Osteoinductive potential of recombinant BMP-9 in bone defects of mice treated with antiresorptive agents.

The aim of the present study was to investigate the effects of recombinant human (rh)BMP-9 on bone regenerative potential in a mouse model of antibody-mediated antiresorptive therapy (AMART). A monoclonal anti-murine receptor activator of nuclear factor-kappa B ligand (RANKL) antibody (mAb) was used to create an AMART model in mice. rhBMP-9 combined with collagen membrane was implanted in calvarial defects in mAb-treated mice. After 4 weeks, the bone formative potential in the defects was evaluated by micro-computed tomography and histological approaches. The groups implanted with rhBMP-9-containing collagen membranes demonstrated substantial osteopromotive potential, with significantly greater new bone volume (Sham + BMP-9 group; 0.86 ± 0.29 mm3 and mAb + BMP-9 group; 0.64 ± 0.16 mm3) than control PBS-membranes (Sham + PBS group; 0.44 ± 0.29 mm3 and mAb + PBS group; 0.24 ± 0.12 mm3) in both sham and mAb-treated mice. In line with in vivo study, bone marrow cells isolated from both sham and mAb-treated mice confirmed greater osteogenic potential upon stimulation with rhBMP-9 in vitro. These findings suggest for the first time that local rhBMP-9 administration might be a strategy to accelerate bone regeneration in the context of AMART.

Thermal processing of bone: in vitro response of mesenchymal cells to bone-conditioned medium.

The autoclaving, pasteurization, and freezing of bone grafts to remove bacteria and viruses, and for preservation, respectively, is considered to alter biological properties during graft consolidation. Fresh bone grafts release paracrine-like signals that are considered to support tissue regeneration. However, the impact of the autoclaving, pasteurization, and freezing of bone grafts on paracrine signals remains unknown. Therefore, conditioned medium was prepared from porcine cortical bone chips that had undergone thermal processing. The biological properties of the bone-conditioned medium were assessed by examining the changes in expression of target genes in oral fibroblasts. The data showed that conditioned medium obtained from bone chips that had undergone pasteurization and freezing changed the expression of adrenomedullin, pentraxin 3, BTB/POZ domain-containing protein 11, interleukin 11, NADPH oxidase 4, and proteoglycan 4 by at least five-fold in oral fibroblasts. Bone-conditioned medium obtained from autoclaved bone chips, however, failed to change the expression of the respective genes. Also, when bone-conditioned medium was prepared from fresh bone chips, autoclaving blocked the capacity of bone-conditioned medium to modulate gene expression. These in vitro results suggest that pasteurization and freezing of bone grafts preserve the release of biologically active paracrine signals, but autoclaving does not.

Effect of a plasmaelectrolytic coating on the strength retention of in vivo and in vitro degraded magnesium implants.

The strength decrease in magnesium implants was studied in vitro and in vivo, with and without a protective plasmaelectrolytic coating. In vivo, degradation was examined by implanting rectangular plates on top of the nasal bone of miniature pigs. The presence of gas pockets in the soft tissue surrounding the implants was evaluated with intermediate X-rays and computed X-ray tomography scans before euthanasia. After 12 and 24 weeks of in vivo degradation, the large rectangular plates were removed and mechanically tested in three-point bending. In vitro, identical plates were immersed in simulated body fluid for 4, 8 and 12 weeks. In vitro and in vivo results showed that onset of gas release can be delayed by the plasmaelectrolytic coating. Mass loss and strength retention during in vivo degradation is about four times slower than during in vitro degradation for the chosen test conditions. Despite the slow degradation of the investigated WE43 alloy, the occurrence of gas pockets could not be completely avoided. Nevertheless, uniformity of degradation and reliable strength retention make this alloy a prime candidate for the use of magnesium in cranio-maxillofacial surgery.

Premature craniosynostosis--the role of skull base surgery in its correction. A surgical and radiological experience of 172 operated infants/children.

BACKGROUND: Most craniofacial abnormalities are non-syndromic craniosynostoses due to premature fusion of one or more craniofacial sutures. Functional impairment is caused either by a pathological growth pattern or increased intracranial pressure. The indications for surgery are to increase intracranial volume and to correct aesthetics. PATIENTS AND METHODS: We retrospectively reviewed 172 patients who had been operated on for premature craniosynostosis, including fronto-orbital advancement, from 1992 to 2002. Demographic data, clinical follow-up findings, and regular photo documentation were analyzed. RESULTS: After a mean follow-up of 6 years the overall outcome for those operated on within the first 6 months of life was satisfactory in 97%. The remaining 3% were reoperated at between 4 and 6 years of age. All cephalometric indices normalized postoperatively. Eight patients underwent SPECT studies which showed preoperative perfusion asymmetry corresponding to the fused sutures that were normalized following surgical decompression. No severe perioperative complications were seen. DISCUSSION: Cephalometric parameters represent an excellent method to compare the postoperative outcome. Standard skull base procedures need to be adapted carefully to the individual form of craniosynostosis to avoid an unfavourable result. Single Photon Emissin Computed Tomography (SPECT) studies give evidence that correction of single cranial suture synostosis allows for normalization of cerebral blood flow and should be performed within first 6-8 months of life.

