Ten years of war: a characterization of craniomaxillofacial injuries incurred during operations Enduring Freedom and Iraqi Freedom.

BACKGROUND: Improved armor and battlefield medicine have led to better survival in the wars in Iraq and Afghanistan than any previous ones. Increased frequency and severity of craniomaxillofacial injuries have been proposed. A comprehensive characterization of the injury pattern sustained during this 10-year period to the craniomaxillofacial region is needed to improve our understanding of these unique injuries, to optimize the treatment for these patients, and to potentially direct strategic development of protective equipment in the future. METHODS: The Joint Theater Trauma Registry was queried from October 19, 2001, to March 27, 2011, covering operations Enduring Freedom and Iraqi Freedom for battle injuries to the craniomaxillofacial region, including patient demographics and mechanism of injury. Injuries were classified according to type (wounds, fractures, burns, vascular injuries, and nerve injuries) using DRG International Classification of Diseases-9th Rev. diagnosis codes. RESULTS: In this 10-year period, craniomaxillofacial battle injuries to the head and neck were found in 42.2% of patients evacuated out of theater. There is a high preponderance of multiple wounds and open fractures in this region. The primary mechanism of injury involved explosive devices, followed by ballistic trauma. CONCLUSION: Modern combat, characterized by blast injuries, results in higher than previously reported incidence of injury to the craniomaxillofacial region. LEVEL OF EVIDENCE: Epidemiologic study, level IV.

Mechanical stress-activated integrin α5ß1 induces opening of connexin 43 hemichannels.

The connexin 43 (Cx43) hemichannel (HC) in the mechanosensory osteocytes is a major portal for the release of factors responsible for the anabolic effects of mechanical loading on bone formation and remodeling. However, little is known about how the Cx43 molecule responds to mechanical stimulation leading to the opening of the HC. Here, we demonstrate that integrin α5ß1 interacts directly with Cx43 and that this interaction is required for mechanical stimulation-induced opening of the Cx43 HC. Direct mechanical perturbation via magnetic beads or conformational activation of integrin α5ß1 leads to the opening of the Cx43 HC, and this role of the integrin is independent of its association with an extracellular fibronectin substrate. PI3K signaling is responsible for the shear stress-induced conformational activation of integrin α5ß1 leading to the opening of the HC. These results identify an unconventional function of integrin that acts as a mechanical tether to induce opening of the HC and provide a mechanism connecting the effect of mechanical forces directly to anabolic function of the bone.

Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading.

Bone tissues respond to mechanical loading/unloading regimens to accommodate (re)modeling requirements; however, the underlying molecular mechanism responsible for these responses is largely unknown. Previously, we reported that connexin (Cx) 43 hemichannels in mechanosensing osteocytes mediate the release of prostaglandin, PGE(2), a crucial factor for bone formation in response to anabolic loading. We show here that the opening of hemichannels and release of PGE(2) by shear stress were significantly inhibited by a potent antibody we developed that specifically blocks Cx43-hemichannels, but not gap junctions or other channels. The opening of hemichannels and release of PGE(2) are magnitude-dependent on the level of shear stress. Insertion of a rest period between stress enhances this response. Hemichannels gradually close after 24 h of continuous shear stress corresponding with reduced Cx43 expression on the cell surface, thereby reducing any potential negative effects of channels staying open for extended periods. These data suggest that Cx43-hemichannel activity associated with PGE(2) release is adaptively regulated by mechanical loading to provide an effective means of regulating levels of extracellular signaling molecules responsible for initiation of bone (re)modeling.

Roles of gap junctions and hemichannels in bone cell functions and in signal transmission of mechanical stress.

Gap junctions formed by connexins (Cx) play an important role in transmitting signals between bone cells such as osteoblasts and osteoclasts, cells responsible for bone formation and bone remodeling, respectively. Gap junction intercellular communication (GJIC) has been demonstrated to mediate the process of osteoblast differentiation and bone formation. Furthermore, GJIC propagates Ca2+ signaling, conveys anabolic effects of hormones and growth factors, and regulates gene transcription of osteoblast differentiation markers. GJIC is also implicated to regulate osteoclast formation, survival and apoptosis. Compared with other bone cells, the most abundant type are osteocytes, which express large amounts of connexins. Mechanosensing osteocytes connect and form gap junctions with themselves and other cells only through the tips of their dendritic processes, a relatively small percent of the total cell surface area compared to other cells. Recent studies show that in addition to gap junctions, osteoblasts and osteocytes express functional hemichannels, the un-opposed halves of gap junction channels. Hemichannels are localized at the cell surface and function independently of gap junctions. Hemichannels in osteocytes mediate the immediate release of prostaglandins in response to mechanical stress. The major challenges remaining in the field are how the functions of these two types of channels are coordinated in bone cells and what the asserted, distinct effects of these channels are on bone formation and remodeling processes, and on conveying signals elicited by mechanical loading.

