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  • Rosfors, Stefan, et al. (författare)
  • Venous occlusion plethysmography in patients with post-thrombotic venous claudication
  • 2013
  • Ingår i: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 58:3, s. 722-726
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Post-thrombotic venous claudication is a serious condition that may be treated with iliac vein stenting or open surgery, and there is a need for hemodynamic tests in the preoperative evaluation. The purpose of this study was to describe the results of venous occlusion plethysmography in patients with venous claudication and to analyze the outflow curve to find variables that best describe the functional abnormality in this patient group.METHODS: Twenty-nine patients with previous deep venous thrombosis and with clinical evidence of venous claudication were retrospectively identified. The results of venous occlusion plethysmography in these patients were compared with results obtained in a group of 63 healthy control subjects of similar age and sex. Computerized strain-gauge plethysmography was used in a capacitance mode where the occlusion time is determined by an electronic detector allowing the maximal venous volume to be achieved in all limbs. Outflow volumes (OV1, OV4) and outflow fractions (OF1, OF4) were calculated at 1 and 4 seconds after cuff release. Outflow fraction is OV divided by maximal venous volume.RESULTS: Both outflow volumes and outflow fractions were significantly reduced in patients compared with healthy control subjects. Outflow fractions were more sensitive than outflow volumes in identifying patients with venous claudication. The most discriminating variable was OF4 that was reduced below the normal lower limit in 69% of the patients, most severely reduced in patients with severe claudication.CONCLUSIONS: Patients with venous claudication attributable to remaining post-thrombotic iliofemoral obstructive disease are characterized by a functional disturbance shown with venous occlusion plethysmography as a reduced venous outflow during the initial 4 seconds following cuff release in relation to their true maximal venous volume. Our results suggest that venous occlusion plethysmography can be a valuable tool in the preoperative workup for selection of patients with iliofemoral vein obstruction that may benefit from venous intervention.
  • Danielsson, Olof, 1963- (författare)
  • The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies : Implications for pathogenesis, classification and diagnosis
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background: Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.Aims: We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle  fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.The studies: We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.Conclusion: We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.
  • Enblad, Gunilla (författare)
  • A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia
  • 2018
  • Ingår i: ; 24:24, s. 6185-6194
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.
  • Eskelund, Christian W., et al. (författare)
  • 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2) : prolonged remissions without survival plateau
  • 2016
  • Ingår i: ; 175:3, s. 410-418
  • Tidskriftsartikel (refereegranskat)abstract
    • In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.
  • Husby, Simon, et al. (författare)
  • miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator
  • 2015
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 125:17, s. 2669-2677
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2trial (screening cohort). Prognosticmi RNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
  • Håkansson, Irene, 1976-, et al. (författare)
  • Complement activation in cerebrospinal fluid in clinically isolated syndrome and early stages of relapsing remitting multiple sclerosis
  • 2020
  • Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 340
  • Tidskriftsartikel (refereegranskat)abstract
    • To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p ≀ .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information.
  • Johansson, Hanna K, et al. (författare)
  • Metagenomic sequencing of "HPV-negative" condylomas detects novel putative HPV types.
  • 2013
  • Ingår i: Virology. - : Elsevier. - 1096-0341. ; 440:1, s. 1-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Condylomas are caused by human papillomavirus (HPV), but may in rare cases be "negative for HPV" by PCR. Metagenomic sequencing can be used for an unbiased assessment of the presence of virus. Ten swab sample pools, each containing four cases of "HPV-negative" condylomas, were subjected to metagenomic sequencing. One pool contained Molluscum contagiosum. Five pools contained HPV, of which three pools contained novel putative HPV-types. The 12 samples in these three pools were sequenced individually. Six of these contained HPV and two contained Molluscum contagiosum. Altogether, 1337 HPV-related reads were detected, representing 23 novel putative Gammapapillomaviruses, 10 established HPV types (genital HPV types 6, 57, 58 and 66, Betapapillomavirus types 5, 105, 124, and Gammapapillomavirus types 50, 130, 150) and two described HPV sequences (KC7 and FA69). Complete genomes of Gammapillomavirus FA69 and SE87 were compiled. Metagenomic sequencing reveals that seemingly "HPV-negative" condylomas contain known and previously unknown HPV types.
  • Malmström, Annika, 1957- (författare)
  • Studies for Better Treatment of Patients with Glioma
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.
  • Mansouri, Larry, et al. (författare)
  • Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
  • 2016
  • Ingår i: ; 128:23, s. 2666-2670
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
  • Nordström, Lena, et al. (författare)
  • SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma : a Nordic Lymphoma Group study
  • 2014
  • Ingår i: British Journal of Haematology. - 0007-1048 .- 1365-2141. ; 166:1, s. 98-108
  • Tidskriftsartikel (refereegranskat)abstract
    • Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment-related morbidity, additional parameters need to be evaluated to enable risk-adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki-67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.
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