Quality of care for patients with a fracture of the hip in major trauma centres: a national observational study.

AIMS: In this study, we aimed to determine whether designation as a major trauma centre (MTC) affects the quality of care for patients with a fracture of the hip. PATIENTS AND METHODS: All patients in the United Kingdom National Hip Fracture Database, between April 2010 and December 2013, were included. The indicators of quality that were recorded included the time to arrival on an orthopaedic ward, to review by a geriatrician, and to operation. The clinical outcomes were the development of a pressure sore, discharge home, length of stay, in-hospital mortality, and re-operation within 30 days. RESULTS: There were 289 466 patients, 49 350 (17%) of whom were treated in hospitals that are now MTCs. Using multivariable logistic and generalised linear regression models, there were no significant differences in any of the indicators of the quality of care or clinical outcomes between MTCs, hospitals awaiting MTC designation and non-MTC hospitals. CONCLUSION: These findings suggest that the regionalisation of major trauma in England did not improve or compromise the overall care of elderly patients with a fracture of the hip. TAKE HOME MESSAGE: There is no evidence that reconfiguring major trauma services in England disrupted the treatment of older adults with a fracture of the hip.

Evolution of lung breathing from a lungless primitive vertebrate.

Air breathing was critical to the terrestrial radiation and evolution of tetrapods and arose in fish. The vertebrate lung originated from a progenitor structure present in primitive boney fish. The origin of the neural substrates, which are sensitive to metabolically produced CO2 and which rhythmically activate respiratory muscles to match lung ventilation to metabolic demand, is enigmatic. We have found that a distinct periodic centrally generated rhythm, described as "cough" and occurring in lamprey in vivo and in vitro, is modulated by central sensitivity to CO2. This suggests that elements critical for the evolution of breathing in tetrapods, were present in the most basal vertebrate ancestors prior to the evolution of the lung. We propose that the evolution of breathing in all vertebrates occurred through exaptations derived from these critical basal elements.

Isoflurane causes concentration-dependent inhibition of medullary raphé 5-HT neurons in situ.

BACKGROUND: Anesthetics have a profound influence on a myriad of autonomic processes. Mechanisms of general anesthesia, and how these mechanisms give rise to the multifaceted state of anesthesia, are largely unknown. The ascending and descending serotonin (5-HT) networks are key modulators of autonomic pathways, and are critically involved in homeostatic reflexes across the motor, somatosensory, limbic and autonomic systems. These 5-HT networks are thought to contribute to anesthetic effects, but how anesthetics affect 5-HT neuron function remains a pertinent question. We hypothesized that the volatile anesthetic isoflurane inhibits action potential discharge of medullary raphé 5-HT neurons. METHODS: We conducted extracellular recordings on individual neurons in the medullary raphé region of the unanesthetized in situ perfused brainstem preparation to determine how exposure to isoflurane affects 5-HT neurons. We examined changes in 5-HT neuron baseline firing in response to treatment with either 1, 1.5, or 2% isoflurane. We measured isoflurane concentrations by gas chromatography-mass spectrometry (GC-MS) analysis. RESULTS: Exposure to isoflurane inhibited action potential discharge in raphé 5-HT neurons. We document a concentration-dependent inhibition over a range of concentrations approximating isoflurane MAC (minimum alveolar concentration required for surgical anesthesia). Delivered concentrations of isoflurane were confirmed using GC-MS analysis. CONCLUSIONS: These findings illustrate that halogenated anesthetics greatly affect 5-HT neuron firing and suggest 5-HT neuron contributions to mechanisms of general anesthesia.

Validation of multisociety combined task force definitions of abnormal disk morphology.

