Promising Strategy (promising + strategy)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Balancing Intermolecular and Molecule,Substrate Interactions in Supramolecular Assemblies

Dimas G. de Oteyza
Abstract Self-assembly of functional supra-molecular nanostructures is among the most promising strategies for further development of organic electronics. However, a poor control of the interactions driving the assembling phenomena still hampers the tailored growth of designed structures. Here exploration of how non-covalent molecule-substrate interactions can be modified on a molecular level is described. For that, mixtures of DIP and F16CuPc, two molecules with donor and acceptor character, respectively are investigated. A detailed study of their structural and electronic properties is performed. In reference to the associated single-component layers, the growth of binary layers results in films with strongly enhanced intermolecular interactions and consequently reduced molecule-substrate interactions. This new insight into the interplay among the aforementioned interactions provides a novel strategy to balance the critical interactions in the assembly processes by the appropriate choice of molecular species in binary supra-molecular assemblies, and thereby control the self-assembly of functional organic nanostructures. [source]

The Endocannabinoid System and the Control of Glucose Homeostasis

R. Nogueiras
Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. The first selective CB1 receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity. [source]

To prosper, organizational psychology should, bridge application and scholarship,

Wayne F. Cascio
Academics and practitioners differ on so many dimensions that researchers have described them as living in different "thought worlds." That gap persists, and there are important explanations for it, but a confluence of economic and organizational forces is driving academics and practitioners toward each other. To date, much of the effort by academics to reach out to practitioners has focused on the diffusion of scientific knowledge, not its creation. This paper explores several promising strategies for improving both the bidirectional diffusion of knowledge as well as its creation. It argues that for genuine change to occur, it is necessary to modify academic reward systems and to promote much closer collaboration between academics and practitioners. Copyright © 2008 John Wiley & Sons, Ltd. [source]

"I Am Not Alone": The Feasibility and Acceptability of Interactive Voice Response-Facilitated Telephone Peer Support Among Older Adults With Heart Failure

Michele Heisler MD
Patient self-management is a critical determinant of heart failure (HF) outcomes, yet patients with HF are often frail and socially isolated, factors that may limit their ability to manage self-care and access clinic-based services. Mobilizing peer support among HF patients is a promising strategy to improve self-management support. In this pilot, the authors evaluated the feasibility and acceptability of an interactive voice response (IVR)-based platform to facilitate telephone peer support among older adults with HF. Participants completed a baseline survey, were offered a 3-hour training session in peer communication skills, and were paired with another patient who had HF. Participants were asked to contact their partner weekly using a toll-free IVR phone system that protected their anonymity and provided automated reminders if contacts were not made. Times and duration of participants' telephone contacts were monitored and recorded. After the 7-week intervention, participants completed surveys and brief face-to-face interviews. The authors found high levels of use and satisfaction and improvements in depressive symptoms among the 20 pilot study participants. An IVR peer-support intervention is feasible, is acceptable to patients, and may have positive effects on patients' HF social support and health outcomes, in conjunction with structured health system support, that warrant more rigorous evaluation in a randomized trial. [source]

Effect of muscle activity and botulinum toxin dilution volume on muscle paralysis

Hyeon Sook Kim MD PhD
The purpose of this study was to evaluate the effects of botulinum toxin A (BTX-A, Botox) dilution volume and post-injection exercise with electrical stimulation on muscle paralysis. We injected 10 units of BTX-A diluted with 0.1 ml (B1, n=8) or 0.5 ml (B5, n=8) normal saline into both gastrocnemius muscles of 16 New Zealand white rabbits; two controls received no BTX-A. After BTX-A injection, all rabbits received calf muscle stretching exercise and electrical stimulation for 2 hours on the left leg. The compound muscle action potential (CMAP) decrease was most pronounced at 1 week and progressive recovery was observed (i.e. recovery from paralysis, increase of CMAP). There was a significant decrease of CMAP amplitudes in the B5 group compared with the B1 group at week 1 and week 4 (p<0.001). Left limbs with stretching exercise and electrical stimulation showed lower CMAP amplitudes compared with control right limbs of all rabbits. To maximize the muscle paralysis effect of BTX-A, increasing dilution volume and performing post-injection stretching exercise with electrical stimulation may be a promising strategy for increasing the beneficial effect of BTX-A treatment. Future studies are needed to investigate the clinical application of this finding. [source]

Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy

Yumiko Yoshida
Abstract Background Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. We investigated here whether and how PEDF could prevent the development of diabetic retinopathy. Methods Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Early neuronal derangements were evaluated by electroretinogram (ERG) and immunofluorescent staining of glial fibrillary acidic protein (GFAP). Expression of PEDF and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was localized by immunofluorescence. Vascular endothelial growth factor (VEGF) and p22phox expression were evaluated with western blots. Breakdown of blood retinal barrier (BRB) was quantified with fluorescein isothiocynate (FITC)-conjugated dextran. NADPH oxidase activity was measured with lucigenin luminescence. Results Retinal PEDF levels were reduced, and amplitudes of a- and b-wave in the ERG were decreased in diabetic rats, which were in parallel with GFAP overexpression in the Müller cells. Further, retinal 8-OHdG, p22phox and VEGF levels and NADPH oxidase activity were increased, and BRB was broken in diabetic rats. Administration of PEDF ameliorated all of the characteristic changes in early diabetic retinopathy. Conclusions Results suggest that PEDF could prevent neuronal derangements and vascular hyperpermeability in early diabetic retinopathy via inhibition of NADPH oxidase-driven oxidative stress generation. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Early detection and intervention in first-episode schizophrenia: a critical review

T. K. Larsen
Objective: To review the literature on early intervention in psychosis and to evaluate relevant studies. Method: Early intervention was defined as intervention in the prodromal phase (primary prevention) and intervention after the onset of psychosis, i.e. shortening of duration of untreated psychosis (DUP) (secondary prevention). Results: We found few studies aimed at early intervention, but many papers discussing the idea at a more general level. We identified no studies that prove that intervention in the prodromal phase is possible without a high risk for treating false positives. We identified some studies aimed at reducing DUP, but the results are ambiguous and, until now, no follow-up data showing a positive effect on prognosis have been presented. Conclusion: Early intervention in psychosis is a difficult and important challenge for the psychiatric health services. At the time being reduction of DUP seems to be the most promising strategy. Intervention in the prodromal phase is more ethically and conceptually problematic. [source]

Delivery of bioactive, gel-isolated proteins into live cells

Jennifer E. Taylor
Abstract The delivery of proteins into live cells is a promising strategy for the targeted modulation of protein-protein interactions and the manipulation of specific cellular functions. Cellular delivery can be facilitated by complexing the protein of interest with carrier molecules. Recently, an amphipatic peptide was identified, Pep-1 (KETWWETWWTE WSQPKKKRKV), which crosses the plasma membrane of many cell types to carry and deliver proteins as large as antibodies. Pep-1 effectively delivers proteins in solution; but Pep-1 is not suitable for delivering sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) isolated proteins because Pep-1 complexes with cargo proteins are destroyed by SDS. Here, we report cellular delivery of SDS-PAGE-isolated proteins, without causing cellular damage, by using a nonionic detergent, Triton X-100, as carrier. To determine the specificity of our method, we separated antibodies against different intracellular targets by nonreducing SDS-PAGE. Following electrophoresis, the antibody bands were detected by zinc-imidazole reverse staining, excised, in-gel refolded with Triton X-100, and eluted in detergent-free phosphate-buffered saline. When overlaid on cultured NIH 3T3 cells, the antibodies penetrated the cells localizing to their corresponding intracellular targets. These results are proof-of-principle for the delivery of gel-isolated bioactive proteins into cultured cells and suggest new ways for experimental protein therapy and for studying protein-protein interactions using gel-isolated protein. [source]

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Petra Hoffmann
Abstract The adoptive transfer of CD4+CD25+ natural regulatory T cells (Treg) is a promising strategy for the treatment of autoimmune diseases and the prevention of alloresponses after transplantation. Clinical trials exploring this strategy require efficient in vitro expansion of this rare cell population. Protocols developed thus far rely on high-grade purification of Treg prior to culture initiation, a process still hampered by the lack of Treg cell-specific surface markers. Depletion of CD127+ cells was shown to separate activated conventional T cells from natural Treg cell populations allowing the isolation of highly enriched FOXP3+ cells with all functional and molecular characteristics of natural Treg. Here, we demonstrate that upon in vitro expansion, CpG methylation in a conserved region within the FOXP3 gene locus increased in CD4+CD25+CD127low Treg, correlating with loss of FOXP3 expression and emergence of pro-inflammatory cytokines. Further analysis identified CD45RA,FOXP3+ memory-type Treg as the main source of converting cells, whereas CD45RA+FOXP3+ Treg from the same donors showed no conversion within 3,wk of in vitro expansion. Thus, Treg cell lineage differentiation does not seem to represent a final fate decision, as natural Treg can lose their cell-type-specific characteristics after repetitive TCR stimulation. [source]

A recombinant bispecific single-chain antibody induces targeted, supra-agonistic CD28-stimulation and tumor cell killing

Ludger Grosse-Hovest
Abstract Endowing tumor cells with costimulatory signals for T cell activation has emerged as a promising strategy for tumor immunotherapy. Costimulatory molecules were either transfected into tumor cells to generate vaccines or were fused, e.g. to antibodies against tumor-associated antigens, to achieve targeted T cell costimulation in vivo. Here we report the production and purification of rM28, a recombinant bispecific single-chain antibody directed to a melanoma-associated proteoglycan and to the costimulatory CD28 molecule on human T cells. We found that a dimer of the recombinant molecule, bound to tumor target cells, induced pronounced T cell activation in peripheral blood mononuclear cell preparations without additional TCR/CD3 stimulation being required. Thelytic activity generated after 3,days of stimulation effectively prevented tumor cell growth. However, it was unspecific and predominantly mediated by non T cells. Our findings demonstrate that presentation of a CD28 antibody within a suitable recombinant, bispecific format may result in a "targeted supra-agonistic stimulation" of the CD28 molecule, which leads to effective tumor cell killing after induction of unspecifically lytic cells. [source]

Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia

GLIA, Issue 9 2010
Lijun Xu
Abstract Brief forebrain ischemia is a model of the delayed hippocampal neuronal loss seen in patients following cardiac arrest and resuscitation. Previous studies demonstrated that selective dysfunction of hippocampal CA1 subregion astrocytes occurs hours to days before delayed neuronal death. In this study we tested the strategy of directing protection to astrocytes to protect neighboring neurons from forebrain ischemia. Two well-studied protective proteins, heat shock protein 72 (Hsp72) or superoxide dismutase 2 (SOD2), were genetically targeted for expression in astrocytes using the astrocyte-specific human glial fibrillary acidic protein (GFAP) promoter. The expression constructs were injected stereotacticly immediately above the hippocampal CA1 region on one side of the rat brain two days prior to forebrain ischemia. Cell type specific expression was confirmed by double label immunohistochemistry. When the expression constructs were injected two days before transient forebrain ischemia, the loss of CA1 hippocampal neurons observed seven days later was significantly reduced on the injected side compared with controls. This neuroprotection was associated with significantly better preservation of astrocyte glutamate transporter-1 immunoreactivity at 5-h reperfusion and reduced oxidative stress. Improving the resistance of astrocytes to ischemic stress by targeting either the cytosolic or mitochondrial compartment was thus associated with preservation of CA1 neurons following forebrain ischemia. Targeting astrocytes is a promising strategy for neuronal preservation following cardiac arrest and resuscitation. © 2010 Wiley-Liss, Inc. [source]

NMR Conformational Analysis and Theoretical Calculations for 2-Aryl- 1,3-dihydroxy-4,4,5,5-tetramethylimidazolidines

Conformational studies of 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(pyridin-1-yl)imidazolidine (1a) and 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(pyridin-3-yl)imidazolidine (1b), carried out by using 1D 1H- and 13C-NMR and 2D HMQC, HMBC, and NOESY experiments and with the aid of theoretical calculations, indicate that the OH groups are trans to the pyridinyl substituent. Because the two 1H-NMR signals of the Me groups are distinguishable and do not change between 290 and 380,K, it is proposed that 1a and 1b have each only one conformation in this temperature range. This behavior was not found with 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(pyridin-2-yl)imidazolidine (1c) because its Me 1H-NMR signals cross over at 300,K. Hence, more than one conformation must be present, beyond those produced by simple inversions. Theoretical calculations including temperature and solvent effects were performed to provide further information on the conformational analysis and to help to assign the NMR data. The combination of NMR measurements and quantum-chemical calculations is shown to be a very promising strategy for conformational analysis studies in solution. [source]

Delivery of Nucleic Acids via Disulfide-Based Carrier Systems

ADVANCED MATERIALS, Issue 32-33 2009
Sonja Bauhuber
Abstract Nucleic acids are not only expected to assume a pivotal position as "drugs" in the treatment of genetic and acquired diseases, but could also act as molecular cues to control the microenvironment during tissue regeneration. Despite this promise, the efficient delivery of nucleic acids to their side of action is still the major hurdle. One among many prerequisites for a successful carrier system for nucleic acids is high stability in the extracellular environment, accompanied by an efficient release of the cargo in the intracellular compartment. A promising strategy to create such an interactive delivery system is to exploit the redox gradient between the extra- and intracellular compartments. In this review, emphasis is placed on the biological rationale for the synthesis of redox sensitive, disulfide-based carrier systems, as well as the extra- and intracellular processing of macromolecules containing disulfide bonds. Moreover, the basic synthetic approaches for introducing disulfide bonds into carrier molecules, together with examples that demonstrate the benefit of disulfides at the individual stages of nucleic acid delivery, will be presented. [source]

Targeted therapy of renal cell carcinoma: Synergistic activity of cG250-TNF and IFNg

