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  • 1.
    Diczfalusy, Ulf
    et al.
    Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden .
    Olofsson, Katarina E
    Department of Clinical Sciences, Malmö University Hospital, Lund University, Sweden .
    Carlsson, Ann-Margreth
    Department of Clinical Sciences, Malmö University Hospital, Lund University, Sweden .
    Gong, Mei
    Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA .
    Golenbock, Douglas T
    Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA .
    Rooyackers, Olav
    Department of Anesthesia and Intensive Care, Karolinska University Hospital, Stockholm, Sweden .
    Fläring, Urban
    Department of Pediatric Anaesthesia and Intensive Care, Karolinska University Hospital, Stockholm, Sweden .
    Björkbacka, Harry
    Department of Clinical Sciences, Malmö University Hospital, Lund University, Sweden .
    Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide2009In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 50, no 11, p. 2258-2264Article in journal (Refereed)
    Abstract [en]

    During screening of genes upregulated by lipopolysaccharide (LPS; endotoxin) treatment of bone marrow-derived mouse macrophages, it was unexpectedly found that cholesterol 25-hydroxylase (Ch25h) was strongly upregulated. Treatment of macrophages with 10 ng/ml of LPS for 2 h resulted in a 35-fold increase in the expression of Ch25h. In contrast, LPS treatment did not increase the expression of Cyp27a1 or Cyp7b1. The increased Ch25h expression was found to be independent of Myeloid differentiation protein 88 signaling but dependent on Toll-like receptor 4 signaling. LPS treatment of macrophages caused a 6- to 7-fold increase in cellular 25-hydroxycholesterol concentration. When macrophages were treated with increasing concentrations of 25-hydroxycholesterol, a dose-dependent release of CCL5 into the culture medium was observed. Intravenous injection of LPS in eight healthy volunteers resulted in an increase in plasma 25-hydroxycholesterol concentration. The possibility is discussed that 25-hydroxycholesterol may have a role in the inflammatory response, in addition to its more established role in the regulation of cholesterol homeostasis.

  • 2. Forslund, Ola
    et al.
    Schwartz, Stefan
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Rydell, Roland
    Viral load and mRNA expression of HPV type 6 among cases with recurrent respiratory papillomatosis2016In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 126, no 1, p. 122-127Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES/HYPOTHESIS: To determine viral load of human papillomavirus type 6 (HPV6), physical state of HPV6-DNA, and transcription level of HPV6 E7-mRNA in laryngeal papilloma and in adjacent healthy mucosa.

    STUDY DESIGN: Case series.

    METHODS: A papilloma biopsy was collected from each of 25 adult patients with respiratory recurrent papillomatosis. From 14 of the 25 patients, we first collected a biopsy from healthy mucosa of the false vocal fold and another from the papilloma. Quantity of HPV6 and E7-mRNA was measured by polymerase chain reaction.

    RESULTS: For the papilloma, the median load of HPV6 was 41 copies/cell, and the lowest amount was 5.4 copies/cell. Human papillomavirus type 6 was detected in 50% (7/14) of the healthy mucosa, with a median of 1.1 copies/cell, and the highest amount was 6.6 copies/cell. Overall, viral load was higher in papilloma than in healthy mucosa (P < 0.05). The average HPV6 E2/E7-DNA ratio was 1.3, indicating an episomal state. Human papillomavirus type 6-mRNA was detected in all HPV6-DNA-positive samples. The transcription median ratio of HPV6-mRNA/HPV6-DNA was 1.5 in papilloma and 3.8 in healthy mucosa.

    CONCLUSION: The amount of HPV6-DNA was consistently higher in the papilloma than in healthy mucosa. The transcription level of HPV6 E7 mRNA was similar in the papilloma and in normal mucosa. We suggest that interfering with replication of HPV6 and suppression of HPV6 to fewer than five copies/cell may be curative.

    LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:122-127, 2016.

  • 3.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Gärskog, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 32579Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.

  • 4.
    Hertegård, Stellan
    et al.
    Department of Logopedics and Phoniatrics, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
    Hallén, Lars
    Department of Otorhinolaryngology, Central Hospital, Falun, Sweden.
    Laurent, Claude
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lindström, Elisabeth
    Department of Logopedics and Phoniatrics, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Testad, Per
    Department of Speech Pathology, Central Hospital, Falun, Sweden.
    Dahlqvist, Åke
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Cross-linked hyaluronan used as augmentation substance for treatment of glottal insufficiency: safety aspects and vocal fold function2002In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 112, no 12, p. 2211-2219Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine safety aspects and vocal fold function after vocal fold augmentation with a cross-linked hyaluronan derivative (hylan B gel) as compared with bovine collagen.

    STUDY DESIGN; A prospective, randomized trial.

    METHODS: Eighty-three patients with glottal insufficiency were treated with injection augmentation with hylan B gel and bovine collagen and were examined at 1, 6, and 12 months after treatment. Seventy patients with unilateral vocal fold paresis (n = 35) or atrophy (n = 35) were randomly assigned to receive either hylan B gel (n = 47) or collagen (n = 23) injections into one vocal fold. Thirteen patients with glottal insufficiency caused by scar defects or paresis resulting from malignant disease were included in a nonrandomized group and were treated only with hylan B gel. Evaluations were made from patients' subjective ratings (visual analogue scales), digitized videostroboscopic measurements, phonetograms, maximum phonation time, and phonation quotients.

    RESULTS: Twelve months after injections, the patients' self-ratings were significantly improved for both the hylan B gel and the collagen groups. In addition, the videostroboscopic measurements showed significantly improved glottal closure for both groups. However, for the hylan B gel group, vibration amplitude and glottal area variations were preserved, and this group showed significantly less resorption at the injected vocal fold edge. Furthermore, maximum phonation time had increased significantly for the hylan B gel patients (collagen, nonsignificant). No serious adverse events were observed; three patients injected with hylan B gel had temporary inflammation at the injection site, which resolved without sequelae.

    CONCLUSIONS: The results showed that both hylan B gel and collagen can be safely used for injection treatment of glottal insufficiency. Both treatments resulted in significantly improved voice as rated by the patients. However, the patients treated with hylan B gel showed better vocal fold status and longer maximum phonation time at 12 months after treatment as compared with patients treated with collagen.

  • 5.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Laurell, Göran
    Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papillomaManuscript (preprint) (Other academic)
    Abstract [en]

    Objectives: Sinonasal inverted papilloma (SIP) is a relatively rare disease, and its etiology is not understood. It is characterized by locally aggressive growth and a strong tendency to recur despite its benign histology.

    Aims: The aim of this study was to identify the presence of human papilloma virus (HPV) and its surrogate marker p16 in SIP tissue samples from a regional cohort.

