Using dihydropyridine-release strategies to enhance load effects in engineered human bone constructs

We report on the development of a novel biodegradable scaffold capable of enhancing mechanical signals for tissue-engineering applications. It has been shown that mechanotransduction enhances bone formation in vitro and in vivo; in tissue-engineering applications, this phenomenon is exploited through the use of mechanical bioreactors to generate bone tissue. The dihydropyridine agonist Bay K8644 (Bay) acts to increase the opening time of mechanosensitive voltage-operated calcium channels (VOCCs), specifi- cally L-type VOCCs, which are known to play a fundamental role in the early mediation of mechanotransduction. We have produced porous 3-dimensional, Bay-encapsulated biodegradable poly(L-lactide) acid scaffolds using a solvent-casting and salt-leaching technique. The effects of the released Bay on osteoid production and mineralization in human bone cell-seeded constructs following incubation in a perfusion-compression bioreactor in vitro was investigated using Western blotting techniques and a calcium assay protocol developed in our lab. Our newly developed scaffolds act by slowly releasing the calcium channel agonist Bay K8644 as observed using ultraviolet spectroscopy, maintaining the open state of mechanosensitive VOCCs responding to load, which augments the load signal at sites of strain across the scaffold. Our results demonstrate that, in the presence of physiological loading regimes in vitro, release of Bay enhances collagen I protein production and osteoid calcification more than non-Bay control constructs do. Osteopontin and alpha2delta1 VOCC subunit protein levels were also higher as a result of perfusion-compression conditioning. These results indicate that Bay-encapsulated scaffolds can be used in the presence of load to enhance the production of load-bearing engineered tissue.     

Clinical impact of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay related to methicillin-resistant Staphylococcus aureus bloodstream infections

Antimicrobial resistance is threatening the successful management of nosocomial infections worldwide. Despite the therapeutic limitations imposed by methicillin-resistant Staphylococcus aureus (MRSA), its clinical impact is still debated. The objective of this study was to estimate the excess mortality and length of hospital stay (LOS) associated with MRSA bloodstream infections (BSI) in European hospitals. Between July 2007 and June 2008, a multicenter, prospective, parallel matched-cohort study was carried out in 13 tertiary care hospitals in as many European countries. Cohort I consisted of patients with MRSA BSI and cohort II of patients with methicillin-susceptible S. aureus (MSSA) BSI. The patients in both cohorts were matched for LOS prior to the onset of BSI with patients free of the respective BSI. Cohort I consisted of 248 MRSA patients and 453 controls and cohort II of 618 MSSA patients and 1,170 controls. Compared to the controls, MRSA patients had higher 30-day mortality (adjusted odds ratio [aOR] = 4.4) and higher hospital mortality (adjusted hazard ratio [aHR] = 3.5). Their excess LOS was 9.2 days. MSSA patients also had higher 30-day (aOR = 2.4) and hospital (aHR = 3.1) mortality and an excess LOS of 8.6 days. When the outcomes from the two cohorts were compared, an effect attributable to methicillin resistance was found for 30-day mortality (OR = 1.8; P = 0.04), but not for hospital mortality (HR = 1.1; P = 0.63) or LOS (difference = 0.6 days; P = 0.96). Irrespective of methicillin susceptibility, S. aureus BSI has a significant impact on morbidity and mortality. In addition, MRSA BSI leads to a fatal outcome more frequently than MSSA BSI. Infection control efforts in hospitals should aim to contain infections caused by both resistant and susceptible S. aureus.     

How much does it cost to care for survivors of colorectal cancer? Caregiver’s time, travel and out-of-pocket costs

Purpose

Cancer treatment is increasingly delivered in an outpatient setting. This may entail a considerable economic burden for family members and friends who support patients/survivors. We estimated financial and time costs associated with informal care for colorectal cancer.

Methods

Two hundred twenty-eight carers of colorectal cancer survivors diagnosed on October 2007–September 2009 were sent a questionnaire. Informal care costs included hospital- and domestic-based foregone caregiver time, travel expenses and out-of-pocket (OOP) costs during two phases: diagnosis and treatment and ongoing care (previous 30 days). Multiple regression was used to determine cost predictors.