Stefan Bauer
Abstract Immunotherapeutic targeting of G250/Carbonic anhydrase IX (CA-IX) represents a promising strategy for treatment of renal cell carcinoma (RCC). The well characterized human-mouse chimeric G250 (cG250) antibody has been shown in human studies to specifically enrich in CA-IX positive tumors and was chosen as a carrier for site specific delivery of TNF in form of our IgG-TNF-fusion protein (cG250-TNF) to RCC xenografts. Genetically engineered TNF constructs were designed as CH2/CH3 truncated cG250-TNF fusion proteins and eucariotic expression was optimized under serum-free conditions. In-vitro characterization of cG250-TNF comprised biochemical analysis and bioactivity assays, alone and in combination with Interferon-, (IFN,). Biodistribution data on radiolabeled [125J] cG250-TNF and antitumor activity of cG250-TNF, alone and in combination with IFN,, were measured on RCC xenografts in BALB/c nu/nu mice. Combined administration of cG250-TNF and IFN, caused synergistic biological effects that represent key mechanisms displaying antitumor responses. Biodistribution studies demonstrated specific accumulation and retention of cG250-TNF at CA-IX-positive RCC resulting in growth inhibition of RCC and improved progression free survival and overall survival. Antitumor activity induced by targeted TNF-based constructs could be enhanced by coadministration of low doses of nontargeted IFN, without significant increase in side effects. Administration of cG250-TNF and IFN, resulted in significant synergistic tumoricidal activity. Considering the poor outcome of renal cancer patients with advanced disease, cG250-TNF-based immunotherapeutic approaches warrant clinical evaluation. © 2009 UICC [source]

Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model

Eunyoung Chun
Abstract Inhibition of angiogenesis is emerging as a promising strategy for the treatment of cancer. In our study reported here, the effects of 4 highly potent methionine aminopeptidase 2 (MetAP2) inhibitors, IDR-803, IDR-804, IDR-805 and CKD-732 (designed by structure-based molecular modeling), on angiogenesis and tumor growth were assessed. Concentrations of these inhibitors as low as 2.5 nM were able to inhibit the growth of human umbilical vein endothelial cells (HUVEC) by as much as 50%, arresting growth in the G1 stage of mitosis. An intracellular accumulation of p21WAF1/Cip1 protein was also observed. Furthermore, at higher concentrations (25 nM) of these 4 MetAP2 inhibitors, a significant induction of apoptosis was apparent in the same HUVEC cultures. As a result of these findings, the possible anticancer effects of these inhibitors were examined, utilizing the SNU-398 hepatoma cell line. Interestingly, pretreatment with these inhibitors led to an increased number of apoptotic cells of up to 60% or more, compared to untreated controls. Moreover, utilizing an in vivo xenografted murine model, these inhibitors suppressed the growth of engrafted tumor. In conclusion, these 4 inhibitory compounds potently exert an antiangiogenic effect to inhibit the growth of cancers in vivo and could potentially be useful for the treatment of a variety of cancers. © 2004 Wiley-Liss, Inc. [source]

Doctors' assistants' views of case management to improve chronic heart failure care in general practice: a qualitative study

Rebecca Olbort
Abstract Title.,Doctors' assistants' views of case management to improve chronic heart failure care in general practice: a qualitative study. Aim., This paper is a report of a study to explore the views, concerns and experiences of doctors' assistants of case management for patients with chronic heart failure, while experiencing the new role of being a case manager within the Heidelberg Integrated Case Management trial. Background., Case management is being investigated as part of a randomised controlled trial aiming to improve care for patients with chronic systolic heart failure. In a complex, multifaceted intervention, trained doctors' assistants (equivalent to a nursing role) adopted new tasks using standardised case management involving telephone monitoring, home visits and diagnostic screening. Method., In April 2007, 3 months after implementation of the intervention programme, 27 doctors' assistants participated in four focus group interviews discussing their views on, and experiences of, case management. Thematic analysis of the data was undertaken. Findings., Participants believed that the most positive factors in case management were about interaction with patients, including opportunities for identifying disease and psychosocial problems. However, barriers included lack of time allocated to perform case management in addition to their normal role and poor cooperation within the practice team. According to the doctors' assistants, the routine implementation of case management was acceptable, feasible and effective in improving the management of patients with chronic systolic heart failure. Conclusion., Case management enhanced the role of doctors' assistants, leading to increased awareness of the perspective of patients with chronic disease. In the wider international primary care practice nursing context, the orchestrated delegation of tasks using specific case management may be a promising strategy for improving the quality of care of chronically ill patients and enabling patient self-management. [source]

Healthcare Cost Differences with Participation in a Community-Based Group Physical Activity Benefit for Medicare Managed Care Health Plan Members

Ronald T. Ackermann MD
OBJECTIVES: To determine whether participation in a physical activity benefit by Medicare managed care enrollees is associated with lower healthcare utilization and costs. DESIGN: Retrospective cohort study. SETTING: Medicare managed care. PARTICIPANTS: A cohort of 1,188 older adult health maintenance organization enrollees who participated at least once in the EnhanceFitness (EF) physical activity benefit and a matched group of enrollees who never used the program. MEASUREMENTS: Healthcare costs and utilization were estimated. Ordinary least squares regression was used, adjusting for demographics, comorbidity, indicators of preventive service use, and baseline utilization or cost. Robustness of findings was tested in sensitivity analyses involving continuous propensity score adjustment and generalized linear models with nonconstant variance assumptions. RESULTS: EF participants had similar total healthcare costs during Year 1 of the program, but during Year 2, adjusted total costs were $1,186 lower (P=.005) than for non-EF users. Differences were partially attributable to lower inpatient costs (,$3,384; P=.02), which did not result from high-cost outliers. Enrollees who attended EF an average of one visit or more per week had lower adjusted total healthcare costs in Year 1 (,$1,929; P<.001) and Year 2 (,$1,784; P<.001) than nonusers. CONCLUSION: Health plan coverage of a preventive physical activity benefit for seniors is a promising strategy to avoid significant healthcare costs in the short term. [source]

