Katarina Olofsson

Cross-linked hyaluronan used as augmentation substance for treatment of glottal insufficiency: Safety aspects and vocal fold function

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.

Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide

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.

Cross-linked hyaluronan versus collagen for injection treatment of glottal insufficiency : 2-year follow-up.

Objectives—To evaluate the long-term (24 months) clinical performance (vocal fold function) and safety of hylan B gel as compared with bovine cross-linked collagen in the treatment of patients with glottal insufficiency. Material and Methods—In a prospective trial, 70 patients with glottal insufficiency due to unilateral vocal fold paresis (n=35) or atrophy (n=35) were randomized to received either hylan B gel (n=47) or collagen (n=23) injections into 1 vocal fold. Forty-two of the patients were examined 24 months after treatment. Evaluations were made based on patients’ subjective ratings, digitized videostroboscopic measurements, maximum phonation time and phonation quotient. Results—The patients’ self-ratings were significantly improved in both the hylan B gel and collagen groups. Videostroboscopic measurements of glottal closure were significantly improved for both groups. The hylan B gel group showed a trend towards less resorption at the injected vocal fold edge in comparison with the collagen group (p=0.05). No serious adverse events were observed. Twenty-eight patients dropped out of the study after 12 months: 18 had been re-injected or operated on with medialization laryngoplasty due to insufficient voice and 10 had either died of causes unrelated to the study or refused to attend follow-up. Conclusions—No long-term side-effects were found for either the hylan B gel or collagen groups after injection treatment. Both treatments resulted in significantly improved voice as rated by the patients and significantly improved glottal closure. Some resorption was noted for both substances, and ≈25% of the patients chose re-treatment 2 years after the initial treatment.

Nanomolar concentrations of lysophosphatidylcholine recruit monocytes and induce pro-inflammatory cytokine production in macrophages

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.

FcgammaRIIB inhibits the development of atherosclerosis in low-density lipoprotein receptor-deficient mice

The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcγR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcγRIIB in atherosclerosis has not been defined. Bone marrow cells from FcγRIIB-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 FcγRIIB than in control mice (2.75 ± 2.57 versus 0.44 ± 0.42%; p < 0.01). Moreover, the FcγRIIB 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 FcγRIIB 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.

CD1d-Dependent NKT Cells Play a Protective Role in Acute and Chronic Arthritis Models by Ameliorating Antigen-Specific Th1 Responses

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-γ production accompanied these findings rather than changes in IL-17α. 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.

The surface epithelium of recurrent infected palatine tonsils is rich in gammadelta T cells

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+γδ T cells utilizing Vδ1 and Vγ9. In both patient groups the majority of the intraepithelial γδ T cells expressed Vδ1 and Vγ9. Subepithelially, γδ T cells utilizing Vγ9 dominated over cells utilizing Vγ8, while equal proportions expressed Vδ1 and Vδ2. These results suggest that cells utilizing the otherwise rare combination Vδ1/Vγ9 in their T cell receptors (TCR) may constitute a major γδ T cell population in palatine tonsils and are probably reactive to antigens specific to the tonsillar milieu. Furthermore, they indicate that preferentially this γδ T cell subpopulation is involved in immune reactions within the surface epithelium in RT. We speculate that γδ 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 γδ T cells in RT patients.

Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus in Patients with Parkinson's Disease: Effects on Voice Intensity

Deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinsons disease (PD) affects speech inconsistently. Recently, stimulation of the caudal zona incerta (cZi-DBS) has shown superior motor outcomes for PD patients, but effects on speech have not been systematically investigated. The aim of this study was to compare the effects of cZi-DBS and STN-DBS on voice intensity in PD patients. Mean intensity during reading and intensity decay during rapid syllable repetition were measured for STN-DBS and cZi-DBS patients (eight patients per group), before- and 12 months after-surgery on- and off-stimulation. For mean intensity, there were small significant differences on- versus off-stimulation in each group: 74.2 (2.0) dB contra 72.1 (2.2) dB (P = .002) for STN-DBS, and 71.6 (4.1) dB contra 72.8 (3.4) dB (P = .03) for cZi-DBS, with significant interaction (P < .001). Intensity decay showed no significant changes. The subtle differences found for mean intensity suggest that STN-DBS and cZi-DBS may influence voice intensity differently.

Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1.

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.

Swallowing function in Parkinson's patients following Zona Incerta deep brain stimulation

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