On the Importance of Including Cohesive Zone Models in Modelling Mixed-Mode Aneurysm Rupture.

INTRODUCTION: The precise mechanism of rupture in abdominal aortic aneurysms (AAAs) has not yet been uncovered. The phenomenological failure criterion of the coefficient of proportionality between von Mises stress and tissue strength does not account for any mechanistic foundation of tissue fracture. Experimental studies have shown that arterial failure is a stepwise process of fibrous delamination (mode II) and kinking (mode I) between layers. Such a mechanism has not previously been considered for AAA rupture. METHODS: In the current study we consider both von Mises stress in the wall, in addition to interlayer tractions and delamination using cohesive zone models. Firstly, we present a parametric investigation of the influence of a range of AAA anatomical features on the likelihood of elevated interlayer traction and delamination. RESULTS: We observe in several cases that the location of peak von Mises stress and tangential traction coincide. Our simulations also reveal however, that peak von Mises and intramural tractions are not coincident for aneurysms with Length/Radius less than 2 (short high-curvature aneurysms) and for aneurysms with symmetric intraluminal thrombus (ILT). For an aneurysm with (L/R = 2.0), the peak σ vm moves slightly towards the origin while the peak T t is near the peak bulge with a separation distance of ~ 17 mm. Additionally, we present three patient-specific AAA models derived directly from CT scans, which also illustrate that the location of von Mises stress does not correlate with the point of interlayer delamination. CONCLUSION: This study suggests that incorporating cohesive zone models into clinical based FE analyses may capture a greater proportion of ruptures in-silico.

Influence of shape-memory stent grafts on local aortic compliance.

The effect of repair techniques on the biomechanics of the aorta is poorly understood, resulting in significant levels of postoperative complications for patients worldwide. This study presents a computational analysis of the influence of Nitinol-based devices on the biomechanical performance of a healthy patient-specific human aorta. Simulations reveal that Nitinol stent-grafts stretch the artery wall so that collagen is stretched to a straightened high-stiffness configuration. The high-compliance regime (HCR) associated with low diastolic lumen pressure is eliminated, and the artery operates in a low-compliance regime (LCR) throughout the entire cardiac cycle. The slope of the lumen pressure-area curve for the LCR post-implantation is almost identical to that of the native vessel during systole. This negligible change from the native LCR slope occurs because the stent-graft increases its diameter from the crimped configuration during deployment so that it reaches a low-stiffness unloading plateau. The effective radial stiffness of the implant along this unloading plateau is negligible compared to the stiffness of the artery wall. Provided the Nitinol device unloads sufficiently during deployment to the unloading plateau, the degree of oversizing has a negligible effect on the pressure-area response of the vessel, as each device exerts approximately the same radial force, the slope of which is negligible compared to the LCR slope of the native artery. We show that 10% oversizing based on the observed diastolic diameter in the mid descending thoracic aorta results in a complete loss of contact between the device and the wall during systole, which could lead to an endoleak and stent migration. 20% oversizing reaches the Dacron enforced area limit (DEAL) during the pulse pressure and results in an effective zero-compliance in the later portion of systole.

Development of an FEA framework for analysis of subject-specific aortic compliance based on 4D flow MRI.

