Active gels, heavy tails, and the cytoskeleton.

The eukaryotic cell's cytoskeleton is a prototypical example of an active material: objects embedded within it are driven by molecular motors acting on the cytoskeleton, leading to anomalous diffusive behavior. Experiments tracking the behavior of cell-attached objects have observed anomalous diffusion with a distribution of displacements that is non-Gaussian, with heavy tails. This has been attributed to "cytoquakes" or other spatially extended collective effects. We show, using simulations and analytical theory, that a simple continuum active gel model driven by fluctuating force dipoles naturally creates heavy power-law tails in cytoskeletal displacements. We predict that this power law exponent should depend on the geometry and dimensionality of where force dipoles are distributed through the cell; we find qualitatively different results for force dipoles in a 3D cytoskeleton and a quasi-two-dimensional cortex. We then discuss potential applications of this model both in cells and in synthetic active gels.

Cell-free vascular grafts that grow with the host.

Cell-free small diameter vascular grafts, based on small intestinal submucosa (SIS) functionalized with heparin and vascular endothelial growth factor (VEGF) manufactured and implanted successfully into the arterial system of neonatal lambs, where they remained patent and grew in size with the host to a similar extent and with similar rate as native arteries. Acellular tissue engineered vessels (A-TEV) integrated seamlessly into the native vasculature and developed confluent, functional endothelium that afforded patency. The medial layer was infiltrated by smooth muscle cells, showed no signs of calcification and developed contractile function. The vascular wall underwent remarkable extracellular matrix remodeling exhibiting elastin fibers and even inner elastic lamina within six months. Taken together, our results suggest that VEGF-based A-TEVs may be suitable for treatment of congenital heart disorders to alleviate the need for repeated surgeries, which are currently standard practice.

Animal models of cardiovascular disease as test beds of bioengineered vascular grafts.

The last two decades have seen many advances in regenerative medicine, including the development of tissue engineered vessels (TEVs) for replacement of damaged or diseased arteries or veins. Biomaterials from natural sources as well as synthetic polymeric materials have been employed in engineering vascular grafts. Recently, cell-free grafts have become available opening new possibilities for the next generation, off-the-shelf products. These TEVs are first tested in small or large animal models, which are usually young and healthy. However, the majority of patients in need of vascular grafts are elderly and suffer from comorbidities that may complicate their response to the implants. Therefore, it is important to evaluate TEVs in animal models of vascular disease in order to increase their predictive value and learn how the disease microenvironment may affect the patency and remodeling of vascular grafts. Small animals with various disease phenotypes are readily available due to the availability of transgenic or gene knockout technologies and can be used to address mechanistic questions related to vascular grafting. On the other hand, large animal models with similar anatomy, hematology and thrombotic responses to humans have been utilized in a preclinical setting. We propose that large animal models with certain pathologies or age range may provide more clinically relevant platforms for testing TEVs and facilitate the clinical translation of tissue engineering technologies by increasing the likelihood of success in clinical trials.

Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration.

BACKGROUND: The Neonatal Resuscitation Program (NRP) recommends upper and lower limits of preductal saturations (SpO2) extrapolated from studies in infants resuscitated in room air. These limits have not been validated in asphyxia and lung disease. METHODS: Seven control term lambs delivered by cesarean section were ventilated with 21% O2. Thirty lambs with asphyxia with meconium aspiration were randomly assigned to resuscitation with 21% O2 (n = 6), 100% O2 (n = 6), or initiation with 21% O2 followed by variable FIO2 to maintain NRP target SpO2 ranges (n = 18). Hemodynamic and ventilation parameters were recorded for 15 min. RESULTS: Control lambs maintained preductal SpO2 near the lower limit of NRP target range. Asphyxiated lambs had low SpO2 (38 ± 2%), low arterial pH (6.99 ± 0.01), and high PaCO2 (96 ± 7 mm Hg) at birth. Resuscitation with 21% O2 resulted in SpO2 values below the target range with low pulmonary blood flow (Qp) compared to variable FIO2 group. The increase in PaO2 and Qp with variable FIO2 resuscitation was similar to control lambs. CONCLUSION: Maintaining SpO2 as recommended by NRP by actively adjusting inspired O2 leads to effective oxygenation and higher Qp in asphyxiated lambs with lung disease. Our findings support the current NRP SpO2 guidelines for O2 supplementation during resuscitation of an asphyxiated neonate.

Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration.

BACKGROUND: Current neonatal resuscitation guidelines recommend tracheal suctioning of nonvigorous neonates born through meconium-stained amniotic fluid. METHODS: We evaluated the effect of tracheal suctioning at birth in 29 lambs with asphyxia induced by cord occlusion and meconium aspiration during gasping. RESULTS: Tracheal suctioning at birth (n = 15) decreased amount of meconium in distal airways (53 ± 29 particles/mm(2) lung area) compared to no suction (499 ± 109 particles/mm(2); n = 14; P < 0.001). Three lambs in the suction group had cardiac arrest during suctioning, requiring chest compressions and epinephrine. Onset of ventilation was delayed in the suction group (146 ± 11 vs. 47 ± 3 s in no-suction group; P = 0.005). There was no difference in pulmonary blood flow, carotid blood flow, and pulmonary or systemic blood pressure between the two groups. Left atrial pressure was significantly higher in the suction group. Tracheal suctioning resulted in higher Pao2/FiO2 levels (122 ± 21 vs. 78 ± 10 mm Hg) and ventilator efficiency index (0.3 ± 0.05 vs.0.16 ± 0.03). Two lambs in the no-suction group required inhaled nitric oxide. Lung 3-nitrotyrosine levels were higher in the suction group (0.65 ± 0.03 ng/µg protein) compared with the no-suction group (0.47 ± 0.06). CONCLUSION: Tracheal suctioning improves oxygenation and ventilation. Suctioning does not improve pulmonary/systemic hemodynamics or oxidative stress in an ovine model of acute meconium aspiration with asphyxia.

New sector morphologies emerge from anisotropic colony growth.

Competition during range expansions is of great interest from both practical and theoretical view points. Experimentally, range expansions are often studied in homogeneous Petri dishes, which lack spatial anisotropy that might be present in realistic populations. Here, we analyze a model of anisotropic growth, based on coupled Kardar-Parisi-Zhang and Fisher-Kolmogorov-Petrovsky-Piskunov equations that describe surface growth and lateral competition. Compared to a previous study of isotropic growth, anisotropy relaxes a constraint between parameters of the model. We completely characterize spatial patterns and invasion velocities in this generalized model. In particular, we find that strong anisotropy results in a distinct morphology of spatial invasion with a kink in the displaced strain ahead of the boundary between the strains. This morphology of the out-competed strain is similar to a shock wave and serves as a signature of anisotropic growth.

Packed red cell transfusions alter mesenteric arterial reactivity and nitric oxide pathway in preterm lambs.

BACKGROUND: Cases of necrotizing enterocolitis occurring within 48 h of packed red blood cell (PRBC) transfusions are increasingly being described in observational studies. Transfusion-associated gut injury is speculated to result from an abnormal mesenteric vascular response to transfusion. However, the mechanism of disruption of the balance between mesenteric vasoconstriction and relaxation following transfusion is not known. METHODS: Preterm lambs (n = 16, 134 d gestation; term: 145-147 d) were delivered and ventilated for 24 h. All the lambs received orogastric feeds with colostrum. In addition, 10 of these lambs received PRBC transfusions. Vasoreactivity was evaluated in isolated mesenteric arterial rings using norepinephrine and endothelin-1 as vasoconstrictors. Endothelium-dependent (A23187, a calcium ionophore) and endothelium-independent (SNAP) nitric oxide (NO) donors were used as vasorelaxants. Mesenteric arterial endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase 5 (PDE5) mRNA analyses and protein assays were performed. RESULTS: Transfusion with PRBC significantly increased mesenteric vasoconstriction to norepinephrine and endothelin-1 and impaired relaxation to A23187 and SNAP. Mesenteric arterial eNOS protein decreased following PRBC transfusion. No significant changes were noted in sGC and PDE5 mRNA or protein assays. CONCLUSION: PRBC transfusion in enterally fed preterm lambs promotes mesenteric vasoconstriction and impairs vasorelaxation by reducing mesenteric arterial eNOS.

Competition on the edge of an expanding population.

In growing populations, the fate of mutations depends on their competitive ability against the ancestor and their ability to colonize new territory. Here we present a theory that integrates both aspects of mutant fitness by coupling the classic description of one-dimensional competition (Fisher equation) to the minimal model of front shape (KPZ equation). We solved these equations and found three regimes, which are controlled solely by the expansion rates, solely by the competitive abilities, or by both. Collectively, our results provide a simple framework to study spatial competition.

