Monitoring uterine contractility in mice using a transcervical intrauterine pressure catheter.

In mouse models used to study parturition or pre-clinical therapeutic testing, measurement of uterine contractions is limited to either ex vivo isometric tension or operative intrauterine pressure (IUP). The goal of this study was to: (1) develop a method for transcervical insertion of a pressure catheter to measure in vivo intrauterine contractile pressure during mouse pregnancy, (2) determine whether this method can be utilized numerous times in a single mouse pregnancy without affecting the timing of delivery or fetal outcome and (3) compare the in vivo contractile activity between mouse models of term and preterm labor (PTL). Visualization of the cervix allowed intrauterine pressure catheter (IUPC) placement into anesthetized pregnant mice (plug = day 1, delivery = day 19.5). The amplitude, frequency, duration and area under the curve (AUC) of IUP was lowest on days 16-18, increased significantly (P < 0.05) on the morning of day 19 and reached maximal levels during by the afternoon of day 19 and into the intrapartum period. An AUC threshold of 2.77 mmHg discriminated between inactive labor (day 19 am) and active labor (day 19 pm and intrapartum period). Mice examined on a single vs every experimental timepoint did not have significantly different IUP, timing of delivery, offspring number or fetal/neonatal weight. The IUP was significantly greater in LPS-treated and RU486-treated mouse models of PTL compared to time-matched vehicle control mice. Intrapartum IUP was not significantly different between term and preterm mice. We conclude that utilization of a transcervical IUPC allows sensitive assessment of in vivo uterine contractile activity and labor progression in mouse models without the need for operative approaches.

Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.

Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.

Delayed intracerebral hemorrhage after uneventful embolization of brain arteriovenous malformations is related to volume of embolic agent administered: multivariate analysis of 13 predictive factors.

BACKGROUND: The mechanisms and management of delayed intracerebral hemorrhage (dICH) after treatment of brain arteriovenous malformations (AVMs) are poorly understood and widely debated. Many clinical predictive factors have been theorized for dICH after an otherwise uneventful AVM embolization, but there is an absence of data to discern their significance. OBJECTIVE: To analyze 13 proposed predictive factors and to assess their potential in guiding prevention strategies. METHODS: One hundred sixty-eight embolization procedures were performed on 67 patients with brain AVMs by a single surgeon. Patients were divided into 2 groups: those with symptomatic dICH and control subjects. Thirteen factors were analyzed: age, sex, race, previous ICH, Spetzler-Martin grade, AVM size, eloquence, embolic volume, embolic agent, percent obliteration, and timing, number, and stage of embolizations. Univariate and multivariate analyses were performed on these factors to determine significance. RESULTS: Six procedures were complicated by dICH; 5 (83%) occurred after the final planned procedure. The volume of embolic agent was significantly higher in the dICH group (4.5 ± 1.0 mL) compared with control subjects (1.7 ± 0.2 mL) in both univariate and multivariate analyses (P < .01), even after controlling for AVM size. AVM size was significant in univariate analysis but not multivariate analysis. There were no statistically significant differences between the groups for any of the other possible predictive factors. CONCLUSION: High volume of embolic agent administered per procedure is an independent predictive factor for dICH. Limiting the injected volume for each procedure may reduce this poorly understood complication.

Findings on preoperative brain MRI predict histopathology in children with cerebellar neoplasms.

BACKGROUND/AIMS: The majority of pediatric patients with cerebellar neoplasms harbor pilocytic astrocytomas (PAs), medulloblastomas, or ependymomas. Knowledge of a preoperative likelihood of histopathology in this group of patients has the potential to influence many aspects of care. Previous studies have demonstrated hyperintensity on diffusion-weighted imaging to correlate with medulloblastomas. Recently, measurement of T(2)-weighted signal intensity (T2SI) was shown to be useful in identification of low-grade cerebellar neoplasms. The goal of this study was to assess whether objective findings on these MRI sequences reliably correlated with the underlying histopathology. METHODS: We reviewed the radiologic findings of 50 pediatric patients who underwent resection of a cerebellar neoplasm since 2003 at our institution. Region of interest placement was used to calculate the relative diffusion-weighted signal intensity (rDWSI) and relative T2SI (rT2SI) of each neoplasm. RESULTS: Tukey's multiple comparison test demonstrated medulloblastomas to have significantly higher rDWSIs than PAs/ependymomas, and PAs to have significantly higher rT2SIs than medulloblastomas/ependymomas. A simple method consisting of sequential measurement of rDWSI and rT2SI to predict histopathology was then constructed. Using this method, 39 of 50 (78%) tumors were accurately predicted. CONCLUSION: Measurement of rDWSI and rT2SI using standard MRI of the brain can be used to predict histopathology with favorable accuracy in pediatric patients with cerebellar tumors.

Safety and cost effectiveness of early discharge following microscopic trans-sphenoidal resection of pituitary lesions.

BACKGROUND: Inpatient hospitalization following trans-sphenoidal resection of a pituitary neoplasm has traditionally involved a hospital stay of 2 days or more. It has been the policy of the senior pituitary neurosurgeon (GSA) since February 2008 to allow discharge home on postoperative day (POD) 1 if thirst mechanism is intact and the patient is tolerating oral hydration. The goal of this study was to evaluate the safety and cost-effectiveness of this practice. METHODS: We reviewed the charts of 30 patients, designated the early discharge group, who consecutively underwent microscopic trans-sphenoidal resection from February 2008 to December 2009. We then reviewed the charts of 30 patients, designated the standard discharge group, who consecutively underwent trans-sphenoidal resection from May 2007 to February 2008 before discharge home on POD1 was considered an appropriate option. Safety and cost-effectiveness of the two patient groups were retrospectively evaluated. RESULTS: Patients in the early discharge group went home, on average, on POD 1.3. Following exclusion of two outliers, the average date of discharge of patients in the standard discharge group was POD 2.2. The policy of early discharge saved an average of $1,949 per patient-approximately 4% the total cost of the procedure. Trends toward decreased costs did not reach statistical significance. While no patient suffered any measurable morbidity as a result of early discharge home, 1 in 3 patients in the early discharge group required unscheduled postoperative re-evaluation-a figure significantly higher than the standard discharge group. CONCLUSIONS: At a dedicated pituitary center with the resources to closely monitor outpatient endocrinological and postsurgical issues, early discharge home following trans-sphenoidal surgery is a safe option that is associated with an increase in the number of unscheduled postoperative visits and a trend toward lower costs.

