Electrophysiological detection of electrode fold-over in perimodiolar cochlear implant electrode arrays: a multi-center study case series.

PURPOSE: It is important for the surgeon to determine the position of the CI electrode array during and after its placement within the cochlea. Most preferably, this should be within the scala tympani to obtain the best audiological outcome. Thus, misplacement into the scala vestibuli or tip fold-over should be prevented. Since there are different ways to ensure proper positioning of the electrode array within the scala tympani (e.g., intraoperative radiography, electrophysiological recordings), our study was aimed at detecting intraoperative electrophysiologic characteristics to better understand the mechanisms of those electrode tip fold-overs. MATERIAL AND METHODS: In a multi-centric, retrospective case-control series, patients with a postoperatively by radiography detected tip fold-over in perimodiolar electrodes were included. The point of fold-over (i.e., the electrode position) was determined and the intraoperative Auto-NRT recordings were analysed and evaluated. RESULTS: Four patients were found to have an electrode tip fold-over (out of 85 implantees). Significant changes of the Auto-NRT recordings were not detected. All tip fold-overs occurred in the most apical part of the electrodes. DISCUSSION: Cochlear implantation for hearing impaired patients plays a decisive role in modern auditory rehabilitation. Perimodiolar electrode arrays may fold over during the insertion and, hence, could have a negative impact on audiological outcome. Characteristic electrophysiologic changes to possibly predict this were not found in our series.

Clinical experience and results with a Rhombic Plate for transoral endoscopically-assisted osteosynthesis of fractures of the condylar neck.

The intraoral approach is favoured by many patients and surgeons for the treatment of fractures of the condylar neck, but the limited space offered by this approach can make positioning and fixation of the osteosynthesis plate difficult. A rhombic-shaped plate was designed specifically for use with the intraoral approach, and introduced into our clinical practice in 2012. We present the clinical and functional results in 81 patients with 98 fractures of the condylar neck who we have treated with this technique. Of these six required surgical revision, and ultimately all but two had satisfactory occlusion and mandibular function. Our complication rate of 6/81 (7.4%) compares favourably with those reported elsewhere, and confirms that open reduction and internal fixation of condylar fractures using the Rhombic plate through an intra-oral approach provides good outcomes.

IFN-free therapy is associated with restoration of type I IFN response in HIV-1 patients with acute HCV infection who achieve SVR.

Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1ß levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

Fixation of fractures of the condylar head of the mandible with a new magnesium-alloy biodegradable cannulated headless bone screw.

It is difficult to fix fractures of the condylar head of the mandible. Several techniques have been described which show satisfactory outcomes, but stability can be questionable, and some can cause irritation of the soft tissues. We describe a technique and first results of treating such fractures with resorbable magnesium-based headless bone screws (Magnezix® 2.7mm CS; Syntellix AG, Hanover, Germany).

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections.

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 ß=-0.06, P-value=2.7 × 10-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.

Phylogenetic analysis of full-length, early infection, hepatitis C virus genomes among people with intravenous drug use: the InC3 Study.

Cross-continental phylogenetic analysis is important to understand subtle molecular differences of currently circulating hepatitis C virus (HCV) subtypes. Existence of such differences can be crucial in pursuing a universal hepatitis C vaccine. We characterized molecular epidemiology of early HCV infections identified across nine cohorts [North America (n=4), Australia (n=4) and Europe (n=1)] in the International Collaborative of Incident HIV and Hepatitis C in Injecting Cohorts (InC3 ). One hundred and ninety-two full-length HCV genomes were amplified from plasma of incident infections and subjected to next generation sequencing to establish the largest cross-continental, full-length acute HCV genomic data set available to date. Genomes from the most common subtypes (1a: n=94, 2b: n=15 and 3a: n=68) were used in phylogenetic analysis. Using full genome trees, 78 sequences (44%) were found to lie within 29 phylogenetic clusters/pairs defined on the basis of molecular similarity of consensus sequences. Of these, 26 each had exclusively Australian or North American sequences indicating a strong geographical bias for molecular similarity. On further analysis of behavioural and demographic associations, binary logistic regression analysis showed that older age and non-Caucasian ethnicity were significantly associated with clustering. HCV probably evolves in micro-epidemics within geographically isolated communities.

