Efficacy of lysostaphin-coated titanium plates on implant-associated MRSA osteitis in minipigs.

PURPOSE: The growing incidence of implant-associated infections (IAIs) caused by biofilm-forming Staphylococcus aureus in combination with an increasing resistance to antibiotics requires new therapeutic strategies. Lysostaphin has been shown to eliminate this biofilm. Own studies confirm the effectiveness in a murine model. The current study characterizes the effects of lysostaphin-coated plates in an IAI minipig model. METHODS: The femur of 30 minipigs was stabilized with a five-hole plate, a bone defect was created, and in 20 cases methicillin-resistant Staphylococcus aureus was applied. Ten animals served as control group. After 14 days, local debridement, lavage, and plate exchange (seven-hole plate) were performed. Ten of the infected minipigs received an uncoated plate and 10 a lysostaphin-coated plate. On day 84, the minipigs were again lavaged, followed by euthanasia. Bacterial load was quantified by colony-forming units (CFU). Immunological response was determined by neutrophils, as well as interleukins. Fracture healing was assessed radiologically. RESULTS: CFU showed significant difference between infected minipigs with an uncoated plate and minipigs with a lysostaphin-coated plate (p = 0.0411). The infection-related excessive callus formation and calcification was significantly greater in the infected animals with an uncoated plate than in animals with a lysostaphin-coated plate (p = 0.0164/p = 0.0033). The analysis of polymorphonuclear neutrophils and interleukins did not reveal any pioneering findings. CONCLUSION: This study confirms the minipig model for examining IAI. Furthermore, coating of plates using lysostaphin could be a promising tool in the therapeutic strategies of IAI. Future studies should focus on coating technology of implants and on translation into a clinical model.

Plate-associated localized osteitis in mini-pig by biofilm-forming Methicillin-resistant Staphylococcus aureus (MRSA): establishment of a novel experimental model.

PURPOSE: The increasing number of implant-associated infections during trauma and orthopedic surgery caused by biofilm-forming Staphylococcus aureus in combination with an increasing resistance of conventional antibiotics requires new therapeutic strategies. One possibility could be testing for different therapeutic strategies with differently coated plates. Therefore, a clinically realistic model is required. The pig offers the best comparability to the human situation, thus it was chosen for this model. The present study characterizes a novel model of a standardized low-grade acute osteitis with bone defect in the femur in mini-pigs, which is stabilized by a titanium locking plate to enable further studies with various coatings. METHODS: A bone defect was performed on the femur of 7 Aachen mini-pigs and infected with Methicillin-resistant S. aureus (MRSA ATCC 33592). The defect zone was stabilized with a titanium plate. After 14 days, a plate change, wound debridement and lavage were performed. Finally, after 42 days, the animals were lavaged and debrided again, followed by euthanasia. The fracture healing was evaluated radiologically and histologically. RESULTS: A local osteitis with radiologically visible lysis of the bone could be established. The unchanged high Colony-forming Units (CFU) in lavage, the significant differences in Interleukin (IL)-6 in blood compared to lavage and the lack of increase in Alkaline Phosphates (ALP) in serum over the entire observation period show the constant local infection. CONCLUSION: The study shows the successful induction of local osteitis with lysis of the bone and the lack of enzymatic activity to mineralize the bone. Therefore, this standardized mini-pig model can be used in further clinical studies, to investigate various coated implants, bone healing, biofilm formation and immune response in implant-associated osteitis.

Effect of antibiotic infused calcium sulfate/hydroxyapatite (CAS/HA) insets on implant-associated osteitis in a femur fracture model in mice.

