315 E 13Th St
Merced CA 95341
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Angiogenesis: an adaptive dynamic biological patterning problem. - PLoS computational biology
Formation of functionally adequate vascular networks by angiogenesis presents a problem in biological patterning. Generated without predetermined spatial patterns, networks must develop hierarchical tree-like structures for efficient convective transport over large distances, combined with dense space-filling meshes for short diffusion distances to every point in the tissue. Moreover, networks must be capable of restructuring in response to changing functional demands without interruption of blood flow. Here, theoretical simulations based on experimental data are used to demonstrate that this patterning problem can be solved through over-abundant stochastic generation of vessels in response to a growth factor generated in hypoxic tissue regions, in parallel with refinement by structural adaptation and pruning. Essential biological mechanisms for generation of adequate and efficient vascular patterns are identified and impairments in vascular properties resulting from defects in these mechanisms are predicted. The results provide a framework for understanding vascular network formation in normal or pathological conditions and for predicting effects of therapies targeting angiogenesis.
Anesthetic Challenges in Robotic-assisted Urologic Surgery. - Reviews in urology
Robotic-assisted surgery has evolved over the past two decades with constantly improving technology, assisting surgeons in multiple subspecialty disciplines. The surgical requirements of lithotomy and steep Trendelenburg positions, along with the creation of a pneumoperitoneum and limited access to the patient, all present anesthetic management challenges in urologic surgery. Patient positioning requirements can cause significant physiologic effects and may result in many complications. Good communication among team members and knowledge of the nuances of robotic surgery have the potential to improve patient outcomes, increase efficiency, and reduce surgical and anesthetic complications.
Endovascular vs open repair for ruptured abdominal aortic aneurysm. - Journal of vascular surgery
Endovascular repair (EVAR) of ruptured abdominal aortic aneurysm (rAAA) has become first-line therapy at our institution and is performed under a standardized protocol. We compare perioperative mortality, midterm survival, and morbidity after EVAR and open surgical repair (OSR).Records were retrospectively reviewed from May 2000 to September 2010 for repair of infrarenal rAAAs. Primary end points included perioperative mortality and midterm survival. Secondary end points included acute limb ischemia, length of stay, ventilator-dependent respiratory failure, myocardial infarction, renal failure, abdominal compartment syndrome, and secondary intervention. Statistical analysis was performed using the t-test, Ï‡(2) test, the Fisher exact test, and logistic regression calculations. Midterm survival was assessed with Kaplan-Meier analysis and Cox proportional hazard models.Seventy-four infrarenal rAAAs were repaired, 19 by EVAR and 55 by OSR. Despite increased age and comorbidity in the EVAR patients, perioperative mortality was 15.7% for EVAR, which was significantly lower than the 49% for OSR (odds ratio, 0.19; 95% CI, 0.05-0.74; P = .008). Midterm survival also favored EVAR (hazard ratio, 0.40; 95% CI, 0.21-0.77; P = .028, adjusted for age and sex). Mean follow-up was 20 months, and 1-year survival was 60% for EVAR vs 45% for OSR. Mean length of stay for patients surviving >1 day was 10 days for EVAR and 21 days for OSR (P = .004). Ventilator-dependent respiratory failure was 5% in the EVAR group vs 42% for OSR (odds ratio, 0.08; 95% CI, 0.01-0.62; P = .001).EVAR of rAAA has a superior perioperative survival advantage and decreased morbidity vs OSR. Although not statistically significant, overall survival favors EVAR. We recommend that EVAR be considered as the first-line treatment of rAAAs and practiced as the standard of care.Copyright Â© 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
Seizure sensitivity is ameliorated by targeted expression of K+-Cl- cotransporter function in the mushroom body of the Drosophila brain. - Genetics