This paper presents a subject-specific in-silico framework in which we uncover the relationship between the spatially varying constituents of the aorta and the non-linear compliance of the vessel during the cardiac cycle uncovered through our MRI investigations. A microstructurally motivated constitutive model is developed, and simulations reveal that internal vessel contractility, due to pre-stretched elastin and actively generated smooth muscle cell stress, must be incorporated, along with collagen strain stiffening, in order to accurately predict the non-linear pressure-area relationship observed in-vivo. Modelling of elastin and smooth muscle cell contractility allows for the identification of the reference vessel configuration at zero-lumen pressure, in addition to accurately predicting high- and low-compliance regimes under a physiological range of pressures. This modelling approach is also shown to capture the key features of elastin digestion and SMC activation experiments. The volume fractions of the constituent components of the aortic material model were computed so that the in-silico pressure-area curves accurately predict the corresponding MRI data at each location. Simulations reveal that collagen and smooth muscle volume fractions increase distally, while elastin volume fraction decreases distally, consistent with reported histological data. Furthermore, the strain at which collagen transitions from low to high stiffness is lower in the abdominal aorta, again supporting the histological finding that collagen waviness is lower distally. The analyses presented in this paper provide new insights into the heterogeneous structure-function relationship that underlies aortic biomechanics. Furthermore, this subject-specific MRI/FEA methodology provides a foundation for personalised in-silico clinical analysis and tailored aortic device development. STATEMENT OF SIGNIFICANCE: This study provides a significant advance in in-silico medicine by capturing the structure/function relationship of the subject-specific human aorta presented in our previous MRI analyses. A physiologically based aortic constitutive model is developed, and simulations reveal that internal vessel contractility must be incorporated, along with collagen strain stiffening, to accurately predict the in-vivo non-linear pressure-area relationship. Furthermore, this is the first subject-specific model to predict spatial variation in the volume fractions of aortic wall constituents. Previous studies perform phenomenological hyperelastic curve fits to medical imaging data and ignore the prestress contribution of elastin, collagen, and SMCs and the associated zero-pressure reference state of the vessel. This novel MRI/FEA framework can be used as an in-silico diagnostic tool for the early stage detection of aortic pathologies.

A Dual-VENC Four-Dimensional Flow MRI Framework for Analysis of Subject-Specific Heterogeneous Nonlinear Vessel Deformation.

Advancement of subject-specific in silico medicine requires new imaging protocols tailored to specific anatomical features, paired with new constitutive model development based on structure/function relationships. In this study, we develop a new dual-velocity encoding coefficient (VENC) 4D flow MRI protocol that provides unprecedented spatial and temporal resolution of in vivo aortic deformation. All previous dual-VENC 4D flow MRI studies in the literature focus on an isolated segment of the aorta, which fail to capture the full spectrum of aortic heterogeneity that exists along the vessel length. The imaging protocol developed provides high sensitivity to all blood flow velocities throughout the entire cardiac cycle, overcoming the challenge of accurately measuring the highly unsteady nonuniform flow field in the aorta. Cross-sectional area change, volumetric flow rate, and compliance are observed to decrease with distance from the heart, while pulse wave velocity (PWV) is observed to increase. A nonlinear aortic lumen pressure-area relationship is observed throughout the aorta such that a high vessel compliance occurs during diastole, and a low vessel compliance occurs during systole. This suggests that a single value of compliance may not accurately represent vessel behavior during a cardiac cycle in vivo. This high-resolution MRI data provide key information on the spatial variation in nonlinear aortic compliance, which can significantly advance the state-of-the-art of in-silico diagnostic techniques for the human aorta.

Quantification of the regional bioarchitecture in the human aorta.

Regional variance in human aortic bioarchitecture responsible for the elasticity of the vessel is poorly understood. The current study quantifies the elements responsible for aortic compliance, namely, elastin, collagen and smooth muscle cells, using histological and stereological techniques on human tissue with a focus on regional heterogeneity. Using donated cadaveric tissue, a series of samples were excised between the proximal ascending aorta and the distal abdominal aorta, for five cadavers, each of which underwent various staining procedures to enhance specific constituents of the wall. Using polarised light microscopy techniques, the orientation of collagen fibres was studied for each location and each tunical layer of the aorta. Significant transmural and longitudinal heterogeneity in collagen fibre orientations were uncovered throughout the vessel. It is shown that a von Mises mixture model is required accurately to fit the complex collagen fibre distributions that exist along the aorta. Additionally, collagen and smooth muscle cell density was observed to increase with increasing distance from the heart, whereas elastin density decreased. Evidence clearly demonstrates that the aorta is a highly heterogeneous vessel which cannot be simplistically represented by a single compliance value. The quantification and fitting of the regional aortic bioarchitectural data, although not without its limitations, including mean cohort age of 77.6 years, facilitates the development of next-generation finite element models that can potentially simulate the influence of regional aortic composition and microstructure on vessel biomechanics.

Adjuvant specific active lung cancer immunotherapy trials. Tumor-associated antigens.

The 10-year cumulative experiences of five year survivals of patients entered into a successful phase II specific active tumor-associated antigen (TAA) immunotherapy trial, a successful phase III specific active immunotherapy trial A and of patients from centers with acceptable protocol violation levels of an unsuccessful specific active immunotherapy trial B are evaluated. Here the authors report the efficacy of specific active TAA immunotherapy when the protocol is adhered to strictly, where the induction of cell-mediated immunity to TAA indicated a successful adherence to the protocol rather than the strategic result when centers from the third trial with major violations are included. The authors repeat here a summary of each of the three separate trials, each of the three trials having been reported elsewhere in their entirety, so that these total results may be compared to the present analysis. The survival experiences of a total of 234 lung cancer Stage I and Stage II patients, including all violations, from centers in northern New York, northern New Jersey, western Pennsylvania and eastern Canada show a statistically valid (P = 0.0002) 5-year survival difference between the control groups (receiving adjuvant alone or no treatment) at 49% survival and the specific active immunotherapy groups at 69% survival. The best promise of specific active immunotherapy alone in an adjunctive treatment setting is with early stage lung cancer. In addition to tests which monitor the effect of TAA immunotherapy induction of long-lasting cell-mediated immunity, tests (monoclonal antibody-derived epitope enzyme immunoassays) were developed to monitor specific, early antibody rises in the bloodstream (circulating humoral immunity).

Stability of aqueous solutions of amoxicillin sodium in the frozen and liquid states.

The stability of aqueous admixtures of amoxicillin sodium in both the liquid and frozen (solid) states was studied. Admixtures of amoxicillin sodium were prepared in sterile water for injection to a theoretical concentration of 10 mg/mL. For each experimental run, 2-mL aliquots of the admixture were placed in stoppered glass volumetric flasks and stored at temperatures ranging from 19.5 degrees C to -30 degrees C; 16 flasks were stored at each temperature. After equilibration for approximately 20 minutes, duplicate flasks at each temperature were removed from storage conditions for time-zero assay. Subsequently, duplicate flasks were assayed at various times, depending on the storage temperature, for up to 13 days or until more than 80% of the drug had degraded. All samples were assayed at least in duplicate using high-performance liquid chromatography. When amoxicillin solutions were in the liquid state (at temperatures between 19.5 and 0 degrees C), the time required for the amoxicillin concentration to decrease to 90% of its initial value (t90) increased as temperature decreased. However, between 0 degree C and -7 degrees C, the t90 of frozen solutions decreased from two days to 1.08 hours. As temperature declined further, the rate of degradation decreased until the solution was completely frozen; at -30 degrees C, the t90 had increased to 13 days. Amoxicillin sodium is unstable in aqueous solutions stored between 0 degrees C and -20 degrees C. If admixtures of this drug are to be frozen for later use, the storage temperature should be below -30 degrees C.

Length of the distal esophageal sphincter and competency of the cardia.

Pressure and abdominal length of the distal esophageal sphincter are important factors in maintaining competency of the cardia against challenges of intraabdominal pressure. Some patients with normal distal esophageal sphincter pressure and position may have reflux which could be due to the inability of the cardia to overcome challenges of intragastric pressure. Three experimental studies and one clinical study were designed to evaluate this problem. The results showed that the resistance to flow through the cardia is related to the integrated effect of distal esophageal sphincter pressure and length; the ratio of distal esophageal sphincter to intragastric pressure necessary to maintain competency is inversely related to the length of sphincter present; gastric dilatation has an adverse effect on the degree of competency achieved by a given distal esophageal sphincter length; and patients with an overall distal esophageal sphincter length of 2 cm or less measured at rest in the fasting state are subject to reflux caused by gastric dilatation, increased intragastric pressure independent of intraabdominal pressure, or both.

Prophylactic versus no brain irradiation in regional small cell lung carcinoma.

Among 104 complete responders entered in a randomized prospective trial of treatments for regional small cell undifferentiated carcinoma of the lung, 52 received prophylactic irradiation of the brain, 3,000 rad in 10 fractions, and 52 did not. The median survivals were 53 and 52 weeks respectively, and the incidences of brain metastases were 5% and 20%. Prophylactic brain irradiation was not associated with significant long-term toxicity.

Antishock trousers in pediatrics--a case management report.

A pediatric trauma patient whose initial management was assisted by antishock trousers is presented along with a discussion of the usage and cautions of this device.

Differential effects of apomorphine in 6-hydroxydopamine-treated and aged rats.

Effects of dopamine depletion and old age were tested on the ability of rats to discriminate the interoceptive cue produced by IP administered apomorphine. In Experiment 1, rats were administered IC injections of 6-hydroxydopamine or its vehicle at 5 days of age. Administration of this dopamine neurotoxin resulted in significant depletion of whole-brain dopamine to 27.2% of controls as indicated when the brains of littermate rats, killed at 35 days of age, were analyzed by high-pressure liquid chromatography. Although this dopamine depletion was significant, toxin-treated rats learned to discriminate 0.16 mg/kg apomorphine from saline at the same rate as control rats. However, the dose-response curve for apomorphine discrimination after doses of 0.04-0.24 mg/kg suggested hypersensitivity to the dopamine agonist in toxin-treated rats. In Experiment 2, senescent rats were similarly trained to discriminate apomorphine in the two-lever food-motivated operant task. Dose-response testing indicated hypersensitivity similar to that found in 6-OHDA-treated rats. This increased behavioral responsiveness of aged rats to dopamine agonists is discussed in relation to receptor supersensitivity, metabolic rates, and blood-brain barrier permeability.

Pre- and postnatal effects of caffeine on brain biogenic amines, cyclic nucleotides and behavior in developing rats.

To examine the perinatal effects of caffeine on pup behavior and brain neurochemistry, rat mothers were exposed to caffeine in a choice situation prenatally, postnatally, at both times or at neither time. Prenatally, caffeine-exposed mothers drank approximately 14 mg/kg/day, an amount ineffective in altering mothers' overall prenatal body weight, although it did reliably decrease birth femur length of offspring. Postnatal pup activity measures revealed that postnatal caffeine exposure depressed activity, with an additional contribution of prenatal caffeine exposure. Those effects occurred at caffeine intake levels (circa 48 mg/kg/day) which minimally affected pup body weight, body length, femur length or eye-opening. Postwithdrawal (35 days of age) biochemical determinations revealed significant postnatal effects of caffeine by depressing cyclic AMP/"whole-brain" and elevating the cyclic GMP/cyclic AMP ratio in cerebellum. Whole-brain levels of dopamine and norepinephrine, however, were not affected by the caffeine treatments. These results suggest that activity profiles may be a more sensitive index of caffeine "toxicity" than other indices of physical development, and that cyclic nucleotides may play at least some role in the hypoactivity-inducing effects of caffeine in developing rats.

Combined modality treatment of regional small cell undifferentiated carcinoma of the lung: a cooperative study of the RTOG and ECOG.

Between 1975 and 1979, 271 patients with regional small cell undifferentiated (including oat cell) carcinoma of the lung were entered into a study involving treatment by radiation therapy (4500 cGy (rad) in five weeks) to the primary tumor, mediastinum and supraclavicular lymph nodes, and a randomization to receive or not receive prophylactic treatment of the brain (3000 cGy in two weeks) and a randomization to prophylactic or delayed chemotherapy (cyclophosphamide and CCNU). Analysis of the data indicates that the median survival for responders (53 weeks) was significantly longer than that of the non-responders and partial responders (37 and 34 weeks). Median survival by treatment arm was 48 weeks for thoracic irradiation (TI), brain irradiation (BI), and early chemotherapy (CT), 44 weeks for TI alone, 41 weeks for TI and CT, 38 weeks for TI and BI. Regional complete and partial tumor responses were 52 and 25% for prophylactic chemotherapy and 44 and 35% for delayed chemotherapy. The site of first failure was regional in 12%, regional and distant simultaneously in 21%, and distant only in 46%. Elective brain irradiation significantly reduced the incidence of brain metastases from 21 and 5%, but did not improve survival.

The development of brain biogenic amines, cyclic nucleotides and hyperactivity in 6-OHDA-treated rat pups.

