Stimulation of the Sphenopalatine Ganglion Induces Reperfusion and Blood-Brain Barrier Protection in the Photothrombotic Stroke Model

The treatment of stroke remains a challenge. Animal studies showing that electrical stimulation of the sphenopalatine ganglion (SPG) exerts beneficial effects in the treatment of stroke have led to the initiation of clinical studies. However, the detailed effects of SPG stimulation on the injured brain are not known.The effect of acute SPG stimulation was studied by direct vascular imaging, fluorescent angiography and laser Doppler flowmetry in the sensory motor cortex of the anaesthetized rat. Focal cerebral ischemia was induced by the rose bengal (RB) photothrombosis method. In chronic experiments, SPG stimulation, starting 15 min or 24 h after photothrombosis, was given for 3 h per day on four consecutive days. Structural damage was assessed using histological and immunohistochemical methods. Cortical functions were assessed by quantitative analysis of epidural electro-corticographic (ECoG) activity continuously recorded in behaving animals.Stimulation induced intensity- and duration-dependent vasodilation and increased cerebral blood flow in both healthy and photothrombotic brains. In SPG-stimulated rats both blood brain-barrier (BBB) opening, pathological brain activity and lesion volume were attenuated compared to untreated stroke animals, with no apparent difference in the glial response surrounding the necrotic lesion.SPG-stimulation in rats induces vasodilation of cortical arterioles, partial reperfusion of the ischemic lesion, and normalization of brain functions with reduced BBB dysfunction and stroke volume. These findings support the potential therapeutic effect of SPG stimulation in focal cerebral ischemia even when applied 24 h after stroke onset and thus may extend the therapeutic window of currently administered stroke medications

Animal models of focal brain ischemia

Stroke is a leading cause of disability and death in many countries. Understanding the pathophysiology of ischemic injury and developing therapies is an important endeavor that requires much additional research. Animal stroke models provide an important mechanism for these activities. A large number of stroke models have been developed and are currently used in laboratories around the world. These models are overviewed as are approaches for measuring infarct size and functional outcome

Translational Stroke Research Using a Rabbit Embolic Stroke Model: A Correlative Analysis Hypothesis for Novel Therapy Development

Alteplase (tissue plasminogen activator, tPA) is currently the only FDA-approved treatment that can be given to acute ischemic stroke (AIS) patients if patients present within 3 h of an ischemic stroke. After 14 years of alteplase clinical research, evidence now suggests that the therapeutic treatment window can be expanded 4.5 h, but this is not formally approved by the FDA. Even though there remains a significant risk of intracerebral hemorrhage associated with alteplase administration, there is an increased chance of favorable outcome with tPA treatment. Over the last 30 years, the use of preclinical models has assisted with the search for new effective treatments for stroke, but there has been difficulty with the translation of efficacy from animals to humans. Current research focuses on the development of new and potentially useful thrombolytics, neuroprotective agents, and devices which are also being tested for efficacy in preclinical and clinical trials. One model in particular, the rabbit small clot embolic stroke model (RSCEM) which was developed to test tPA for efficacy, remains the only preclinical model used to gain FDA approval of a therapeutic for stroke. Correlative analyses from existing preclinical translational studies and clinical trials indicate that there is a therapeutic window ratio (ARR) of 2.43-3 between the RSCEM and AIS patients. In conclusion, the RSCEM can be used as an effective translational tool to gauge the clinical potential of new treatments

Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems

Rodent models of focal cerebral ischemia are essential tools in experimental stroke research. They have added tremendously to our understanding of injury mechanisms in stroke and have helped to identify potential therapeutic targets. A plethora of substances, however, in particular an overwhelming number of putative neuroprotective agents, have been shown to be effective in preclinical stroke research, but have failed in clinical trials. A lot of factors may have contributed to this failure of translation from bench to bedside. Often, deficits in the quality of experimental stroke research seem to be involved. In this article, we review the commonest rodent models of focal cerebral ischemia - middle cerebral artery occlusion, photothrombosis, and embolic stroke models - with their respective advantages and problems, and we address the issue of quality in preclinical stroke modeling as well as potential reasons for translational failure