The kcc(DHS1) allele of kazachoc (kcc) was identified as a seizure-enhancer mutation exacerbating the bang-sensitive (BS) paralytic behavioral phenotypes of several seizure-sensitive Drosophila mutants. On their own, young kcc(DHS1) flies also display seizure-like behavior and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The product of kcc shows substantial homology to KCC2, the mammalian neuronal K(+)-Cl(-) cotransporter. The kcc(DHS1) allele is a hypomorph, and its seizure-like phenotype reflects reduced expression of the kcc gene. We report here that kcc functions as a K(+)-Cl(-) cotransporter when expressed heterologously in Xenopus laevis oocytes: under hypotonic conditions that induce oocyte swelling, oocytes that express Drosophila kcc display robust ion transport activity observed as a Cl(-)-dependent uptake of the K(+) congener (86)Rb(+). Ectopic, spatially restricted expression of a UAS-kcc(+) transgene was used to determine where cotransporter function is required in order to rescue the kcc(DHS1) BS paralytic phenotype. Interestingly, phenotypic rescue is largely accounted for by targeted, circumscribed expression in the mushroom bodies (MBs) and the ellipsoid body (EB) of the central complex. Intriguingly, we observed that MB induction of kcc(+) functioned as a general seizure suppressor in Drosophila. Drosophila MBs have generated considerable interest especially for their role as the neural substrate for olfactory learning and memory; they have not been previously implicated in seizure susceptibility. We show that kcc(DHS1) seizure sensitivity in MB neurons acts via a weakening of chemical synaptic inhibition by GABAergic transmission and suggest that this is due to disruption of intracellular Cl(-) gradients in MB neurons.
CT colonography versus colonoscopy for the detection of advanced neoplasia. - The New England journal of medicine
Advanced neoplasia represents the primary target for colorectal-cancer screening and prevention. We compared the diagnostic yield from parallel computed tomographic colonography (CTC) and optical colonoscopy (OC) screening programs.We compared primary CTC screening in 3120 consecutive adults (mean [+/-SD] age, 57.0+/-7.2 years) with primary OC screening in 3163 consecutive adults (mean age, 58.1+/-7.8 years). The main outcome measures included the detection of advanced neoplasia (advanced adenomas and carcinomas) and the total number of harvested polyps. Referral for polypectomy during OC was offered for all CTC-detected polyps of at least 6 mm in size. Patients with one or two small polyps (6 to 9 mm) also were offered the option of CTC surveillance. During primary OC, nearly all detected polyps were removed, regardless of size, according to established practice guidelines.During CTC and OC screening, 123 and 121 advanced neoplasms were found, including 14 and 4 invasive cancers, respectively. The referral rate for OC in the primary CTC screening group was 7.9% (246 of 3120 patients). Advanced neoplasia was confirmed in 100 of the 3120 patients in the CTC group (3.2%) and in 107 of the 3163 patients in the OC group (3.4%), not including 158 patients with 193 unresected CTC-detected polyps of 6 to 9 mm who were undergoing surveillance. The total numbers of polyps removed in the CTC and OC groups were 561 and 2434, respectively. There were seven colonic perforations in the OC group and none in the CTC group.Primary CTC and OC screening strategies resulted in similar detection rates for advanced neoplasia, although the numbers of polypectomies and complications were considerably smaller in the CTC group. These findings support the use of CTC as a primary screening test before therapeutic OC.Copyright 2007 Massachusetts Medical Society.
Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. - Journal of the National Cancer Institute
Because of the inefficient vasculature of solid tumors, anticancer drugs must penetrate relatively long distances through the extravascular compartment. The requirement for such diffusion may limit their activity, especially that of hypoxia-targeted drugs. We tested whether a three-dimensional pharmacokinetic/pharmacodynamic (PK/PD) model based on a representative mapped tumor microvascular network could predict the therapeutic activity of anticancer drugs in mouse xenograft tumors.Diffusion coefficients of the hypoxia-activated anticancer drug tirapazamine (TPZ) and of 15 TPZ analogs were estimated by measuring their transport through HT29 colon cancer multicellular layers (MCLs). Anoxic cytotoxic potency (by clonogenic assay) and metabolism of the TPZ analogs were measured in HT29 cell suspensions, and their plasma pharmacokinetics was measured in CD-1 nude mice. This information was used to create a spatially resolved PK/PD model for the tumor microvascular network. Model predictions were compared with actual hypoxic cell kill as measured by clonogenic assays on HT29 xenograft tumors 18 hours after treatment with each TPZ analog.Modeling TPZ transport in the tumor microvascular network showed substantial drug depletion in the most hypoxic regions, with predicted maximum cell kill of only 3 logs, compared with more than 10 logs if there were no transport impediment. A large range of tissue diffusion coefficients (0.027 x 10(-6)-1.87 x 10(-6) cm2/s) was observed for the TPZ analogs. There was a strong correlation between model-predicted and measured hypoxic cell kill (R2 = 0.89) but a poor correlation when the model did not include extravascular transport (R2 = 0.32).Extravascular transport in tumors, and its consequences for tumor cell killing, can be predicted by measuring drug penetration through MCLs in vitro and modeling pharmacokinetics at each position in three-dimensional microvascular networks.
