Karsten Winter

Early Detection of Nerve Fiber Loss by Corneal Confocal Microscopy and Skin Biopsy in Recently Diagnosed Type 2 Diabetes

We sought to determine whether early nerve damage may be detected by corneal confocal microscopy (CCM), skin biopsy, and neurophysiological tests in 86 recently diagnosed type 2 diabetic patients compared with 48 control subjects. CCM analysis using novel algorithms to reconstruct nerve fiber images was performed for all fibers and major nerve fibers (MNF) only. Intraepidermal nerve fiber density (IENFD) was assessed in skin specimens. Neurophysiological measures included nerve conduction studies (NCS), quantitative sensory testing (QST), and cardiovascular autonomic function tests (AFTs). Compared with control subjects, diabetic patients exhibited significantly reduced corneal nerve fiber length (CNFL-MNF), fiber density (CNFD-MNF), branch density (CNBD-MNF), connecting points (CNCP), IENFD, NCS, QST, and AFTs. CNFD-MNF and IENFD were reduced below the 2.5th percentile in 21% and 14% of the diabetic patients, respectively. However, the vast majority of patients with abnormal CNFD showed concomitantly normal IENFD and vice versa. In conclusion, CCM and skin biopsy both detect nerve fiber loss in recently diagnosed type 2 diabetes, but largely in different patients, suggesting a patchy manifestation pattern of small fiber neuropathy. Concomitant NCS impairment points to an early parallel involvement of small and large fibers, but the precise temporal sequence should be clarified in prospective studies.

The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw

OBJECTIVES Bisphosphonate-related osteonecrosis of the jaw (BRONJ) seems resistant to conventional treatment approaches. We report a study with a surgical concept characterized by resection of the necrotic bone followed by sufficient wound closure. STUDY DESIGN In a clinical study of 24 patients with 33 sites of BRONJ, the surgical basis of the treatment was as follows: (1) conservative treatment with antimicrobiological rinsing, (2) resection of the entire necrotic bone and smoothening of any sharp bone edges, and (3) coverage of the remaining bone by use of a bilayered wound closure. RESULTS In 88% of cases, BRONJ could be treated with success by use of this surgical therapy. Median follow-up was 60 weeks. There was no statistically significant difference between treatment results irrespective of whether or not bisphosphonate treatment was continued. CONCLUSION Because of the high success rate of this surgical technique it seems that patients with BRONJ may benefit from this approach.

Imaging and Quantification of Subbasal Nerve Plexus in Healthy Volunteers and Diabetic Patients with or without Retinopathy

Background The alterations of subbasal nerve plexus (SBP) innervation and corneal sensation were estimated non-invasively and compared with the values in healthy volunteers. Additionally, this study addressed the relation of SBP changes to the retinal status, glycemic control and diabetes duration. Methodology/Principal Findings Eighteen eyes of diabetic patients with peripheral diabetic neuropathy aged 68.8±8.8 years and twenty eyes of healthy volunteers aged 66.3±13.3 yrs. were investigated with in vivo confocal laser-scanning microscopy (CLSM). An adapted algorithm for image analysis was used to quantify the morphological and topological properties of SBP. These properties were correlated to incidence of diabetic retinopathy (DR) and corneal sensation (Cochet-Bonnet esthesiometer). The developed algorithm allows a fully automated analysis of pre-segmented SBP structures. Altogether, 10 parameters were analysed, and all of them revealed significant differences between diabetic patients and healthy volunteers. The nerve fibre density, total fibre length and nerve branches were found to be significantly lower in patients with diabetes than those of control subjects (nerve fibre density 0.006±0.002 vs. 0.020±0.007 mm/mm2; total fibre length 6223±2419 vs. 19961±6553 µm; nerve branches 25.3±28.6 vs. 141.9±85.7 in healthy volunteers). Also the corneal sensation was significantly lower in diabetic group when compared to controls (43±11 vs. 59±18 mm). There was found no difference in SBP morphology or corneal sensation in the subgroups with (DR) or without (NDR) diabetic retinopathy. Conclusions/Significance SBP parameters were significantly reduced in diabetic patients, compared to control group. Interestingly, the SBP impairment could be shown even in the diabetic patients without DR. Although automatic adapted image analysis simplifies the evaluation of in vivo CLSM data, image acquisition and quantitative analysis should be optimised for the everyday clinical practice.

Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw

OBJECTIVES The purpose of this study was to investigate the sensitivity of F-18 fluoride and F-18 fluorodeoxyglucose (FDG) positron-emission tomography (PET) in the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ), and to test their suitability for assessing the severity of BRONJ. STUDY DESIGN Nine patients with BRONJ were studied using F-18 fluoride and F-18 FDG PET. For analysis, 8 regions of interest (ROI) were defined in the jaws of each patient. Maximum count rates for each ROI in both PET examinations were analyzed. RESULTS In both studies, increased tracer enhancement was observed in regions with BRONJ. Uptake of fluoride significantly exceeded that of FDG. FDG uptake increased systematically, but not significantly, with increasing severity of BRONJ. CONCLUSION F-18 fluoride PET is a sensitive method for diagnosis of BRONJ. FDG PET could be useful for evaluation of the severity of BRONJ. Further studies are required to prove the specificity of the methods.