    Material and Methods: Subjects were identified from our regional center cohort of 88 SIP patients treated between 1984-2014. From these subjects, 54 were included in this study.  Of these, 53 biopsies were analyzed with PCR, and 54 samples were immunohistochemically stained for p16. DNA was extracted from histopathologically verified SIP.  Genotype screening for 13 high risk-, 5 oncogenic and 6 low risk HPV types was performed using the PapilloCheck® HPV-screening test.

    Results: HPV analysis was successful for 38 of 53 samples. Of the 38 successfully analyzed samples, only 2 samples were positive for HPV 11.  Notably, p16 was present in the epithelia in all samples, and in the papilloma lesions in 37 samples.

    Conclusion: Since only 2 out of 38 SIPs were positive for HPV (type 11), and at the same time p16 was positive in epithelia in all samples and in 37 of 38 papilloma lesions of the samples, it is concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP. We are currently planning a prospective, multicenter study in order to increase the study power and in order to be able to better evaluate the clinical implications of HPV-and p16 in SIP.

  • 6.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Forslund, Ola
    Rydell, Roland
    Olofsson, Katarina
    Kirurgi vid respiratoriska papillom kräver god ventilation: personalen måste skyddas mot HPV-smitta – högfrekvent jetventilationsteknik kan ge bättre operationsresultat2016In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 113, no 41, article id D3CPArticle in journal (Refereed)
    Abstract [en]

    We describe a non-smoking patient with juvenile onset recurrent respiratory papillomatosis (RRP), genotyped as human papilloma virus (HPV)11. The patient has undergone a total of 133 surgical CO2 laser sessions, whereof the last 28 using a high frequency jet ventilation technique (HFJV). Since completed vaccination (Gardasil) in February 2013, the patient underwent one surgery in September 2013 and was considered being in remission. In March 2015, the patient was diagnosed with a left-sided lung cancer, genotyped as HPV11, a HPV subtype associated with a more aggressive disease with higher morbidity and mortality. We advocate that RRP patients should be ventilated with HFJV technique in order to enhance surgical radicality. Furthermore, the operation should be performed in operating theaters with high air exchange/minute, optimized local exhaust ventilation, and specific masks to ensure safe conditions for patients and staff.

  • 7.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Laurent, Claude
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Speech and Language Pathology and Audiology, University of Pretoria, South Africa.
    Laurell, Göran
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis2018In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 138, no 11, p. 1020-1027Article in journal (Refereed)
    Abstract [en]

    Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).

    Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.

    Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).

    Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.

    Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.

  • 8.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lymphocyte profile and cytokine mRNA expression in peripheral blood mononuclear cells of patients with recurrent respiratory papillomatosis suggest dysregulated cytokine mRNA response and impaired cytotoxic capacity2017In: Immunity, Inflammation and Disease, E-ISSN 2050-4527, Vol. 5, no 4, p. 541-550Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is a relatively rare, chronic disease caused by Human Papilloma Virus (HPV) 6 and 11, and characterized by wart-like lesions in the airway affecting voice and respiratory function. The majority of HPV infections are asymptomatic and resolve spontaneously, however, some individuals are afflicted with persistent HPV infections. Failure to eliminate HPV 6 and 11 due to a defect immune responsiveness to these specific genotypes is proposed to play a major role in the development of RRP.

    METHODS: We performed a phenotypic characterization of peripheral blood mononuclear cells (PBMC) collected from 16 RRP patients and 12 age-matched healthy controls, using immunoflow cytometry, and monoclonal antibodies against differentiation and activation markers. The cytokine mRNA profile of monocytes, T helper-, T cytotoxic-, and NK cells was assessed using RT-qPCR cytokine analysis, differentiating between Th1-, Th2-, Th3/regulatory-, and inflammatory immune responses.

    RESULTS: We found a dominance of cytotoxic T cells, activated NK cells, and high numbers of stressed MIC A/B expressing lymphocytes. There was an overall suppression of cytokine mRNA production and an aberrant cytokine mRNA profile in the activated NK cells.

    CONCLUSION: These findings demonstrate an immune dysregulation with inverted CD4(+) /CD8(+) ratio and aberrant cytokine mRNA production in RRP patients, compared to healthy controls.

  • 9.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Schindele, Alexandra
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Östersunds hospital, Sweden.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Sandström, Karl
    Laurell, Göran
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease2019In: Laryngoscope Investigative Otolaryngology, E-ISSN 2378-8038, Vol. 4, no 3, p. 285-291Article in journal (Refereed)
    Abstract [en]

    Objectives: Due to their location in the entrance of the aero‐digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein‐Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs.

    Aim: To investigate if tonsils are infected with HPV and EBV, to study the co‐expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease.

    Materials and Methods: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER‐ISH (Epstein‐Barr encoding region–in situ hybridization).

    Results: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER‐positive cell was seen in 65% of cases. Larger numbers of EBER‐expressing cells were only seen in two cases.

    Conclusion: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship.

    Level of Evidence: Cross‐sectional study

  • 10.
    Karlsson, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    van Doorn, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Control of phonatory onset and offset in Parkinson patients following deep brain stimulation of the subthalamic nucleus and caudal Zona Incerta2012In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 18, no 7, p. 824-827Article in journal (Refereed)
    Abstract [en]

    Laryngeal hypokinesia is a common symptom in Parkinson’s disease (PD) that affects quality of life. Deep brain stimulation (DBS) is well recognized as a complementary method for treatment of motor symptoms in PD but the outcomes on patients’ control over phonatory alternation have yet not been clearly elucidated. The present study examined the effect of subthalamic nucleus STN-DBS (n=8, aged 51-72 yrs; median=63 yrs) and caudal Zona incerta cZi-DBS (n=8,aged 49-71 yrs; median=61 yrs) on control of onset and offset of phonation in connected speech. The patients were evaluated in a preoperatively (Med ON, 1.5 times the ordinary Levodopa dose) and 12 months postoperatively (Med ON, ordinary Levodopa dose). The results provided evidence of a progressive reduction in the ability to manifest alternations between voicing and voiceless states in a reading task. Mean proportion produced with inappropriate voicing increased from 47.6% to 55.3% and from 62.9% to 68.6% of the total duration for the two groups of patients between Pre-op and Post-op, Stim OFF evaluations. The medial and final parts of the fricative were more affected than the initial part, indicating an increased voicing lead into the following vowel. We propose that this reduction in phonatory control is be due to either progression of the disease, an effect of reduced Levodopa dosage or a microlesional effect. Patients’ proficiency in alternating between voiced and voiceless states in connected speech remained unaffected by both STN-DBS and cZi-DBS.

  • 11.
    Karlsson, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Malinova, Elin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Voice Tremor Outcomes of Subthalamic Nucleus and Zona Incerta Deep Brain Stimulation in Patients With Parkinson Disease2018In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588Article in journal (Refereed)
    Abstract [en]

    ObjectivesWe aimed to study the effect of deep brain stimulation (DBS) in the subthalamic nucleus (STN) and caudal zona incerta (cZi) on level of perceived voice tremor in patients with Parkinson disease (PD).

