Which health research gets used and why? An empirical analysis of 30 cases

Background: While health research is considered essential for improving health worldwide, it remains unclear how it is best organized to contribute to health. This study examined research that was part of a Ghanaian-Dutch research program that aimed to increase the likelihood that results would be used by funding research that focused on national research priorities and was led by local researchers. The aim of this study was to map the contribution of this research to action and examine which features of research and translation processes were associated with the use of the results. Methods: Using Contribution Mapping, we systematically examined how 30 studies evolved and how results were used to contribute to action. We combined interviews with 113 purposively selected key informants, document analysis and triangulation to map how research and translation processes evolved and contributions to action were realized. After each case was analysed separately, a cross-case analysis was conducted to identify patterns in the association between features of research processes and the use of research. Results: The results of 20 of the 30 studies were used to contribute to action within 12 months. The priority setting and proposal selection process led to the funding of studies which were from the outset closely aligned with health sector priorities. Research was most likely to be used when it was initiated and conducted by people who were in a position to use their results in their own work. The results of 17 out of 18 of these user-initiated studies were translated into action. Other features of research that appeared to contribute to its use were involving potential key users in formulating proposals and developing recommendations. Conclusions: Our study underlines the importance of supporting research that meets locally-expressed needs and that is led by people embedded in the contexts in which results can be used. Supporting the involvement of health sector professionals in the design, conduct and interpretation of research appears to be an especially worthwhile investment

Viral vector-mediated gene transfer of neurotrophins to promote regeneration of the injured spinal cord

Injuries to the adult mammalian spinal cord often lead to severe damage to both ascending (sensory) pathways and descending (motor) nerve pathways without the perspective of complete functional recovery. Future spinal cord repair strategies should comprise a multi-factorial approach addressing several issues, including optimalization of survival and function of spared central nervous system neurons in partial lesions and the modulation of trophic and inhibitory influences to promote and guide axonal regrowth. Neurotrophins have emerged as promising molecules to augment neuroprotection and neuronal regeneration. Although intracerebroventricular, intrathecal and local protein delivery of neurotrophins to the injured spinal cord has resulted in enhanced survival and regeneration of injured neurons, there are a number of drawbacks to these methods. Viral vector-mediated transfer of neurotrophin genes to the injured spinal cord is emerging as a novel and effective strategy to express neurotrophins in the injured nervous system. Ex vivo transfer of neurotrophic factor genes is explored as a way to bridge lesions cavities for axonal regeneration. Several viral vector systems, based on herpes simplex virus, adenovirus, adeno-associated virus, lentivirus, and moloney leukaemia virus, have been employed. The genetic modification of fibroblasts, Schwann cells, olfactory ensheathing glia cells, and stem cells, prior to implantation to the injured spinal cord has resulted in improved cellular nerve guides. So far, neurotrophic factor gene transfer to the injured spinal cord has led to results comparable to those obtained with direct protein delivery, but has a number of advantages. The steady advances that have been made in combining new viral vector systems with a range of promising cellular platforms for ex vivo gene transfer (e.g., primary embryonic neurons, Schwann cells, olfactory ensheating glia cells and neural stem cells) holds promising perspectives for the development of new neurotrophic factor-based therapies to repair the injured nervous system

Profound differences in spontaneous long-term functional recovery after defined spinal tract lesions in the rat

The purpose of this study was to compare spontaneous functional recovery after different spinal motor tract lesions in the rat spinal cord using three methods of analysis, the BBB, the rope test, and the CatWalk. We transected the dorsal corticospinal tract (CSTx) or the rubrospinal tract (RSTx) or the complete dorsal half of the spinal cord (Hx) at thoracic level T8. Functional recovery was monitored for 31 weeks. We found no recovery of consistent inter limb coordination in any experimental group over time using the BBB locomotor rating scale. Quantitative CatWalk analysis revealed significant differences between experimental groups for inter limb coordination (RI). RSTx and Hx animals showed a significant decrease in the RI, and only in the RSTx group did the RI improve from 6 weeks post-lesion onward. Significant differences between experimental groups in step sequence patterns and base of support were also observed. In the rope test all experimental groups had significantly higher error percentages compared to control animals. Tracing of the CST revealed enhanced collateral formation rostral to the lesion in the CSTx group, not in other groups. The results presented here show that locomotor function in all, but CSTx groups gradually improved over time. This is important for studies that employ pharmacological, cell-, and/or gene therapy– based interventions to improve axonal regeneration and functional recovery after spinal cord injury

NT-3 expression from engineered olfactory ensheathing glia promotes spinal sparing and regeneration

Adenoviral (AdV) vectors encoding neurotrophin-3 (AdV-NT-3) or the bacterial marker enzyme beta-galactosidase (LacZ gene) were used to transduce olfactory ensheathing glia (OEG) cultures. AdV vector-transduced OEG expressed high levels of recombinant neurotrophin as shown by in situ hybridization and enzyme-linked immunosorbent assay techniques. The biological activity of vector-derived NT-3 was determined in a dorsal root ganglia neurite outgrowth assay. Engineered cell suspensions were then injected into adult Fischer 344 rat spinal cord immediately after unilateral cervical (C4) corticospinal tract (CST) transection. Transplanted animals received a total of 200 000 cells; either non-transduced OEG or OEG transduced with AdV vectors encoding NT-3 or LacZ, respectively. At 3 months after injury, lesion volumes were significantly smaller in all OEG-transplanted rats when compared with control (medium-injected) rats. Anterograde tracing of the lesioned CST projection, originating from the contralateral sensorimotor cortex, showed a significantly greater number of distal CST axons only in OEG-NT-3-transplanted rats. Behavioural analysis was performed on all rats using open field locomotion scoring, and a forelimb reaching task with Eshkol-Wachman movement notation. Analysis of behavioural tests revealed no significant differences in recovery between experimental groups, although movement analysis indicated that possible compensatory mechanisms were occurring after OEG implantation. The results demonstrate that OEG transplantation per se can promote tissue sparing after injury, but, after appropriate genetic modification, these olfactory-derived cells become far more effective in promoting long-distance maintenance/regeneration of lesioned adult CST axons