Realignment Osteotomy in Fibular Malunion

Category: Ankle Introduction/Purpose: The exact incidence of distal fibula malunions after fibular reconstructions is not known, but incidence up to 33% is described in the literature. The most frequent malunions of the fibula are shortening and malrotation, resulting in the widening of the ankle mortise and talar instability. It has been demonstrated that substantial fibular displacement may substantially increase the contact pressures in the ankle joint. Therefore distal fibular malunion is a risk factor for development of posttraumatic ankle osteoarthritis. The objectives of this study were to (1) describe our treatment algorithm and surgical technique in patients with posttraumatic fibula malunions; (2) determine intra- and postoperative complications rates, and (3) to describe mid-term clinical and radiological outcomes and quality of life. Methods: 19 consecutive patients (11 male, 8 female, mean age 42 years, range 19 – 68) with symptomatic fibular malunions were included into this prospective study. The initial injury was Weber B and C fracture in 7 and 12 ankles, respectively. The mean time between the injury and reconstructive surgery was 17 months (range 6 – 101). In all patients a z-shaped osteotomy of the fibula was performed to achieve the appropriate length/rotation of the fibula. Fixation was performed using a plate. If necessary, supramalleolar and inframalleolar deformities were corrected by supramalleolar tibial and calcaneal osteotomies, respectively. Prior to the osteotomies an anterior ankle arthroscopy was performed in all patients. All patients were evaluated pre- and postoperatively (mean follow-up 4.9 years, range 3.2 – 6.7). Radiological outcomes were assessed using standardized weight- bearing radiographs. Clinical outcomes were assessed using visual analogue scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scale, and SF-36 questionnaire. Results: There were no intraoperative complications. In two patients early wound healing problems were observed, and resolved with i.v. antibiotics. Osseous healing was observed in all ankles within 10 weeks after surgery. The length and rotation of the fibula was improved in all patients, according to Weber criteria. All patients experienced significant pain relief (VAS: 6.5 ± 1.1 to 0.9 ± 0.8, P < 0.001) and functional improvement (AOFAS hindfoot scale: 48.4 ± 14.5 to 85.7 ± 7.4, P < 0.001; ROM:37° ± 6° to 46° ± 5°, P < 0.001). The SF-36 score also significantly increased in all 8 subgroups. In 11 patients hardware was removed due a discomfort after a mean of 11.8 months (range 7.2 – 22.8). Conclusion: A z-shaped osteotomy is an efficient and successful method to restore fibula length and rotation in patients with posttraumatic malunion. Our findings in this series confirm that this realignment surgery results in significant pain relief and functional improvement

Stress vs. Non-Stress Radiographs in Subtle Syndesmotic Injuries

Category: Sports Introduction/Purpose: Between 1-18% of all ankle sprains and 23% of all ankle fractures involve injury to the distal tibio-fibular syndesmosis. Syndesmotic injuries can create a substantial diagnostic and therapeutic challenge for orthopaedic surgeons. While acute injuries can be assessed using conventional radiographs, subtle syndesmotic injuries may be misdiagnosed using X-rays. Misdiagnoses may result in chronic ankle instability, pain and post-traumatic osteoarthritis of the tibio-talar joint. The purpose of this study was to investigate whether syndesmotic injury was more easily diagnosed with stress vs. non-stress radiographs.radiographs.sed with stress vs. non-stress radiographs. Methods: Five pairs of cadavers (tibia plateau to toe-tip, mean 61 years, range 52-70 years) were scanned with weight-bearing CT (170 lb, w/ and w/o 10 Nm static external rotation torque). Digitally reconstructed radiographs (DRRs), which are comparable to conventional radiographs, were reconstructed from the 3D CT data. The following conditions were tested: First, intact ankles (Native) were tested. Second, one specimen from each pair underwent AITFL resection, while the contralateral underwent deltoid resection (Condition 1). Third, the remaining intact deltoid ligament or AITFL was resected in each ankle (Condition 2). Finally, the interosseous membrane (IOM) was resected in all ankles (Condition 3). Condition 3 was defined as acute syndesmotic injury. Using antero-posterior (AP) views, the tibio-fibular clear space (TFCS), tibiofibular overlap (TFO) and medial clear space (MCS) were assessed. Statistical analysis was performed using paired (comparison within groups) and unpaired (comparison between groups) t-test where p=0.05 was considered significant. Results: Regarding the TFCS, Native vs. Condition 3 in 10 Nm stress radiographs was significantly different in the deltoid group (p=0.021). Using TFO in stress and non-stressed radiographs, Native vs. Condition 2 and 3 was significantly different for the deltoid group (p=0.043), and Native vs. Condition 3 in the syndesmotic group (p=0.027). Regarding the MCS in non-stress radiographs, Native vs. Condition 3 was significantly different in the deltoid group (p=0.007), while in stress views, Native vs. Condition 2 was significant different in the syndesmotic (p=0.026) and Native vs. Condition 3 in the deltoid group (p=0.030). No differences were found comparing the conditions of the AITFL with the same conditions of the deltoid group. Conclusion: The TFCS cannot be used to assess subtle or acute syndesmotic injuries in stress and non-stress radiographs. The TFO can be used to assess a combined injury to the AITFL and deltoid ligament in stress and non-stress radiographs. The MCS can be used to assess acute syndesmotic injuries in stress and non-stress radiographs. Radiographs (stress or non-stress) cannot be used to distinguish between injuries to the AITFL or deltoid ligament. Therefore, stress and non-stress radiographs are not useful in assessment of subtle syndesmotic injuries. Stress-radiographs are not superior compared to non-stress radiographs in assessment of acute syndesmotic injuries