  • 12.
    Karlsson, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Doorn, Jan van
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Pitch variability in patients with Parkinson’s disease: effects of deep brain stimulation of caudal zona incerta and subthalamic nucleus2013In: Journal of Speech, Language and Hearing Research, ISSN 1092-4388, E-ISSN 1558-9102, Vol. 56, no 1, p. 150-158Article in journal (Refereed)
    Abstract [en]

    Objective The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of con- nected speech in patients with Parkinson’s disease (PD).

    Methods Sixteen patients were evaluated preoperatively and 12 months after DBS surgery. Eight pa- tients were implanted in the STN (aged 51-72 yrs; xC=63 yrs). Six received bilateral implanta- tion and two unilateral (left) implantation. Eight patients were bilaterally implanted in the cZi (aged 49-71 yrs; xC=60.8 yrs). Preoperative assessments were made after an L-Dopa challenge (approximately 1.5 times the ordinary dose). All postoperative examinations were made off and on stimulation, with a clinically optimized dose of L-dopa. Measurements of pitch range and var- iability were obtained from each utterance in a recorded read speech passage.

    Results Pitch range and coefficient of variation showed an increase in patients under STN-DBS. Patients under cZi-DBS showed no significant effects of treatment on investigated pitch properties.

    Conclusions STN-DBS was shown to increase pitch variation and range. The results provided no evidence of cZi-DBS having a beneficial effect on PD patients’ pitch variability. 

  • 13.
    Karlsson, Fredrik
    et al.
    Umeå University, Faculty of Arts, Department of language studies. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Blomstedt, Patric
    Linder, Jan
    Nordh, Erik
    van Doorn, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Articulatory closure proficiency in Parkinson's disease patients following deep brain stimulation of the subthalamic nucleus and caudal zona incerta.2014In: Journal of Speech, Language and Hearing Research, ISSN 1092-4388, E-ISSN 1558-9102, Vol. 57, p. 1178-1190Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on Parkinson's disease patients' proficiency in achieving oral closure and release during plosive production. METHODS Nineteen patients were evaluated preoperatively and 12 months after DBS surgery. Nine patients were implanted in the STN, seven bilaterally and two unilaterally (left). Ten were bilaterally implanted in the cZi. Postoperative examinations were made off and on stimulation. All patients received simultaneous L-dopa treatment in all conditions. For a series of plosives extracted from a reading passage, absolute and relative measures of duration of frication and amplitude of plosive release were compared between conditions within each treatment group. RESULTS Relative duration of frication increased in voiceless plosives in the on stimulation condition in cZi patients. Similar trends were observed across the data set. Duration of pre-release frication and the release peak prominence increased in voiceless plosives on stimulation for both groups. CONCLUSIONS The increased release prominence suggests that patients achieved a stronger closure gesture due to DBS, but that the increased energy available resulted in increased frication.

  • 14.
    Kulneff, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Sundstedt, Stina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    van Doorn, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Deep brain stimulation: effects on swallowing function in Parkinson's disease2013In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, no 5, p. 329-336Article in journal (Refereed)
    Abstract [en]

    Objective: In patients with Parkinson’s disease (PD), deep brainstimulation of the subthalamic nucleus (STN DBS) is well recognizedin improving limb function, but the outcome on swallowing functionhas rarely been studied. The aim of this work was to evaluate theeffect of STN DBS on pharyngeal swallowing function in patientswith PD using self-estimation and fiberoptic endoscopic evaluation ofswallowing.

    Methods: Eleven patients (aged 41–72, median 61 years)were evaluated preoperatively and at 6 and 12 months after STN DBSsurgery. All patients were evaluated with self-estimation on a visualanalogue scale, and eight of them with a fiberoptic endoscopicexamination with a predefined swallowing protocol includingRosenbek’s Penetration-Aspiration Scale, Secretion Severity Scale,preswallow spillage, pharyngeal residue, and pharyngeal clearance.

    Results: The self-assessments of swallowing function revealed asubjective improvement with STN DBS stimulation, whereas the datafrom the swallowing protocol did not show any significant effect ofthe STN DBS treatment itself. The prevalence of aspiration was notaffected by the surgery.

    Conclusions: The results show thatswallowing function was not negatively affected by STN DBS and therisk of aspiration did not increase. Self-estimation of swallowingfunction showed a subjective improvement due to stimulation.

  • 15.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Arvidsson, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Recurrent respiratory papillomatosis in northern Sweden: Clinical characteristics and practical guidance2015In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 135, no 10, p. 1058-1064Article in journal (Refereed)
    Abstract [en]

    Conclusion: Recurrent respiratory papillomatosis (RRP) patients with high surgical treatment frequency (>= 1/year, HF) were significantly younger and had a more widespread laryngeal disease compared to a low frequency treated group (< 1 treatment/year, LF). This study confirms the existence of a clinical RRP group, not primarily related to HPV sub-type, but more care-intensive and in need of more vigilant follow-up. Objectives: RRP is associated with high morbidity due to its influence on breathing and voice. The purpose of this study was to characterize RRP patients in northern Sweden and investigate possible predictor factors affecting therapeutic needs. Method: Patients from the regional referral area (northern Sweden) were categorized for age, disease duration, juvenile or adult onset, profile of disease development, number of surgical sessions in relation to disease duration, laryngeal deposition of papilloma, gender, and HPV sub-types, in order to identify patients with increased need for frequent surgical treatment. Results: The median age of the RRP patients (n = 48) was 44.5 years; 34 (71%) were males and 14 (29%) females, most were infected with HPV 6. Patients with high surgical treatment frequency/year were significantly younger and showed more widespread papillomatous vegetation in the larynx, compared to the low frequency treated group.

  • 16.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Voice and quality of life in patients with recurrent respiratory papillomatosis in a northern Sweden cohort2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, ISSN 1651-2251 (online), Vol. 134, no 4, p. 401-406Article in journal (Refereed)
    Abstract [en]

    Abstract Conclusion:

    The frequency of operations, age at onset, gender and subtype of the human papilloma virus (HPV) may be used as factors to predict voice disability.

    Objectives:

    Patients with recurrent respiratory papillomatosis (RRP) are characterized by morbid consequences due to a lifelong repetitive influence on voice and breathing ability and the need for recurrent surgical treatments. The aim of the study was to measure the quality of voice and life using evaluated and validated questionnaires in a northern Sweden RRP population.

    Methods:

    A total of 27 consecutive patients with RRP (age 21-71 years, median 47 years) were evaluated 3 months postoperatively (CO2 laser treatment) using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in an RRP population. The values were compared to historical normative data, VHI ≤ 20.

