Hybrid Equation/Agent-Based Model of Ischemia-Induced Hyperemia and Pressure Ulcer Formation Predicts Greater Propensity to Ulcerate in Subjects with Spinal Cord Injury

Pressure ulcers are costly and life-threatening complications for people with spinal cord injury (SCI). People with SCI also exhibit differential blood flow properties in non-ulcerated skin. We hypothesized that a computer simulation of the pressure ulcer formation process, informed by data regarding skin blood flow and reactive hyperemia in response to pressure, could provide insights into the pathogenesis and effective treatment of post-SCI pressure ulcers. Agent-Based Models (ABM) are useful in settings such as pressure ulcers, in which spatial realism is important. Ordinary Differential Equation-based (ODE) models are useful when modeling physiological phenomena such as reactive hyperemia. Accordingly, we constructed a hybrid model that combines ODEs related to blood flow along with an ABM of skin injury, inflammation, and ulcer formation. The relationship between pressure and the course of ulcer formation, as well as several other important characteristic patterns of pressure ulcer formation, was demonstrated in this model. The ODE portion of this model was calibrated to data related to blood flow following experimental pressure responses in non-injured human subjects or to data from people with SCI. This model predicted a higher propensity to form ulcers in response to pressure in people with SCI vs. non-injured control subjects, and thus may serve as novel diagnostic platform for post-SCI ulcer formation. © 2013 Solovyev et al

Identification of Nedd4 E3 Ubiquitin Ligase as a Binding Partner and Regulator of MAK-V Protein Kinase

MAK-V/Hunk is a scantily characterized AMPK-like protein kinase. Recent findings identified MAK-V as a pro-survival and anti-apoptotic protein and revealed its role in embryonic development as well as in tumorigenesis and metastasis. However molecular mechanisms of MAK-V action and regulation of its activity remain largely unknown. We identified Nedd4 as an interaction partner for MAK-V protein kinase. However, this HECT-type E3 ubiquitin ligase is not involved in the control of MAK-V degradation by the ubiquitin-proteasome system that regulates MAK-V abundance in cells. However, Nedd4 in an ubiquitin ligase-independent manner rescued developmental defects in Xenopus embryos induced by MAK-V overexpression, suggesting physiological relevance of interaction between MAK-V and Nedd4. This identifies Nedd4 as the first known regulator of MAK-V function

COPD exacerbations in general practice: variability in oral prednisolone courses

<p>Abstract</p> <p>Background</p> <p>The use of oral corticosteroids as treatment of COPD exacerbations in primary care is well established and evidence-based. However, the most appropriate dosage regimen has not been determined and remains controversial. Corticosteroid therapy is associated with a number of undesirable side effects, including hyperglycaemias, so differences in prescribing might be relevant. This study examines the differences between GPs in dosage and duration of prednisolone treatment in patients with a COPD exacerbation. It also investigates the number of general practitioners (GPs) who adjust their treatment according to the presence of diabetic co-morbidity.</p> <p>Methods</p> <p>Cross-sectional study among 219 GPs and 25 GPs in training, located in the Northern part of the Netherlands.</p> <p>Results</p> <p>The response rate was 69%. Nearly every GP prescribed a continuous dose of prednisolone 30 mg per day. Among GPs there were substantial differences in treatment duration. GPs prescribed courses of five, seven, ten, or fourteen days. A course of seven days was most common. The duration of treatment depended on exacerbation and disease severity. A course of five days was especially prescribed in case of a less severe exacerbation. In a more severe exacerbation duration of seven to fourteen days was more common. Hardly any GP adjusted treatment to the presence of diabetic co-morbidity.</p> <p>Conclusion</p> <p>Under normal conditions GPs prescribe prednisolone quite uniformly, within the range of the current Dutch guidelines. There is insufficient guidance regarding how to adjust corticosteroid treatment to exacerbation severity, disease severity and the presence of diabetic co-morbidity. Under these circumstances, there is a substantial variation in treatment duration.</p