Results

One hundred fifty-four completed questionnaires were received (response rate?=?68 %). In the diagnosis and treatment phase, weekly informal care costs per person were: hospital-based costs, incurred by 99 % of carers, mean?=?€393 (interquartile range (IQR), €131–€541); domestic-based time costs, incurred by 85 %, mean?=?€609 (IQR, €170–€976); and domestic-based OOP costs, incurred by 68 %, mean?=?€69 (IQR, €0–€110). Ongoing costs included domestic-based time costs incurred by 66 % (mean?=?€66; IQR, €0–€594) and domestic-based OOP costs incurred by 52 % (mean?=?€52; IQR, €0–€64). The approximate average first year informal care cost was €29,842, of which 85 % was time costs, 13 % OOP costs and 2 % travel costs. Significant cost predictors included carer age, disease stage, and survivor age.

Conclusion

Informal caregiving associated with colorectal cancer entails considerable time and OOP costs. This burden is largely unrecognised by policymakers, service providers and society in general. These types of studies may facilitate health decision-makers in better assessing the consequences of changes in cancer care organisation and delivery.     

Clinical review: Stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype?

ABSTRACT: A growing understanding of the complexity of the pathophysiology of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), coupled with advances in stem cell biology, has led to a renewed interest in the therapeutic potential of stem cells for this devastating disease. Mesenchymal stem cells appear closest to clinical translation, given the evidence that they may favourably modulate the immune response to reduce lung injury, while maintaining host immune-competence and also facilitating lung regeneration and repair. The demonstration that human mesenchymal stem cells exert benefit in the endotoxin-injured human lung is particularly persuasive. Endothelial progenitor cells also demonstrate promise in reducing endothelial damage, which is a key pathophysiological feature of ALI. Embryonic and induced pluripotent stem cells are at an earlier stage in the translational process, but offer the hope of directly replacing injured lung tissue. The lung itself also contains endogenous stem cells, which may ultimately offer the greatest hope for lung diseases, given their physiologic role in replacing and regenerating native lung tissues. However, significant deficits remain in our knowledge regarding the mechanisms of action of stem cells, their efficacy in relevant pre-clinical models, and their safety, particularly in critically ill patients. These gaps need to be addressed before the enormous therapeutic potential of stem cells for ALI/ARDS can be realised.     

Influence of n-3 polyunsaturated fatty acids on soluble cellular adhesion molecules as biomarkers of cardiovascular risk in young healthy subjects

Background and aimSerum levels of soluble cellular adhesion molecules (CAMs) and blood lipid parameters have been used as markers of inflammatory processes associated with cardiovascular disease (CVD) events. The present study evaluated the effects of the intake of n-3 polyunsaturated fatty acids (PUFAs) in fish and fish oil within energy-restricted diets, on soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1).Methods and resultsTwo hundred and seventy-five healthy European subjects aged between 20 and 40 years, were randomized to one of four hypocaloric dietary groups: control (sunflower oil capsules, no seafood), lean fish (3 × 150 g portions of cod/week), fatty fish (3 × 150 g portions of salmon/week), fish oil ((docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) capsules, no seafood)). Diets rich in lean fish significantly decreased ICAM-1 levels, around 5% from baseline to endpoint (p < 0.05), and had no effect on VCAM-1 levels. No significant differences were observed in sICAM-1 levels after the intervention with fatty fish or fish oils. On the other hand, these two seafood based diets were responsible for a significant increase of VCAM-1 levels [fatty fish; 16.1% and fish oil; 21.9%] respectively (p < 0.05).ConclusionsCAMs as inflammatory biomarkers in young and healthy subjects are not conclusive for the evaluation of CVD risk. Hypocaloric fish diets had a different effect on CAMs, being lean fish responsible for the highest decrease in ICAM-1. On the other hand, VCAM-1 results allow speculation that a low dose of n-3 PUFA may be anti-inflammatory contrarily to a high dose which can have a pro-inflammatory effect. CAMs mechanism is complex and affected by multiple factors such as lifestyle, gender, and n-3 dose and source.     