    Results:

    Patients that underwent more than one operation per year were younger (p = 0.028) than those treated less frequently. The mean VHItotal score in patients with RRP was 39.3, indicating a statistically significant impairment of voice quality (p < 0.001) as compared with normal subjects. Voice dysfunction was observed in 21 patients (78%). Significantly lower values than the normal population regarding the quality of life in patients with RRP were obtained in the domain of social functioning (p = 0.029). Females, patients with frequent surgical treatment sessions and patients with the high-risk HPV types scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. The results should be interpreted with caution due to the limited number of subjects.

  • 17.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus2015In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 10, no 6, p. 3565-3572Article in journal (Refereed)
    Abstract [en]

    The incidence rate of tonsillar cancer is increasing worldwide. The current study identifies a parallel increase in the incidence of tonsillar cancer, human papilloma virus (HPV) and p16 expression among a population from northern Sweden, a sparsely populated area, confirming the strong association between p16 and HPV infection in tonsillar tissue. Data from the Swedish Cancer Registry was assessed to identify cases of tonsillar cancer in the northern territorial area of Sweden. HPV DNA was extracted from paraffin embedded diagnostic biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of p16 was identified by immunochemistry. Patients were grouped into urban or rural residence categories. A total of 214 cases were identified, comprising 155 (72.4%) men and 59 (27.6%) women, and 65 of these patients, who presented between 2000 and 2012, were analyzed. The overall median age for the analyzed patients was 58 years; 48 (74%) were males (median age, 57.5 years) and 17 (26%) were females (median age, 65 years). Of the 65 specimens, 59 (91%) were positive for HPV, and 62 (95%) expressed p16. The incidence of tonsillar cancer in the cohort demonstrated a 2-fold increase between 1990 and 2013; specifically, a 2.7-fold increase was observed in men whilst the female group exhibited only a small increase. These findings demonstrate a strong association between p16 expression and HPV infection in tonsillar malignancies. The incidence of HPV-positive tonsillar cancer has increased in recent years, even in sparsely populated regions, as demonstrated in northern Sweden.

  • 18.
    Louise, Johansson
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Sofia, Möller
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Doorn, Jan van
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Karlsson, Fredrik
    Umeå University, Faculty of Arts, Department of language studies. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Word-level intelligibility after caudal zona incerta stimulation for Parkinson’s disease2014In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 130, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

    Objectives – To investigate the effect of caudal zona incerta-deep brain stimulation (cZi-DBS) on word-level speech intelligibility in patients with Parkinson’s disease, under both an optimal listening condition and a simulated more naturalistic listening condition.

    Materials and methods – Spoken single words were extracted from read samples collected from 10 bilaterally implanted patients with PD pre- and post-cZi-DBS. Intelligibility was assessed through a transcription task performed by 32 naive listeners under two listening conditions: (i) with low-amplitude conversational speech added as background and (ii) with no added background noise. The listeners′ responses were scored in terms of agreement with the intended words.

    Results – Post-operatively, the total intelligibility score was significantly lower when cZi stimulation was switched on compared with off, for both listening conditions (with and without added background noise). Intelligibility was also significantly lower on stimulation compared with preoperative recordings, but only when assessed in the listening condition without background noise. The listening condition with added background noise resulted in significantly lower intelligibility scores compared with the no added noise condition for all stimulation conditions.

    Conclusions – The results of this study indicate that cZi-DBS in patients with PD can be detrimental to word-level speech intelligibility. 

  • 19.
    Lundgren, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Saeys, Thomas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Karlsson, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zafar, Hamayun
    Umeå University, Faculty of Medicine, Department of Odontology, Clinical Oral Physiology.
    Doorn, Jan van
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Deep brain stimulation of caudal zona incerta and subthalamic nucleus in patients with Parkinson’s disease: effects on voice intensity2011In: Parkinson’s Disease, ISSN 2042-0080, Vol. 2011, p. 658956-Article in journal (Refereed)
    Abstract [en]

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson’s disease (PD) affects speech in small, inconsistent ways. However, voice intensity generally increases. Recently the caudal zona inserta (cZi) has been investigated as an alternate target in DBS treatment of PD. The effects of cZi-DBS on voice intensity have not yet been investigated. The aim of this study was to compare the voice intensity effects of cZi-DBS and STN-DBS in PD patients. Voice intensity during reading and intensity decay during rapid syllable repetition were measured for eight STN-DBS and eight cZi-DBS patients in a pre-surgical baseline and then on- and off-stimulation 12 months after surgery. Voice intensity on-stimulation was larger than off-stimulation for the STN-DBS patients, but smaller for the cZi-DBS patients. There were no significant changes in intensity decay. The results suggest that cZi and STN are involved differently in neuromuscular control of the speech respiratory subsystem.

  • 20. Nellgård, Per
    et al.
    Ejnell, Hasse
    Olofsson, Katarina
    Hallén, Katarina
    Schien, Matthias
    Papatziamos, Georgios
    Hellgren, Johan
    National recommendations for tracheotomy and for tracheostomy care2017In: Abstracts from the Scandinavian Society of Anesthesiology and Intensive Care Medicine 34th Congress, John Wiley & Sons, 2017, Vol. 61, p. 1034-1035, article id 118Conference paper (Refereed)
    Abstract [en]

    Background: Every year 2000 tracheotomies are performed in Sweden. Severe or lethal complications and shortcomings in the valuation of risks pre-, per- and postoperatively occurs. This work intends, based on best available evidence, to reduce injuries related to tracheotomy.

    Material and Method: Anaesthesiologists and otorhinolaryngologists from University Hospitals compiled a document with guidelines to reduce risks to cause severe complications and death at tracheotomy operations. Landstingens Omse- € sidiga Fors € €akringsbolag (LOF, Swedish insur- € ance company for publicly funded health care providers) also took part.

    Results: Surgical tracheotomy is recommended for children and adults with known or expected difficult intubation such as Cormack-Lehane IIIIV, short/thick neck, distance between cricoid cartilage and jugulum<15 mm, neck circumference >45 cm, tumors in head and neck area, BMI >35, rheumatoid arthritis, severe obstructive sleep apnea syndrome, high intracranial pressure, unstable neck fracture and coagulopathies. Acta Anaesthesiologica Scandinavica 61 (2017) 962–1062 1034 ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd SSAI ABSTRACTS Percutaneous tracheostomy (PCT) could be performed in intensive care patients. A tracheotomy cannula with an inner cannula should be used. Common complications include acute obstruction of tracheal cannula, dislocation, emphysema of the neck, trauma to dorsal tracheal wall. Some deaths have occurred due to lack of education to perform a surgical tracheotomy in patients where percutaneous tracheostomy were not possible to perform.

    Conclusion: Tracheotomy should be performed at hospitals where competence exist for surgical tracheotomy, including patients with difficult anatomy, regardless of the tracheotomy technique. At each hospitals the distribution between percutaneous and surgical tracheostomies must be weighted as to preserve overall competence for both techniques. A guideline of acute tracheal cannula occlusion is presented (Figure). 

