509 research outputs found
Plasma Disappearance Rate of Indocyanine Green for Determination of Liver Function in Three Different Models of Shock
The measurement of the liver function via the plasma disappearance rate of indocyanine
green (PDRICG) is a sensitive bed-side tool in critical care. Yet, recent evidence has questioned the value
of this method for hyperdynamic conditions. To evaluate this technique in different hemodynamic
settings, we analyzed the PDRICG and corresponding pharmacokinetic models after endotoxemia or
hemorrhagic shock in rats. Male anesthetized Sprague-Dawley rats underwent hemorrhage (mean
arterial pressure 35 ± 5 mmHg, 90 min) and 2 h of reperfusion, or lipopolysaccharide (LPS) induced
moderate or severe (1.0 vs. 10 mg/kg) endotoxemia for 6 h (each n = 6). Afterwards, PDRICG was
measured, and pharmacokinetic models were analyzed using nonlinear mixed effects modeling
(NONMEMÂź). Hemorrhagic shock resulted in a significant decrease of PDRICG, compared with sham
controls, and a corresponding attenuation of the calculated ICG clearance in 1- and 2-compartment
models, with the same log-likelihood. The induction of severe, but not moderate endotoxemia, led to
a significant reduction of PDRICG. The calculated ICG blood clearance was reduced in 1-compartment
models for both septic conditions. 2-compartment models performed with a significantly better log
likelihood, and the calculated clearance of ICG did not correspond well with PDRICG in both LPS
groups. 3-compartment models did not improve the log likelihood in any experiment. These results
demonstrate that PDRICG correlates well with ICG clearance in 1- and 2-compartment models after
hemorrhage. In endotoxemia, best described by a 2-compartment model, PDRICG may not truly
reflect the ICG clearance
Understanding NF-ÎșB signaling via mathematical modeling
Mammalian inflammatory signaling, for which NF-ÎșB is a principal transcription factor, is an exquisite example of how cellular signaling pathways can be regulated to produce different yet specific responses to different inflammatory insults. Mathematical models, tightly linked to experiment, have been instrumental in unraveling the forms of regulation in NF-ÎșB signaling and their underlying molecular mechanisms. Our initial model of the IÎșBâNF-ÎșB signaling module highlighted the role of negative feedback in the control of NF-ÎșB temporal dynamics and gene expression. Subsequent studies sparked by this work have helped to characterize additional feedback loops, the inputâoutput behavior of the module, crosstalk between multiple NF-ÎșB-activating pathways, and NF-ÎșB oscillations. We anticipate that computational techniques will enable further progress in the NF-ÎșB field, and the signal transduction field in general, and we discuss potential upcoming developments
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Using automated patch clamp electrophysiology platforms in pain-related ion channel research: insights from industry and academia
Automated patch clamp (APC) technology was first developed at the turn of the millennium. The increased throughput it afforded promised a new paradigm in ion channel recordings: it offered the potential to overcome the time-consuming, low-throughput bottleneck arising from manual patch clamp (MPC) investigations. This has relevance to the fast-paced development of novel therapies for chronic pain. This review highlights the advances in technology, using select examples, that have facilitated APC usage in both industry and academia. It covers both first generation and the latest developments in second-generation platforms. In addition, it also provides an overview of the pain research field and how APC platforms have furthered our understanding of ion channel research and the development of pharmacological tools and therapeutics. APC platforms have much to offer the ion channel research community and this review highlights areas of 'best practice' for both academia and industry. The impact of APC platforms and the prospects for chronic pain ion channel research and improved therapeutics will be evaluated
Dynamic early identification of hip replacement implants with high revision rates. Study based on the NJR data from UK during 2004-2012
BACKGROUND: Hip replacement and hip resurfacing are common surgical procedures with an estimated risk of revision of 4% over 10 year period. Approximately 58% of hip replacements will last 25 years. Some implants have higher revision rates and early identification of poorly performing hip replacement implant brands and cup/head brand combinations is vital. AIMS: Development of a dynamic monitoring method for the revision rates of hip implants. METHODS: Data on the outcomes following the hip replacement surgery between 2004 and 2012 was obtained from the National Joint Register (NJR) in the UK. A novel dynamic algorithm based on the CUmulative SUM (CUSUM) methodology with adjustment for casemix and random frailty for an operating unit was developed and implemented to monitor the revision rates over