BACKGROUND AND PURPOSE: The multisociety task force descriptively defined abnormal lumbar disk morphology. We aimed to use their definitions to provide a higher level of evidence for the validation of MR imaging in the evaluation of this pathology in patients who have undergone diskectomy by retrospectively classifying their preoperative MRI. MATERIALS AND METHODS: This retrospective, institutional review board-approved study included 54 of 86 consecutive patients (47 men; average age, 44 years) enrolled in an ongoing prospective trial of surgically treated lumbar disk herniation who had preoperative MRI and documented intraoperative classification of the abnormal disk as protrusion, extrusion, or sequestration by the treating surgeon. Preoperative MRI was classified by 2 blinded radiologists; discrepancies were resolved by a third reader. Statistical analysis of interobserver agreement and imaging compared with surgical findings was performed. RESULTS: The readers disagreed on only 1 of the 54 cases. The third reader resolved the disagreement. Eight protrusions and 46 extrusions were found on imaging, with no sequestrations. At surgery, there were 13 protrusions and 40 extrusions, with 2 of the extrusions also containing sequestrations; the remaining case had only sequestration. There were 16 discrepancies between imaging and surgery, resulting in 70% agreement. CONCLUSIONS: This study, which was intended to validate the multisociety combined task force definitions of abnormal disk morphology by using MR imaging with a surgical criterion standard, found 70% agreement between imaging diagnosis and surgical findings. Although reasonable, this finding highlights differences that often exist between intraoperative and preoperative imaging findings of lumbar disk herniation.

A group of non-serotonergic cells is CO2-stimulated in the medullary raphé.

Serotonin/substance P synthesizing cells in the raphé nuclei of the brain are candidates for designation as central chemoreceptors that are stimulated by CO2/pH. We have previously demonstrated that these neurons are CO2-stimulated in situ. Evidence also suggests that CO2-inhibited raphé neurons recorded in vitro and in situ synthesize GABA. Unknown is whether there are other types of chemosensitive cells in the raphé. Here, we showed that a previously unrecognized pool of raphé neurons also exhibit chemosensitivity, and that they are not serotonergic. We used extracellular recording of individual raphé neurons in the unanesthetized juvenile rat in situ perfused decerebrate brainstem preparation to assess chemosensitivity of raphé neurons. Subsequent juxtacellular labeling of individually recorded cells, and immunohistochemistry for the serotonin synthesizing enzyme tryptophan hydroxylase and for neurokinin-1 receptor (NK1R; the receptor for substance P) indicated a group of CO2-stimulated cells that are not serotonergic, but express NK1R and are closely apposed to surrounding serotonergic cells. CO2-stimulated 5-HT and non-5-HT cells constitute distinct groups that have different firing characteristics and hypercapnic sensitivities. Non-5-HT cells fire faster and are more robustly stimulated by CO2 than are 5-HT cells. Thus, we have characterized a previously unrecognized type of CO2-stimulated medullary raphé neuron that is not serotonergic, but may receive input from neighboring serotonin/substance P synthesizing chemosensitive neurons. The potential network properties of the three types of chemosensitive raphé neurons (the present non-5-HT cells, serotonergic cells, and CO2-inhibited cells) remain to be elucidated.

Cardiovascular disease risk following a 758 km pilgrimage.

Millions of people participate in pilgrimages around the world such as the Camino de Santiago. However, few studies have examined the effects of this type of activity on cardiovascular disease risk factors. The aim of this study is to evaluate changes in cardiovascular disease risk factors: c-reactive protein, cholesterol, triglycerides, blood pressure, and cardiorespiratory fitness levels following a 758 km, 30-day pilgrimage. 11 healthy male and female subjects between the ages of 18-56 participated in pre and post pilgrimage blood pressure and blood tests, as well as pre, during, and post pilgrimage weight, skin-fold, and aerobic fitness testing. Heart rate monitors and pedometers provided maximum, average, and minimum heart rates as well as distances covered during the exercise. The mean daily walking distance was 25 km at an average intensity of 55.96% (±1.93%) of maximum heart rate. Statistically significant changes were seen in body weight (79.3 kg±3.4 pre vs. 76.4±2.98 post, p<0.05), body fat percentage (24.48%±2.31% pre vs. 23.01%±2.12 post, p<0.05), systolic and diastolic blood pressure (119±3.82/75±2.73 pre vs. 110±5.07/69±3.10 post, p<0.05), as well as cardiorespiratory fitness. These data suggest that some cardiovascular disease risk factors can be improved in healthy subjects participating in a low intensity, long duration, high frequency activity such as a walking pilgrimage.

Lung respiratory rhythm and pattern generation in the bullfrog: role of neurokinin-1 and mu-opioid receptors.