  • 21.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Immune cells in human pharyngeal and palatine tonsils and in the uvula: tissue distribution, cellular composition and functional properties1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The adenoid (pharyngeal tonsil), the palatine tonsils and the uvula are strategically located at the entrance of the upper airodigestive tract. By virtue of their location they are incessantly exposed to inhaled and ingested antigens. Severe nasal obstruction, otitis media with effusion, recurrent tinsillitis and obstructive airways during sleep are conditions often due to diseases in these organs.

    To advance our knowledge about the etiology and pathogenesis of these diseases, we have compared immune cell composition, cytokine expression and microbial colonisation in adenoids from children with hypertrophic obstructive adenoid (HOA) and chronically infected adenoid (CIA). Similarly, we compared immune cell composition in palatine tonsils from children with idiopathic tonsillar hypertrophy and recurrent tonsillitis. Finally, we wanted to characterise the human uvula from an immunological point of view, which had previously not been done. Its composition and distribution of immune cells, its cytokine profile, connective tissue elements and ultrastructure was studied.

    When comparing adenoids from children with HOA and CIA, the most striking finding was their similarity. A cytokine profile that was independent of diagnosis but seemed characteristic for the adenoid emerged. T cell expression of IL-5 and TGF-β1 but not IL-4 suggested an ongoing humoral response driven by a "mucosal TH2" cell. αβ T cells also expressed TNF-α, IFN-γ and IL-2, indicating a concomitant cell mediated response. Cell mediated immune responses often reflect viral infection. In line with this, adenovirus DNA was found in 80% of the adenoid samples. Furthermore, IL-6, IL-8 and TNF-α expressed in the non-T cell fraction suggested that the tissue macrophages were activated. TNF-α, IFN-γ and TGF-β1 were expressed by γδ T cells. The following differences between HOA and CIA were however, noted: i) most intraepithelial lymphocytes were CD8+ γδ T cells in HOA, while CD8+ αβ T cells dominated intraepithelially in CIA; ii) the number of follicles was twice as high in CIA as in HOA; iii) there were signifacantly more granulocytes in the interfollicular area in CIA than in HOA; iv)IL-6 mRNA expressing γδ T cells were only found in HOA and v) there was a tendency of higher TNF-α mRNA levels in non-T cells of CIA compared to HOA. The following scenarios emerge: in CIA there appears to be an inadequate first line of defence, with a low frequency of intraepithelial γδ T cells and a high frequency of cytotoxic CD8+ αβ T cells eliminating infected epithelial cells. Togehter, these two conditions cause a "leaky" epithelium, allowing infiltration of microbes into the underlying tissue and subsequent recruitment of granulocytes and follicle formation initiated by activated macrophages. In HOA, activated intraepithelial γδ T cells appear to be involved in antimicrobial defence reactions and surveillance of the epithelium.

    The difference in leukocyte profiles between tonsils from patients subjected to surgery due to idiopathic tonsillar hypertrophy or recurrent tonsillitis was limited to the surface epithelium. CD8+ γδ T cells utilising the unusual combination Vδ1/Vγ9 in their T cell receptor constituted the majority of intraepithelial lymphocytes in both groups. However, the frequency of these cells was significantly higher in recurrent tonsillitis. These results suggest that CD8+ Vδ1/Vγ9+ γδ T cells are characteristic of palatine tonsils and selectively expanded in recurrent tonsillitis. These γδ T cells may be involved in clearing infectious bacteria at the surface of the tonsil.

    Tissue macrophages, αβ T cells, γδ T cells, mast cells and B cells constituted, in declining order, the immune cell populations in the uvula. No fillicle-like structures were present. Most T cells had a CD8+ CD28-TCR-αβ+ phenotype, suggesting a down-regulatory function. Production of the down-regulatory cytokine TGF-β was also noted. This is consistent with the hypothesis that the uvula contributes to the development of mucosal tolerance. Furthermore, the uvula seems to be protected from pathogens penetrating the internal milieu by a subepithelial barrier of γδ T cells and macrophages. TNF-α secreting immune cells were found at this location. TNF-α and TGF-β may cause tissue fibrosis, TNF-α indirectly by stimulating mast cells to release histamine. Tissue fibrosis in conjunction with water binding to hyaluronan present in the connective tissue is the most likely explanation for the observed enlargement of the uvula in patients with sleeping disorders.

  • 22.
    Olofsson, Katarina E
    et al.
    aDepartment of Clinical Sciences, Experimental Cardiovascular Research, CRC Lund University, Malmö University Hospital, Malmö, Sweden.
    Andersson, Linda
    aDepartment of Clinical Sciences, Experimental Cardiovascular Research, CRC Lund University, Malmö University Hospital, Malmö, Sweden.
    Nilsson, Jan
    aDepartment of Clinical Sciences, Experimental Cardiovascular Research, CRC Lund University, Malmö University Hospital, Malmö, Sweden.
    Björkbacka, Harry
    aDepartment of Clinical Sciences, Experimental Cardiovascular Research, CRC Lund University, Malmö University Hospital, Malmö, Sweden.
    Nanomolar concentrations of lysophosphatidylcholine recruit monocytes and induce pro-inflammatory cytokine production in macrophages2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 370, no 2, p. 348-352Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidylcholine (LPC) has been attributed a pro-inflammatory role in atherosclerosis. Cell culture studies have identified stimulation of cytokine expression and chemotaxis by micromolar (muM) concentrations of LPC. In the present study we have investigated if LPC, in similarity with many other lipid mediators, has pro-inflammatory effects also at nanomolar (nM) concentrations. Cultured mouse bone marrow derived and RAW264.7 macrophages exposed to LPC demonstrated two peaks of increased MIP-2 release and mRNA expression; one at 0.1-10nM and another at muM concentrations. Both concentration ranges of LPC were also found to stimulate THP-1 monocyte chemotaxis. However, stimulation of the cells with muM concentrations of LPC may cause cell injury as increased release of lactate dehydrogenase was observed. Our findings demonstrate two peaks of LPC-induced pro-inflammatory activity, one in the nM and one in the muM range, and indicate that the latter may involve a stress response to lipid cytotoxicity.