Analysis of resistance-associated substitutions in acute hepatitis C virus infection by deep sequencing across six genotypes and three continents.

Several direct-acting antivirals (DAAs) have been approved for the treatment of chronic hepatitis C virus (HCV) infections, opening the door to highly effective interferon-free treatment regimens. Resistance-associated substitutions (RASs) have been reported both in treatment-naïve patients and following treatment with protease (NS3), phosphoprotein (NS5A) and polymerase (NS5B) inhibitors. The prevalence of naturally occurring RASs in untreated HCV-infected individuals has mostly been analysed in those infected with genotype 1 (GT1), in the late phase of infection, and only within limited regions of the genome. Furthermore, the geographic distribution of RASs remains poorly characterized. In this study, we used next-generation sequencing to analyse full-length HCV genomes for the prevalence of RASs in acute HCV infections identified in nine international prospective cohorts. RASs were analysed in 179 participants infected with all six major HCV genotypes (GT1-GT6), and the geographic distribution of RASs was assessed in 107 GT1a and GT3a samples. While RASs were detected at varied frequencies across the three genomic regions, and between genotypes, RASs relevant to multiple DAAs in the leading IFN-free regimens were rarely detected in combination. Low-frequency RASs (<10% of the viral population) were also shown to have a GT-specific distribution. The main RASs with geographic associations were NS3 Q80K in GT1a samples and NS5B N142T in GT3a. These data provide the backdrop for prospective surveillance of RASs during DAA treatment scale-up.

Autogenous bone and a bovine bone substitute for ridge preservation: preliminary clinical and histologic findings.

BACKGROUND: Tooth extractions lead to morphological changes of the alveolar ridge. For oral rehabilitation sufficient bone volume of the alveolar ridge is required. This clinical study compared the ability of Bio-Oss® Collagen to autogenous bone to preserve bone volume after tooth extraction. METHODS: A total of 17 patients with 20 extraction sites were examined. After extraction, 10 sockets were each filled with either autogenous bone or Bio-Oss® Collagen and covered with a resorbable membrane. The width of the alveolar ridge was measured postoperatively, and after 4 and 6 months respectively. Prior to implant insertion, a bone biopsy was taken from the grafted sites and evaluated histologically. RESULTS: The width of the alveolar ridge in the Bio-Oss® Collagen group decreased about 5.33 ± 6.62% after 4 months and 9.45 ± 10.51% after 6 months. The reduction in the group augmented with autogenous bone was 14.31 ± 21.41% after 4 months and 19.17 ± 8.38% after 6 months. No statistically significant differences were observed. The histological examination showed comparable area fractions of total bone in both groups (Bio-Oss® Collagen: 59.99 ± 24.23%; autogenous bone: 61.55 ± 25.13%; p = 1.0). CONCLUSIONS: The present study demonstrated that autogenous bone and Bio-Oss® Collagen are suitable for ridge preservation. However, both techniques could not entirely prevent tissue volume loss.

[Bisphosphonate-associated osteonecrosis of the jaw]. / Bisphosphonat-assoziierte Kiefernekrosen.