time. The Benjamini-Hochberg FDR method was used to adjust for multiple testing of numerous hip replacement implant brands and cup/ head combinations at each time point. RESULTS: Three poorly performing cup brands and two cup/ head brand combinations have been detected. Wright Medical UK Ltd Conserve Plus Resurfacing Cup (cup o), DePuy ASR Resurfacing Cup (cup e), and Endo Plus (UK) Limited EP-Fit Plus Polyethylene cup (cup g) showed stable multiple alarms over the period of a year or longer. An addition of a random frailty term did not change the list of underperforming components. The model with added random effect was more conservative, showing less and more delayed alarms. CONCLUSIONS: Our new algorithm is an efficient method for early detection of poorly performing components in hip replacement surgery. It can also be used for similar tasks of dynamic quality monitoring in healthcare
A novel Dual Amylin and Calcitonin Receptor Agonist (DACRA), KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference
BACKGROUND AND PURPOSE: Obesity and associated coâmorbidities, such as type 2 diabetes and nonâalcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the coâmorbidities. EXPERIMENTAL APPROACH: The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBPâ089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weightâindependent effects of KBPâ089 using a weightâmatched group. KEY RESULTS: Rats fed a highâfat diet were treated, s.c., with KBPâ089 0.625, 1.25, 2.5 Όg·kg(â1) or vehicle. KBâ089 induced in a doseâdependent and sustained weight loss (~17% by 2.5 Όg·kg(â1)). Moreover, KBPâ089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBPâ089 improved glucose homeostasis through improved insulin action. To obtain a weightâmatched group, significantly less food was offered (9% less than in the KBPâ089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBPâ089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBPâ089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. CONCLUSIONS AND IMPLICATIONS: The novel DACRA, KBPâ089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by dietâinduced weight loss
What is the biological basis of pattern formation of skin lesions?
Pattern recognition is at the heart of clinical dermatology and dermatopathology. Yet, while every practitioner of the art of dermatological diagnosis recognizes the supreme value of diagnostic cues provided by defined patterns of 'efflorescences', few contemplate on the biological basis of pattern formation in and of skin lesions. Vice versa, developmental and theoretical biologists, who would be best prepared to study skin lesion patterns, are lamentably slow to discover this field as a uniquely instructive testing ground for probing theoretical concepts on pattern generation in the human system. As a result, we have at best scraped the surface of understanding the biological basis of pattern formation of skin lesions, and widely open questions dominate over definitive answer. As a symmetry-breaking force, pattern formation represents one of the most fundamental principles that nature enlists for system organization. Thus, the peculiar and often characteristic arrangements that skin lesions display provide a unique opportunity to reflect upon â and to experimentally dissect â the powerful organizing principles at the crossroads of developmental, skin and theoretical biology, genetics, and clinical dermatology that underlie these â increasingly less enigmatic â phenomena. The current 'Controversies' feature offers a range of different perspectives on how pattern formation of skin lesions can be approached. With this, we hope to encourage more systematic interdisciplinary research efforts geared at unraveling the many unsolved, yet utterly fascinating mysteries of dermatological pattern formation. In short: never a dull pattern
Sex-linked mating strategies diverge with a manipulation of genital salience
Trivers (Sexual selection and the descent of man, Aldine-Atherton, Chicago, pp 136â179, 1972) proposed that evolutionary factors should favor divergent mating strategies for males versus females. Such differences may be less pronounced among human beings than other animals and social norms and sex roles are also pertinent influences. The present experiment (N = 133 college undergraduates, 74 female) sought to bypass some of these other influences. Participants were randomly assigned to a condition designed to increase attention to the genital region (a downward pointing arrow) or not (an upward pointing arrow). They then reported on their interest in short-term (e.g., a one-night stand) and long-term (e.g., a potential marital partner) mating opportunities. A theory-consistent three-way interaction occurred such that the genital salience manipulation primed a shorter-term reproductive strategy among men and a longer-term reproductive strategy among women. The results provide unique support for evolution-linked ideas about sex differences in the form of a role for bodily attention
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