  • 23.
    Olofsson, Katarina E
    et al.
    Department of Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden.
    Björkbacka, Harry
    Department of Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden.
    Atherosclerosis: cell biology and lipoproteins2009In: Current Opinion in Lipidology, ISSN 0957-9672, E-ISSN 1473-6535, Vol. 20, no 1, p. 82-84Article in journal (Refereed)
  • 24. Olofsson, Katarina
    et al.
    Hellström, S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Abundance of intraepithelial gamma delta T cells in hypertrophic obstructive but not in chronically infected adenoids1996In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 106, no 2, p. 396-403Article in journal (Refereed)
    Abstract [en]

    Using quantitative morphometric analysis of immunohistochemically stained tissue sections we compared hypertrophic obstructive adenoids (HOA, n = 10) from children without middle ear disease with chronically infected adenoids (CIA, n = 10) from children with middle ear disease. gamma delta T cell receptor (TCR)+ cells constituted the dominating T cell population in the surface epithelium of HOA, while alpha beta TCR+ cells were the dominating intraepithelial T cell population in CIA. Intraepithelially CD8+ cells dominated over CD4+ cells in both diseases. Intraepithelially B cells were not detected. The cellular composition of follicles, with B cells dominating followed by activated CD4+ alpha beta TCR+ cells, was the same in both groups. However, the number of follicles in CIA was twice as many as in HOA. In the deeper interfollicular areas granulocytes were more abundant in CIA than in HOA. The latter two findings suggest a more pronounced inflammatory response in the adenoids of patients with middle ear disease. There was no significant difference with regard to pathogenic bacterial strains colonizing the adenoid surface when comparing the two patient groups. These results suggest that in patients with HOA gamma delta TCR+ T cells help to maintain the integrity of the surface epithelium, thereby preserving its protective function. On the basis of our results we speculate that CIA have a malfunctioning defence, thereby facilitating long-standing infections deep in the adenoid. This may be the main reason for development of middle ear disease and an indication for adenoidectomy in patients with CIA.

  • 25.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hellström, S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Human uvula: characterization of resident leukocytes and local cytokine production2000In: Annals of Otology, Rhinology and Laryngology, ISSN 0003-4894, E-ISSN 1943-572X, Vol. 109, no 5, p. 488-496Article in journal (Refereed)
    Abstract [en]

    Upper airway infections often lead to macroscopic changes in the architecture of the uvula. Using immunomorphometric analysis, we investigated the frequency and distribution of immune cells and of cytokine-producing cells in uvular samples. Tissue macrophages, alphabeta T cells, gammadelta T cells, and B cells were, in declining order, the main cell populations. Gammadelta T cells and B cells exhibited reciprocal localization, with almost all gammadelta T cells residing in the vicinity of the epithelium, and all B cells in the glandular area. The presence of cells expressing the suppressor phenotype CD8+CD28- alphabeta T cells is suggested. Fifteen to twenty-five percent of the immune cells expressed the down-regulatory cytokine tumor growth factor beta. Most macrophages were located subepithelially, in the vicinity of the basal lamina. The composition and cytokine profile of leukocytes in the tissue suggest that the uvula may be a site, additional to the jejunal mucosa, for induction of mucosal tolerance to inhaled and ingested antigens. Concomitantly, the uvula appears to be protected from invasion of microbial pathogens by a subepithelial barrier of macrophages and gammadelta T cells.

  • 26.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hellström, S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The surface epithelium of recurrent infected palatine tonsils is rich in gammadelta T cells1998In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 111, no 1, p. 36-47Article in journal (Refereed)
    Abstract [en]

    Using a large panel of MoAbs in quantitative morphometric analysis of immunohistochemically stained tissue sections, we compared the frequency and distribution of immune cells in palatine tonsils from patients with recurrent tonsillitis (RT) and patients with idiopathic tonsillar hypertrophy (ITH). We found that differences between the two patient groups in leucocyte populations were limited to the surface epithelium, whereas the cellular composition of interfollicular and follicular areas was similar. Most intraepithelial lymphocytes were CD8+ T cells in both groups. However, the number of intraepithelial T cells was significantly higher in RT compared with ITH. This was due to a selective increase in the number of intraepithelial CD8+ gammadelta T cells utilizing Vdelta1 and Vgamma9. In both patient groups the majority of the intraepithelial gammadelta T cells expressed Vdelta1 and Vgamma9. Subepithelially, gammadelta T cells utilizing Vgamma9 dominated over cells utilizing Vgamma8, while equal proportions expressed Vdelta1 and Vdelta2. These results suggest that cells utilizing the otherwise rare combination Vdelta1/Vgamma9 in their T cell receptors (TCR) may constitute a major gammadelta T cell population in palatine tonsils and are probably reactive to antigens specific to the tonsillar milieu. Furthermore, they indicate that preferentially this gammadelta T cell subpopulation is involved in immune reactions within the surface epithelium in RT. We speculate that gammadelta T cells are involved in clearing infectious bacteria at the tonsillar surface and in limiting inflammatory responses in the tonsils. Both local expansion and infiltration of blood cells probably contribute to the high numbers of gammadelta T cells in RT patients.

  • 27.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Studie av larynxpapillom i norra Sverige: två fall av onkogena HPV bland 26 patienter2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 21, p. 1187-1189Article in journal (Refereed)
    Abstract [en]

    Laryngeal papilloma is associated with human papillomavirus (HPV) 6, 11, 16, 18 and 31. The variation in the frequency of surgical treatment between patients for the same subtypes of HPV is inconsistent and poorly understood. Comparisons of the female laryngeal papilloma group (n?=?8, median age 46 yrs) with the male (n= 18, median age 32 yrs) with respect to gender, age, time of disease, period of life for diagnosis, disease progression profile, frequency of surgery (CO2 laser) during time of disease, localisation of papilloma in the upper airway and HPV subtype did not reach significance. In contrast the comparison between the high frequency (Ž 1 treatment/yr, n?=?11, median age 31 yrs) and low frequency (<1 treatment/yr, n?=?15 median age 45 yrs) treatment groups with regard to the same parameters as the female-male comparison, showed a clear-cut higher median age in the low frequency group (P?=?0,01).

  • 28.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Mattsson, C
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hellström, S
    Structure of the human uvula1999In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 119, no 6, p. 712-717Article in journal (Refereed)
    Abstract [en]

    Eleven uvular biopsies were investigated for their morphology, the presence of mast cells and the distribution of hyaluronan and its major ligand CD44. Three microanatomical sites--surface epithelium, subepithelial area and area of glands--were examined. The oral side of the uvula was covered by a 15-20 cell thick layer of keratinized/parakeratinized surface epithelium, firmly anchored to the underlying connective tissue by connective tissue papillae. The width of the intercellular spaces in the epithelium increased toward the basal lamina, a location that exhibited intense hyaluronan and anti-CD44 staining. Most mast cells were located in the vicinity of blood vessels, at which sites there was high staining intensity of hyaluronan. Tissue mast cells could also be observed in the connective tissue septa enclosing the acini. Glands and muscle fibres became more sparse from the proximal part of the uvula to the distal end, while the amount of connective tissue increased. The localization and architecture of connective tissue elements and mast cells are consistent with the ability of the uvula to resist mechanical stresses and to develop oedema and fibrosis, respectively.