30-Day Post-Discharge Prophylaxis with Rivaroxaban Prevents Porto-mesenteric Venous Thrombosis Following Laparoscopic Sleeve Gastrectomy.

INTRODUCTION: Porto-mesenteric venous thrombosis (PMVT) is a significant complication that occurs more frequently after laparoscopic sleeve gastrectomy (SG) than other bariatric procedures and presents later than other venous thromboembolic (VTE) events often 2 weeks after the operation. The common current practice in bariatric surgery of perioperative chemoprophylaxis until discharge may not adequately prevent PMVT. Therefore, a 30-day post-discharge chemoprophylaxis (PDC) might reduce the incidence of PMVT. The objective of this study is to determine whether 30-day PDC with rivaroxaban 10 mg daily following SG can reduce the incidence of PMVT. METHODS: In a retrospective cohort study, 292 consecutive patients undergoing SG by a single surgeon were either prescribed rivaroxaban 10 mg daily for 30 days upon discharge (group A) or did not receive any PDC (group B). Primary outcome was PMVT and secondary outcome was bleeding. Patients on chronic anticoagulation therapy were excluded from the study. RESULTS: PMVT events differences were significant between the groups while bleeding events were not. Group A had zero PMVT events, while group B had four (p = .045). There were 4 bleeding events in group A and 7 bleeding events on group B (p = .341). CONCLUSION: A 30-day PDC regimen of rivaroxaban 10 mg daily is both safe and effective. This study demonstrated zero PMVT events without an increased risk of bleeding using this regimen.

Interplay between morphology and competition in two-dimensional colony expansion.

In growing populations, the fate of mutations depends on their competitive ability against the ancestor and their ability to colonize new territory. Here we present a theory that integrates both aspects of mutant fitness by coupling the classic description of one-dimensional competition (Fisher equation) to the minimal model of front shape (Kardar-Parisi-Zhang equation). We solve these equations and find three regimes, which are controlled solely by the expansion rates, solely by the competitive abilities, or by both. Collectively, our results provide a simple framework to study spatial competition.

A novel ovine ex vivo arteriovenous shunt model to test vascular implantability.

The major objective of successful development of tissue-engineered vascular grafts is long-term in vivo patency. Optimization of matrix, cell source, surface modifications, and physical preconditioning are all elements of attaining a compatible, durable, and functional vascular construct. In vitro model systems are inadequate to test elements of thrombogenicity and vascular dynamic functional properties while in vivo implantation is complicated, labor-intensive, and cost-ineffective. We proposed an ex vivo ovine arteriovenous shunt model in which we can test the patency and physical properties of vascular grafts under physiologic conditions. The pressure, flow rate, and vascular diameter were monitored in real-time in order to evaluate the pulse wave velocity, augmentation index, and dynamic elastic modulus, all indicators of graft stiffness. Carotid arteries, jugular veins, and small intestinal submucosa-based grafts were tested. SIS grafts demonstrated physical properties between those of carotid arteries and jugular veins. Anticoagulation properties of grafts were assessed via scanning electron microscopy imaging, en face immunostaining, and histology. Luminal seeding with endothelial cells greatly decreased the attachment of thrombotic components. This model is also suture free, allowing for multiple samples to be stably processed within one animal. This tunable (pressure, flow, shear) ex vivo shunt model can be used to optimize the implantability and long-term patency of tissue-engineered vascular constructs.

Seascape origin of Richards growth.

First proposed as an empirical rule over half a century ago, the Richards growth equation has been frequently invoked in population modeling and pandemic forecasting. Central to this model is the advent of a fractional exponent γ, typically fitted to the data. While various motivations for this nonanalytical form have been proposed, it is still considered foremost an empirical fitting procedure. Here, we find that Richards-like growth laws emerge naturally from generic analytical growth rules in a distributed population, upon inclusion of (i) migration (spatial diffusion) among different locales, and (ii) stochasticity in the growth rate, also known as "seascape noise." The latter leads to a wide (power law) distribution in local population number that, while smoothened through the former, can still result in a fractional growth law for the overall population. This justification of the Richards growth law thus provides a testable connection to the distribution of constituents of the population.