An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. - The Journal of experimental medicine
Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.
Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. - Blood
Following bone marrow transplantation, delayed donor leukocyte infusions (DLIs) can induce graft-versus-leukemia (GVL) effects without graft-versus-host disease (GVHD). These antitumor responses are maximized by the presence of host hematopoietic antigen-presenting cells (APCs) at the time of DLI. Using a tumor-protection model, we demonstrate here that GVL activity following administration of DLIs to established mixed chimeras is dependent primarily on reactivity to allogeneic MHC antigens rather than minor histocompatibility or tumor-associated antigens. CD8(+) T-cell-dependent GVL responses against an MHC class II-negative tumor following delayed DLI require CD4(+) T-cell help and are reduced significantly when host APCs lack MHC class II expression. CD4(+) T cells primed by host APCs were required for maximal expansion of graft-versus-host reactive CD8(+) T cells but not their synthesis of IFN-gamma. In contrast, the GVL requirement for CD4(+) T-cell help was bypassed almost completely when DLI was administered to freshly irradiated recipients, indicating that the host environment is a major factor influencing the cellular mechanisms of GVL.
Blockade of melanocortin transmission inhibits cocaine reward. - The European journal of neuroscience
Melanocortins and the melanocortin-4 receptor (MC4-R) are enriched in the nucleus accumbens, a brain region that has been implicated in the rewarding action of cocaine and other drugs of abuse. In the present study we use a number of rat behavioral models to show that infusion of a melanocortin peptide antagonist into the nucleus accumbens blocks the reinforcing, incentive motivational, and locomotor sensitizing effects of cocaine. We also show that locomotor responses to repeated cocaine exposure are completely blocked in MC4-R null mutant mice and reduced in Agouti mice that overexpress an endogenous inhibitor of melanocortins in the brain. The results also demonstrate that cocaine administration increases the expression of MC4-R in the nucleus accumbens and striatum, and that MC4-R is co-localized with prodynorphin in medium spiny neurons in the nucleus accumbens. Together, these findings indicate that the behavioral actions of cocaine are dependent on activation of MC4-R, and suggest that upregulation of this receptor by drug exposure may contribute to sensitization of these behavioral responses. Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction.
Green's function methods for analysis of oxygen delivery to tissue by microvascular networks. - Annals of biomedical engineering
Delivery of oxygen to tissue is an essential function of the circulatory system. The distance that oxygen can diffuse into oxygen-consuming tissue is small, and so tissue oxygenation is critically dependent on the spatial arrangement of microvessels in tissue. Theoretical methods have been developed to simulate the spatial distribution of oxygen levels in tissue surrounding a network of microvessels. Here, numerical methods based on a Green's function approach are presented, for realistic three-dimensional network geometries derived from observations of skeletal muscle, brain, and tumor tissues. Relative to finite-difference methods, the Green's function approach reduces the number of unknowns in the numerical formulation and allows rapid computations even for complex vascular geometries. Generally, the boundary conditions on the exterior of the computational domain are not known. Imposition of a no-flux boundary condition can lead to exaggerated estimates of the extent of hypoxia in the tissue region. A new version of the method is described that avoids this problem and can be applied to arbitrarily shaped tissue domains.
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315 E 13Th St Merced, CA 95341
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