  • 29.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Sjöstedt, M
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hellström, S
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The cytokine profile of T cells in the pharyngeal tonsil of childrenManuscript (preprint) (Other academic)
  • 30.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Van Doorn, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Kulneff, Linda
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Djup hjärnstimulering vid dysfagi hos parkinsonpatienter: den självskattade sväljningsfunktionen förbättrades i pilotstudie2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 17, p. 1150-1154Article in journal (Other academic)
  • 31.
    Sgaramella, Nicola
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Naples, Italy.
    Coates, P. J.
    Dundee, U.K..
    Strindlund, K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Loljung, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Colella, G.
    Naples, Italy.
    Laurell, G.
    Uppsala, Sweden.
    Rossiello, R.
    Naples, Italy.
    Muzio, L. L.
    Foggia, Italy.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Tartaro, G.
    Naples, Italy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Danielsson, Karin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Fåhraeus, R.
    Brno, Czech Republic; Paris, France.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-12015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 113, no 2, p. 321-326Article in journal (Refereed)
    Abstract [en]

    Background: Tongue squamous cell carcinoma (TSCC) is increasing in incidence, especially among young patients and preferably females. Infection with human papilloma virus (HPV) has been suggested as a cause of SCC in the head and neck, and the proportion of oropharyngeal cancers caused by HPV has steadily increased. Methods: Samples from 109 patients with primary TSCC were analysed for the presence of HPV16 by in situ hybridisation and for expression of its surrogate marker p16 and the HPV receptor syndecan-1 by immunhistochemistry. Results: No evidence of HPV16 DNA was observed in the tumours, although one-third showed p16 staining. There was no difference in the expression of the primary HPV receptor, syndecan-1, between TSCC and a group of tonsil SCC. Conclusion: Whereas p16 is expressed in some TSCCs, HPV16 is undetectable, therefore, p16 cannot be used as a surrogate marker for high-risk HPV-infection in this tumour. Despite presence of the HPV-receptor syndecan-1 in TSCC, HPV prefers the tonsillar environment. Lack of p16 associates with worse prognosis primarily in patients aged <= 40 years with tongue SCC. The improved prognosis seen in p16-positive TSCC can be due to induction of a senescent phenotype or an inherent radiosensitivity due to the ability of p16 to inhibit homologous recombination repair.

  • 32.
    Sundstedt, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Holmén, Lina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Rova, Elin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Swallowing safety in Parkinson's disease after zona incerta Deep Brain Stimulation2017In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 7, no 6, article id e00709Article in journal (Refereed)
    Abstract [en]

    Objectives: The objective of this study was to examine swallowing function in patients with Parkinson's disease before and after caudal zona incerta deep brain (cZI DBS) surgery. The aims were to examine the effect of cZI DBS on swallowing safety regarding liquid and solid food, as well as to identify the effect of cZI DBS on body mass index (BMI) and specific items from part II of the Unified Parkinson's Disease Rating Scale (UPDRS).

    Materials and Methods: The median age of the 14 patients was 57 years (range 46–71), with a median disease duration of 6 years (range 2–13). The present sample is an extension of a previous report, into which six additional patients have been added. Fiber endoscopic examinations of swallowing function, measures of BMI, and evaluation of UPDRS part II items were made before and 12 months after surgery, with and without activated DBS.

    Results: There were no significant changes due to cZI DBS regarding penetration/aspiration, pharyngeal residue or premature spillage (> .05). Median BMI increased by +1.1 kg/m2 12 months after surgery (= .01, = .50). All reported specific symptoms from the UPDRS part II were slight or mild. A significant improvement regarding handling of utensils was seen 12 months postoperatively (= .03, = −.42).

    Conclusions: Caudal zona incerta DBS was found not to have a negative impact on swallowing safety. A significant increase in postoperative weight was observed, and speech seemed to be slightly negatively affected, whereas handling of utensils was improved with cZI DBS.

  • 33.
    Sundstedt, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hedström, Johanna
    Department of Otorhinolaryngology, Head and Neck Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Finizia, Caterina
    Department of Otorhinolaryngology, Head and Neck Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    ­­Swallowing quality of life after zona incerta Deep brain stimulation2017In: Annals of Otology, Rhinology and Laryngology, ISSN 0003-4894, E-ISSN 1943-572X, Vol. 126, no 2, p. 110-116Article in journal (Refereed)
    Abstract [en]

    Objectives: The management of Parkinson’s disease (PD) has been improved, but management of features like swallowing problems is still challenging. Deep Brain Stimulation (DBS) alleviates the cardinal motor symptoms and improves quality of life, but its effect on swallowing is not fully explored. The purpose of this study was to examine self-reported swallowing specific quality of life, before and after caudal zona incerta DBS (cZI DBS), in comparison with a control group.

    Methods: Nine PD patients (2 women and 7 men) completed the self-report Swallowing Quality of Life questionnaire (SWAL-QOL) before and 12 months after cZI DBS surgery. The postoperative data were compared to nine controls. Median ages were 53 years (range 40-70) for patients and 54 years (range 42-72) for controls.

    Results: No significant differences were found between the pre-, or postoperative scores. The SWAL-QOL total scores did not differ significantly between PD patients and controls. PD patients reported significantly lower scores in the 'burden' subscale and in the 'symptom' scale.

    Conclusions: PD patients selected for cZI DBS showed a good self-reported swallowing specific quality of life, in many aspects equal to controls. CZI DBS did not negatively affect swallowing specific quality of life in this study.

  • 34.
    Sundstedt, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    van Doorn, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Speech and Language Therapy.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Swallowing function in Parkinson’s patients following Zona Incerta deep brain stimulation2012In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 126, no 5, p. 350-356Article in journal (Refereed)
    Abstract [en]

    Objective The purpose of the present study was to examine if there was a negative effect of caudal Zona Incerta deep brain stimulation (cZI DBS) on pharyngeal swallowing function in Parkinson’s patients (PD). There are no former reports on swallowing and cZI DBS.

    Methods Eight patients (aged 49 to 71 years; median 62) were evaluated pre- and postoperatively, at six and 12 months after DBS surgery. Evaluation tools were Fiberoptic Endoscopic Evaluation of Swallowing examinations and patients’ self-assessments of the swallowing function including a visual analogue scale and quality of life related questions. The swallowing protocol included Rosenbeck’s Penetration-Aspiration Scale, Secretion Severity Scale and parameters for pre-swallow spillage, pharyngeal residue and pharyngeal clearance.

    Results There was no clear-cut effect of neurostimulation postoperatively at six and 12 months on any of the swallowing parameters except for pre-swallow spillage which was slightly worsened in the stimulation on condition 12m postoperatively. The answers to the self assessment questions did not vary significantly.

    Conclusions The effect of the stimulation on swallowing function varied among individuals but the overall outcome was that cZI DBS did not seem to have a negative influence on swallowing function in the eight patients studied.