Developmental changes in the behavior and brain biochemistry of rat pups were investigated in rats administered intracisternal injections of 6-hydroxydopamine (6-OHDA) or its vehicle at 5 days of age. Although pups of both groups were equivalent in their activity at 15 days of age, 6-OHDA-induced hyperactivity emerged at 20 and 30 days of age in a between-group design in which rats were only tested at one age. Body weight measurements revealed that 6-OHDA-treated rats were underweight at 15, 25 and 30 days of age. Furthermore, at 20 days of age, total activity was inversely related to body weights in the 6-OHDA-treated pups. Whole-brain levels of dopamine (DA) were decreased at every age by the 6-OHDA treatment, whereas norepinephrine (NE) levels were virtually unaffected by 6-OHDA at these same ages. Total activity was inversely correlated with whole-brain DA levels at 20 and 30 days of age when 6-OHDA-treated pups were hyperactive. Measures of cerebellar and "rest-of-brain" adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) were not uniformly altered by either the 6-OHDA treatment or by maturation. Results are discussed both in terms of brain biochemistry modulation of hyperactivity and the contribution of decreased body weights induced by 6-OHDA to the production of hyperactivity.

Open-field behavior in dopamine-depleted rat pups and their mothers.

Possible changes in the behavior of rat mothers and their pups were investigated by administering intracisternal injections of 6-hydroxydopamine (6-OHDA) or its vehicle to 5-day-old rats. Administration of the neurotoxin resulted in a significant depletion of whole-brain dopamine levels to 23% of control levels, whereas norepinephrine levels were reduced to 83% of controls. Open-field behavior revealed that the 6-OHDA-treated rat pups were hypoactive, in terms of decreased square crossings, at 15 days of age, yet were hyperactive at 30 days of age. Toxin-treated pups also showed lower urination scores at 25 and 30 days of age. Mothers' open-field behavior was virtually unaffected by the treatment status of their offspring (i.e., 6-OHDA vs. vehicle-treated), although several of the mothers' behaviors decreased with repeated measures over days.

Can ACTH analogs support discriminative learning in rats?

Ten rats were trained to discriminate between the stimulus properties of subcutaneously (SC) administered MSH/ACTH4-10 and saline in a two-lever, food-motivated operant task. After 12 weeks of discriminative training with 100 micrograms/kg MSH/ACTH4-10, half the rats received 200 micrograms/kg MSH/ATCH4-10, whereas the other half were administered 400 micrograms/kg, for 6 additional weeks. Subsequently, all rats continued training on 50 micrograms/kg ORG 2766 (SC) and, after 12 weeks of training, were randomly assigned to receive either 100 or 200 micrograms/kg ORG 2766. The results of this extensive 36 week training schedule indicate that only 1 of the 10 rats learned to discriminate the interoceptive cues produced by the ACTH analogs. However, this rat's performance was so sustained and errorless that the possibility exists that it was relatively more sensitive to the effects of MSH/ACTH4-10 and its analogs and that these substances may support discriminative learning in the rat.

Dopaminergic activity of quipazine.

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Administration of 1.0 mg/kg quipazine, a putative serotonin agonist, produced apomorphine-appropriate responding with a maximal effect occurring at 45 min post-injection. Pretreatment with either 2.0 mg/kg methysergide or 0.4 mg/kg haloperidol reduced quipazine-induced responding upon the apomorphine-appropriate lever to levels observed with methysergide or haloperidol administered alone. These results evidence a dopaminergic action for quipazine and suggest that central serotonergic and dopaminergic pathways may interact cooperatively to control behavior.

Pre-test epinephrine injections reverse DDC-induced retrograde amnesia.

The effects of pre-test systemic administration of epinephrine on DDC-induced retrograde amnesia (RA) for discriminated Pavlovian fear-conditioning were examined in rats. Epinephrine reversed RA with the optimal dosage being 0.05 mg/kg. Apparently, the effect was specifically reversal of amnesia since (a) performance was restored to control levels, but no higher, and (b) sensitization and activity-related artifacts were minimized. These results are consistent with those showing reversal of RA by pre-test administration of hormones or catecholamine agonists. That is, they suggest that amnesia is due to a retrieval deficit rather than to failure of memory storage. Results are discussed in terms of epinephrine-induced modulation of storage and retrieval processes through central and peripheral mechanisms.