 1-hyoscyamine binding is concerned. In order that optimal parameters can be determined, therefore, the model needs further development in the new stock of mice. Keywords: Acetylcholine, Choline, Diazepam, Hyoscyamine, HI-6, Cholinesterase inhibitors, RA 5.

In intoxications by organophosphates conventional prophylaxis and therapy by atropine and oximes have shown to benefit from the addition of diazepam treatment. The implication of the cholinergic system in such intoxications prompted us to study the direct effects of diazepam on this system. In this context acetylcholine (ACh) turnover in mouse brain in vivo is a suitable cholinergic model. Turnover of ACh was studied by following the incorporation of Ch into ACh after i.v. injection of deuterated Ch. To study the functional muscarinic receptor pool, we have developed a method utilizing the pharmacologically 'active' antipode of atropine, l-hyoscyamine. By injecting this compound and measuring its concentration in the brain of mice, it is possible to study specific receptor binding. The concentration of l-hyoscyamine after equilibration is assumed to correspond to the size of the functional muscarinic receptor pool. At this concentration, l-hyoscyamine prevented oxotremorine (OT)-induced tremor, confirming its physiological relevance. The effects of diazepam on the ACh dynamics are consistent with diazepam's known potentiation of gamma-aminobutyric acid's inhibitory function in nerve transmission, with a decreased turnover rate of ACh and increased levels of ACh and Ch as results. The modulating effect of diazepam on the binding properties of muscarinic receptors is probably one of the mechanisms responsible for its profound effects in treatment of intoxications with anticholinesterases. Keywords: Antidotes, Cholinesterase inhibitors.

Monoclonal murine IgG antibodies against Gp120 from HIV-1 were found to induce significant enhancement of HIV-1 replication in vitro when used at low antibody concentrations. This enhancement was dependent on the presence of FcR:s for IgG and was completely blocked by anti-CD4 monoclonal antibodies. HIV-1 seropositive individuals at a low frequency do produce antibodies reactive with Gp12O and 'mimicking' CD4 molecules as evidenced by their reactivity with certain CD4 monoclonal antibodies. It was, however, not possible to show that such 'mimicking' antibodies were especially efficient in neutralizing, nor was presence of such antibodies linked to a particular clinical progression behaviour. Presence of antibodies to peptides covering the respective cysteins in the V3 loop of a particular HIV-1 isolate were found using two Italian cohorts to be positively linked to a reduced rate of transmission of virus from mother to child.

The present project is aiming to define components within the humoral immune response against (human immunodeficiency virus) which may act in a beneficial or detrimental manner for the host. Identification of such components may subsequently allow for the applied use of positive components or the elimination of negative reactions. One major focus of the project is to analyze the impact of humoral immunity in relation to the early events of HIV infection, that is, in the steps where virus particles or virus-producing cells come in contact with uninfected cells. In these studies we have developed assays allowing quantitative studies of early HIV binding and infection in presence or absence of antibodies against HIV. Using fresh monocytes or human monocytoid cell lines and subclones from such cells it has been possible to show that antibodies against HIV may at high concentrations neutralize the virus, that is, block infection in vitro. Keywords: HIV, Immunity benefit hazard, RA 1, CD4, Gp120, Viral enhancement, Antiserum. (jg)

Gp120 binding to CD4 requires beta-glycanase sensitive carbohydrate chains to retain binding ability. A 28Kd fragment of Gp120 has been identified with complete retention of CD4 binding capacity. Human monocytes can be readily infected with HIV. In the absence of anti-HIV antibodies, phagocytic or non-phagocytic monocytes are equally sensitive. Anti-HIV antibodies at certain high dilutions may enhance HIV proliferation in human monocytes although exact conditions causing such enhancement are not yet defined. Certain human HIV-seropositive individuals produce high titered antibodies which display molecular mimicry with CD4 and bind to Gp120. Such antibodies may tentatively be linked to good prognosis. Keywords: Human immunodeficiency virus, Immunosuppression, Immunity.

The development of X-ray analytical methods applicable to the study of problems in cell physiology has advanced considerably in recent years. One can distinguish between methods based on absorption, on diffraction and on emission of X-rays, and these three groups of techniques can now be applied to specimens in the micron range in size. In the present paper the most recent advances in X-ray micro-methods for cell chemical analysis will be briefly summarized. (Author), Sponsored in part by grants from Swedish Medical Research Council and Rockefeller Foundation.

To access publisher's full text version of this article click on the hyperlink below, INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field., Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.