Location of the lung respiratory rhythm generator (RRG) in the bullfrog brainstem was investigated by examining neurokinin-1 and mu-opioid receptor (NK1R, muOR) colocalization by immunohistochemistry and characterizing the role of these receptors in lung rhythm and episodic pattern generation. NK1R and muOR occurred in brainstems from all developmental stages. In juvenile bullfrogs a distinct area of colocalization was coincident with high-intensity fluorescent labeling of muOR; high-intensity labeling of muOR was not distinctly and consistently localized in tadpole brainstems. NK1R labeling intensity did not change with development. Similarity in colocalization is consistent with similarity in responses to substance P (SP, NK1R agonist) and DAMGO (muOR agonist) when bath applied to bullfrog brainstems of different developmental stages. In early stage tadpoles and juvenile bullfrogs, SP increased and DAMGO decreased lung burst frequency. In juvenile bullfrogs, SP increased lung burst frequency, episode frequency, but decreased number of lung bursts per episode and lung burst duration. In contrast, DAMGO decreased lung burst frequency and burst cycle frequency, episode frequency, and number of lung bursts per episode but increased all other lung burst parameters. Based on these results, we hypothesize that NK1R and muOR colocalization together with a metamorphosis-related increase in muOR intensity marks the location of the lung RRG but not necessarily the lung episodic pattern generator.

Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage.

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified ("gene activated") tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible.

Importance of vitamin D in hospital-based fracture care pathways.

OBJECTIVES: This project was developed to identify ways to support hospital-based improvements for the identification and management of osteoporosis following treatment of a fragility fracture. DESIGN: This is a retrospective review of medical records of sets of consecutive patients who were admitted for surgical treatment of fragility fracture following introduction of several versions of admission and discharge care pathways. Effectiveness of the admission pathway was defined as % subjects with measurement of serum 25- hydroxyvitamin D (25(OH)D) during hospitalization; effectiveness of the discharge pathway was defined as % subjects with documentation of instructions for calcium and/or vitamin D supplementation. SETTING: This study reviewed medical records of patients admitted to hospital for surgical treatment of a fragility fracture. PARTICIPANTS: Medical records were evaluated for 98 patients older than 50-years who were admitted with a fragility fracture of the hip or femur. MEASUREMENTS: Medical records were reviewed for the % subjects with documentation of an in-hospital order for serum 25(OH)D and with documentation of instructions to patients upon discharge concerning calcium and vitamin D intake. Median value of serum 25(OH)D was calculated. RESULTS: In accordance with the admission pathway, serum 25(OH)D was measured in 37% (36/98). The median 25(OH)D level was 19.5 ng/mL; 78% were vitamin D insufficient [serum 25(OH)D < or = 32 ng/mL] and 58% were vitamin D deficient [serum 25(OH)D < or = 20 ng/mL]. In accordance with the discharge pathway, 74% (71/96) were discharged on calcium and/or vitamin D. CONCLUSION: The high prevalence of vitamin D insufficiency (78%) observed in this study affirms the importance of incorporating vitamin D supplementation in hospital-based fracture care pathways. The discharge pathway was more effective than the newer admission pathway, a finding attributable to effects of familiarity, retraining, and introduction of computer-prompts. These evolving pathways represent a much-needed paradigm shift in the care of fragility fracture patients.

Activation of 5-HT1A receptors in the paragigantocellularis lateralis decreases shivering during cooling in the conscious piglet.

Activation of 5-HT(1A) receptors in the medullary raphé decreases sympathetic outflow to thermoregulatory mechanisms, including brown adipose tissue (BAT), thermogenesis, and peripheral vasoconstriction when these mechanisms are previously activated with leptin, prostaglandins, or cooling. These same mechanisms are also inhibited during rapid eye movement (REM) sleep. It is not known whether shivering is also modulated by medullary raphé neurons. We previously showed in the conscious piglet that activation of 5-HT(1A) receptors with 8-OH-DPAT (DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the midline raphé that contains 5-HT neurons, decreases heart rate, body temperature and muscle activity during non-rapid eye movement (NREM) sleep. We therefore hypothesized that activation of 5-HT(1A) receptors in the PGCL would also attenuate shivering and peripheral vasoconstriction during cooling. During REM sleep in a cool environment, shivering, carbon dioxide production, and body temperature decreased, and ear capillary blood flow and ear skin temperature increased. Shivering associated with rapid cooling was attenuated after dialysis of DPAT into the PGCL. In animals maintained in a continuously cool environment, dialysis of DPAT into the PGCL attenuated shivering and decreased body temperature, but there were no significant increases in ear capillary blood flow or ear skin temperature. We conclude that both naturally occurring REM sleep and exogenous activation of 5-HT(1A) receptors in the PGCL are associated with a suspension of shivering during cooling. Our data are consistent with the hypothesis that 5-HT neurons in the PGCL facilitate oscillating spinal motor circuits involved in shivering but are less involved in modulating sympathetically mediated thermoregulatory mechanisms.