Cerament (Bonesupport Holding, Lund, Sweden) is a bioresorbable synthetic bone substitute consisting of calcium sulfate and hydroxyapatite which is successfully used as a bone graft in bone defects or in delayed and non-unions after fractures. Besides, calcium sulfate/ hydroxyapatite (CAS/HA) could have, attributed to its composition and osteoinductive properties, have great importance in the treatment of bone infections with critical size defects (CSD). Aim of the study was to evaluate the effects of antibiotic infused CAS/HA on inflammation and bone healing in an implant-associated osteitis mice model. In a standardized murine model, the left femur of 72 BALB/c mice were osteotomized, generating a CSD (2,5 mm) with stabilization through a 6-hole titanium locking plate. Osteitis has been induced through inoculation of Staphylococcus aureus (SA) into the fracture gap. To analyze the effect of CAS/HA, following groups were generated with either CAS/HA, CAS/HA with gentamycin (CAS/ HA-G) or CAS/HA with vancomycin (CAS/HA-V) insets placed into the osteotomy. Debridément and lavages were progressed on day 7 and 42 to determine the local bacterial growth and the immune reaction. Fracture healing was quantified on day 7 and 42 by x-ray and bone healing markers from blood samples. Progression of infection was assessed by estimation of colony-forming units (CFU) and immune response was analyzed by determination of Interleukin (IL)- 6 and polymorphonuclear neutrophils (PMN) in lavage samples. Osteitis induced higher IL-6 and PMN-levels in the lavage samples on day 7. Both parameters showed a reduction in all groups on day 42. CAS/HA-V revealed a significant reduction of CFU and PMNs in lavage samples on day 42. A positive effect on bone healing could only be shown in non-infected mice. Whereas, application of mere CAS/HA in infected mice did show tendencies of bone destruction and lysis, independent of impregnation with antibiotics or not. Thus, application of CAS/HA in acute implant-associated infections is not recommended. In non-infectious environments or after infect-convalescence CAS/HA could albeit serve as a suggestive tool in trauma and orthopedic surgery.

Vestibular migraine screening in a migraine-diagnosed patient population, and assessment of vestibulocochlear function.

OBJECTIVE: The primary aim of this study is to do a vestibular migraine scan in a population of patients with migraine diagnosis using the most recent standardized diagnosis criterion which is International Classification of Headache Disorders (ICHD) 3 Beta and to identify the epidemiological data. The second part of the study involves performing several vestibulocochlear tests on patients who received vestibular migraine (VM) diagnosis to collect data that may be important for diagnostic purposes by comparing the patients with normal population when necessary. DESIGN: Blind, cross-sectional study. SETTING: Tertiary referral hospital. PARTICIPANTS: One hundred patients were scanned for VM using ICHD 3 Beta guideline. MAIN OUTCOME MEASURES: In order to evaluate the vestibulocochlear functions of the patients with VM diagnosis, audiometry, tympanometry, electrocochleography (EcochG), computerized dynamic posturography (CDP) and video head impulse test (vHIT) were performed; besides in order to evaluate the significance of the results of the tests, second group was formed with migraine patients without any vestibular complaints and control group was formed from healthy population when needed. RESULTS: VM prevalence was determined to be 21% in migraine patients which is much higher than stated in current literature. No significant difference was observed between migraine and VM patients with respect to audiometric and tympanometric measurements. According to the CDP results, balance defects were present in VM patients, even during attack-free periods. EcochG data suggests average SP/AP scores of VM patients are significantly higher than migraine patients. Furthermore, the number of patients who exceeded a limit value of 0.4 or 0.5 in SP/AP scores was significantly higher in VM patients than in migraine patients. Also vHIT results show that nearly half the VM patients, which is a significant ratio, have saccadic movements and this is thought to be compatible with peripheral vestibular involvement. CONCLUSION: Our results suggest VM disease is more common than previously thought. We believe that further EcochG-based studies would shed light on the controversial topic on the intersection and disjunction sets of MD and VM diseases. Although the results of the present study are compatible with peripheral vestibular effects, it is not possible to rule out another central mechanism at some other level.

Abnormal white matter integrity as a structural endophenotype for bipolar disorder.

BACKGROUND: Several lines of evidence suggest that bipolar disorder (BD) is associated with white matter (WM) pathology. Investigation of unaffected first-degree relatives of BD patients may help to distinguish structural biomarkers of genetic risk without the confounding effects of burden of illness, medication or clinical state. In the present study, we applied tract-based spatial statistics to study WM changes in patients with BD, unaffected siblings and controls. METHOD: A total of 27 euthymic patients with BD type I, 20 unaffected siblings of bipolar patients and 29 healthy controls who did not have any current or past diagnosis of Axis I psychiatric disorders were enrolled in the study. RESULTS: Fractional anisotropy (FA) was significantly lower in BD patients than in the control group in the corpus callosum, fornix, bilateral superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, posterior thalamic radiation, cingulum, uncinate fasciculus, superior corona radiata, anterior corona radiata and left external capsule. In region-of-interest (ROI) analyses, we found that both unaffected siblings and bipolar patients had significantly reduced FA in the left posterior thalamic radiation, the left sagittal stratum, and the fornix compared with healthy controls. Average FA for unaffected siblings was intermediate between the healthy controls and bipolar patients within these ROIs. CONCLUSIONS: Decreased FA in the fornix, left posterior thalamic radiation and left sagittal stratum in both bipolar patients and unaffected siblings may represent a potential structural endophenotype or a trait-based marker for BD.