Prevalence of cone beam computed tomography imaging findings according to the clinical stage of bisphosphonate-related osteonecrosis of the jaw

OBJECTIVES Investigations of cone beam computed tomography (CBCT) for bisphosphonate-related osteonecrosis of the jaw (BRONJ) imaging are rare. The purpose of this study was to investigate the prevalence of typical radiological findings of BRONJ in CBCT. METHODS Twenty-seven CBCTs of BRONJ sites were assessed on the basis of the radiological findings (cancellous bone destruction, cortical bone erosion, sequestration, osteosclerosis, and periostal bone formation) and put in relation to the severity of the BRONJ sites. RESULTS Cancellous bone destruction and cortical bone erosion were the most common findings. Occurrence seems to decrease with decreasing BRONJ severity. Sequestration and osteosclerosis were less frequent and could be seen across all stages. Periosteal bone formation occurred in high-stage BRONJ only. CONCLUSION Cancellous bone destruction, cortical bone erosion, sequestration, and osteosclerosis can be seen across all stages and prevalence seems to decrease with decreasing severity of BRONJ. The occurrence of periosteal new bone formation seems to start in high-stage BRONJ.

Association of central serotonin transporter availability and body mass index in healthy Europeans.

UNLABELLED Serotonin-mediated mechanisms, in particular via the serotonin transporter (SERT), are thought to have an effect on food intake and play an important role in the pathophysiology of obesity. However, imaging studies that examined the correlation between body mass index (BMI) and SERT are sparse and provided contradictory results. The aim of this study was to further test the association between SERT and BMI in a large cohort of healthy subjects. METHODS 127 subjects of the ENC DAT database (58 females, age 52 ± 18 years, range 20-83, BMI 25.2 ± 3.8 kg/m(2), range 18.2-41.1) were analysed using region-of-interest (ROI) and voxel-based approaches to calculate [(123)I]FP-CIT specific-to-nonspecific binding ratios (SBR) in the hypothalamus/thalamus and midbrain/brainstem as SERT-specific target regions. RESULTS In the voxel-based analysis, SERT availability and BMI were positively associated in the thalamus, but not in the midbrain. In the ROI-analysis, the interaction between gender and BMI showed a trend with higher correlation coefficient for men in the midbrain albeit not significant (0.033SBRm(2)/kg, p=0.1). CONCLUSIONS The data are in agreement with previous PET findings of an altered central serotonergic tone depending on BMI, as a probable pathophysiologic mechanism in obesity, and should encourage further clinical studies in obesity targeting the serotonergic system.

Local Variability of Parameters for Characterization of the Corneal Subbasal Nerve Plexus

Abstract Purpose: The corneal subbasal nerve plexus (SNP) offers high potential for early diagnosis of diabetic peripheral neuropathy. Changes in subbasal nerve fibers can be assessed in vivo by confocal laser scanning microscopy (CLSM) and quantified using specific parameters. While current study results agree regarding parameter tendency, there are considerable differences in terms of absolute values. The present study set out to identify factors that might account for this high parameter variability. Materials and methods: In three healthy subjects, we used a novel method of software-based large-scale reconstruction that provided SNP images of the central cornea, decomposed the image areas into all possible image sections corresponding to the size of a single conventional CLSM image (0.16 mm2), and calculated a set of parameters for each image section. In order to carry out a large number of virtual examinations within the reconstructed image areas, an extensive simulation procedure (10,000 runs per image) was implemented. Results: The three analyzed images ranged in size from 3.75 mm2 to 4.27 mm2. The spatial configuration of the subbasal nerve fiber networks varied greatly across the cornea and thus caused heavily location-dependent results as well as wide value ranges for the parameters assessed. Distributions of SNP parameter values varied greatly between the three images and showed significant differences between all images for every parameter calculated (p < 0.001 in each case). Conclusions: The relatively small size of the conventionally evaluated SNP area is a contributory factor in high SNP parameter variability. Averaging of parameter values based on multiple CLSM frames does not necessarily result in good approximations of the respective reference values of the whole image area. This illustrates the potential for examiner bias when selecting SNP images in the central corneal area.

Longitudinal evaluation of effects of intra-articular mesenchymal stromal cell administration for the treatment of osteoarthritis in an ovine model.