The effects of long-term total parenteral nutrition on gut mucosal immunity in children with short bowel syndrome: a systematic review

BACKGROUND: Short bowel syndrome (SBS) is defined as the malabsorptive state that often follows massive resection of the small intestine. Most cases originate in the newborn period and result from congenital anomalies. It is associated with a high morbidity, is potentially lethal and often requires months, sometimes years, in the hospital and home on total parenteral nutrition (TPN). Long-term survival without parenteral nutrition depends upon establishing enteral nutrition and the process of intestinal adaptation through which the remaining small bowel gradually increases its absorptive capacity. The purpose of this article is to perform a descriptive systematic review of the published articles on the effects of TPN on the intestinal immune system investigating whether long-term TPN induces bacterial translocation, decreases secretory immunoglobulin A (S-IgA), impairs intestinal immunity, and changes mucosal architecture in children with SBS. METHODS: The databases of OVID, such as MEDLINE and CINAHL, Cochran Library, and Evidence-Based Medicine were searched for articles published from 1990 to 2001. Search terms were total parenteral nutrition, children, bacterial translocation, small bowel syndrome, short gut syndrome, intestinal immunity, gut permeability, sepsis, hyperglycemia, immunonutrition, glutamine, enteral tube feeding, and systematic reviews. The goal was to include all clinical studies conducted in children directly addressing the effects of TPN on gut immunity. RESULTS: A total of 13 studies were identified. These 13 studies included a total of 414 infants and children between the ages approximately 4 months to 17 years old, and 16 healthy adults as controls; and they varied in design and were conducted in several disciplines. The results were integrated into common themes. Five themes were identified: 1) sepsis, 2) impaired immune functions: In vitro studies, 3) mortality, 4) villous atrophy, 5) duration of dependency on TPN after bowel resection. CONCLUSION: Based on this exhaustive literature review, there is no direct evidence suggesting that TPN promotes bacterial overgrowth, impairs neutrophil functions, inhibits blood's bactericidal effect, causes villous atrophy, or causes to death in human model. The hypothesis relating negative effects of TPN on gut immunity remains attractive, but unproven. Enteral nutrition is cheaper, but no safer than TPN. Based on the current evidence, TPN seems to be safe and a life saving solution

Lipid Classes and Fatty Acid Patterns are Altered in the Brain of γ-Synuclein Null Mutant Mice

The well-documented link between α-synuclein and the pathology of common human neurodegenerative diseases has increased attention to the synuclein protein family. The involvement of α-synuclein in lipid metabolism in both normal and diseased nervous system has been shown by many research groups. However, the possible involvement of γ-synuclein, a closely-related member of the synuclein family, in these processes has hardly been addressed. In this study, the effect of γ-synuclein deficiency on the lipid composition and fatty acid patterns of individual lipids from two brain regions has been studied using a mouse model. The level of phosphatidylserine (PtdSer) was increased in the midbrain whereas no changes in the relative proportions of membrane polar lipids were observed in the cortex of γ-synuclein-deficient compared to wild-type (WT) mice. In addition, higher levels of docosahexaenoic acid were found in PtdSer and phosphatidylethanolamine (PtdEtn) from the cerebral cortex of γ-synuclein null mutant mice. These findings show that γ-synuclein deficiency leads to alterations in the lipid profile in brain tissues and suggest that this protein, like α-synuclein, might affect neuronal function via modulation of lipid metabolism

Framingham cardiovascular disease risk scores and incident frailty:the English longitudinal study of ageing

Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1,726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95 % confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors, the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74), respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty

Measures of frailty in population-based studies: An overview

Although research productivity in the field of frailty has risen exponentially in recent years, there remains a lack of consensus regarding the measurement of this syndrome. This overview offers three services: first, we provide a comprehensive catalogue of current frailty measures; second, we evaluate their reliability and validity; third, we report on their popularity of use