BACKGROUND: Bisphosphonates (BP) are used in the treatment of severe osteoporosis and metastasis of malignant diseases. A possible relationship between the occurrence of osteonecrosis of the jaw and BP therapy was first described in 2003. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is difficult to treat. In some cases the condition of the patients is so compromised that only minimally invasive surgery is possible. Histopathologically, osteonecrosis shows the features of chronic sequestered osteomyelitis, which can be found in different areas of the upper and lower jaw. Sometimes extensive resections of the jaw are necessary. Thus, BRONJ can cause mutilation, impairment of function and esthetics in the orofacial system and, thereby, compromise the life quality of the patients. Triggering factors are often tooth extraction without surgical plastic wound closure of the alveoli, but can also be associated with bruises from denture or other minor wounds. OBJECTIVES: The purpose of this article is to present results from our own patient collective, including therapy regime, success rate, and therapy recommendations. METHODS: The patient populations at three German hospitals were analyzed using a standard questionnaire. The patients in the study group, entered into a follow-up system for early detection of possible BRONJ, were evaluated for treatement outcome. RESULTS: The success rate for prophylactic surgery in asymptomatic patients was very high at 96 %. In the group with symptomatic BRONJ, the outcome was significantly lower (76.4 %). CONCLUSIONS: Because of the complex symptoms, close cooperation between oncologists, dentists, and maxillofacial surgeons is required in the treatment of BRONJ. Before starting therapy with bisphosphonates and during the therapy, dental treatment and monitoring of the patient' oral health is necessary.

Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis.

The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.

Efficacy of tissue engineered bone grafts containing mesenchymal stromal cells for cleft alveolar osteoplasty in a rat model.

UNLABELLED: The development of sufficient tissue engineered bone grafts for alveolar cleft osteoplasty could reduce the necessity of autogenous bone grafts and its donor site morbidity. The aim of the study was to evaluate tissue engineered bone grafts in an artificially created bone defect. Bone grafts were created in vitro colonizing a synthetic hydroxyapatite-tricalciumphosphate scaffold (BONITmatrix(®)) with either undifferentiated mesenchymal stromal cells (group 1) or osteogenic differentiated mesenchymal stromal cells (group 2). Cells were multiplied from bone marrow of donor rats. Unmodified scaffolds (group 3) and the tissue engineered bone grafts were inserted into artificial maxillary defects of 54 Lewis rats. In 18 animals the defects remained unfilled (control). After one, three and six weeks the rats were sacrificed. The defect was evaluated radiologically and histologically with regard to the remaining defect volume and diameter. Statistical analysis followed. The bone grafts led to a specific bone formation at the defect margin. No complete reunion of any defect was observed within the healing time. After six weeks, the remaining defect volume was 6.86 ± 3.21 mm(3) (control), 4.08 ± 1.36 mm(3) (group 1), 5.00 ± 0.84 mm(3) (group 2) 5.50 ± 1.05 mm(3) (group 3). The remaining defect diameter measured 2.63 ± 0.52 mm (control), 2.39 ± 0.23 mm (group 1), 2.53 ± 0.22 mm (group 2) and 2.70 ± 0.66 mm (group 3). In all experimental groups the defect volume and diameter decreased over time, which was significant for group 1 (p = 0.014), group 2 (p = 0.025) and group 3 (p = 0.048). The defect volume and width was significantly reduced for bone grafts containing undifferentiated cells compared to control (p = 0.035) or scaffolds only (p = 0.05). CONCLUSION: Tissue engineered bone grafts induce a pronounced bone formation in artificial bone defects compared to unfilled controls or scaffolds only.

Acute hepatitis C infection lowers serum lipid levels.

Chronic hepatitis C infection is associated with hypolipidaemia that resolves with viral clearance. Lipid levels in a subgroup of patients rebound to levels that may increase the risk of coronary heart disease. The impact of acute hepatitis C infection and its clearance on lipid levels is unknown. We undertook a retrospective evaluation of subjects with acute hepatitis C infection evaluating lipid levels before, during and following acute infection. Thirty-eight subjects with acute hepatitis C infection had lipid levels available. Twelve patients had pre-infection and intra-infection lipid levels available. Cholesterol (197.8-152.4 mg/dL, P = 0.025), low-density lipoprotein (LDL) (116.1-76.3 mg/dL, P = 0.001) and non-high-density lipoprotein (non-HDL) cholesterol (164.0-122.7 mg/dL, P = 0.007) decreased dramatically during acute hepatitis C virus infection. Nineteen patients who achieved viral clearance had lipid levels available during infection and following resolution of infection. In these patients, cholesterol (145.0-176.0 mg/dL, P = 0.01), LDL (87.0-110.1 P = 0.0046) and non-HDL cholesterol (108.6-133.6 mg/dL, P = 0.008) increased significantly. No change was seen in patients who developed chronic infection. Four patients had lipid levels before, during and following resolution of infections and had increased postinfection LDL, cholesterol and non-HDL cholesterol from pre-infection levels, indicating acute infection may be associated with an increase in postinfection lipid levels and may confer an increased risk of coronary heart disease. Acute hepatitis C infection results in hypolipidaemia with decreased LDL, cholesterol and non-HDL cholesterol levels that increase following infection resolution. Levels may increase above pre-infection baseline lipid levels and should be monitored.