Late administration of antenatal vitamin A promotes pulmonary structural maturation and improves ventilation in the lamb model of congenital diaphragmatic hernia.

PURPOSE: The lungs in congenital diaphragmatic hernia (CDH) are hypoplastic and immature making respiratory support one of the most challenging aspects of caring for these neonates. Vitamin A is essential for normal lung growth and development. It also promotes alveolarization. The aim of this study is to investigate the effects of antenatal vitamin A on lung growth and alveolarization and ventilation in the lamb model of CDH. METHODS: This study was approved by the Animal Care Committee of the State University of New York at Buffalo, and conforms to the National Institute of Health guidelines. Diaphragmatic defects were created at 79-81 days gestation. Group 1 lambs (CDH, n = 5) were untreated. In group 2 (CDH + vitamin A, n = 6) and group 3 lambs (control + vitamin A, n = 3) right jugular venous catheters were inserted at 118-120 days and retinyl palmitate (vitamin A) was administered until 135 days. The control group (n = 5) consisted of twin littermates. Lambs were delivered at 136-139 days and ventilated for 2 h according to a set protocol. The left lungs were harvested and fixed for histology. RESULTS: Lung compliance was significantly higher in CDH + vitamin A (median 0.27, range 0.1-0.48 ml/cmH(2)O/kg) versus CDH lambs (median 0.07, range 0.07-0.18 ml/cmH(2)O/kg), P < 0.05. At 1 h CDH + vitamin A lambs experienced significantly lower PaCO(2) (median 115, range 35-194 mmHg vs. median 192, range 168-234 mmHg) and higher arterial pH (median 7.0, range 6.74-7.35 vs. median 6.73, range 6.5-6.81) than CDH lambs, P < 0.05. The lung weight to body weight ratio of CDH + vitamin A lambs was significantly less than that of CDH lambs (P < 0.05). Histology showed small thick walled air-spaces and no true alveoli in CDH lambs. In contrast, true alveoli and thinning of the inter-alveolar septums were seen in CDH + vitamin A lambs. CONCLUSION: This is the first study to demonstrate an improvement in lung function and structural maturation when antenatal vitamin A is given in a surgical model of CDH.

Exposure to supplemental oxygen and its effects on oxidative stress and antioxidant enzyme activity in term newborn lambs.

The optimal oxygen concentration for the resuscitation of term infants remains controversial. We studied the effects of 21 versus 100% oxygen immediately after birth, and also exposure for 24 h to 100% oxygen, on oxidant lung injury and lung antioxidant enzyme (AOE) activities in term newborn lambs. Lambs at 139 d gestation were delivered and ventilated with 21% (RAR) or 100% (OXR) for 30 min. A third group of newborn lambs were ventilated with 100% O2 for 24 h (OX24). Oxidized glutathione levels in whole blood were significantly different among the groups with lower values in the RAR group, and these values correlated highly with partial pressure of arterial oxygen (Pao2). The reduced to oxidized glutathione ratio was significantly different among the groups, the ratio decreasing with increasing oxygen exposure. Lipid hydroperoxide (LPO) activity was significantly higher in the OXR and OX24 groups. AOE activity was higher in the whole lung and in red cell lysate in the OX24 group. Increased myeloperoxidase (MPO) activity, percent neutrophils, and proteins in lung lavage suggested inflammation in the OX24 group after maximal oxygen exposure. We conclude that even relatively brief exposure of the lung to 100% oxygen increases systemic oxidative stress and lung oxidant injury in ventilated term newborn lambs.

Student experiences and satisfaction with a novel clerkship patient scheduling.

Background: Outpatient primary care clerkships are an important part of medical students' education.Traditional clerkships usually partner a student with a single preceptor in that physician's clinic. However, it can be quite difficult for the preceptor to balance the educational needs of the students, the expectations of the patients and the organizational demands of the clinic practice.Objective: An innovative scheduling model (named "Patients as Teachers" [PAT] clinic) was developed as part of our third-year Family Medicine clerkship. The goal was to increase the students' opportunities for independence and improve their satisfaction without negatively impacting the flow of the clinic or patient satisfaction.Design: The third-year medical students spent part of their clerkship working in the PAT clinic and part of the time working with an individual preceptor in that preceptor's clinic in the traditional, usual fashion (PAU clinic-precepting as usual). The students completed patient-logs regarding the patients they saw and their level of participation. They also completed a voluntary survey regarding their experiences.Results: Students performed more independent interviews (90.3 vs 59.0%) and independent exams (96.2 vs 63.3%) in the PAT clinic than while working with their traditional preceptor (both p<0.01). Students were highly satisfied with the experience with 89.5% stating they would recommend it and 87.7% finding the PAT clinic to be an equal or superior experience to the PAU experience.Conclusions: Using a combination of time in the PAT clinic and time with a one on one preceptor in the usual fashion was successful in increasing opportunities for student autonomy and achieving a high level of student satisfaction in our third-year Family Medicine clerkship. Additional opportunities for innovative scheduling could be considered for meeting a variety of clerkship and clinic needs.