The potential teratogenic effects of interferon beta-1a and interferon beta-1b on in vitro embryonic development.

BACKGROUND: Interferon beta (IFNb) was the first proven drug for the treatment of multiple sclerosis (MS). The diagnosis of MS frequently occurs in women at childbearing age (especially in twenties and thirties). Therefore, the pregnancy process is major concern for many women with MS. Data on women exposed to IFNb during pregnancy are limited. The aim of our study was to investigate the teratogenic potential of IFNb on embryonic development via embryo culture technique. Recently, this technique has been often used for determining teratogenic effect of pharmacologic drugs and potential teratogens on embryonic development. MATERIALS AND METHODS: In this study, IFNb was applied to the culture medium and after 48 h of culture effects of IFNbs (1000 IU/IFNb-1a and 1000 IU/IFNb-1b) on embryonic development were morphologically investigated. RESULTS: According to morphologic scoring system, total morphologic score, somite number and protein contents were similar between control group and two experimental groups (p > 0.05). On the other hand, yolk sac diameter, crown- -rump length and head length were significantly decreased in two experimental groups compared with control group (p < 0.05). CONCLUSIONS: Consequently, IFNb-1a and IFNb-1b, applied to the culture medium, have no macroscopic teratogenic effect on embryonic development. However, in respect of morphometric measurements, IFNb-1a and IFNb-1b have caused growth retardation in embryo. This research related to interferon was the first study using vitro embryo culture technique; thus, in our point of view, future studies which will be performed by using different doses of IFN will contribute to the literature.

Surgical and audiological evaluation of the Baha BA400.

OBJECTIVE: Despite extensive soft tissue reduction, the most common complications associated with bone-anchored hearing aid systems, also known as bone-anchored hearing implants, are related to adverse skin reactions around the abutment. The necessary soft tissue reduction also adds complexity to the surgical procedure. This study aimed to evaluate the surgical and audiological outcomes of a new connective interface of the Cochlear™ Baha® BA400 device implanted using the one-stage surgical technique. METHOD: A multicentre, retrospective case series is presented, including data collected from three tertiary care institutions. RESULTS: In total, 16 patients who had undergone bone-anchored hearing aid surgery over a 10- to 12-month period were assessed for hearing performance, implant stability and surgical complications. CONCLUSION: This case series indicates that new abutments with a hydroxyapatite coating can be implanted percutaneously without soft tissue reduction. Furthermore, device implantation using this surgical technique may have some advantages compared with a conventional device and procedure combination over 12- to 16-months of follow up.

Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have essential roles in synaptic plasticity which is involved in pathogenesis and treatment of psychiatric disorders. However, it is not clear whether they act simultaneously during illness states in major psychiatric disorders. METHODS: BDNF and GDNF serum levels were measured concomitantly by enzyme-linked immunosorbent assay (ELISA) method in 171 patients diagnosed with schizophrenia (n=33), bipolar disorder-manic episode (n=39), bipolar/unipolar depression (n=64, 24/40) and obsessive-compulsive disorder (n=35) according to DSM-IV, and 78 healthy volunteers. SCID-I and SCID non-patient version were used for clinical evaluation of the patients and healthy volunteers, respectively. Correlations between the two trophic factor levels, and illness severity scores, duration of illness and medication dosages were studied across different illnesses. RESULTS: While patients had equally lower BDNF levels in all diagnoses, GDNF levels were significantly higher in mania and lower in schizophrenia compared to healthy controls. BDNF levels were negatively correlated to illness severity scores in affective episodes (mania and depression). Longer duration of illness (>5 years) had an impact on lower GDNF levels in schizophrenia. BDNF levels and antipsychotic drug dosages in schizophrenia, and GDNF levels and antidepressant drug dosages in obsessive-compulsive disorder were positively correlated. CONCLUSION: Our data confirmed the evidence of equally deficient neuronal support by BDNF in all major psychiatric illnesses, but suggested a diverse glial functioning between schizophrenia and mania.

Lysostaphin-coated titan-implants preventing localized osteitis by Staphylococcus aureus in a mouse model.