The glycoprotein fibulin-3 regulates morphology and motility of olfactory ensheathing cells \u3cem\u3ein vitro\u3c/em\u3e

The primary olfactory pathway in adult mammals has retained a remarkable potential for self-repair. A specialized glial cell within the olfactory nerve, called olfactory ensheathing cell (OEC), and their associated extracellular matrix are thought to play an important role during regenerative events in this system. To gain insight into novel molecules that could mediate the OEC-supported growth of axons within the olfactory nerve, gene expression profiling experiments were conducted which revealed high expression of the glycoprotein fibulin-3 in OECs. This observation was confirmed with quantitative PCR. In vivo, the distribution of all members of the fibulin family, fibulin-3 included, was localized to the lamina propria underneath the olfactory epithelium, in close association within olfactory nerve bundles. To manipulate fibulin-3 gene expression in cultured OECs, lentiviral vector constructs were designed to either transgenically express or knock-down fibulin-3. Experimental data showed that increased levels of fibulin-3 induced profound morphological changes in cultured OECs, impeded with their migratory abilities and also suppressed OEC-mediated neurite outgrowth. Knock-down of fibulin-3 levels resulted in reduced OEC proliferation. In conclusion, the data provide novel insights into a putative role for fibulin-3 in the regulation of cell migration and neurite outgrowth within the primary olfactory pathway

Adeno-associated viral vector-mediated gene transfer of brain-derived neurotrophic factor reverses atrophy of rubrospinal neurons following both acute and chronic spinal cord injury

Rubrospinal neurons (RSNs) undergo marked atrophy after cervical axotomy. This progressive atrophy may impair the regenerative capacity of RSNs in response to repair strategies that are targeted to promote rubrospinal tract regeneration. Here, we investigated whether we could achieve long-term rescue of RSNs from lesion-induced atrophy by adeno-associated viral (AAV) vector-mediated gene transfer of brain-derived neurotrophic factor (BDNF). We show for the first time that AAV vectors can be used for the persistent transduction of highly atrophic neurons in the red nucleus (RN) for up to 18 months after injury. Furthermore, BDNF gene transfer into the RN following spinal axotomy resulted in counteraction of atrophy in both the acute and chronic stage after injury. These novel findings demonstrate that a gene therapeutic approach can be used to reverse atrophy of lesioned CNS neurons for an extended period of time. © 2004 Elsevier Inc. All rights reserved

N-terminal pro-B-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease

In women with congenital heart disease (CHD), cardiovascular complications during pregnancy are common, but the risk assessment of these patients remains difficult. This study sought to determine the independent role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in addition to other parameters in predicting adverse cardiovascular events during pregnancy in women with CHD. We conducted a national, prospective multicentre cohort study. Follow-up with clinical evaluation and echocardiography and NT-proBNP measurement was performed at 20-week gestation. Adverse cardiovascular events occurred in 10.3% of 213 pregnancies. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20-week gestation, the presence of a mechanical valve, and subpulmonary ventricular dysfunction before conception were independently associated with events [odds ratio (OR) 10.6 (P = 0.039), OR 12.0 (P = 0.016), and OR 4.2 (P = 0.041), respectively]. The negative predictive value of NT-proBNP levels <128 pg/mL was 96.9%. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20 weeks of gestation had an additional value in predicting the occurrence of adverse cardiovascular events on the top of the other identified predictors (area under the curve 0.90 vs. 0.78, P = 0.035). Increased NT-proBNP levels at 20 weeks of gestation are an independent risk predictor of cardiovascular events during pregnancy in women with CH

Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor.

Following avulsion of a spinal ventral root, motoneurons that project through the avulsed root are axotomized. Avulsion between, for example, L2 and L6 leads to denervation of hind limb muscles. Reimplantation of an avulsed root directed to the motoneuron pool resulted in re-ingrowth of some motor axons. However, most motoneurons display retrograde atrophy and subsequently die. Two neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), promote the survival of motoneurons after injury. The long-term delivery of these neurotrophic factors to the motoneurons in the ventral horn of the spinal cord is problematic. One strategy to improve the outcome of the neurosurgical reinsertion of the ventral root following avulsion would involve gene transfer with adeno-associated viral (AAV) vectors encoding these neurotrophic factors near the denervated motoneuron pool. Here, we show that AAV-mediated overexpression of GDNF and BDNF in the spinal cord persisted for at least 16 weeks. At both 1 and 4 months post-lesion AAV-BDNF- and -GDNF-treated animals showed an increased survival of motoneurons, the effect being more prominent at 1 month. AAV vector-mediated overexpression of neurotrophins also promoted the formation of a network of motoneuron fibers in the ventral horn at the avulsed side, but motoneurons failed to extent axons into the reinserted L4 root towards the sciatic nerve nor to improve functional recovery of the hind limbs. This suggests that high levels of neurotrophic factors in the ventral horn promote sprouting, but prevent directional growth of axons of a higher number of surviving motoneurons into the implanted root.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe