Hydraulic Fracture

We consider a variation of Griffith's analysis of rupture, one which simulates the process of hydrofracturing, where fluid forced into a crack raises the fluid pressure until the crack begins to grow. Unlike that of Griffith, in this analysis fluid pressure drops as a hydrofracture grows. We find that growth of the fracture depends on the ratio of the compliances of the fluid and the fracture, a non-dimensional parameter called $\alpha_0$ here. The pressure needed to initiate a hydrofracture is found to be the same as that derived by Griffith. Once a fracture initiates, for relatively low values of the model parameter $\alpha_0$ ($\alpha_0 \leq 0.2$) the fracture advances spontaneously to a new radius which depends on the value of $\alpha_0$. For $\alpha_0 \leq 0.2$ further fluid injection is required to increase the fracture radius after spontaneous growth stops. For the case where $\alpha_0 > 0.2$ each increment of fracture growth requires injection of more fluid. For the extreme case where $\alpha_0 = 0$ our results are the same as Griffith's, i.e., a fracture once initiated grows without limit.Comment: 10 pages, 4 figure

Physical and social environmental characteristics of physical activity for Mexican-origin children: examining differences between school year and summer perceptions

BACKGROUND: Colonias are substandard residential areas along the U.S.-Mexico border. Families of Mexican-origin living in colonias face health burdens characterized by environmental and socioeconomic hardships. Mexican Americans and low-income families, including colonias children, do not frequently participate in physical activity despite the known link to disease risk reduction. For colonias children, schools are the most commonly reported location for physical activity. School closures and extreme temperatures during summer months create a need to explore seasonal differences in environmental supports and barriers in this population. The purpose of this study was to examine the effect of seasonality on perceived environmental barriers, opportunities, and social support for physical activity among colonias children. As a secondary aim, mother-child discordance for each factor was analyzed. METHODS: Promotora-researchers recruited mother-child dyads (n=101 dyads, n=202 participants) from colonias in Hidalgo County, Texas. Mothers and children were separately administered surveys at two time points to capture perceived barriers, opportunities, and social support for physical activity (school-year: February-May; summertime: July-August). Summative scores for each outcome were calculated and three multilevel longitudinal models for continuous outcomes were examined; children were nested within households. Mother-child discordance was measured using Cohen’s Kappa statistic. RESULTS: Physical activity barriers and environmental opportunities (household and neighborhood) increased from school-year to summer by 1.16 and 2.83 points respectively (p≤0.01), after adjusting for covariates. Significant predictors of increased barriers included household income of >$900/month and having more household members. Children of mothers with significant others who were employed part-time or full-time saw significant decreases in barriers. Mother-child agreement of barriers, environmental opportunities, and social support across seasons was slight to fair (range: median κ=0.047 to κ=0.262). CONCLUSIONS: These results suggest a complex relationship between dimensions of economic hardship (employment status, household income, etc…) and perceived opportunities and barriers of children’s physical activity engagement during the school-year and summer. In this study, both barriers and opportunities increased from school-year to summer, further demonstrating that interactions among these characteristics need to be better understood and addressed when considering physical activity initiatives for colonias and other Mexican-American children, specifically during summer when school-based physical activity resources are unavailable

High Glucose-enhanced Acetylcholine Stimulated CGMP Masks Impaired Vascular Reactivity in Tail Arteries from Short-Term Hyperglycemic Rats

Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several models of long-term hyperglycemia. However, the effects of short-term ambient hyperglycemia are poorly understood. Since oxidative stress has been implicated as a contributor to impaired vascular function, we investigated the following

Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity

BACKGROUND: The pathogenesis of HIV-1 glycoprotein 120 (gp120) associated neuroglial toxicity remains unresolved, but oxidative injury has been widely implicated as a contributing factor. In previous studies, exposure of primary human central nervous system tissue cultures to gp120 led to a simplification of neuronal dendritic elements as well as astrocytic hypertrophy and hyperplasia; neuropathological features of HIV-1-associated dementia. Gp120 and proinflammatory cytokines upregulate inducible nitric oxide synthase (iNOS), an important source of nitric oxide (NO) and nitrosative stress. Because ascorbate scavenges reactive nitrogen and oxygen species, we studied the effect of ascorbate supplementation on iNOS expression as well as the neuronal and glial structural changes associated with gp120 exposure. METHODS: Human CNS cultures were derived from 16–18 week gestation post-mortem fetal brain. Cultures were incubated with 400 μM ascorbate-2-O-phosphate (Asc-p) or vehicle for 18 hours then exposed to 1 nM gp120 for 24 hours. The expression of iNOS and neuronal (MAP2) and astrocytic (GFAP) structural proteins was examined by immunohistochemistry and immunofluorescence using confocal scanning laser microscopy (CSLM). RESULTS: Following gp120 exposure iNOS was markedly upregulated from undetectable levels at baseline. Double label CSLM studies revealed astrocytes to be the prime source of iNOS with rare neurons expressing iNOS. This upregulation was attenuated by the preincubation with Asc-p, which raised the intracellular concentration of ascorbate. Astrocytic hypertrophy and neuronal injury caused by gp120 were also prevented by preincubation with ascorbate. CONCLUSIONS: Ascorbate supplementation prevents the deleterious upregulation of iNOS and associated neuronal and astrocytic protein expression and structural changes caused by gp120 in human brain cell cultures

Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice

Antifungal prophylaxis in chemotherapy-associated neutropenia: a retrospective, observational study

<p>Abstract</p> <p>Background</p> <p>In August 2002, the antifungal prophylaxis algorithm for neutropenic hematology/oncology (NHO) patients at the Medical Center was changed from conventional amphotericin (AMB) to an azole (AZ) based regimen (fluconazole [FLU] in low-risk and voriconazole [VOR] in high-risk patients). The aim of our study was to compare outcomes associated with the two regimens, including breakthrough fungal infection, adverse drug events, and costs.</p> <p>Methods</p> <p>Adult, non-febrile, NHO patients who received prophylactic AMB from 8/01/01-7/30/02 or AZ from 8/01/02-7/30/03 were retrospectively evaluated.</p> <p>Results</p> <p>A total of 370 patients (AMB: n = 181; AZ: n = 216) associated with 580 hospitalizations (AMB: n = 259; AZ: n = 321) were included. The incidence of probable/definite breakthrough Aspergillus infections was similar among regimens (AMB: 1.9% vs AZ: 0.6%; p=0.19). A greater incidence of mild/moderate (24.7% vs. 5.3%; p < 0.0001) and severe renal dysfunction (13.5% vs. 4.4%; p < 0.0012) was observed with AMB. In contrast, patients treated with VOR were found to have an increased rate of severe hepatic toxicity (32.5%) compared with patients treated with either AMB (22.6%) or FLU (21.4%) (p = 0.05). While the AZ period was associated with a >$9,000 increase in mean total costs/hospitalization, the mean acquisition cost associated with AZ was only$947/hospitalization more than AMB.</p> <p>Conclusion</p> <p>While an AZ-based regimen is associated with increased cost, the reduced rate of nephrotoxicity and availability of oral dosage forms, suggests that azoles be used preferentially over AMB. However, an increased rate of severe hepatic toxicity may be associated with VOR.</p

Multicenter Collaborative Study of the Interaction of Antifungal Combinations against BrowZine Journal Cover Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis

Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5−4, indicating no significant pharmacodynamic interactions for all of the strain−combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p \u3c 0.0001). Using a narrower additivity range of 1−2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found