The book distills the available information on osteoporosis into an easily comprehensible format that serves as a practical guide for busy clinicians. Contents:Definition & epidemiology -- Basic bone pathophysiology -- Bone densitometry -- Diagnosis -- Identifying patients at risk of fractures -- Non-pharmacologic management of osteopenia and osteoporosis -- Pharmacologic management of osteoporosis, part 1 -- Pharmacologic management of osteoporosis, part 2 -- Monitoring patients on treatment -- Vertebral augmentation procedures -- Corticosteroid-induced bone loss -- Primary hyperparathyroidism -- Premenopausal women -- Men -- Atypical femoral shaft fractures -- Osteonecrosis of the jaw -- Osteoporosis in children and adolescents. / https://dc.etsu.edu/etsu_books/1077/thumbnail.jpg

Introduction An increasing proportion of the patients undergoing cardiac surgery have diabetes mellitus, in particular type II diabetes. In spite of this, diabetic patients have received limited attention in this setting. Although diabetes is a metabolic disease cardiac metabolism in association with surgery has previously not been explored in diabetics. This investigation was carried out to describe the metabolic state of the heart in diabetics after cardiac surgery and to study if it is accessible to metabolic intervention with high-dose GIK. Also, the potential hazards associated with such a regime in clinical practice were evaluated. Furthermore, a comparison of the outcome in diabetic and nondiabetic patients after coronary surgery was done. Methods Myocardial metabolism and how it was influenced by high-dose GIK was assessed with coronary sinus catheter technique in a prospective randomized study on 20 type II diabetic patients undergoing CABG (paper I, II). Safety issues concerning high-dose GIK were assessed in two retrospective studies. The potential role of metabolic interventions for neurological injury was assessed in a cohort of 775 consecutive patients undergoing CABG or combined CABG + valve surgery, in whom metabolic interventions gradually replaced traditional treatment for postoperative heart failure (paper III). A detailed analysis of blood glucose and electrolyte control was done in all cases (n=89) receiving high-dose GIK during one year (paper IV). The hemodynamic impact of highdose GIK was assessed with standard postoperative monitoring including Swan-Ganz catheters (paper II, IV). Outcome and prognosis after CABG in diabetic patients (n=540) were compared with nondiabetics (n=2239) with the aid of the institutional database comprising all isolated CABG procedures from 1995-1999 (paper V). Results The metabolism of the diabetic heart after CABG was characterized by predominant uptake of FFA and restricted uptake of carbohydrate substrates. A high extraction rate of beta-hydroxybutyric acid and glutamate was also found. Alanine was released from the heart (paper I). High-dose GIK induced a shift towards uptake of carbohydrates, in particular lactate, at the expense of FFA and betahydroxybutyric acid (paper II). A substantial systemic glucose uptake was found during high-dose GIK treatment but the uptake tended to be lower and blood glucose higher if adrenergic drugs were used or/and if the patient was a diabetic (paper IV). High-dose GIK was associated with beneficial effects on cardiac output both in the prospective and retrospective analyses (paper II, IV). No evidence for untoward neurological effects associated with GIK treatment was found. History of cerebrovascular disease was the most important risk factor for postoperative cerebral complications and in general markers for advanced atherosclerotic disease were found to be of importance (paper III). High-dose GIK in clinical practice was associated with acceptable blood glucose and electrolyte control and no serious adverse events were recorded (paper IV). Patients with diabetes undergoing CABG had an acceptable short-term mortality that did not differ significantly from non-diabetic patients. However, diabetic patients had a higher early postoperative morbidity particularly with regard to stroke, renal- and infectious complications. Also, long-term survival was markedly reduced in diabetic patients, particularly in