New molecular knowledge towards the trigemino-cardiac reflex as a cerebral oxygen-conserving reflex.

The trigemino-cardiac reflex (TCR) represents the most powerful of the autonomous reflexes and is a subphenomenon in the group of the so-called "oxygen-conserving reflexes". Within seconds after the initiation of such a reflex, there is a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF), with no changes in the cerebral metabolic rate of oxygen (CMRO2) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently. Features of the reflex have been discovered during skull base surgery, mediating reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus, which finally engage a small population of neurons in the cortex. This cortical center appears to be dedicated to transduce a neuronal signal reflexively into cerebral vasodilatation and synchronization of electrocortical activity; a fact that seems to be unique among autonomous reflexes. Sympathetic excitation is mediated by cortical-spinal projection to spinal preganglionic sympathetic neurons, whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to the brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Previous studies showed a great variability in the human TCR response, in special to external stimuli and individual factors. The TCR gives, therefore, not only new insights into novel therapeutic options for a range of disorders characterized by neuronal death, but also into the cortical and molecular organization of the brain.

Gender-related differences in pituitary adenomas.

Pituitary adenomas account for about 10% of all intracranial neoplasms and for about 85% of all pituitary tumors. In addition, prospective studies of normal persons and postmortem examinations reveal pituitary adenomas in up to 10% of adults indicating that not all pituitary adenomas are clinically significant. With clinically significant pituitary adenomas, patients may present with hyper- or under-secretion of pituitary hormones or with symptoms and signs of space occupying intracranial tumor like headache and visual compromise. Like other differentiated neuroendocrine cells, the anterior pituitary displays remarkable plasticity in response to physiological demands, as exemplified by the lactotroph differentiation and proliferation of pregnancy or the thyrotroph hyperplasia of primary hypothyroidism. These reversible changes are mediated by a diverse array of signals that have been interpreted to support a role for hormonal stimulation in the pathogenesis of pituitary adenomas. Different investigators have shown a tendency to gender-related differences not only in surgical outcome, but also in the presenting symptoms and signs, duration of symptoms, tumor size, tumor histology, and restoration of normal pituitary function in patients who are surgically treated and histologically proven pituitary adenomas. In this review, we will try to give a systematic insight into gender related differences of pituitary adenomas. Special reference is given on potential different biology of these tumors as suggested by the gender related differences. The manuscript therefore gives new insights into the cellular understanding of the pituitary adenomas.

Trigemino-cardiac reflex in humans initiated by peripheral stimulation during neurosurgical skull-base operations. Its first description.

BACKGROUND: The trigemino-cardiac reflex (TCR) is a well-recognised phenomenon (first described in skull base surgery by the authors in 1999) that consists of bradycardia, arterial hypotension, apnoea, and gastric hypermobility. TCR occurs during skull base surgery at or around structures that are innervated by any sensory branch of the trigeminal nerve. Thus far, it has not been shown that peripheral stimulation of a trigeminal nerve can also cause this reflex. METHODS: The TCR was defined as clinical hypotension with a drop in mean arterial blood pressure (MABP) and in heart rate (HR) of more than 20% compared to the baseline level and coinciding with the surgical manipulation at or around any branches of the trigeminal nerve. The anaesthesiological and the operative techniques that were used were standardised. CLINICAL FEATURES: We describe here a 29-year-old woman with an endocrinological and imaging-proved micro-prolactinoma in which a TCR with a decrease in "arterial blood pressure" (130/70 mmHg up to a 100/40 mmHg) and an accompanying decrease of the HR (70 beats/min to 50 beats/min) was seen during preparation of the nasal mucosa for a transsphenoidal approach under general anaesthesia, lasting a few seconds until normalisation. After immediate application of atropine, the surgical procedure and the post-operative course was uneventful. MANAGEMENT: We present the first report of peripheral stimulation of a sensory branch of the trigeminal nerve that leads to a TCR under general anaesthesia according to our strict criteria as defined in 1999. The present finding is therefore a key research development and gives substantial evidence that TCR is coincident enhancement of sympathetic and parasympathetic outflows to the heart, suggesting that genetic differences may affect the susceptibility for TCR.

