Noninvasive assessment of visco-elasticity in the presence of accumulated soft tissue fluid

BACKGROUND: The diagnosis of compartment syndrome is made by clinical examination, but direct compartmental measurements are important and serve an adjunctive role in establishing the diagnosis. This study examines a noninvasive screening method for differentiating compartmental syndrome from edema without elevated internal pressure. MATERIALS AND METHODS: The study groups consisted of 16 normals, 22 subjects with edema, and 2 subjects with compartmental syndrome. Force-displacement curves on the posterior and anterior surface of the extremity at mid-calf of each extremity were recorded using a noninvasive mechanical tester. A cyclic force peaking at 120 N was applied over a skin area of 1.5 cm(2). In a uniform applied force environment, the peak force would be comparable to an applied pressure of 60 mm Hg. Mechanical parameters associated with tissue softness (SOFT), degree of hysteresis, and departure from linear elastic behavior were calculated. In seven subjects, direct intracompartment pressure readings were obtained by the Stryker method. RESULTS: Posterior SOFT was significantly larger than anterior SOFT, as expected, for all study groups, except those with compartmental syndrome. SOFT for subjects with compartment syndrome fell below the 99% confidence interval of all other groups in the affected compartment(s). Departure from linear elastic behavior values were also depressed in the posterior compartment for subjects with compartment syndrome as compared with the other groups. Degree of hysteresis was significantly increased for pitting edema. Extremities with nonpitting edema were not distinguishable from normal extremities for the levels of applied pressure used in this study. CONCLUSION: Noninvasively measured mechanical properties were significantly different between normal tissues and tissues with pitting and nonpitting edema. The mechanical properties of the extremity with compartmental syndrome were different than those with edema as well as normal extremities. A noninvasive mechanical tester is seen as a possible clinical tool to diagnose and monitor compartmental syndrome.     

Prominent phenotypic variability associated with mutations in Progranulin

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.     

The modification of PLA and PLGA using electron-beam radiation

The degradable polymers polylactide (PLA) and polylactide-co-glycolide (PLGA) have found widespread use in modern medical practice. However, their slow degradation rates and tendency to lose strength before mass have caused problems. The aim of this study was to ascertain whether treatment with e-beam radiation could address these problems. Samples of PLA and PLGA were manufactured and placed in layered stacks, 8.1 mm deep, before exposure to 50 kGy of e-beam radiation from a 1.5 MeV accelerator. Gel permeation chromatography testing showed that the molecular weight of both materials was depth-dependent following irradiation, with samples nearest to the treated surface showing a reduced molecular weight. Samples deeper than 5.4 mm were unaffected. Computer modeling of the transmission of a 1.5 MeV e-beam in these materials corresponded well with these findings. An accelerated mass-loss study of the treated materials found that the samples nearest the irradiated surface initiated mass loss earlier, and at later stages showed an increased percentage mass loss. It was concluded that e-beam radiation could modify the degradation of bioabsorbable polymers to potentially improve their performance in medical devices, specifically for improved orthopedic fixation.     

Toxin-Mediated Effects on the Innate Mucosal Defenses: Implications for Enteric Vaccines