insulin treated patients (paper V). Comments FFA were the main source of energy for the heart in type II diabetics after CABG whereas the uptake of carbohydrates was restricted. The high extraction rates of beta-hydroxybutyric acid and glutamate may represent an adaptation to the unfavorable metabolic situation of the post-ischemic diabetic heart. High-dose GIK can be used in type II diabetic patients after cardiac surgery to promote carbohydrate uptake at the expense of FFA and beta-hydroxybutyric acid. The magnitude of this shift was sufficient to account for the entire myocardial oxygen consumption assuming that the substrates extracted were oxidized. This could have implications for the treatment of the diabetic heart in association with surgery and ischemia. Provided careful monitoring high-dose GIK can be safely used in clinical practice and this treatment deserves further evaluation in the treatment of postoperative heart failure. High-dose GIK also provides a means for strict blood glucose control and as substantial amounts of glucose can be infused even in critically ill patients, it may prove useful for nutrition in critical care. Several of the risk factors for neurological injury identified constitute markers for advanced atherosclerotic disease, thus, also providing an explanation for the increased risk of neurological injury in diabetics after cardiac surgery. Short-term mortality was acceptable in diabetics after CABG. However, further efforts are warranted to address postoperative morbidity and late outcome. This represents a challenge as diabetic patients are accounting for an increasing proportion of the patients undergoing CABG. / On the day of the public defence the status of article IV was: Submitted and the title of article IV was in the printed version: High-dose GIK in cardiac surgery - clinical safety issues and lessons learned.

Chronic aortic regurgitation (AR) of varying degree affects 13% of men and 8.5% of women. In persons with severe AR, the expected length of life and its quality are influenced. Some individuals remain asymptomatic for a long period, due to effective compensatory mechanisms, but dysfunction of the left ventricle (LV) usually begins before symptoms appear and can be irreversible by then. This thesis addresses questions of LV function and optimal time for operation of patients suffering from chronic AR. Moreover, detailed echocardiographic studies of the anatomy of the normal aortic valve have been performed to obtain a better understanding of the in vivo anatomic relations within the aortic root. Patients with chronic AR, without concomitant cardiac disease, were studied both retrospectively (n=88) and prospectively (n=29) and the aortic valves of persons (n=32) free from cardiac disease were investigated. For the retrospectively studied patients, survival was 82% at 10 years which is an improvement compared with previously published results. The majority of the patients, however, had LV dysfunction preoperatively. By studying patients prospectively by echocardiography, radionuclide ventriculography (MUGA) and cardiopulmonary exercise testing (CPET) our aim was to evaluate the predictive value of measurements of LV function at rest and during exercise for postoperative outcome. LV diameters were markedly elevated prior to and diminished significantly after surgery. Patients with an abnormal exercise ejection fraction (EF) response by MUGA preoperatively, presented the same reaction postoperatively. This could not be predicted by LV function determination at rest, or by NYHA functional class. In spite of median NYHA class II, these patients had a low work capacity on CPET, which was neither improved 6 months postoperatively nor correlated to echocardiographic LV dimensions. Thus, both MUGA and CPET may be useful complements for timing of surgery in patients with chronic AR. Assuming that patients would benefit from preservation of their native valves the normal aortic valve was studied to gain detailed information about the echocardiographic anatomy and relations within the normal aortic root. This extended examination of the aortic root may facilitate a better planning of aortic valve‐preserving interventions in the future.

Amyloidoses are a group of protein misfolding diseases characterized by deposits of insoluble fibrillar protein aggregates. Medin amyloid, which is the focus of this thesis, appears in the media of the thoracic aorta in nearly all individuals over 50 years. The fibrils are derived from a 50 amino acid residue fragment of the precursor protein lactadherin. How medin amyloid arises is unknown, but in paper I we demonstrated, with immunohistochemical and in vitro binding experiments, that both lactadherin and medin interact with elastin, implying that the elastic fibre is central in amyloid formation. In paper II, we further showed that the last 18-19 amino acid residues constitute the amyloid-promoting region. In paper III, the consequence of medin deposition was investigated. Aortic specimens from patients with thoracic aorta aneurysm and dissection were examined for medin content. The tissue findings indicated that the two disease groups contained more medin oligomers than normal aortas. Interestingly, recent reports demonstrate that the toxicity of amyloid proteins is attributed to prefibrillar oligomeric aggregates rather than to mature fibrils. In support of this finding, we observed that prefibrillar medin, in contrast to medin fibrils, was toxic in cell culture. Amyloid formation is a nucleation-dependent process. Addition of preformed fibrils to an amyloid protein solution dramatically accelerates fibrillation, a phenomenon called seeding. In paper IV, serum amyloid A-derived (AA) amyloid was found co-localized with medin deposits in the aorta. In vitro, medin fibrils enhanced the formation of AA fibrils, indicative of a seeding mechanism. The data are of great importance as they suggest that one type of amyloid is capable of inducing fibrillation and deposition of another amyloid type. In conclusion, the results of this thesis shed light on how medin is formed, the function of lactadherin and the consequences of medin deposition for aortic pathology.

Introduction: Neurological complications and stroke in association with cardiac surgery is a serious problem. The stroke event can occur during surgery (early stroke) or in the postoperative period with a symptom free interval (delayed stroke). Particle embolization due to aortic manipulation during surgery has been suspected as a mechanism for early stroke. The present thesis address mechanisms and survival effects of stroke both clinically (I-III) and experimentally (IV-V). Methods: Study I) Within a cohort of 2641 consecutive cases, a group of cardiac surgery patients with stroke and evaluated by computed tomography (CT) were studied (n=77). CT-findings were analyzed in relation to stroke symptoms. Study II) Data from 9122 patients undergoing coronary surgery were analyzed. Records of patients with any signs of neurological complications were reviewed to extract 149 subjects with stroke at extubation (early, 1.6%) versus 99 patients having a free interval (delayed, 1.1%). Early and delayed stroke were evaluated separately. Independent risk factors for stroke were analyzed by logistic regression and survival by Cox regression (9.3 years median follow-up). Study III) Patients with early (n=223) and delayed stroke (n=116) were identified among 10809 patients undergoing cardiac and aortic surgery, both groups exposed to cardiopulmonary bypass. Stroke patients were subdivided by the hemispheric location of lesions. Subgroups were compared and their associated pre- and peroperative variables and survival were analyzed. Study IV) Aortic cross-clamp manipulation was studied in a human cadaveric perfusion model. The pressurized aorta was repeatedly cross-clamped and washout samples were collected before and after clamp maneuvers. Particles in the washout samples were evaluated by microscopy and by digital image analysis. Study V) Pig aortas were pressurized and cannulated. Washout samples were collected before and after cannulation (n = 40). Particles were deposited onto a 10-μm filter to be evaluated by microscopy and digital image analysis. Results: Study I) In the group of patients exposed to routine cardiac surgery (i.e., clamping and cannulation) and with early stroke, right-hemispheric lesions were more frequent than of the contra-lateral side (P=0.005). Patients with aortic dissections had a strong dominance of bilateral findings, which was different from the unilateral pattern in the routine-surgery group (P<0.001). Study II) Early and delayed stroke did not share any risk factors. Both early and delayed stroke explained mortality in the early postoperative period (P<0.001, P<0.001 respectively) but also at long term follow-up (P=0.008, P<0.001 respectively). For patients surviving their first postoperative year, delayed but not early stroke influenced long-term mortality (P=0.001 and P=0.695, respectively). Study III) Stroke lesions in association to cardiac surgery were near exclusively ischemic. Early stroke had a preponderance for right-hemispheric lesions (P=0.009). In contrast, patients with early stroke that had undergone surgery of the aorta with circulatory arrest showed a pattern with more bilateral lesions compared to ‘cardiac-type’ operations (P<0.001). Patients with bilateral lesions had a dramatically impaired survival compared to those with unilateral lesions (P<0.001). Study IV) In the cadaveric perfusion model, cross-clamping produced a significant output of particles, which was seen for size intervals of 1 mm and smaller (P=0.002 to P=0.022). In all size intervals the particle output correlated with the degree of overall aortic calcification (P =0.002 to P=0.025). Study V) At cannulation of the pig aorta, more particles were noted after cannulation compared to before the maneuver (P<0.001). This increase included small (<0.1 mm, P<0.001) and intermediate-size particles (0.1-0.5 mm, P< 0.001). Particles above 0.5 mm were few and were not associated with cannulation. Conclusions: The influence of stroke on mortality was devastating, for both early and delayed stroke. These two stroke groups had obvious differences in both their risk factors and their hemispheric distribution. It is here emphasized that early and delayed stroke should be considered as two separate entities with suggested mechanistic differences. Ischemic lesions accounted for near all stroke events seen in association to cardiac surgery. For early stroke, these were mostly located within the right hemisphere. Results from the experimental studies underscore microembolic risks associated with aortic manipulation.

Although there have been tremendous improvements in crash safety there has been an increasing trend in side impact fatalities, rising from 30% to 37% of total fatalities from 1975 to 2004 (NHTSA, 2004). Between 1979 and 2004, 63% of AIS≥4 injuries in side impact resulted from thoracic trauma (NHTSA, 2004). Lateral impact fatalities, although decreasing in absolute numbers, now comprise a larger percentage of total fatalities. Safety features are typically more effective in frontal collisions compared to side impact due to the reduced distance between the occupant and intruding vehicle in side impact collisions. Therefore, an increased understanding of the mechanisms governing side impact injury is necessary in order to improve occupant safety in side impact auto crash. This study builds on an advanced numerical human body model with focus on a detailed thoracic model, which has been validated using available post mortem human subject (PMHS) test data for pendulum and side sled impact tests (Forbes, 2005). Crash conditions were investigated through use of a modified side sled model used to reproduce the key conditions present in full scale crash tests. The model accounts for several important factors that contribute to occupant response based on the literature. These factors are; the relative velocities between the seat and door, the occupant to door distance, the door shape and compliance. The side sled model was validated by reproducing the crash conditions present in FMVSS 214 and IIHS side impact tests and comparing the thoracic compression, velocity, and Viscous Criterion (VC) response determined by the model to the response of the ES-2 dummy used in the crash tests. Injury was predicted by evaluating VCmax, selected for its ability to predict rate-sensitive soft tissue injury during thoracic compression (Lau & Viano, 1986). The Ford Taurus FMVSS 214 and Nissan Maxima IIHS tests were selected from side impact crash test data found in the NHTSA database because they included factors not present in standard side impact test procedures. These factors were; the presence of door accelerometers used to provide input velocities to the side impact model and the use of a ES-2 (rather than the SID) to facilitate comparison of VC response to the human body model. Also, the two crash test procedures (FMVSS 214 & IIHS) were selected to ensure accurate side impact model response to different impact scenarios. The side impact model was shown to closely reproduce the timing and injury response of the full-scale FMVSS 214 side impact test of a Ford Taurus, as well as the IIHS side impact test of a Nissan Maxima. The side impact model was then used to investigate the effects of door to occupant spacing, door velocity profile, armrest height, seat foam, restraint system, and arm position. It was found that the VCmax was controlled by both the first and second peaks typically found in door velocity profiles, but the effect of each varies depending on the situation. This study found that VCmax was reduced by 73-88% when door intrusion was eliminated compared to the VC response incurred by an intruding door. Also, the presence of a deformable door based on physical geometry and material characteristics rather than a simplified rigid door reduced VCmax by 16% in this study. The study on seat foam determined that significant effects on VC response can be made by modest adjustments in foam properties. Low stiffness seat foam was found to increase VCmax by 41% when compared to the VC response when using high stiffness foam. Arm position has been proven to be a relevant factor in side impact crash. Positioning the arms parallel to the thorax, in the “down” position, caused a 42% increase in VCmax when compared to the VC response determined with the arms positioned at 45 degrees. Finally, although restraint systems have limited influence on side impact crash safety compared to front and rear impacts, this study found that the presence of a pre-tensioning restraint system reduced VCmax by 13% when compared to the VC response of an un-belted occupant. It should be noted that the current study was limited to velocity profiles obtained from a specific FMVSS 214 test and therefore results and observations are restricted to the confines of the input conditions used. However, the side impact model developed is a useful tool for evaluating factors influencing side impact and can be used to determine occupant response in any side impact crash scenario when the appropriate input conditions are provided.