Endothelialization of arterial vascular grafts by circulating monocytes.

Recently our group demonstrated that acellular tissue engineered vessels (A-TEVs) comprised of small intestinal submucosa (SIS) immobilized with heparin and vascular endothelial growth factor (VEGF) could be implanted into the arterial system of a pre-clinical ovine animal model, where they endothelialized within one month and remained patent. Here we report that immobilized VEGF captures blood circulating monocytes (MC) with high specificity under a range of shear stresses. Adherent MC differentiate into a mixed endothelial (EC) and macrophage (Mφ) phenotype and further develop into mature EC that align in the direction of flow and produce nitric oxide under high shear stress. In-vivo, newly recruited cells on the vascular lumen express MC markers and at later times they co-express MC and EC-specific proteins and maintain graft patency. This novel finding indicates that the highly prevalent circulating MC contribute directly to the endothelialization of acellular vascular grafts under the right chemical and biomechanical cues.

Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension.

The effect of oxygen concentration on lowering pulmonary vascular resistance (PVR) during resuscitation in a model of persistent pulmonary hypertension of the newborn (PPHN) is not known. PPHN was induced in fetal lambs by ductal ligation 9 d before delivery. After delivery by cesarean section, resuscitation of PPHN lambs with 21%, 50%, or 100% O2 (n = 6 each) for 30 min produced similar decreases in PVR. Lambs were then ventilated with 50% O2 for 60 min and exposed to inhaled nitric oxide (iNO, 20 ppm). Initial resuscitation with 100% O2 significantly impaired the subsequent response to iNO compared with 21% O2 (42 +/- 9% vs 22 +/- 4% decrease from baseline PVR). Finally, each lamb was randomly and sequentially ventilated with 10%, 21%, 50%, or 100% O2. PVR decreased with increased concentrations of inhaled O2 up to 50%, there being no additional decrease in PVR with 100% O2. When PVR was correlated with Pao2, the maximal change in PVR was achieved at Pao2 values <60 mm Hg. We conclude that resuscitation with 100% O2 does not enhance pulmonary vasodilation compared with 21% and 50% O2, but impairs the subsequent response to iNO in PPHN lambs. Hypoxia increases PVR but hyperoxia does not confer significant additional pulmonary vasodilation in lambs with PPHN.

Bile reflux after Roux-en-Y gastric bypass: an unrecognized cause of postoperative pain.

BACKGROUND: To determine, in a private practice, whether symptomatic bile reflux can occur after Roux-en-Y gastric bypass (RYGB) for morbid obesity and the outcome after laparoscopic alimentary (Roux) limb lengthening. Bile reflux as a cause of pain after laparoscopic RYGB has not been previously described. We report on a series of patients with chronic pain after RYGB as a result of bile reflux owing an abnormally short alimentary limb. METHODS: A prospective database of patients who underwent revisional surgery to treat symptomatic bile reflux at our center was retrospectively reviewed and analyzed for the onset of symptoms, interval to revision, length of alimentary limb, and outcome after revision. RESULTS: A total of 16 patients were diagnosed with bile reflux and underwent revisional surgery. The onset of symptoms occurred at 58.3 +/- 22.2 months after RYGB. All patients complained of pain, 13 (81.3%) had vomiting, and 7 (43.8%) had dysphagia. Endoscopy was performed in all patients and confirmed the presence of bile in all patients and detected marginal ulceration in 5 (31.3%) and gastritis in 8 (50.0%). At revisional surgery, the mean alimentary limb length was 37.7 +/- 12.4 cm (range 20-62 cm). At a mean follow-up of 14.9 months after revision, all patients had reported resolution of their symptoms. CONCLUSION: Although previously unreported after RYGB, bile reflux can be an important possible cause of chronic pain. Bile reflux, however, responds favorably to alimentary limb lengthening to 100 cm and was not been seen in patients with an alimentary limb length >62 cm.