Hypoxia tolerance in mammalian heterotherms.

Heterothermic mammals tolerate severe hypoxia, as well as a variety of central nervous system insults, better than homeothermic mammals. Tolerance to hypoxia may stem from adaptations associated with the ability to survive hibernation and periodic arousal thermogenesis. Here, we review evidence and mechanisms of hypoxia tolerance during hibernation, euthermy and arousal in heterothermic mammals and consider potential mechanisms for regenerative-like processes, such as synaptogenesis, observed within hours of hypoxic stress associated with arousal thermogenesis.

Magnitude of abdominal incision affects the duration of postoperative ileus in rats.

BACKGROUND: The pathogenesis of reduced postoperative ileus (POI) in laparoscopic gastrointestinal (GI) surgery still remains controversial. The aim of this study was to investigate the effect of surgical incision on postoperative ileus. METHODS: The effects of length, depth, and site of the incision on GI transit were compared using the geometric center of 51Cr in rats. The inhibitory mechanism of abdominal incision on GI transit also was studied. RESULTS: The findings showed that 5 cm of abdominal skin and the 5-cm back muscle incision had no significant effect on GI transit. However, the 5-cm abdominal muscle-fascia incision and a 5-cm laparotomy significantly delayed GI transit. Gastrointestinal transit after a 5-cm laparotomy was significantly delayed, as compared with that of a 1-cm laparotomy regardless whether intestinal manipulation was performed or not. Guanethidine and yohimbine, but not propranolol, significantly improved the impaired GI transit after a 5-cm laparotomy. CONCLUSIONS: The results suggest that the longer and deeper abdominal incision more profoundly inhibits GI transit. The inhibitory effect of abdominal incision is mediated via the activation of the somatosympathetic reflex and alpha-2 adrenoceptors.

Evidence that ventilatory rhythmogenesis in the frog involves two distinct neuronal oscillators.

In Rana catesbeiana the upper airways are used for two distinct yet highly coordinated ventilatory behaviours: buccal ventilation and lung inflation cycles. How these behaviours are generated and coordinated is unknown. The purpose of this study was to identify putative rhythmogenic brainstem loci involved in these ventilatory behaviours. We surveyed the isolated postmetamorphic brainstem to determine sites where local depolarization, produced by microinjecting the non-NMDA glutamate receptor agonist, AMPA, augmented the ventilatory motor patterns. Two sites were identified: a caudal site, at the level of cranial nerve (CN) X, where AMPA injections caused increased buccal burst frequency but abolished lung bursts, and a rostral site, between the levels of CN VIII and IX, where injections increased the frequency of both types of ventilatory bursts. These two sites were further examined using GABA microinjections to locally inhibit cells. GABA injected into the caudal site suppressed the buccal rhythm but the lung rhythm continued, albeit at a different frequency. When GABA was injected into the rostral site the lung bursts were abolished but the buccal rhythm continued. When the two sites were physically separated by transection, both rostral and caudal brainstem sections were capable of rhythmogenesis. The results suggest the respiratory network within the amphibian brainstem is composed of at least two distinct but interacting oscillators, the buccal and lung oscillators. These putative oscillators may provide a promising experimental model for studying coupled oscillators in vertebrates.

Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial.

PURPOSE: Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy. PATIENTS AND METHODS: Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m2 per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin. RESULTS: One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases. CONCLUSIONS: Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal.

Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study.