[Trigeminocardiac reflex in pituitary surgery. A prospective pilot study]. / Trigeminokardialer Reflex bei Hypophysenoperationen. Eine prospektive Pilotstudie.

BACKGROUND: The trigeminocardiac reflex (TCR) is a relatively recently described brainstem reflex in the fields of neurosurgery which leads to a simultaneous drop in mean arterial pressure (MAP) and heart rate of at least 20% from baseline levels after stimulation of a sensible branch of the trigeminal nerve. PATIENTS AND METHODS: The purpose of this study was to register prospectively for the first time the rate of TCR during trans-sphenoidal surgery and to describe possible predispositional factors. This was examined by determining selected biomarkers thought to correlate with possible intraoperative ischemic events after occurrence of TCR and furthermore with neuroprotective mechanisms ("ischemic tolerance"). RESULTS: Three of the 40 patients included (7.5%) demonstrated intraoperative occurrence of TCR after exposure of the cavernous sinus. One (2.5%) demonstrated a TCR during preparation of the nasal mucosa. Permanent cardiovascular damage or unfavorable postoperative outcome through the appearance of TCR was not found. There was a trend to lower C-reactive protein levels after occurrence of TCR (32 mg/dl vs 14 mg/dl) following normal values before operations in all cases. Considering that no clinical clue of ischemia was detected, this could mean that some neuroprotective cascades are initiated. There was a correlation between tumor necrosis factor A and noradrenalin levels with the size (invasivity) of the pituitary adenoma. The administration of atropine was necessary in only one patient with intraoperative occurrence of TCR. CONCLUSION: On the basis of this study, it cannot be said to what extent neuroprotective mechanisms after TCR are activated, but a trend is still apparent. Considering the adverse effects and the reflex arc, prophylactic or therapeutic treatment with atropine is not justified.

Difference in functional outcome of ipsilateral tinnitus after intraoperative occurrence of the trigemino-cardiac reflex in surgery for vestibular schwannomas.

OBJECT: Surgical manipulation of the fifth cranial nerve in its intra- or extracranial course may lead to bradycardia or even asystole as well as arterial hypotension, a phenomenon described as the trigemino-cardiac reflex (TCR), first described by the authors previously [11]. The authors report here the impact of this reflex on post-operative ipsilateral tinnitus in patients undergoing vestibular schwannoma surgery. METHODS: Thirty six patients scheduled for vestibular schwannoma surgery were studied retrospectively for parameters influencing the post-operative ipsilateral tinnitus function. According to the occurrence of intra- operative TCR the patients were divided into a TCR-subgroup and a non-TCR subgroup. There was no difference in tumour size between these subgroups. RESULTS: The TCR occurred in 17% of the patients during vestibular schwannoma surgery and influenced the occurrence of post-operative ipsilateral tinnitus: the overall incidence of post-operative ipsilateral tinnitus was 22%. Sixty (60) percent of the patients in the TCR subgroup and 17% of those in the non-TCR subgroup experienced ipsilateral tinnitus postoperatively. There was no correlation between tinnitus and pre- or post-operative hearing function. CONCLUSION: Hypotension after intra-operative TCR is not only a negative prognostic factor for hearing preservation but also for ipsilateral tinnitus in patients undergoing vestibular schwannoma surgery. In combination with worse hearing function after intra-operative TCR, the present finding underlines the importance of the TCR during skull base surgery in relation to improved functional outcome.

Trigemino-cardiac reflex during transsphenoidal surgery for pituitary adenomas: methodological description of a prospective skull base study protocol.

A systematic clinical neuroscience protocol is described for the use to examine the trigemino-cardiac reflex (TCR) response in humans. Target neurosurgical conditions are operations that require manipulations around the peripheral and central part of the trigeminal nerve and its branches, e.g. the cerebellopontine angle or the sellar region. To assess the hemodynamic and cardiac responses of patients after TCR initiation, anesthetic monitoring has been applied. The TCR is defined as a drop of more than 20% of the heart rate and the mean arterial blood pressure compared with the baseline values before the stimulus and coinciding with the surgical manipulation at or around any branches of the trigeminal nerve. By help of illustrative cases, we present for the first time preliminary results regarding the differentiation of the TCR in a central and a peripheral induction during transsphenoidal surgery of pituitary adenomas. Based on these results, we can conclude that we have developed a battery of preoperative examination procedures based on event-related diagnostics that was useful to differentiate different subgroups of TCR during transsphenoidal surgery. The presented protocol can be performed directly pre-, intra- and postoperatively and applied for assessment of TCR even in patients with known risk factors.

Molecular imaging of brain tumors: a bridge between clinical and molecular medicine?