An automated algorithm to improve the precision of basilar artery diameter measurements before and after subarachnoid hemorrhage-induced vasospasm in an animal model.

OBJECTIVE: Quantifying vasospasm has traditionally been performed manually, a method prone to imprecision and user bias. An alternative approach is to use computerized image analysis techniques to define and quantify the diameter of a vessel. The goal of this article is to demonstrate a novel automated vessel measurement algorithm specific to the needs of vasospasm studies and to compare it with traditional manual measurements in an animal model of vasospasm. METHODS: A total of 576 arterial diameter measurements were collected by 4 independent, blinded examiners from 24 angiograms in a rabbit subarachnoid hemorrhage (SAH) model. Measurements were taken from 3 segments of the basilar artery in anteroposterior and lateral projections, both before SAH and after SAH-induced vasospasm. Means and standard deviations of 288 manual measurements were compared with 288 automated measurements. RESULTS: The precision of automated measurements was significantly improved compared with standardized manual measurements (85.7% decrease in variation; P < .001). When using automated measurements, the precision was not affected by vessel size, but when using manual measurements, smaller arteries were less precise (P = .04). There was no significant difference in precision between 2 different contrast concentrations (P = .32). CONCLUSION: Automated measurements of basilar artery diameters are more precise than manual measurements, both before and after SAH-induced vasospasm. The variability in the manual group worsens when the artery is smaller secondary to vasospasm, indicating a need for the use of this segmentation method.

Multispectral molecular imaging of capillary endothelium to facilitate preoperative endovascular brain mapping.

OBJECT: Brain mapping aims to localize neurological function to specific regions of the human brain. Preoperative endovascular brain mapping (PEBM) is a novel approach that allows clear visualization of nonfunctional (silent) brain parenchyma in real time during a resection. It has potential to improve neurosurgical guidance because brain shift does not alter the maps, and the map is visualized directly on the brain in situ rather than on a nearby image. Therefore, the risk of a new neurological deficit should be reduced. The authors report the first PEBM approach that combines selective molecular targeting of brain endothelium with multispectral (optical) imaging in preclinical animal models. METHODS: Sprague-Dawley rats and New Zealand white rabbits were selectively catheterized, and a fluorescein isothiocyanate-derivatized tomato lectin-based imaging probe was administered into the carotid artery or posterior cerebral artery, measuring < 500 microm in diameter. After binding/uptake of the imaging probe, and removal of unbound probe, a craniotomy was performed to directly visualize the "brain map." RESULTS: Selective localization of the imaging probe to the right hemisphere in rats or right posterior cerebral artery in rabbits was clearly visualized after craniotomy. Cross-sections of stained capillaries demonstrated that the imaging probe did not cause vascular occlusion. Gross regional selectivity of the imaging probe was documented by multispectral molecular imaging of intact brains, with discrete localization and endothelium-directed targeting validated by histological examination. CONCLUSIONS: The authors have demonstrated the first molecular endothelium-targeted approach to PEBM that does not require manipulation of the intact blood-brain barrier or result in vascular occlusion. Furthermore, the presented multispectral molecular imaging technique appears to be a suitable methodology for the generation of region-selective brain maps of vascularized brain parenchyma. Further refinement of the PEBM approach, as well as the development of improved imaging probes, may result in clinical advancement of PEBM where direct visual discrimination of nonfunctional silent brain parenchyma at the time of resection could significantly improve neurosurgical outcomes.

Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood-brain barrier.

A major functional component of the blood-brain barrier is P-glycoprotein. In principle, inhibition of this efflux transporter would permit greater distribution of its substrates into the brain and increased central effects. Tariquidar and elacridar, potent and selective P-glycoprotein inhibitors, were investigated in this regard using the opioid loperamide as an in vivo probe in mice. Pretreatment with both inhibitors converted intravenous loperamide from a drug without central effects to one producing antinociception. Radiolabeled loperamide tissue distribution studies indicated that inhibition was associated with increased uptake into brain and testes in the absence of changes in plasma levels, along with enhanced efflux of rhodamine 123 from CD3e+ T-lymphocytes. However, with tariquidar, the loperamide dose-response curves for testes/plasma and brain/plasma concentration ratios were shifted 6- (p = 0.07) and 25-fold (p < 0.01) to the right, respectively (ED50 = 1.48 and 5.65 mg/kg), compared with the rhodamine 123 efflux curve (ED50 0.25 mg/kg). Less pronounced shifts were noted with elacridar where the brain/plasma ratio was shifted only 2-fold relative to the rhodamine 123 efflux data (ED50 = 2.36 versus 1.34 mg/kg, respectively; p 0.01). These results indicate that the P-glycoprotein localized in the blood-brain barrier and, to a lesser extent, the testes-blood barrier is more resistant to inhibition than at other tissue sites such as the lymphocyte; moreover, the extent of this effect depends on the inhibitor. Such resistance can be overcome by a sufficiently high dose of an inhibitor; however, whether this is safely attainable in the clinical situation remains to be determined.