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Karine Loulier,
Justin D Lathia,
Veronique Marthiens,
Jenne Relucio,
Mohamed R Mughal,
Sung-Chun Tang,
Turhan Coksaygan, Peter E Hall,
Srinivasulu Chigurupati,
Bruce Patton,
Holly Colognato,
Mahendra S Rao,
Mark P Mattson,
Tarik F Haydar,
Charles Ffrench-Constant
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ABSTRACT: During embryogenesis, the neural stem cells (NSC) of the developing cerebral cortex are located in the ventricular zone (VZ) lining the cerebral ventricles. They exhibit apical and basal processes that contact the ventricular surface and the pial basement membrane, respectively. This unique architecture is important for VZ physical integrity and fate determination of NSC daughter cells. In addition, the shorter apical process is critical for interkinetic nuclear migration (INM), which enables VZ cell mitoses at the ventricular surface. Despite their importance, the mechanisms required for NSC adhesion to the ventricle are poorly understood. We have shown previously that one class of candidate adhesion molecules, laminins, are present in the ventricular region and that their integrin receptors are expressed by NSC. However, prior studies only demonstrate a role for their interaction in the attachment of the basal process to the overlying pial basement membrane. Here we use antibody-blocking and genetic experiments to reveal an additional and novel requirement for laminin/integrin interactions in apical process adhesion and NSC regulation. Transient abrogation of integrin binding and signalling using blocking antibodies to specifically target the ventricular region in utero results in abnormal INM and alterations in the orientation of NSC divisions. We found that these defects were also observed in laminin alpha2 deficient mice. More detailed analyses using a multidisciplinary approach to analyse stem cell behaviour by expression of fluorescent transgenes and multiphoton time-lapse imaging revealed that the transient embryonic disruption of laminin/integrin signalling at the VZ surface resulted in apical process detachment from the ventricular surface, dystrophic radial glia fibers, and substantial layering defects in the postnatal neocortex. Collectively, these data reveal novel roles for the laminin/integrin interaction in anchoring embryonic NSCs to the ventricular surface and maintaining the physical integrity of the neocortical niche, with even transient perturbations resulting in long-lasting cortical defects.
PLoS Biology 09/2009; 7(8):e1000176. · 11.45 Impact Factor
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ABSTRACT: Lornoxicam is one of the oxicam class of non-steroidal anti-inflammatory drugs (NSAIDs), producing analgesic and antipyretic effects in part through the non-selective inhibition of cyclo-oxygenase-1 and -2. It is prescribed for osteoarthritis, rheumatoid arthritis, acute lumbar-sciatica conditions and for postoperative pain management. Lornoxicam is available in 31 countries in Europe, the Middle East, Far East and South America, and is becoming more widely available.
To assess the efficacy, the time to onset of analgesia, the time to use of rescue medication and any associated adverse events of single dose oral lornoxicam in acute postoperative pain.
We searched CENTRAL, MEDLINE, EMBASE and PubMed to June 2009.
Single oral dose, randomised, double-blind, placebo-controlled trials of lornoxicam for relief of established moderate to severe postoperative pain in adults.
Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over 6 hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals (CIs), the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected.
Three studies, with 628 participants, met the inclusion criteria; 434 participants were treated with various doses (2 mg to 32 mg) of lornoxicam, 118 with placebo, and 76 with other active therapies. All the participants had pain following third molar extraction, and study duration was 8 to 24 hours. The NNT for at least 50% pain relief over 6 hours after a single dose of lornoxicam 8 mg was 2.9 (2.3 to 4.0). There were insufficient data to analyse other doses or use of rescue medication. No serious adverse events or withdrawals were reported by any of the studies.
Oral lornoxicam is effective at treating moderate to severe acute postoperative pain, based on limited data. Adverse events did not differ significantly from placebo.
Cochrane database of systematic reviews (Online) 01/2009; · 5.72 Impact Factor
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ABSTRACT: Human neural stem cells (hNSC) have the potential to provide novel cell-based therapies for neurodegenerative conditions such as multiple sclerosis and Parkinson's disease. In order to realise this goal, protocols need to be developed that allow for large quantities of hNSC to be cultured efficiently. As such, it is important to identify factors which enhance the growth of hNSC. In vivo, stem cells reside in distinct microenvironments or niches that are responsible for the maintenance of stem cell populations. A common feature of niches is the presence of the extracellular matrix molecule, laminin. Therefore, this study investigated the effect of exogenous laminin on hNSC growth.
To measure hNSC growth, we established culture conditions using B27-supplemented medium that enable neurospheres to grow from human neural cells plated at clonal densities. Limiting dilution assays confirmed that neurospheres were derived from single cells at these densities. Laminin was found to increase hNSC numbers as measured by this neurosphere formation. The effect of laminin was to augment the proliferation/survival of the hNSC, rather than promoting the undifferentiated state. In agreement, apoptosis was reduced in dissociated neurospheres by laminin in an integrin beta1-dependent manner.
The addition of laminin to the culture medium enhances the growth of hNSC, and may therefore aid their large-scale production.
BMC Neuroscience 01/2008; 9:71. · 3.04 Impact Factor
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ABSTRACT: Studies were undertaken to assess the capability, competence and capacity of manufacturers of oral and injectable hormonal contraceptives in lower- and middle-income countries.
A qualitative study on 41 companies, which comprised in-depth interviews and facility observations, was undertaken. Also an in-depth quantitative study of 14 companies was undertaken, of which 3 have not been included in the first study. Following review of a questionnaire and other documentation, a visit was undertaken to each factory to assess staff competence, manufacturing facilities, manufacturing processes, quality management, worker safety and environmental protection.
Of the 44 companies from 15 countries, less than 30% would meet the current Good Manufacturing Practice requirements of the World Health Organization (WHO), the Pharmaceutical Inspection Cooperation Scheme or any stringent regulatory authority; a further 20% could comply with investment and improvements in quality management. Few companies are able to develop adequate registration dossiers.
There is a limited number of companies that are capable of manufacturing high-quality generic products and which can provide a complete registration dossier for use outside their home markets. It is essential that, in the future, procurement agencies only use suppliers that are prequalified by WHO for the procurement of hormonal contraceptives.
Contraception 05/2007; 75(4):311-7. · 2.72 Impact Factor
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ABSTRACT: The identification of markers for the isolation of human neural stem cells (hNSCs) is essential for studies of their biology and therapeutic applications. This study investigated expression of the integrin receptor family by hNSCs as potential markers. Selection of alpha6(hi) or beta1(hi) cells by fluorescence-activated cell sorting led to an enrichment of human neural precursors, as shown by both neurosphere forming assays and increased expression of prominin-1, sox2, sox3, nestin, bmi1, and musashi1 in the beta1(hi) population. Cells expressing high levels of beta1 integrin also expressed prominin-1 (CD133), a marker previously used to isolate hNSCs, and selection using integrin beta1(hi) cells or prominin-1(hi) cells was found to be equally effective at enriching for hNSCs from neurospheres. Therefore, integrin subunits alpha6 and beta1 are highly expressed by human neural precursors and represent convenient markers for their prospective isolation.
Stem Cells 10/2006; 24(9):2078-84. · 7.78 Impact Factor
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ABSTRACT: The identification of markers for the isolation of human neural stem cells (hNSCs) is essential for studies of their biology and therapeutic applications. This study investigated expression of the integrin receptor family by hNSCs as potential markers. Selection of α6hi or β1hi cells by fluorescence-activated cell sorting led to an enrichment of human neural precursors, as shown by both neurosphere forming assays and increased expression of prominin-1, sox2, sox3, nestin, bmi1, and musashi1 in the β1hi population. Cells expressing high levels of β1 integrin also expressed prominin-1 (CD133), a marker previously used to isolate hNSCs, and selection using integrin β1hi cells or prominin-1hi cells was found to be equally effective at enriching for hNSCs from neurospheres. Therefore, integrin subunits α6 and β1 are highly expressed by human neural precursors and represent convenient markers for their prospective isolation.
Stem Cells 08/2006; 24(9):2078 - 2084. · 7.78 Impact Factor