  • 35.
    Teige, Anna
    et al.
    Neuroinflammation Unit, Department of Clinical Sciences, University of Lund, Lund, Sweden.
    Bockermann, Robert
    Neuroinflammation Unit, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark .
    Hasan, Maruf
    Neuroinflammation Unit, Department of Clinical Sciences, University of Lund, Lund.
    Olofsson, Katarina E
    Neuroinflammation Unit, Department of Clinical Sciences, University of Lund, Lund.
    Liu, Yawei
    Neuroinflammation Unit, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark .
    Issazadeh-Navikas, Shohreh
    Neuroinflammation Unit, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark .
    CD1d-dependent NKT cells play a protective role in acute and chronic arthritis models by ameliorating antigen-specific Th1 responses2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 185, no 1, p. 345-356Article in journal (Refereed)
    Abstract [en]

    A protective and anti-inflammatory role for CD1d-dependent NKT cells (NKTs) has been reported in experimental and human autoimmune diseases. However, their role in arthritis has been unclear, with conflicting reports of CD1d-dependent NKTs acting both as regulatory and disease-promoting cells in arthritis. These differing modes of action might be due to genetic differences of inbred mice and incomplete backcrossing of gene-modified mice. We therefore put special emphasis on controlling the genetic backgrounds of the mice used. Additionally, we used two different murine arthritis models, Ag-induced arthritis (AIA) and collagen-induced arthritis (CIA), to evaluate acute and chronic arthritis in CD1d knockout mice and mice depleted of NK1.1(+) cells. CD1d-deficient mice developed more severe AIA compared with wild-type littermates, with a higher degree of inflammation and proteoglycan depletion. Chronic arthritis in CIA was also worse in the absence of CD1d-dependent NKTs. Elevated levels of Ag-specific IFN-gamma production accompanied these findings rather than changes in IL-17alpha. Depletion of NK1.1(+) cells supported these findings in AIA and CIA. This report provides support for CD1d-dependent NKTs being suppressor cells in acute and chronic arthritis, likely via inhibition of arthritogenic Th1 cells. These results make CD1d-dependent NKTs an attractive target for therapeutic intervention.

  • 36.
    Wigren, Maria
    et al.
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Bengtsson, Daniel
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Dunér, Pontus
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Olofsson, Katarina
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Björkbacka, Harry
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Bengtsson, Eva
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Fredrikson, Gunilla Nordin
    Department of Biomedical Laboratory Science, Malmö University, Sweden.
    Nilsson, Jan
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells2009In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 104, no 12, p. e62-70Article in journal (Refereed)
    Abstract [en]

    The immune system represents a promising novel target for prevention of atherosclerosis. Several pilot vaccines that reduce atherosclerosis in experimental animals have been developed. The aluminum hydroxide adjuvant Alum has been shown to have antiatherogenic properties in itself, suggesting that it may be a suitable adjuvant in possible future atherosclerosis vaccines. To characterize the immune pathways mediating this protection, we treated wild-type C57BL/6 and Apoe(-)(/)(-) mice with Alum or PBS. Analyses of splenocytes isolated from 12-week-old mice demonstrated that Alum increased the presence of CD4(+)CD25(+)FoxP3(+) regulatory T cells and downregulated the expression of T cell activation markers CD28 and ICOS in Apoe(-)(/)(-) mice but not in C57BL/6 wild-type mice. A similar immunosuppressive phenotype was found also in 25-week-old Apoe(-)(/)(-) mice and was associated with reduced atherosclerosis. Alum precipitates recovered from the injection site of Apoe(-)(/)(-) mice contained antigens derived from oxidized LDL. These findings demonstrate that treatment of Apoe(-)(/)(-) mice with Alum results in an increase of regulatory T cells and suggest that these are activated by tolerogenic antigen-presenting cells presenting oxidized LDL antigens. Our findings provide improved mechanistic understanding of the atheroprotective properties of aluminum hydroxide adjuvants but also point to the importance of determining if hypercholesterolemia may compromise the efficacy of Alum-containing vaccines used clinically today.

  • 37.
    Wilms, Torben
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Khan, Gulfaraz
    Coates, Philip J
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno, Czech Republic; Univ Paris Diderot, INSERM, UMRS1162, 27 Rue Juliette Dodu, Paris, France .
    Hassani, Asma
    Philip, Pretty S
    Norberg Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Califano, Luigi
    Colella, Giuseppe
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Franco, Renato
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    No evidence for the presence of Epstein-Barr virus in squamous cell carcinoma of the mobile tongue2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184201Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck (SCCHN) comprises a large group of cancers in the oral cavity and nasopharyngeal area that typically arise in older males in association with alcohol/tobacco usage. Within the oral cavity, the mobile tongue is the most common site for tumour development. The incidence of tongue squamous cell carcinoma (TSCC) is increasing in younger people, which has been suggested to associate with a viral aetiology. Two common human oncogenic viruses, human papilloma virus (HPV) and Epstein-Barr virus (EBV) are known causes of certain types of SCCHN, namely the oropharynx and nasopharynx, respectively. EBV infects most adults worldwide through oral transmission and establishes a latent infection, with sporadic productive viral replication and release of virus in the oral cavity throughout life. In view of the prevalence of EBV in the oral cavity and recent data indicating that it infects tongue epithelial cells and establishes latency, we examined 98 cases of primary squamous cell carcinoma of the mobile tongue and 15 cases of tonsillar squamous cell carcinoma for the presence of EBV-encoded RNAs (EBERs), EBV DNA and an EBV-encoded protein, EBNA-1. A commercially available in situ hybridisation kit targeting EBER transcripts (EBER-ISH) showed a positive signal in the cytoplasm and/or nuclei of tumour cells in 43% of TSCCs. However, application of control probes and RNase A digestion using in-house developed EBER-ISH showed identical EBER staining patterns, indicating non-specific signals. PCR analysis of the BamH1 W repeat sequences did not identify EBV genomes in tumour samples. Immunohistochemistry for EBNA-1 was also negative. These data exclude EBV as a potential player in TSCC in both old and young patients and highlight the importance of appropriate controls for EBER-ISH in investigating EBV in human diseases.

  • 38.
    Zhao, Ming
    et al.
    Department of Pathophysiology, Southern Medical University, Guangdong, People’s Republic of China .
    Wigren, Maria
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Dunér, Pontus
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Kolbus, Daniel
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Olofsson, Katarina E
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Björkbacka, Harry
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Nilsson, Jan
    Department of Clinical Sciences, Malmö University Hospital, Lund University.
    Fredrikson, Gunilla Nordin
    Faculty of Health and Society, Malmö University, Malmö, Sweden.
    FcgammaRIIB inhibits the development of atherosclerosis in low-density lipoprotein receptor-deficient mice2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 5, p. 2253-2260Article in journal (Refereed)
    Abstract [en]

    The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcgammaR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcgammaRIIB in atherosclerosis has not been defined. Bone marrow cells from FcgammaRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was ~5-fold larger in mice lacking FcgammaRIIB than in control mice (2.75 +/- 2.57 versus 0.44 +/- 0.42%; p < 0.01). Moreover, the FcgammaRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 +/- 8.81 versus 2.96 +/- 0.81%, p < 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 +/- 0.64 versus 2.33 +/- 0.25%; p < 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 +/- 4.05 versus 2.45 +/- 0.31%; p < 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcgammaRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.

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