Efficacy of liposomal bupivacaine versus bupivacaine in port site injections on postoperative pain within enhanced recovery after bariatric surgery program: a randomized clinical trial.

BACKGROUND: Use of liposomal bupivacaine (LB) in surgery is reported with decreased postoperative opioid requirements. The efficacy of LB versus standard bupivacaine injections at laparoscopic port sites during bariatric surgery is unknown. OBJECTIVES: To determine whether there was a difference in postoperative hospital opioid requirements after port site injections of LB versus standard bupivacaine during laparoscopic bariatric surgeries. Primary endpoint was total in hospital opioid use expressed as morphine-equivalent use. Secondary endpoints included home opioid use, pain scores, hospital length of stay, and adverse events. SETTING: Academic-affiliated private practice. METHODS: A 2-group randomized, double-blinded trial from November 2017 to August 2018 with patients randomly assigned to receive either LB or bupivacaine alone at trocar site injections during laparoscopic Roux-en-Y gastric bypass (LRYGB) or vertical sleeve gastrectomy (VSG). All patients underwent enhanced recovery after bariatric surgery protocols. RESULTS: All patients undergoing LRYGB or VSG assessed for eligibility. Of 682 patients undergoing LRYGB or VSG, 231 met inclusion criteria, 52 patients excluded intraoperatively. Among 231 patients (mean age, 39.2 years; 79% women; mean body mass index 45.0), 179 patients (77%) completed the trial. Patients randomly assigned to receive either LB (n = 89) or bupivacaine alone (n = 90) at trocar site injection during LRYGB or VSG. Postoperative morphine-equivalent use were similar (LB 8.3 [standard deviation 4.0-13.9] versus bupivacaine group 7.5 [standard deviation 3.6-13.1] P = .94) with highest requirement in first 4 hours after surgery. There was no significant difference in length of stay, pain scores, or complications. There were more patients in the bupivacaine group that did not take pain medications on postoperative days 2 to 4 (P = .032, P = .23, P = .005, respectively). There were more patients in the bupivacaine group 48.1% (n = 39) compared with the LB group 34.2% (n = 27) that did not consume any narcotic tablets at home but this not found to be statistically significant (P value = .07). CONCLUSIONS: Among patients undergoing primary bariatric surgery under enhanced recovery after bariatric surgery protocol, there was no significant difference in postoperative hospital opioid use in those receiving LB compared with standard bupivacaine. A greater percentage of patients in the standard bupivacaine group did not require any narcotics at home, which was significant on postoperative days 2 to 4. To become completely opioid free after bariatric surgery, resources should be focused on multimodal approaches instead of reliance on type of anesthetic medication used.

Nascent aneurysm formation at the basilar terminus induced by hemodynamics.

BACKGROUND AND PURPOSE: Hemodynamic insults at arterial bifurcations are hypothesized to play a key role in intracranial aneurysm formation. This study investigates aneurysm-initiating vascular responses at the rabbit basilar terminus subsequent to common carotid artery ligation. METHODS: Nine adult female New Zealand white rabbits were subjected to sham, unilateral, or bilateral common carotid artery ligation to produce varying degrees of compensatory basilar artery flow increase. Basilar artery flow velocity and geometry were monitored by transcranial Doppler and rotational angiography, respectively, for 12 weeks after surgery. Bifurcation tissues were harvested at 12 weeks and examined histologically. From the histological sections, we quantified the destructive structural changes at the basilar terminus and correlated them with the basilar artery flow rate increase. RESULTS: Subsequent to common carotid artery ligation, basilar artery flow rate increased by 105% to 900% at the maximum. All common carotid artery-ligated rabbits presented nascent aneurysm formation characterized by a bulge with thinned media and absent internal elastic lamina near the basilar terminus. We defined a nascent aneurysm index based on a multiplicative combination of the local destructive remodeling lengths measured at the nascent aneurysm. The nascent aneurysm index strongly correlated with the increase in basilar artery flow rate with R(2)=0.91. CONCLUSIONS: Without other known predisposition, flow increase alone at the basilar bifurcation can lead to a nascent aneurysm. This nascent aneurysm formation is dose-dependent on basilar artery flow increase.