Is failure of condylar neck osteosynthesis predictable based on orthopantomography?

BACKGROUND: Osteosynthesis failure rates of 11.3% with 1 miniplate, 6.7% with 2 miniplates, and 4.4% with a single Medartis condyle plate were reported in previous studies of our clinic. Current science is still focused on the osteosynthesis material. Besides clinical parameters, conventional radiographs are still the first choice to detect osteosynthesis failures. This study scrutinized several factors assessable in postoperative orthopantomographs which might elevate the risk of osteosynthesis failure. STUDY DESIGN: A total of 136 patients (22 with osteosynthesis failure, 114 without) with 151 mandibular condyle fractures were included in this study. Eight parameters were assessed in postoperative orthopantomographs. RESULTS: The best predictor of osteosynthesis failure was a simplified concept of ramus height. In cases of reduced or normal ramus height, the odds of osteosynthesis failure was significantly (P = .000001) reduced to a 10th. Isolated fractures were significantly more error prone (P = .0009). CONCLUSIONS: Postoperative orthopantomographs depict factors which increase the risk of osteosynthesis failure.

Perfusion culture promotes differentiation of oral keratinocytes in vitro.

In order to reconstruct the mucosal lining of the oral cavity tissue engineered autologous mucosa grafts could be of great benefit. In conventional stagnant cultures cells often tend to dedifferentiate. Perfusion culture has been demonstrated to reestablish differentiation in various epithelial cell types. Thus, in secondary cultures of human oral keratinocytes from ten patients conventional stagnant culture versus perfusion culture technique was compared. Proliferation and state of differentiation as expressed morphologically and immunohistochemically were assessed. After 14 days oral keratinocytes in a perfusion culture system tend to be further differentiated. They build up a thicker epithelium (3.4+/-1.0 vs. 2.4+/-0.4 layers), form microridges, express cytokeratins 1, 2, 10, 11, 19 but not 13 in all cells and cytokeratins 5, 6 particularly in cells attached to the carrier membrane. In contrast, oral keratinocytes in stagnant culture do not form microridges and rather express cytokeratins 13, 14, and 19 in mattering amounts.

One-stage palate repair improves speech outcome and early maxillary growth in patients with cleft lip and palate.

There are several types of palatal surgery; each cleft centre chooses its own technique based on experience and treatment philosophy. The aim of this study was to compare speech outcome and maxillary growth in children with cleft lip and palate deformity after palate repair with either a one-stage or a two- stage procedure and to identify the better treatment protocol. In 24 children, speech outcome was assessed regarding resonance, nasal escape, compensatory articulations, facial grimace, and spontaneous speech. In addition, plaster models of 15 children were compared. In 12 children, a two-stage procedure was performed (group A): at the age of 9-12 months, an intravelar veloplasty for repair of the soft palate, and at the age of 24-36 months a bipedicled flap closure of the hard palate. In 12 children, the same techniques were used in a one-stage procedure, at the age of 9-12 months (group B). The children of group B showed less altered resonance and less nasal emission at 4 years of age compared to the children of group A. At 6 years, the children of group A had improved their speech skills, but they did not equal the results of group B. In the study models of group A at age 6 years, the transverse dimension (anterior and posterior width of the dental arch) was smaller than in the models of group B. The one-stage repair of cleft palate at the age of 9-12 months seems to have a more positive influence on speech development and early maxillary growth than the two-stage procedure.

