Development of a glial cell-derived neurotrophic factor-releasing artificial dura for neural tissue engineering applications.

Encapsulated electrospun nanofibers can serve as an artificial dura mater, the membrane that surrounds the brain and spinal cord, due to their desirable drug delivery properties. Such nanofiber scaffolds can be used to deliver drugs such as glial cell-derived neurotrophic factor (GDNF). GDNF promotes the survival of both dopaminergic and motor neurons, making it an important target for treatment of central nervous system injuries and disorders. This work focuses on designing a novel class of encapsulated poly(ε-caprolactone) (PCL) nanofiber scaffolds with different topographies (random and aligned) that generate controlled release of GDNF to potentially serve as a suitable substitute for the dura mater during neurosurgical procedures. Random and aligned scaffolds fabricated using solution electrospinning were characterized for their physical properties and their ability to release GDNF over one month. GDNF bioactivity was confirmed using a PC12 cell assay with the highest concentrations of released GDNF (∼341 ng mL-1 GDNF) inducing the highest levels of neurite extension (∼556 µm). To test the cytocompatibility of aligned GDNF encapsulated PCL nanofibers, we successfully seeded neural progenitors derived from human induced pluripotent stem cells (hiPSCs) onto the scaffolds where they survived and differentiated into neurons. Overall, this research demonstrates the potential of such substrates to act as artificial dura while delivering bioactive GDNF in a controlled fashion. These scaffolds also support the culture and differentiation of hiPSC-derived neural progenitors, suggesting their biocompatibility with the cells of the central nervous system.

Prospective development and validation of a model to predict heart failure hospitalisation.

OBJECTIVE: Acute heart failure syndrome (AHFS) is a major cause of hospitalisation and imparts a substantial burden on patients and healthcare systems. Tools to define risk of AHFS hospitalisation are lacking. METHODS: A prospective cohort study (n=628) of patients with stable chronic heart failure (CHF) secondary to left ventricular systolic dysfunction was used to derive an AHFS prediction model which was then assessed in a prospectively recruited validation cohort (n=462). RESULTS: Within the derivation cohort, 44 (7%) patients were hospitalised as a result of AHFS during 1 year of follow-up. Predictors of AHFS hospitalisation included furosemide equivalent dose, the presence of type 2 diabetes mellitus, AHFS hospitalisation within the previous year and pulmonary congestion on chest radiograph, all assessed at baseline. A multivariable model containing these four variables exhibited good calibration (Hosmer-Lemeshow p=0.38) and discrimination (C-statistic 0.77; 95% CI 0.71 to 0.84). Using a 2.5% risk cut-off for predicted AHFS, the model defined 38.5% of patients as low risk, with negative predictive value of 99.1%; this low risk cohort exhibited <1% excess all-cause mortality per annum when compared with contemporaneous actuarial data. Within the validation cohort, an identically applied model derived comparable performance parameters (C-statistic 0.81 (95% CI 0.74 to 0.87), Hosmer-Lemeshow p=0.15, negative predictive value 100%). CONCLUSIONS: A prospectively derived and validated model using simply obtained clinical data can identify patients with CHF at low risk of hospitalisation due to AHFS in the year following assessment. This may guide the design of future strategies allocating resources to the management of CHF.

Cell-specific insulin resistance: implications for atherosclerosis.

Insulin resistance is increasingly acknowledged as an independent risk factor for cardiovascular disease. Despite this, our understanding of the cellular and molecular mechanisms that might account for this relationship remain incompletely understood. A key challenge has been in distinguishing between a 'whole-body' milieu of inflammation and oxidative stress from the ramifications of cell-specific resistance to insulin. Transgenic models have now begun to explore the cellular influences of insulin resistance on vascular biology, with novel implications for atherosclerosis across a range of cells including endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, macrophages and fibroblasts. Emerging data from these models have also begun to challenge conventional dogma. In particular, the findings across various cell types are disparate with some even implying a protective influence on vascular biology. We now review these data, highlighting recent advances in our understanding of cellular resistance to insulin as well as those areas where there remains a paucity of data.

Is it possible to identify a population in which the incidence of future development of AIS is greatly increased when compared to the normal population?

For future research of predictors of AIS, it would be advantageous to identify a general population in which the development of AIS is greatly increased when compared to the normal population. The probability of predicting future development of AIS among younger relatives of current patients based on the probability of AIS incidence was assessed from the research literature. Although there is considerable literature relating to familial relationships of the probability of developing AIS or having AIS, the probability is relatively low in most cases. Even with the best of predicted probabilities, the identification of patients with a high probability of developing AIS remained low. The identification of people among the general population who have a high probability of developing AIS based on the probabilities expressed in the literature is not possible.

Use of blood donation history of people with HIV infection to identify recipients at risk.

OBJECTIVE: To determine whether previous blood donations from HIV-positive patients posed a threat to recipients. DESIGN: Interviewer-administered questionnaire survey. SETTING: Regional HIV outpatient referral clinic for southern Alberta. PATIENTS: All 478 patients attending the clinic from May 1, 1993, to Mar. 31, 1994; 366 were excluded: 335 had not donated blood, and 31 could not provide reliable information regarding possible donations. INTERVENTIONS: Patients were asked at a routine clinic visit regarding the dates, frequency and location of previous blood donations. The Canadian Red Cross was informed, with patient consent, if the previous donations posed a potential risk of HIV transmission. OUTCOME MEASURES: Number of HIV-positive patients whose donations posed a possible or definite risk to recipients. RESULTS: A total of 545 units of blood had been donated by the 112 patients in the study; 57 units (donated by 29 patients) posed a possible risk, and 12 (given by 11 patients) posed a definite risk of HIV transmission to the recipients. Thirty-two of these donors had been unknown to the Red Cross through its "look-back" and "trace-back" protocols. Only 1 of the 13 patients found to be HIV positive by the Red Cross openly admitted donating blood to undergo HIV antibody testing; the remainder were either ill-informed or did not perceive themselves to be at risk. The patients were highly mobile, 36.7% donating blood at some time in a province other than the one where they had received their positive HIV test result. CONCLUSION: Asking HIV-positive patients about their blood donation history, although subject to recall bias, is a simple and inexpensive method for identifying high-risk blood donations. The Red Cross should routinely be notified, with patient consent, of all donations posing a risk in order to enhance the prospect for identifying HIV-positive blood recipients.