Mesenchymal stem cell interaction with a non-woven hyaluronan-based scaffold suitable for tissue repair

G. Pasquinelli
Summary The fabrication of biodegradable 3-D scaffolds enriched with multipotent stem cells seems to be a promising strategy for the repair of irreversibly injured tissues. The fine mechanisms of the interaction of rat mesenchymal stem cells (rMSCs) with a hyaluronan-based scaffold, i.e. HYAFF®11, were investigated to evaluate the potential clinical application of this kind of engineered construct. rMSCs were seeded (2 × 106 cells cm,2) on the scaffold, cultured up to 21 days and analysed using appropriate techniques. Light (LM), scanning (SEM) and transmission (TEM) electron microscopy of untreated scaffold samples showed that scaffolds have a highly porous structure and are composed of 15-µm-thick microfibres having a rough surface. As detected by trypan blue stain, cell adhesion was high at day 1. rMSCs were viable up to 14 days as shown by CFDA assay and proliferated steadily on the scaffold as revealed by MTT assay. LM showed rMSCs in the innermost portions of the scaffold at day 3. SEM revealed a subconfluent cell monolayer covering 40 ± 10% of the scaffold surface at day 21. TEM of early culture showed rMSCs wrapping individual fibres with regularly spaced focal contacts, whereas confocal microscopy showed polarized expression of CD44 hyaluronan receptor; TEM of 14-day cultures evidenced fibronexus formation. Immunohistochemistry of 21-day cultures showed that fibronectin was the main matrix protein secreted in the extracellular space; decorin and versican were seen in the cell cytoplasm only and type IV collagen was minimally expressed. The expression of CD90, a marker of mesenchymal stemness, was found unaffected at the end of cell culture. Our results show that HYAFF®11 scaffolds support the adhesion, migration and proliferation of rMSCs, as well as the synthesis and delivery of extracellular matrix components under static culture conditions without any chemical induction. The high retention rate and viability of the seeded cells as well as their fine modality of interaction with the substrate suggest that such scaffolds could be potentially useful when wide tissue defects are to be repaired as in the case of cartilage repair, wound healing and large vessel replacement. [source]

Mesencephalic human neural progenitor cells transplanted into the neonatal hemiparkinsonian rat striatum differentiate into neurons and improve motor behaviour

Marine Hovakimyan
Abstract Neural stem cell transplantation is a promising strategy for the treatment of neurodegenerative diseases. To evaluate the differentiation potential of human neural progenitor cells (hNPCs) as a prerequisite for clinical trials, we intracerebrally transplanted in vitro expanded fetal mesencephalic hNPCs into hemiparkinsonian rats. On postnatal day one (P1), 17 animals underwent a unilateral intraventricular 6-hydroxydopamine injection into the right lateral ventricle. At P3, animals (n = 10) received about 100 000 hNPCs (1 µL) in the right striatum. Five weeks after birth, animals underwent behaviour tests prior to fixation, followed by immunohistochemistry on brain slices for human nuclei, glial fibrillary acidic protein, S100,, neuronal nuclei antigen, neuron-specific enolase and tyrosine hydroxylase. Compared with the apomorphine-induced rotations in the lesioned-only group (7.4 ± 0.5 min,1), lesioned and successfully transplanted animals (0.3 ± 0.1 min,1) showed a significant therapeutic improvement. Additionally, in the cylinder test, the lesioned-only animals preferred to use the ipsilateral forepaw. Conversely, the lesioned and transplanted animals showed no significant side bias similar to untreated control animals. Transplanted human nuclei-immunoreactive cells were found to survive and migrate up to 2000 µm into the host parenchyma, many containing the pan-neuronal markers neuronal nuclei antigen and neuron-specific enolase. In the striatum, tyrosine hydroxylase-immunoreactive somata were also found, indicating a dopaminergic differentiation capacity of transplanted hNPCs in vivo. However, the relative number of tyrosine hydroxylase-immunoreactive neurons in vivo seemed to be lower than in corresponding in vitro differentiation. To minimize donor tissue necessary for transplantation, further investigations will aim to enhance dopaminergic differentiation of transplanted cells in vivo. [source]

Effect of the antimicrobial peptide indolicidin on the green peach aphid Myzus persicae (Sulzer)

R. R. Le-Feuvre
Abstract:, The green-peach aphid, Myzus persicae (Sulzer) (Hem., Aphididae), is a major agricultural pest of a wide range of host plants, causing damage by feeding and indirectly by transmitting viruses. In this study we tested the effect of the antimicrobial peptide indolicidin on M. persicae survival and on its essential bacterial endosymbionts. Artificial diet bioassays showed a significant dose-dependent lethal response of indolicidin on M. persicae survival (LD50 of 209 ± 60 ,g/ml). Histological analysis of indolicidin-treated aphids revealed a lower number of distorted mycetocytes, whereas control aphids showed abundant number of rounded and filled mycetocytes. These results suggest that aphid survival could be affected via reduction of its endosymbionts. Thus, aphid control based on antimicrobial substances against endosymbionts could be a promising strategy that needs to be further explored. [source]

Overexpression of malignancy-associated laminins and laminin receptors by angiotropic human melanoma cells in a chick chorioallantoic membrane model

Claire Lugassy
Background: As distinct from intravascular/lymphatic dissemination, extravascular migratory metastasis (EVMM) has been described as a potential additional mechanism of melanoma spread in which tumor cells migrate along the external surfaces of vessels. Angiotropic melanoma cells are linked to the endothelium by a matrix containing laminin. In addition, it has been shown that C16 laminin-derived peptide increases extravascular migration of human green fluorescent protein (GFP) melanoma cells along vessels in a chicken chorioallantoic membrane model (CAM). In this study, we have tested the hypothesis that expression levels of some genes related to lamimin and metastasis are differentially expressed in vascularized angiotropic melanoma areas vs. avascular melanoma areas from the same tumor. Design: C8161 human melanoma cells in a shell-less chick CAM assay were used to study EVMM associated with the presence of vascularized angiotropic melanoma areas. For both high-quality histomorphology and RNA preservation in paraffin-embedded tissue, we used a methanol-based fixative coupled with microwave-assisted rapid tissue processing as previously described. Using laser capture microdissection, angiotropic melanoma areas as well as avascular areas were microdissected. Using quantitative real time polymerase chain reaction (QRT-PCR), six genes have been studied: LAMC2 (laminin ,2 chain), LAMA4 (laminin ,4 chain), ITGB1 (integrin ,1), ITGB3 (integrin ,3), RSPA (ribosomal protein), and MMP2 (matrix metallopeptidase 2). QRT-PCR data were normalized to human GAPDH housekeeping gene and values were compared against Human Total RNA. Final results were expressed as percentage of expression. Results: All tumors demonstrated a similar pattern, i.e. EVMM of angiotropic melanoma cells. The microdissected histopathological sections presented both angiotropic areas and avascular areas. All genes were overexpressed in angiotropic melanoma areas vs. avascular melanoma areas, especially LAMC2, LAMA4 and ITGB3 (respectively, 165.18, 208.86, and 483.69%). Conclusion: This study shows that several genes related to laminin are overexpressed in angiotropic melanoma areas vs. avascular melanoma areas. Since extravascular migration of melanoma cells along vessels has been demonstrated in the CAM model, taken together these results suggests that some laminins and laminin receptors may play a role in extravascular migratory metastasis. This model may represent a promising strategy to analyze differential gene expression in EVMM. [source]

Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection

AGING CELL, Issue 2 2010
Ehud Cohen
Summary Toxic protein aggregation (proteotoxicity) is a unifying feature in the development of late-onset human neurodegenerative disorders. Reduction of insulin/IGF-1 signaling (IIS), a prominent lifespan, developmental and reproductive regulatory pathway, protects worms from proteotoxicity associated with the aggregation of the Alzheimer's disease-linked A, peptide. We utilized transgenic nematodes that express human A, and found that late life IIS reduction efficiently protects from A, toxicity without affecting development, reproduction or lifespan. To alleviate proteotoxic stress in the animal, the IIS requires heat shock factor (HSF)-1 to modulate a protein disaggregase, while DAF-16 regulates a presumptive active aggregase, raising the question of how these opposing activities could be co-regulated. One possibility is that HSF-1 and DAF-16 have distinct temporal requirements for protection from proteotoxicity. Using a conditional RNAi approach, we found an early requirement for HSF-1 that is distinct from the adult functions of DAF-16 for protection from proteotoxicity. Our data also indicate that late life IIS reduction can protect from proteotoxicity when it can no longer promote longevity, strengthening the prospect that IIS reduction might be a promising strategy for the treatment of neurodegenerative disorders caused by proteotoxicity. [source]

Using quality report cards for reshaping dentist practice patterns: a pre-play communication approach