The increasing incidence of implant-associated infections induced by Staphylococcus aureus (SA) in combination with growing resistance to conventional antibiotics requires novel therapeutic strategies. In the current study we present the first application of the biofilm-penetrating antimicrobial peptide lysostaphin in the context of bone infections. In a standardized implant-associated bone infection model in mice beta-irradiated lysostaphin-coated titanium plates were compared with uncoated plates. Coating of the implant was established with a poly(D,L)-lactide matrix (PDLLA) comprising lysostaphin formulated in a stabilizing and protecting solution (SPS). All mice were osteotomized and infected with a defined count of SA. Fractures were fixed with lysostaphin-coated locking plates. Plates uncoated or PDLLA-coated served as controls. All mice underwent debridement and lavage on Days 7, 14, 28 to determine the bacterial load and local immune reaction. Fracture healing was quantified by conventional radiography. On Day 7 bacterial growth in the lavages of mice with lysostaphin-coated plates showed a significantly lower count to the control groups. Moreover, in the lysostaphin-coated plate groups complete fracture healing were observed on Day 28. The fracture consolidation was accompanied by a diminished local immune reaction. However, control groups developed an osteitis with lysis or destruction of the bone and an evident local immune response. The presented approach of terminally sterilized lysostaphin-coated implants appears to be a promising therapeutic approach for low grade infection or as prophylactic strategy in high risk fracture care e.g. after severe open fractures.

Implant-associated localized osteitis in murine femur fracture by biofilm forming Staphylococcus aureus: a novel experimental model.

Staphylococcus aureus (SA) is the most common causative agent for implant-associated osteitis. The present study characterizes a novel model of a low grade acute SA osteitis with bone defect in the femur which is stabilized by a titanium locking plate. Wild-type Balb/c mice were osteotomized, fixed by a locking plate and infected with SA. Mice underwent debridement 7 and 14 days later and were sacrificed at Day 28. At Days 7, 14, and 28 after inoculation local and systemic cell populations and IL-6 were analyzed. Fracture healing was quantified by radiography. The control group underwent the same procedure without infection. The bacterial load of implant-associated osteitis with biofilm formation was quantified by counting CFU and real-time PCR. Fracture healing determined by radiography was delayed in infected compared to non-infected mice. Throughout the investigation period CFU and leukocyte counts, as well as IL-6 levels were found to be significantly elevated in infected mice at the infection site but not systemically. Our murine model allows the detailed investigation of implant associated localized osteitis with biofilm producing SA and its influence on fracture healing. The model provides a tool to analyze therapeutic or prophylactic approaches to the problem of biofilm-associated osteitis.

Desmoplastic fibroma of the skull.

Desmoplastic fibroma is a primary bone tumour which occurs exceedingly rarely in the cranial bones. We report a histopathologically confirmed example in a 21 year old man with a painless swelling over the sagittal suture. In the light of our experience and reports of previous examples, we review the features of the condition and its management.

Aspergillus pituitary abscess.

BACKGROUND: Pituitary abscess is rare and most of the cases are of bacterial origin. True fungal pituitary abscess is extremely rare only five cases have been reported. In this report, we present a case of aspergillus pituitary abscess. Mortality rate in intracranial aspergillosis is close to 100% especially in immunsuppressed patients when undiagnosed and untreated. In focal CNS aspergillosis total cure can be achieved in approximately 30% of the cases by surgical drainage and intensive antifungal therapy. Although this is the first reported case with magnetic resonance imaging examination the definitive diagnosis was established only by histopathological examination. CLINICAL PRESENTATION: A 42 year-old man was referred to our hospital with the diagnosis of sellar suprasellar mass accompanied by frontal headache and decreased visual acuity. His medical history was insignificant. Physical examination was normal and the patient was afebrile. The neurological examination revealed bilateral papilledema and bitemporal hemianopsia but no stiff neck and motor or sensory deficit. In the light of MRI examination, the preoperative diagnosis was pituitary abscess secondary to paranasal sinus infection or hemorrhagic pituitary adenoma. INTERVENTION: The patient was successfully treated by transsphenoidal surgery. Histopathological examination of sphenoid sinus mucosa revealed normal mucosal appearance with inflammation and histopathological examination of the intrasellar mass resulted in the diagnosis of aspergillosis. All cultures obtained from sphenoid sinus were reported as having no growth. However in the second week after the operation fungal culture of the intrasellar mass grew aspergillus. After 8 weeks of amphothericine-B treatment, the patient was discharged. At the last follow up examination two years after the operation, the patient was symptom free with normal pituitary function. CONCLUSION: Aspergillus pituitary abscess should be considered in the differential diagnosis of a pituitary mass. The correct diagnosis of pituitary aspergillosis can only be achieved by histopathological examination because clinical and radiological findings including MRI are not specific and culture results are obtained later. Immediately after the diagnosis, intensive antifungal therapy should be started for a successful treatment.