In this study, the therapeutic effect of intra-articularly injected autologous mesenchymal stromal cells (MSCs) was evaluated in an ovine osteoarthritis (OA) model using consecutive magnetic resonance imaging (MRI), radiography, and macroscopic and histologic postmortem examination. In 12 sheep, OA was induced by bilateral, lateral meniscectomy. After 6 weeks, 20 × 106 bone marrow-derived MSCs (50% MSCs were superparamagnetic iron oxide particle labeled) were injected intra-articularly into one knee joint. The contralateral knee served as negative control. MR images were acquired before OA induction, immediately before and after MSC injection, and 1, 4, 8, and 12 weeks thereafter using a 0.5T unit and a T2* gradient echo sequence. Radiographs were obtained before OA induction, at MSC injection, and 12 weeks thereafter. The MRI scoring system included articular cartilage, bone, joint capsule, and synovial fluid evaluation. The radiographic scoring system included the joint space and bone. Postmortem evaluation entailed macroscopic and histologic assessment. Longitudinal MRI revealed a significant deceleration of OA progression in MSC-treated joints. However, at the conclusion of the study, there was no significant difference in the degree of OA detected by MRI, radiography, and postmortem evaluation between the treatment and control group. The degree of OA on MRI varied among the 12 animals at the time of injection, but there was no difference between the left and right limb. In conclusion, intra-articular MSCs decreased OA progression. However, no significant treatment effects were seen at the conclusion of the study at 12 weeks. This somewhat contradicts previously published results. Nevertheless, the choice of OA model, outcome measures, or lack of additional medication might explain the differences. Our results indicate that OA might benefit from intra-articular MSC injection, but further studies are needed to refine patient selection and injection parameters for a more substantially improved outcome.

In Vivo Tracking and Fate of Intra-Articularly Injected Superparamagnetic Iron Oxide Particle-Labeled Multipotent Stromal Cells in an Ovine Model of Osteoarthritis:

In this study, superparamagnetic iron oxide (SPIO) particle-labeled mesenchymal stromal cells (MSCs) were injected intra-articularly into osteoarthritic knee joints. Their fate and distribution were evaluated using magnetic resonance imaging (MRI) and macroscopic and histologic postmortem examination. Osteoarthritis was induced in 12 sheep by bilateral meniscectomy. After 6 weeks, one knee joint received 10 × 106 SPIO-labeled MSCs (Molday Ion Rhodamine B). Contralateral knees received a control injection of a) PBS, b) SPIO in PBS, c) 10 × 106 nonvital SPIO-labeled MSCs in PBS, or d) no injection. MR images were acquired immediately after injection and 1, 4, 8, and 12 weeks thereafter using a 0.5-T unit and a T2* sequence. Signal intensity of synovial fluid and synovial lining was assessed semiquantitatively using a scoring system. Viable SPIO-labeled MSCs produced a strong hypointense signal in the synovial fluid immediately after injection, but normal signal intensity of the synovial fluid was observed 1 week later. Synovial lining maintained its hypointensity throughout the study period. Nonvital SPIO-labeled MSCs induced hypointense signals of the synovial fluid; synovial lining appeared weak and inconsistently hypointense in the following weeks. Pure SPIO produced a strong hyperintense signal in the synovial fluid at the time of injection only. Histologically, in all knee joints receiving viable SPIO-labeled MSCs, SPIO particles were detected (Prussian blue) within the synovial lining, dorsal fat pad, and neomeniscus tissue, but not in osteochondral samples. Few SPIO particles were detected in joints injected with nonvital SPIO-labeled MSCs. Immunohistologically, no increased cell death (TUNEL) was observed in the area of detected SPIO particles, but we did observe potential chondrogenic cell differentiation (Safranin O or S100β). We conclude that viable SPIO-labeled MSCs remain detectable within the joint for 12 weeks and attach themselves to some but not all diseased joint structures.

Effect of Schneiderian membrane perforation on sinus lift graft outcome using two different donor sites: a retrospective study of 105 maxillary sinus elevation procedures

Background: Sinuslift is meanwhile an established method of bone augmentation in the posterior maxilla. Aim of the study was to evaluate the significance of intraoperative Schneiderian membrane perforations during maxillary sinus floor elevation surgery using autogenous bone harvested from two different donor sites using a Safescraper device on the success rate, graft survival and implant integration. Methods: The investigators conducted a retrospective cohort study at the Department of Oral and Maxillofacial Surgery of Military Hospital Ulm composed of patients with severe maxillary atrophy who underwent sinus augmentation from January 2011 until December 2011. Ninety-nine consecutive patients (89 men, 10 women) with a mean age of 43.1 years underwent sinus graft procedures in a 2-stage procedure using the lateral wall approach, as described by Tatum (1986). Data on patient age, smoking status, donor site and surgical complications were recorded and the relationship between Schneiderian membrane perforation and complication rate was evaluated. Dental implants were inserted 4 months after grafting. Results: A total of 105 sinus lift procedures were performed in 99 patients. Sixty-one patients (61.6%) underwent sinus elevation with autogenous bone from the buccal sinus wall, while 38 patients (38.4%) bone harvesting from the iliac crest. Intraoperative perforation of the Schneiderian membrane was observed in 11 of the 105 sinuses (10.4%). These perforations resulted in 4 (36.3%) of the cases in major postoperative complications accompanied by swelling and wound infection. Membrane perforations were slightly associated with the appearance of postoperative complications (p=0.0762). In 2.4% of all cases, regarding 2 patients the final rehabilitation with dental implants was not possible because of extensive bone resorption. Conclusion: Intraoperative complications performing sinus augmentation may lead to postoperative complications. With careful clinical and radiographic evaluation and appropriate treatment, the complications and risk for graft material displacement and implant loss can be eliminated.