Immunohistochemical comparison of differentiation markers on paraffin and plastic embedded human bone samples.

To assess bone pathologies and bone regeneration immunohistochemistry may provide additional information compared to conventional histology. However, the effectiveness of this technique is limited due to tissue fixation, preparation and embedding. For bone tissue the standard immunohistological procedure includes formalin fixation, followed by decalcification and paraffin embedding. This may lead to a badly preserved trabecular bone structure but allows antibody application. Alternatively, methyl-methacrylate (MMA) resin may be used for embedding, thus circumventing the decalcification procedure. In this study immunohistology of typical bone markers was compared using human bone samples fixed either with alcohol or formalin and further decalcified and embedded in paraffin and decalcified or non decalcified samples embedded in Technovit 9100 New(R). On semi-thin sections immunohistochemistry with bone markers osteocalcin, osteonectin, osteopontin, collagen type I and the cellular markers CD34 and CD68 was performed. Independent of the fixative used, Technovit 9100 New embedded non-decalcified bone yielded a stronger immunostaining for all markers when compared to decalcified bone embedded either in methyl-methacrylate or paraffin. In addition there was a better preservation of the trabecular bone morphology. The immunohistochemical results demonstrate that Technovit 9100 New as a low-temperature acrylic resin embedding method can be favoured over paraffin embedding.

Cell passage and composition of culture medium effects proliferation and differentiation of human osteoblast-like cells from facial bone.

Cells loose their capability to multiply and to differentiate when they are serial subcultivated. However, both, multiplication and differentiation are of utmost importance to obtain sufficient amounts of cells for the translation of tissue regeneration into cell based therapeutic approaches. Thus, for the clinical application more information about ideal culture conditions are necessary. Therefore, aim of this study was to assess culture conditions of human osteoblast-like cells during long-term culture focusing on effects of different culture media and ascorbic acid. Biopsies of maxilla and mandible were obtained from 17 patients to test different cell culture media and from 10 patients to analyse differentiation and proliferation related to number of subcultures and ascorbic acid content. Histochemical and immunhistochemical tests (EZ4U assay, ALP histochemistry, type I collagen immunohistochemistry, osteocalcin Elisa) were performed to determine cell proliferation and differentiation. Opti-MEM with 10% FCS produced statistically significant the highest increase in cell counts. The highest proliferation rate in long-term cultivation was seen in the 4th cell passage. A reciprocal relationship between cell proliferation and differentiation over 5 passages with a turning point in the 4(th) passage was found. An ascorbic acid content of 50 microg/ml triggered an optimal increase in differentiation. For osteoblast-like cells, Opti-MEM with 10% FCS proved to be the best culture medium. After 3 passages there is the highest amount of cells with osteogenic differentiation which is enhanced by the addition of ascorbic acid. This approach is suitable for tissue engineering of bone grafts.

Free DIEP-flap reconstruction of tumour related defects in head and neck.

The free deep inferior epigastric perforator flap (DIEP) is a well-established therapy for plastic reconstruction of the breast or defects of the lower extremity without distinct donor site morbidity. Because of its particular qualities we started to apply the DIEP-flap also in reconstruction of defects in the cranio-maxillofacial area. A series of 10 consecutive patients, who received a DIEP-flap for reconstruction of large soft tissue defects after ablative tumour surgery, was reviewed. Nine of the 10 flaps survived and uneventfully healing was observed in 8 of the 10 flaps. Primary layered closure of the abdominal wall was achieved in all cases and no complications at the donor site were observed. In our experience the DIEP may serve as a well considerable alternative to the rectus abdominis flap and the latissimus dorsi flap for bridging extensive reconstructions in the cranio-maxillofacial region. It offers the possibility for flap elevation simultaneously to the surgical procedures in the head and neck area. A special advantage of the DIEP-flap is the very low donor site morbidity.