As the research on cellular changes has shed invaluable light on the pathophysiology and biochemistry of brain tumors, clinical and experimental use of molecular imaging methods is expanding and allows quantitative assessment. The term molecular imaging is defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level. Molecular imaging sets forth to probe the molecular abnormalities that are the basis of disease rather than to visualize the end effects of these molecular alterations and, therefore, provides different additional biochemical or molecular information about primary brain tumors compared to histological methods "classical" neuroradiological diagnostic studies. Common clinical indications for molecular imaging contain primary brain tumor diagnosis and identification of the metabolically most active brain tumor reactions (differentiation of viable tumor tissue from necrosis), prediction of treatment response by measurement of tumor perfusion, or ischemia. The interesting key question remains not only whether the magnitude of biochemical alterations demonstrated by molecular imaging reveals prognostic value with respect to survival, but also whether it identifies early disease and differentiates benign from malignant lesions. Moreover, an early identification of treatment success or failure by molecular imaging could significantly influence patient management by providing more objective decision criteria for evaluation of specific therapeutic strategies. Specially, as molecular imaging represents a novel technology for visualizing metabolism and signal transduction to gene expression, reporter gene assays are used to trace the location and temporal level of expression of therapeutic and endogenous genes. Molecular imaging probes and drugs are being developed to image the function of targets without disturbing them and in mass amounts to modify the target's function as a drug. Molecular imaging helps to close the gap between in vitro and in vivo integrative biology of disease.

Subcranial approach in the surgical treatment of anterior skull base trauma.

Fractures of the anterior skull base, because of the region's anatomical relationships, are readily complicated by neurological damage to the brain or cranial nerves. This review highlights the use of a subcranial approach in the operative treatment of injuries of the anterior skull base and compares it to the more traditional neurosurgical transcranial approach. The extended anterior subcranial approach takes advantage of the specific features of injuries in this region and allows direct access to the central anterior cranial base in order to repair fractures, close CSF fistulae and relieve of optic nerve compression. It avoids extensive frontal lobe manipulation. The success of the approach in achieving the aims of surgery with low morbidity is reviewed.

Influences of brain tumor-associated pH changes and hypoxia on epileptogenesis.

OBJECTIVE: The pathophysiological changes related to epileptic activity in peri- and intra-tumoral tissue are complex and have been only partly understood until now; possible mechanisms involve different structural, biochemical and histological tumor-related alterations. METHODS: Medical databases were searched for evidence on influence of brain tumor-associated pH changes and hypoxia on epileptogenesis. RESULTS: During the perioperative period, tumor-related hypoxia and acidity related to tumor neovascularization by vascular endothelial growth factor (VEGF) in combination with angiopoietins 1/2 (ang 1/2), may be a major factor contributing to outcomes involving epileptic activity after surgical tumor removal. Because anaerobic fermentation produces far less ATP than oxidative phosphorlyation per molecule of glucose, increased activity of the glycolytic pathway is necessary to maintain free ATP levels in the hypoxic cell. In mammalian cells, this metabolic switch is regulated by the transcription factor hypoxia-inducible factor-1. CONCLUSIONS: From the molecular point of view, therapeutic implications for the perioperative period may have relevance for the future.

Trigeminocardiac reflex. A clinical phenomenon or a new physiological entity?

The trigemino-cardiac reflex (TCR) is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. The sensory nerve endings of the trigeminal nerve send neuronal signals via the Gasserian ganglion to the sensory nucleus of the trigeminal nerve, forming the afferent pathway of the reflex arc. This afferent pathway continues along the short internuncial nerve fibers in the reticular formatio to connect with the efferent pathway in the motor nucleus of the vagus nerve. Clinically, the trigemino-cardiac reflex has been reported to occur during craniofacial surgery, balloon-compression rhizolysis of the trigeminal ganglion, and tumor resection in the cerebellopontine angle. Apart from the few clinical reports, the physiological function of this brainstem-reflex has not yet been fully explored. From experimental findings, it may be suggested that the trigemino-cardiac reflex represents an expression of a central neurogenic reflex leading to rapid cerebrovascular vasodilatation generated from excitation of oxygen-sensitive neurons in the rostral ventrolateral medulla oblongata. By this physiological response, the adjustments of the systemic and cerebral circulations are initiated to divert blood to the brain or to increase blood flow within it. As it is generally accepted that the diving reflex and ischemic tolerance appear to involve at least partially similar physiological mechanisms, the existence of such endogenous neuroprotective strategies may extend the actually known clinical appearance of the TCR and include the prevention of other potentially brain injury states as well. This may be in line with the suggestion that the TCR is a physiological, but not a pathophysiological entity.