Cardiopulmonary exercise tests and lung cancer surgical outcome.

STUDY OBJECTIVES: Surgical resection remains the treatment of choice for anatomically resectable non-small cell lung cancer. However, the presence of associated comorbid conditions increases the risk of death and surgical complications. Several studies have evaluated the usefulness of preoperative exercise testing for predicting postoperative morbidity and mortality. The aim of this study was to establish whether exercise testing could predict poor surgical outcome in lung cancer surgery and whether the absolute value or percentage of predicted value is the better predictor of the surgical outcome. DESIGN: The study was designed as a prospective study. PATIENTS AND SETTING: One hundred thirty patients with potentially operable lung cancer at Papworth Hospital over 2 years were recruited; of these, 101 underwent curative surgery. INTERVENTIONS: Spirometry and cardiopulmonary exercise tests were performed for every patient (n = 99), except for two patients with back problems. We also recorded the outcome of surgery, in particular, complications and mortality. MEASUREMENTS AND RESULTS: Mean maximum oxygen transport at peak exercise (Vo(2)peak) was 18.3 mL/kg/min (SD, 4.7 mL/kg/min), and mean percentage of predicted Vo(2)peak value was 84.4% (SD, 30%). Poor surgical outcome was significantly related to Vo(2)peak percentage of predicted (p < 0.01) but not to the actual oxygen uptake value. CONCLUSIONS: The use of the percentage of predicted Vo(2)peak value would be a better indicator of surgical outcome, since it predicts the surgical outcome better, and corrects for normal physiologic ranges. The threshold of Vo(2)peak for surgical intervention could be set between 50% and 60% of predicted without excess surgical mortality.

Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin.

Mechanosensing bone osteocytes express large amounts of connexin (Cx)43, the component of gap junctions; yet, gap junctions are only active at the small tips of their dendritic processes, suggesting another function for Cx43. Both primary osteocytes and the osteocyte-like MLO-Y4 cells respond to fluid flow shear stress by releasing intracellular prostaglandin E2 (PGE2). Cells plated at lower densities release more PGE2 than cells plated at higher densities. This response was significantly reduced by antisense to Cx43 and by the gap junction and hemichannel inhibitors 18 beta-glycyrrhetinic acid and carbenoxolone, even in cells without physical contact, suggesting the involvement of Cx43-hemichannels. Inhibitors of other channels, such as the purinergic receptor P2X7 and the prostaglandin transporter PGT, had no effect on PGE2 release. Cell surface biotinylation analysis showed that surface expression of Cx43 was increased by shear stress. Together, these results suggest fluid flow shear stress induces the translocation of Cx43 to the membrane surface and that unapposed hemichannels formed by Cx43 serve as a novel portal for the release of PGE2 in response to mechanical strain.

Relationship of shuttle walk test and lung cancer surgical outcome.

OBJECTIVE: Surgery remains the treatment of choice in patients with potentially resectable lung carcinoma. Both the British Thoracic Society and American Chest Physician guidelines for the selection of patients with lung cancer surgery suggest the use of a shuttle walk test to predict outcome in patients with borderline lung function. The guidelines suggest that if the patient is unable to walk 250 m during a shuttle walk test, they are high risk for surgery. However, there is no published evidence to support this recommendation. Therefore, we undertook a prospective study to examine the relationship between shuttle walk test and surgical outcome in 139 patients undergoing assessment for possible lung cancer surgery. METHODS: The shuttle walk test was performed in 139 potentially resectable patients, recruited over a 2 year period, prior to surgery. One hundred and eleven patients underwent surgery. Outcome of surgery, including duration of hospital stay, complication and mortality rates was recorded. Student's t-test was used to compare the shuttle walk distance in patients with good and poor outcome from surgery. RESULTS: Mean age of patients undergoing surgery was 69 years (42-85). Mean shuttle walk distance was 395 m (145-780), with a mean oxygen desaturation of 4% (0-14) during the test. Sixty nine patients had a good surgical outcome and 34 had a poor outcome. The shuttle walk distance was not statistically different in the two outcome groups. CONCLUSION: Shuttle walk distance should not be used to predict poor surgical outcome in lung cancer patients, contrary to current recommendations. It is therefore advisable to perform a formal cardiopulmonary exercise test if at all possible. The usefulness of a shuttle walk test might be improved. It could be compared to a predicted value, as for a formal cardiopulmonary exercise test.