PURPOSE: To determine the response rate of the combination of cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 91 pediatric patients, 83 of whom were fully assessable for response and toxicity, received cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. All patients received filgrastim (5 mcg/kg) daily until the absolute neutrophil count (ANC) was > or = 1,500 microL after the time of the expected ANC nadir. RESULTS: A total of 307 treatment courses were given to the 83 fully assessable patients. Responses (complete response plus partial response) were seen in rhabdomyosarcoma (10 of 15 patients), Ewing's sarcoma (six of 17 patients), and neuroblastoma (six of 13 patients). Partial responses were seen in two of 18 patients with osteosarcoma and in one patient with a Sertoli-Leydig cell tumor. Twenty-three patients had either minor responses (n = 6) or stable disease (n = 17); the median number of courses administered to patients with partial or complete response was six (range, two to 13 courses), and the median administered to those with stable disease was three (range, one to 11 courses). The toxicity of the combination was limited principally to the hematopoietic system. Of 307 courses, 163 (53%) were associated with grade 3 or 4 neutropenia, 84 (27%) with grade 3 or 4 anemia, and 136 (44%) with grade 3 or 4 thrombocytopenia. Despite the severe myelosuppression, only 34 (11%) of 307 courses were associated with grade 3 or 4 infection. Nonhematopoietic toxicity of grades > or = 3 was rare and consisted of nausea and vomiting (two courses), perirectal mucositis (one course), transaminase elevation (one course), and hematuria (two courses). CONCLUSION: The combination of cyclophosphamide and topotecan is active in rhabdomyosarcoma, neuroblastoma, and Ewing's sarcoma. Stabilization of disease was seen in osteosarcoma, although objective responses were rare in this disease. The therapy can be given with acceptable hematopoietic toxicity with the use of filgrastim support.

Paclitaxel for the treatment of progressive or recurrent childhood brain tumors: a pediatric oncology phase II study.

PURPOSE: To assess the efficacy and define the toxicity of paclitaxel given at a dosage of 350 mg/m2 every 3 weeks as a 24-hour continuous infusion to children with recurrent or progressive primary brain tumors. PATIENTS AND METHODS: Seventy-three eligible patients, ages 4 months to 19 years, with progressive or recurrent primary brain tumors were treated according to a Pediatric Oncology Group (POG) phase II protocol with paclitaxel (POG 9330). Tumor histologic strata included: astrocytoma (n = 4), malignant glioma (n = 13), medulloblastoma (n = 16), brain stem glioma (n = 15), ependymoma (n = 13), and miscellaneous histologies (n = 12). All patients had previous histologic confirmation of a primary intracranial or spinal cord tumor with magnetic resonance imaging or computed tomography documentation of unequivocally measurable progressive or recurrent disease. All patients had received previous therapy including surgery, radiation therapy, and/or chemotherapy, but no patient had been previously treated on more than one phase II trial. Paclitaxel was administered as a 24-hour intravenous infusion at a dosage of 350 mg/m2 every 3 weeks. Neurologic and neuroradiologic reevaluations were performed after every second course. Patients were allowed to continue therapy for a total of 18 cycles in the absence of progressive disease or unacceptable toxicity. RESULTS: Seventy-five patients were enrolled onto the POG 9330 protocol; two ineligible patients were removed from the study before receiving any therapy. Of the 73 eligible patients, 72 were evaluable for toxicity and 70 were either fully or partially evaluable for disease response. There was one complete response and three partial responses (5.7%). Twenty patients had stable disease for more than 2 months. Toxicities included mild nausea, central nervous system toxicity, myelosuppression, and febrile neutropenia, including one septic death. One grade 2 and two grade 3 allergic reactions occurred. No cardiac toxicities or arthralgias were reported. CONCLUSION: Paclitaxel is well tolerated in children with recurrent or progressive brain tumors at this dosage and schedule and may result in short-term disease stabilization in this patient population. The lack of a significant number of patients with measurable disease regression, however, precludes it from being identified as an active agent when administered as a single agent by 24-hour continuous infusion.

Modeling of the naked facet sign in the thoracolumbar spine.

On transverse computed tomographic (CT) scan cuts of the thoracolumbar spine, the naked facet sign occurs when the inferior articular facets of the cephalad vertebra do not appear adjacent to the superior facets of the subjacent caudal vertebra. The objective of this study was to determine the angles of rotation required for the naked facet sign to occur in the thoracolumbar spine, with the center of rotation located at various points in or anterior to the vertebral body. A commercial spinal model and visualization software were used to simulate various flexion injuries. Each functional spinal unit (FSU; T11-T12, T12-L1, and L1-L2) was examined separately. In the model, two CT scan slices (each 2 mm thick) were created parallel to the inferior end plate of the cephalad vertebra of each FSU. The cephalad vertebra was rotated in 0.5 degrees increments, and after rotation both modeled CT slices were examined for the presence of the naked facet sign. If the sign did not occur, the process was repeated, rotating the cephalad vertebra an additional 0.5 degrees until the naked facet sign occurred. The angle of rotation necessary for the sign to occur increases as the point of rotation of the vertebra moves from anterior to posterior and from superior to inferior. The naked facet sign occurred at a minimum rotation angle of 5 degrees (with respect to the anterior-superior point on T11) and at a maximum rotation angle of 16.5 degrees (with respect to the posterior-inferior point on L1). For rotations about a point located 3 cm anterior to the vertebral body, the minimum angles required for the sign decreased only 1 degrees for each FSU. These results suggest that the naked facet sign does not consistently imply the presence of posterior column vertebral instability. This will help clinicians to relate the mechanism of injury, radiographic findings (including the naked facet sign), and the implied injury pattern to the determination of stability, and ultimately the management options for the injury.

Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation.

Endothelial nitric-oxide synthase (eNOS) is phosphorylated at Ser-1179 (bovine sequence) by Akt after growth factor or shear stress stimulation of endothelial cells, resulting in increased eNOS activity. Purified eNOS is also phosphorylated at Thr-497 by purified AMP-activated protein kinase, resulting in decreased eNOS activity. We investigated whether bradykinin (BK) stimulation of bovine aortic endothelial cells (BAECs) regulates eNOS through Akt activation and Ser-1179 or Thr-497 phosphorylation. Akt is transiently activated in BK-stimulated BAECs. Activation is blocked completely by wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase, suggesting that Akt activation occurs downstream from phosphatidylinositol 3-kinase. BK stimulates a transient phosphorylation of eNOS at Ser-1179 that is correlated temporally with a transient dephosphorylation of eNOS at Thr-497. Phosphorylation at Ser-1179, but not dephosphorylation at Thr-497, is blocked by wortmannin and LY294002. BK also stimulates a transient nitric oxide (NO) release from BAECs with a time-course similar to Ser-1179 phosphorylation and Thr-497 dephosphorylation. NO release is not altered by wortmannin. BK-stimulated dephosphorylation of Thr-497 and NO release are blocked by the calcineurin inhibitor, cyclosporin A. These data suggest that BK activation of eNOS in BAECs primarily involves deinhibition of the enzyme through calcineurin-mediated dephosphorylation at Thr-497.

Which came first, the lung or the breath?

Lungs are the characteristic air-filled organs (AO) of the Polypteriformes, lungfish and tetrapods, whereas the swimbladder is ancestral in all other bony fish. Lungs are paired ventral derivatives of the pharynx posterior to the gills. Their respiratory blood supply is the sixth branchial artery and the venous outflow enters the heart separately from systemic and portal blood at the sinus venosus (Polypteriformes) or the atrium (lungfish), or is delivered to a separate left atrium (tetrapods). The swimbladder, on the other hand, is unpaired, and arises dorsally from the posterior pharynx. It is employed in breathing in Ginglymodi (gars), Halecomorphi (bowfin) and in basal teleosts. In most cases, its respiratory blood supply is homologous to that of the lung, but the vein drains to the cardinal veins. Separate intercardiac channels for oxygenated and deoxygenated blood are lacking. The question of the homology of lungs and swimbladders and of breathing mechanisms remains open. On the whole, air ventilatory mechanisms in the actinopterygian lineage are similar among different groups, including Polypteriformes, but are distinct from those of lungfish and tetrapods. However, there is extreme variation within this apparent dichotomy. Furthermore, the possible separate origin of air breathing in actinopterygian and 'sarcopterygian' lines is in conflict with the postulated much more ancient origin of vertebrate air-breathing organs. New studies on the isolated brainstem preparation of the gar (Lepisosteus osseus) show a pattern of efferent activity associated with a glottal opening that is remarkably similar to that seen in the in-vitro brainstem preparation of frogs and tadpoles. Given the complete lack of evidence for AO in chondrichthyans, and the isolated position of placoderms for which buoyancy organs of uncertain homology have been demonstrated, it is likely that homologous pharyngeal AO arose in the ancestors of early bony fish, and was pre-dated by behavioral mechanisms for surface (water) breathing. The primitive AO may have been the posterior gill pouches or even the modified gills themselves, served by the sixth branchial artery. Further development of the dorsal part may have led to the respiratory swimbladder, whereas the paired ventral parts evolved into lungs.