A prediction rule for the use of postdischarge medical services

OBJECTIVE: To develop and validate a prediction rule screening instrument, easily incorporated into the routine hospital admission assessment, that could facilitate discharge planning by identifying patients at the time of admission who are most likely to need postdischarge medical services. DESIGN: Prospective cohort study with separate phases for prediction rule development and validation. SETTING: Urban teaching hospital. PATIENTS/PARTICIPANTS: General medical service patients, 381 in the derivation phase and 323 in the validation phase, who provided self-reported medical history, health status, and demographic data as a part of their admission nursing assessment, and were subsequently discharged alive. MEASUREMENTS AND MAIN RESULTS: Use of postdischarge medical services such as visiting nurse or physical therapy, medical equipment, or placement in a rehabilitation or long-term care facility was determined. A prediction rule based on a patient’s age and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) physical function and social function scores stratified patients with regard to their risk of using postdischarge medical services. In the validation set, the rate of actual postdischarge medical service use was 15% (15 of 97), 36% (39 of 107), and 58% (57 of 98) among patients characterized by the prediction rule as being at “low”, “intermediate,” and “high” risk of using postdischarge medical services, respectively. CONCLUSIONS: This prediction rule stratified general medical patients with regard to their likelihood of needing discharge planning to arrange for postdischarge medical services. Further research is necessary to determine whether prospective identification of patients likely to need discharge planning will make the hospital discharge planning process more efficient. Presented at the Society of General Internal Medicine annual meeting, April 1994.     

Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology

Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid β (Aβ) peptide, the major constituent of AD plaques. We expressed human APP₇₅₁ containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes Aβ deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of Aβ in the pathogenesis of the disease.     

Personality and neuropsychological function in violent, sexual and arson offenders

We aimed to test the hypothesis that incarcerated offender populations will not differ in neuropsychological test performance if patients are matched on age, intelligence and personality profile, particularly if impulsive aggressive traits and confounds such as substance misuse and performance anxiety are controlled for. 27 violent offenders, 20 sex offenders and 13 arson offenders detained in maximum security hospitals completed dimensional assessments of personality function and were assessed on a battery of frontal and temporal neuropsychological tests. All patients completed a variety of self-report measures of cognitive, affective and behavioural dispositions relevant to offender populations. Trait impulsivity was further assessed and composite impulsivity scores were derived. Assessments of emotional state were administered prior to neuropsychological testing. All patients met the criteria for a DSM-III-R personality disorder diagnosis. There were no significant group differences in age, IQ, or educational attainment. There were no differences in the personality profile of the offender group although sex offenders scored higher on trait anxiety, depression and tension measures. Groups did not significantly differ in their performance on neuropsychological tests apart from poorer perseverative error scores on the Wisconsin Card Sort Test in arsonists, which could not be accounted for by state anxiety or depression scores.     

Acoustic noise and functional magnetic resonance imaging: current strategies and future prospects

Functional magnetic resonance imaging (fMRI) has become the method of choice for studying the neural correlates of cognitive tasks. Nevertheless, the scanner produces acoustic noise during the image acquisition process, which is a problem in the study of auditory pathway and language generally. The scanner acoustic noise not only produces activation in brain regions involved in auditory processing, but also interferes with the stimulus presentation. Several strategies can be used to address this problem, including modifications of hardware and software. Although reduction of the source of the acoustic noise would be ideal, substantial hardware modifications to the current base of installed MRI systems would be required. Therefore, the most common strategy employed to minimize the problem involves software modifications. In this work we consider three main types of acquisitions: compressed, partially silent, and silent. For each implementation, paradigms using block and event-related designs are assessed. We also provide new data, using a silent event-related (SER) design, which demonstrate higher blood oxygen level-dependent (BOLD) response to a simple auditory cue when compared to a conventional image acquisition.