Occupant thoracic injury incurred during side impact automotive crashes constitutes a significant portion of all fatal and non-fatal automotive injuries. The limited space between the impacting vehicle and occupant can result in significant loads and corresponding injury prior to deceleration of the impacting vehicle. Within the struck vehicle, impact occurs between the occupant and various interior components. Injury is sustained to human structural components such as the thoracic cage or shoulder, and to the internal visceral components such as the heart, lungs, or aorta. Understanding the mechanism behind these injuries is an important step in improving the side impact crash safety of vehicles. This study is focused on the development of a human body numerical model for the purpose of predicting thoracic response and trauma in side impact automotive crash. <br /><br /> The human body model has been created using a previously developed thoracic numerical model, originally used for predicting thoracic trauma under simple impact conditions. The original version of the thorax model incorporated three-dimensional finite element representations of the spine, ribs, heart, lungs, major blood vessels, rib cage surface muscles and upper limbs. The present study began with improvements to the original thorax model and furthered with the development of remaining body components such that the model could be assessed in side impact conditions. <br /><br /> The improvements to the thoracic model included improved geometry and constitutive response of the surface muscles, shoulder and costal cartilage. This detailed thoracic model was complimented with a pelvis, lower limbs, an abdomen and a head to produce the full body model. These components were implemented in a simplified fashion to provide representative response without significant computational costs. The model was developed and evaluated in a stepwise fashion using experimental data from the literature including side abdominal and pelvic pendulum impact tests. <br /><br /> The accuracy of the model response was investigated using experimental testing performed on post mortem human subjects (PMHS) during side and front thoracic pendulum impacts. The model produced good agreement for the side thoracic and side shoulder pendulum impact tests and reasonable correlation during the frontal thoracic pendulum impact test. Complex loading via side sled impact tests was then investigated where the body was loaded unbelted in a NHTSA-type and WSU-type side sled test system. The thorax response was excellent when considering force, compression and injury (viscous criterion) versus time. Compression in the thorax was influenced by the arm position, which when aligned with the coronal plane produced the most aggressive form of compressive loading possible. The simplified components provided good response, falling slightly outside experimental response corridors defined as one standard deviation from the average of the experimental PMHS data. Overall, the predicted model response showed reasonable agreement with the experimental data, while at the same time highlighting areas for future developments. The results from this study suggested that the numerical finite element model developed herein could be used as a powerful tool for improving side impact automotive safety.