Chinho Lin PhD
Abstract Rationale, aims and objectives, Understanding how information disclosure influences dentists' patterns of practice change is important in developing quality-improvement policies and cost containment. Thus, using quality report cards is a promising strategy for investigating whether dentists will reshape their patterns of practice because of the influence of peer comparison. Methods, Based on the coordination game, a data warehouse decision support system (DWDSS) was used as a pre-play communication instrument, along with the disclosure of quality report cards, which allow dentists to search their own service rates of dental restoration and restoration replacement as well as compare those results with others. Results and conclusions, The group using the DWDSS had a greater decrease in two indicators (i.e. service rates of dental restoration and restoration replacement) than the dentists who did not use it, which implies that the DWDSS is a useful facility for helping dentists filter and evaluate information for establishing the maximum utility in their practice management. The disclosure of information makes significant contributions to solving managerial problems associated with dentists' deviation of practice patterns. [source]

Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis

Takanori Kanai
Abstract Background:, Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-, (TNF-,) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis. Methods:, The effects were evaluated of saporin-conjugated anti-CD11b monoclonal antibody (mAb) on the development of chronic colitis in severe combined immunodeficiency (SCID) mice induced by adoptive transfer of CD4+CD45RBhigh T cells as an animal model of CD. Results:, Significantly increased CD11b-expressing macrophages as well as CD4+ T cells were found in inflamed colon from colitic mice. Administration of saporin-conjugated anti-CD11b mAb markedly ameliorated the clinical and histopathological disease. In vivo treatment with saporin-conjugated anti-CD11b mAb decreased CD4+ T-cell infiltration in the colon and suppressed inferferon-, (IFN-,) and TNF-, production by lamina propria CD4+ T cells. Conclusions:, Collectively, the present results suggest an initial role of macrophages in the pathogenesis of T-cell-mediated chronic colitis. Furthermore, the macrophage-specific targeting may be a promising strategy for therapeutic intervention in CD. [source]

Development of RNA interference (RNAi) as potential antiviral strategy against enterovirus 70

Eng Lee Tan
Abstract Enterovirus 70 (EV70) is recognized as the main causative agent of acute hemorrhagic conjunctivitis (AHC), a highly contagious viral infection of the eye. Currently, there is no available treatment for EV70 infections. In this study, we developed a potential intervention strategy using RNA interference (RNAi) against EV70 infection in an in vitro system. Two synthetic 19-mer siRNAs, si-3D1 and si-3D2, were designed to target the 3Dpol region of the EV70 genome. Significant dosage dependent inhibition of EV70 in rhabdomyosarcoma cell line, as shown by reduction of viral RNA and VP1 production, was observed. Both siRNAs prevented EV70 replication in RD cells when transfected into these cells 48 hr prior to virus infection. Introduction of these siRNAs into RD cells 1,3 hr after infection with EV70 reduced production of viral RNA by approximately 60%. Thus, RNAi is a promising strategy to prevent EV70 infections and may have therapeutic potential. J. Med. Virol. 80:1025,1032, 2008. © 2008 Wiley-Liss, Inc. [source]

In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivatives

Lesetja J. Legoabe
Abstract Objectives The aim of this study was to synthesise and determine the transdermal penetration of cytarabine alkylamide derivatives and assess the correlation of flux with physicochemical properties. Methods The alkylamide derivatives of cytarabine were synthesised by acylation at the N4-amino group by the mixed anhydride method. The in-vitro permeation studies were performed using the Franz diffusion cell methodology. Furthermore, partition coefficients (n -octanol,water) and aqueous solubility of the N4-alkylamide derivatives of cytarabine were determined in order to obtain information about their lipophilicity and hydrophilicity. Key findings The N4-alkylamides of cytarabine (acetyl, butanoyl, hexanoyl, octanoyl, and decanoyl derivatives) showed decreased hydrophilicity and increased lipophilicity. The log D values of the alkylamides were higher than that of the parent compound and increased linearly as the alkyl chain lengthened. N4-hexanoyl-4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl] pyrimidin-2-one) showed the highest median steady-state flux (Jss) of 89.0 nmol/cm2 per h in the series, which shows a high statistical difference with the parent compound flux value (3.70 nmol/cm2 per h). Conclusions The prodrug approach appears to be a promising strategy for the enhancement of transdermal penetration of cytarabine. [source]

Analysis of nuclear proteome in C57 mouse liver tissue by a nano-flow 2-D-LC,ESI-MS/MS approach

Jie Zhang
Abstract The analysis of whole cell or tissue extracts is too complex for current protein identification technology and not suitable for the study of proteins with low copy levels. To concentrate and enrich low abundance proteins, organelle proteomics is a promising strategy. This approach can not only reduce the protein sample complexity but also provide information about protein location in cells, organs, or tissues under analysis. Nano-flow two-dimensional strong-cation exchange chromatography (SCX),RPLC,ESI-MS/MS is an ideal platform for analyzing organelle extracts because of its advantages of sample non-bias, low amounts of sample required, powerful separation capability, and high detection sensitivity. In this study, we apply nano-scale multidimensional protein identification technology to the analysis of C57 mouse liver nuclear proteins. Organelle isolation has been optimized to obtain highly pure nuclei. Evaluation of nucleus integrity and purity has been performed to demonstrate the effectiveness of the optimized isolation procedure. The extracted nuclear proteins were identified by five independent nano-flow on-line SCX,RPLC,ESI-MS/MS analyses to improve the proteome coverage. Finally, a total of 462 proteins were identified. Corresponding analyses of protein molecular mass and pI distribution and biological function categorization have been undertaken to further validate our identification strategy. [source]