Recent studies have confirmed older observations that the enterotoxins enhance enteric bacterial colonization and pathogenicity. How and why this happens remains unknown at this time. It appears that toxins such as the heat-labile enterotoxin (LT) from Escherichia coli can help overcome the innate mucosal barrier as a key step in enteric pathogen survival. We review key observations relevant to the roles of LT and cholera toxin in protective immunity and the effects of these toxins on innate mucosal defenses. We suggest either that toxin-mediated fluid secretion mechanically disrupts the mucus layer or that toxins interfere with innate mucosal defenses by other means. Such a breach gives pathogens access to the enterocyte, leading to binding and pathogenicity by enterotoxigenic E. coli (ETEC) and other organisms. Given the common exposure to LT⁺ ETEC by humans visiting or residing in regions of endemicity, barrier disruption should frequently render the gut vulnerable to ETEC and other enteric infections. Conversely, toxin immunity would be expected to block this process by protecting the innate mucosal barrier. Years ago, Peltola et al. (Lancet 338:1285-1289, 1991) observed unexpectedly broad protective effects against LT⁺ ETEC and mixed infections when using a toxin-based enteric vaccine. If toxins truly exert barrier-disruptive effects as a key step in pathogenesis, then a return to classic toxin-based vaccine strategies for enteric disease is warranted and can be expected to have unexpectedly broad protective effects.Enterotoxigenic Escherichia coli (ETEC) infection and cholera are toxin-mediated enteric diseases that are leading causes of morbidity and mortality worldwide (25, 32, 36). Although cholera is generally less frequent than ETEC infection, both cholera and ETEC infection can result in severely dehydrating diarrheal disease (73). While there is a cholera vaccine that confers protection against cholera for up to 3 years (11), there is, by contrast, currently no licensed vaccine to protect humans against ETEC disease. The establishment of a vaccine against ETEC is a major unmet need for both travelers and children in the developing world, as ETEC disease creates an extensive disease burden in both children (94) and travelers (85) and ranks as a top global health priority.The pathogenesis of cholera and that of ETEC disease are quite similar. Each begins with the ingestion of inocula, followed by elaboration of toxin, bacterial colonization, induction of profuse watery diarrhea, and dissemination of organisms back into the environment. The many similarities between cholera and ETEC disease are striking (13, 84), especially in regard to the centrality of the toxins to their pathogenicity. Vibrio cholerae secretes cholera toxin (CT), whereas ETEC elaborates both the heat-labile enterotoxin LT and the heat stable toxin ST. Both LT and CT are 86 kDa A:B5 ADP-ribosylating exotoxins that are functionally and structurally homologous (ca. 80%), highly immunogenic, and characterized by high levels of cross-neutralizing immunity. From a vaccine development perspective, this high level of homology may allow cholera and LT-containing ETEC disease to be addressed simultaneously in a single vaccine (10). However, ETEC disease differs from cholera in that many strains also produce the diarrheagenic heat-stable toxin (ST), a small, poorly immunogenic peptide. The question that remains is whether toxin-based vaccine protection against ST⁺ ETEC strains can be achieved (12, 69). The presence of ST toxin-containing strains complicates ETEC vaccine development, especially given that in some geographic regions ST-containing strains appear to be predominant (36, 72). However, efficacy data from vaccine trials have suggested that LT toxin-neutralizing immunity protects against LT⁺ ETEC and to some degree against both ST⁺ ETEC and non-ETEC organisms (9, 10, 68), indicating that LT toxin immunity may have unexpectedly broad effects. The goals of this review are to consider the role of LT toxin in ETEC pathogenicity in the context of the innate mucosal defenses and to consider how LT immunity may be protective in this context, leading to vaccine protection against non-LT-containing organisms.The intact, innate gut defenses, a combination of mechanical, chemical, environmental, and innate and adaptive immune effectors, are generally sufficient to ward off microbial infections. Consequently, organisms causing enteric diseases have developed a series of strategies to penetrate, disrupt, or modify the innate mucosal barrier, rendering the gut wall susceptible to subsequent pathogen colonization or entry (65). CT and the heat-labile (LT) enterotoxins are exotoxins that have long been known to cause the secretory diarrhea characteristic of these diseases, but the survival advantage the microbe gains by producing these toxins is debated. It has long been suggested that CT aids efficient pathogen colonization in the intestine, and more recent studies have confirmed that LT toxins enhance enteric bacterial colonization and pathogenicity (1, 2, 15, 44). As enteric pathogens must overcome the innate mucosal barrier to cause disease, we suggest here that toxins such as LT and CT are specifically produced to overcome the innate mucosal barrier as a key step in enteric pathogen survival. Given the common exposure of humans visiting or residing in regions with CT-containing vibrios and LT-containing ETEC (see below), one would predict that toxin exposure and subsequent barrier disruption would frequently render the gut generally vulnerable to enteric infection as the toxin-mediated breach in the mucosa is exploited. The corollary is that elimination of localized toxin effects through antitoxin neutralizing immunity could be expected to interrupt a strategy central to the survival of ETEC and possibly other coinfecting enteric pathogens.     

Development of the Burden of Prior Authorization of Psychotherapeutics (BoPAP) Scale to Assess the Effects of Prior Authorization Among Texas Medicaid Providers

This study describes an instrument to measure the perceived effects of prior authorization on quality of care among Texas Medicaid patients with severe mental illness. A questionnaire was mailed to 1,650 prescribers of psychiatric medications and 226 responses were used for analyses (17.5% response rate). Factor analysis revealed a 3-factor, 25-item instrument (BoPAP scale). Overall, prescribers reported a moderate burden of PA (BoPAP Mean = 3.90 ± 0.52, possible range = 1–5). They perceived a high burden (4.49 ± 0.57) on “administrative issues,” a moderate burden (3.93 ± 0.66) on “patient care processes/outcomes” and the lowest burden (3.30 ± 0.74) on “system/societal costs.” BoPAP scores differed based on provider characteristics, indicating evidence of discriminant validity. This paper has been presented in part at the ISPOR 13th Annual International Meeting, Toronto, ON, Canada, May 3–7, 2008.     

Distinct neurophysiological mechanisms mediate mixing costs and switch costs

Using event-related potentials (ERPs), we investigated the neural response associated with preparing to switch from one task to another. We used a cued task-switching paradigm in which the interval between the cue and the imperative stimulus was varied. The difference between response time (RT) to trials on which the task switched and trials on which the task repeated (switch cost) decreased as the interval between cue and target (CTI) was increased, demonstrating that subjects used the CTI to prepare for the forthcoming task. However, the RT on repeated-task trials in blocks during which the task could switch (mixed-task blocks) were never as short as RTs during single-task blocks (mixing cost). This replicates previous research. The ERPs in response to the cue were compared across three conditions: single-task trials, switch trials, and repeat trials. ERP topographic differences were found between single-task trials and mixed-task (switch and repeat) trials at approximately 160 and approximately 310 msec after the cue, indicative of changes in the underlying neural generator configuration as a basis for the mixing cost. In contrast, there were no topographic differences evident between switch and repeat trials during the CTI. Rather, the response of statistically indistinguishable generator configurations was stronger at approximately 310 msec on switch than on repeat trials. By separating differences in ERP topography from differences in response strength, these results suggest that a reappraisal of previous research is appropriate.