Although there have been tremendous improvements in crash safety there has been an increasing trend in side impact fatalities, rising from 30% to 37% of total fatalities from 1975 to 2004 (NHTSA, 2004). Between 1979 and 2004, 63% of AIS≥4 injuries in side impact resulted from thoracic trauma (NHTSA, 2004). Lateral impact fatalities, although decreasing in absolute numbers, now comprise a larger percentage of total fatalities. Safety features are typically more effective in frontal collisions compared to side impact due to the reduced distance between the occupant and intruding vehicle in side impact collisions. Therefore, an increased understanding of the mechanisms governing side impact injury is necessary in order to improve occupant safety in side impact auto crash. This study builds on an advanced numerical human body model with focus on a detailed thoracic model, which has been validated using available post mortem human subject (PMHS) test data for pendulum and side sled impact tests (Forbes, 2005). Crash conditions were investigated through use of a modified side sled model used to reproduce the key conditions present in full scale crash tests. The model accounts for several important factors that contribute to occupant response based on the literature. These factors are; the relative velocities between the seat and door, the occupant to door distance, the door shape and compliance. The side sled model was validated by reproducing the crash conditions present in FMVSS 214 and IIHS side impact tests and comparing the thoracic compression, velocity, and Viscous Criterion (VC) response determined by the model to the response of the ES-2 dummy used in the crash tests. Injury was predicted by evaluating VCmax, selected for its ability to predict rate-sensitive soft tissue injury during thoracic compression (Lau & Viano, 1986). The Ford Taurus FMVSS 214 and Nissan Maxima IIHS tests were selected from side impact crash test data found in the NHTSA database because they included factors not present in standard side impact test procedures. These factors were; the presence of door accelerometers used to provide input velocities to the side impact model and the use of a ES-2 (rather than the SID) to facilitate comparison of VC response to the human body model. Also, the two crash test procedures (FMVSS 214 & IIHS) were selected to ensure accurate side impact model response to different impact scenarios. The side impact model was shown to closely reproduce the timing and injury response of the full-scale FMVSS 214 side impact test of a Ford Taurus, as well as the IIHS side impact test of a Nissan Maxima. The side impact model was then used to investigate the effects of door to occupant spacing, door velocity profile, armrest height, seat foam, restraint system, and arm position. It was found that the VCmax was controlled by both the first and second peaks typically found in door velocity profiles, but the effect of each varies depending on the situation. This study found that VCmax was reduced by 73-88% when door intrusion was eliminated compared to the VC response incurred by an intruding door. Also, the presence of a deformable door based on physical geometry and material characteristics rather than a simplified rigid door reduced VCmax by 16% in this study. The study on seat foam determined that significant effects on VC response can be made by modest adjustments in foam properties. Low stiffness seat foam was found to increase VCmax by 41% when compared to the VC response when using high stiffness foam. Arm position has been proven to be a relevant factor in side impact crash. Positioning the arms parallel to the thorax, in the “down” position, caused a 42% increase in VCmax when compared to the VC response determined with the arms positioned at 45 degrees. Finally, although restraint systems have limited influence on side impact crash safety compared to front and rear impacts, this study found that the presence of a pre-tensioning restraint system reduced VCmax by 13% when compared to the VC response of an un-belted occupant. It should be noted that the current study was limited to velocity profiles obtained from a specific FMVSS 214 test and therefore results and observations are restricted to the confines of the input conditions used. However, the side impact model developed is a useful tool for evaluating factors influencing side impact and can be used to determine occupant response in any side impact crash scenario when the appropriate input conditions are provided.

Mitigating injury in side impact has been an important topic of research for decades. In the mid 1980’s the American government began a program intended to improve the crashworthiness of vehicles in side impact. This program ultimately led to the introduction of a dynamic side impact test (Federal Motor Vehicle Safety Standard (FMVSS) 214), which new vehicles must pass, along with a very similar test aimed at consumer awareness (New Car Assessment Program (NCAP) side impact test). The work presented in this thesis involved the study and simulation of these tests to evaluate occupant response in side impact, with a focus on the thoracic response. In the first portion of the work presented here, an in-depth study of the National Highway Traffic Safety Administration (NHTSA) crash test database was performed. In this study the results of the side impact crash tests of 72 vehicles were examined to understand the general trends seen in this type of testing with regards to vehicle velocity, side intrusion, and occupant injury prediction. A series of average velocity profile curves was created from accelerometer data at 18 measurement points on each vehicle crash tested. Additionally the injury criterion measured by the front seat occupant was plotted against several vehicle variables (such as mass and occupant arm to door distance) to study the effect these variable had on the injury predicted by the occupant. No single variable was shown to have a strong correlation to injury, although increasing door intrusion distance, peak lateral velocity, the Head Injury Criterion (HIC), and pelvic acceleration were found to positively correlate to thoracic injury. In addition, increasing vehicle model year, vehicle mass, and arm to door (AD) distance showed negative correlations with thoracic injury. Following the survey of the NHTSA database, a finite element model of the NHTSA side impact test was developed. This model included a full scale Ford Taurus model, a NHTSA barrier model and three side impact anthropometric test device (ATD) occupant models, each representing a different 50th percentile male dummy. Validation of this model was carried out by comparing the simulated vehicle component velocity results to the corridors developed in the NHSTA crash test database study as well as comparing these velocities, the vehicle deformation profile, and the occupant velocity, acceleration and rib deflection to several Ford Taurus crash tests from a similar vintage to the finite element model. As this model was intended as a ‘baseline’ case to study side impact and occupant kinematics in side impact, side airbags were not included in this model. A lack of experimental data and a lack of consensuses within the automotive crash community on the proper method of modeling these devices and their effectiveness in real world impacts also led to their exclusion. Following model validation, a parametric study was carried out to assess the importance of the initial position of the occupant on the vehicle door velocity profile and the predicted occupant injury response. Additionally the effect of the door trim material properties, arm rest properties and the effect of seat belt use were studied. It was found that the lateral position of the occupant had an effect on the door velocity profile, while the vertical and longitudinal position did not. The use of seatbelts was shown to have no significant effect in these simulations, due to minimal interaction between the restraint system and occupant during side impact. Furthermore, there was a general decreasing trend in the injury predicted as the initial position of the occupant was moved further inboard, down and forward in the vehicle. Stiffer interior trim was found to improve the injury prediction of the occupant, while changing the material of the foam door inserts had no effect. It was found that in general the occupant remained in position, due to the inertia of the occupant, while the seat began moving towards the centerline of the vehicle. Future considerations could include more advanced restraint systems to couple the occupant more effectively to the seat, or to develop side interior trim that engages the occupant earlier to reduce the relative velocity between the occupant and intruding door. Overall, the model correlated well with experimental data and provided insight into several areas which could lead to improved occupant protection in side impact. Future work should include integrating side airbags into the model, widening the focus of the areas of injury to include other body regions and integrating more detailed human body models.

Vagal sensory afferent innervation corresponds to regulation of neurogenic inflammation in the airways. Capsaicin is mostly used for stimulation of sensory nerves that induce pain and inflammatory responses. It can specifically stimulate sensory afferent nerves, inducing neurogenic inflammation in the airways. According the past studies, we have found the right thoracic vagus nerve (RTVN) and right recurrent laryngeal nerve (RRLN); branches of right thoracic vagus trunk (RTVT) mediate different degree of neurogenic inflammation by intraenous injection of capsaicin (300 nmol/ml/kg). In order to investigate the innervation from the RTVN and RRLN of rat tracheobronchi and their involvement in plasma exudation, we injected 3 £gl of capsaicin (10 mg/ml) into RTVT and denervated the RRLN or RTVN and used India ink as tracer dye to label the leaky microvessels. Our observation indicated that injection of capsaicin into the RTVT coud induce obvious plasma exudation in trachea (area density of leaky blood vessels was about 22%), but plasma exudation was significantly decreased after denervation of RRLN. The left upper side of trachea was decreased by 77.6% and the right upper side decreased by 84.5%. This phenomenon was not caused by denervation of RTVN. The results suggest that vagal nerve innervation of upper trachea mostly came from the RLN. Otherwise, capsaicin injection into the RTVT also induced neurogenic inflammation in the larynx. Experimental denervation of both superior and recurrent laryngeal nerves resulted in a decrease of plasma extravasation by 84.98%. Denervation of either RTVN or RRLN also decreased the plasma extravasation in the larynx. The evidence suggest that sensory fibers in the superior laryngeal nerve, recurrent laryngeal nerve, and thoracic vagus nerve might come from the same population of vagal ganglion sensory neurons.