Low oxygen treatment prior to cold storage decreases the incidence of bitter pit in ,Golden Reinders' apples

Jesśs Val
Abstract BACKGROUND: The effect of subjecting ,Golden Reinders' apples to a low O2 pre-treatment (LOT; 1,2% O2) was evaluated as a strategy to decrease the rate of bitter pit (BP) incidence after standard cold storage (ST). Immediately after harvest, apples were stored for 10 days at 20 °C under low O2. Thereafter, apples were cold-stored (0,4 °C) for 4 months and changes were monitored in terms of BP incidence, fruit quality traits and mineral element concentrations. RESULTS: After 4 months cold storage, LOT apples presented a 2.6-fold decrease in the rate of BP incidence (14%) versus the values obtained for standard cold-stored fruits (37% BP incidence). LOT increased flesh firmness, total soluble solids and titratable acidity as compared to the quality traits determined for cold-stored fruits. Lower cortex Ca and Mg concentrations as compared to ST apples were determined in association with LOT, 2 months after cold storage. CONCLUSION: Application of a LOT prior to cold storage may be a promising strategy to reduce the incidence of BP and preserve fruit quality, which should be further investigated. Copyright © 2009 Society of Chemical Industry [source]

Immunosuppressive treatments for immunoglobulin A nephropathy: A meta-analysis of randomized controlled trials

NEPHROLOGY, Issue 4 2004
Review Article
SUMMARY: Immunoglobulin A (IgA) nephropathy is a worldwide disease that causes end-stage kidney disease (ESRD) in up to 15,20% of affected patients within 10 years from the apparent onset of disease and in up to 30,40% of individuals within 20 years from diagnosis. No specific treatment has been established and there is wide variation in current practice. This systematic review evaluates the use of immunosuppressive agents to treat patients with IgA nephropathy. The Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE, EMBASE and article reference lists were searched for randomized or quasi randomized trials. Two independent reviewers assessed studies for inclusion criteria (biopsy proven IgA nephropathy, randomized trial, use of immunosuppressive agents) and extracted data regarding the effects of immunosuppressive agents on ESRD, doubling of serum creatinine, glomerular filtration rate, urinary protein excretion and side-effects. Data were analysed with a random effects model. The published trials were few (13 trials, 623 patients) and were generally of poor quality. Compared with placebo, steroids were associated with a lower risk of progression to ESRD (six trials, 341 patients, RR 0.44, 95% CI 0.25,0.80) and lower end-of-trial proteinuria (six trials, 263 patients, weighted mean difference (WMD) ,0.49 g/day, 95% CI ,0.25 to ,0.72). Treatment with alkylating agents significantly reduced end of treatment proteinuria (two trials, 122 patients, WMD ,0.94, 95% CI ,0.46 to ,1.43). Although the optimal management of patients with IgA nephropathy remains uncertain because of limitations with the existing published data, immunosuppressive agents are a promising strategy and should be investigated further. [source]

Effectiveness of Monetary Incentives in Modifying Dietary Behavior: A Review of Randomized, Controlled Trials

FAFPHM, Joanne Wall MBChB
To review research evidence on the effectiveness of monetary incentives in modifying dietary behavior, we conducted a systematic review of randomized, controlled trials (RCTs) identified from electronic bibliographic databases and reference lists of retrieved relevant articles. Studies eligible for inclusion met the following criteria: RCT comparing a form of monetary incentive with a comparative intervention or control; incentives were a central component of the study intervention and their effect was able to be disaggregated from other intervention components; study participants were community-based; and outcome variables included anthropometric or dietary assessment measures. Data were extracted on study populations, setting, interventions, outcome variables, trial duration, and follow-up. Appraisal of trial methodological quality was undertaken based on comparability of baseline characteristics, randomization method, allocation concealment, blinding, follow-up, and use of intention-to-treat analysis. Four RCTs were identified as meeting the inclusion criteria. All four trials demonstrated a positive effect of monetary incentives on food purchases, food consumption, or weight loss. However, the trials had some methodological limitations including small sample sizes and short durations. In addition, no studies to date have assessed effects according to socioeconomic or ethnic group or measured the cost-effectiveness of such schemes. Monetary incentives are a promising strategy to modify dietary behavior, but more research is needed to address the gaps in evidence. In particular, larger, long-term RCTs are needed with population groups at high risk of nutrition-related diseases [source]