The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidi... more The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidisciplinary expertise and knowledge of both local ultrasonography practices and the local malignancy rates for a given fine-needle aspiration (FNA) result. Even in such a multidisciplinary setting, FNA cytology has the inherent limitation that indeterminate cytology results cannot distinguish between follicular adenomas, follicular thyroid carcinomas or follicular variant papillary thyroid carcinomas. Accumulating evidence suggests that this limitation can be overcome by using molecular diagnostic approaches. In this Review, we present the advantages and disadvantages of the different molecular diagnostic methodologies, which can be divided into two approaches: those that 'rule out' malignancy (to reduce the overtreatment of benign nodules) and those that 'rule in' malignancy (to optimize surgical planning). We identify microRNA classifiers as potential additional markers ...
Pediatric nephrology (Berlin, Germany), Jan 14, 2016
Serum cystatin C (CysC) is a more accurate glomerular filtration rate marker than serum creatinin... more Serum cystatin C (CysC) is a more accurate glomerular filtration rate marker than serum creatinine (SCr) and may rise more quickly with acute kidney injury (AKI). We performed a prospective cohort study of 81 non-critically ill children during 110 aminoglycoside (AG) treatments. We calculated area under the curve (AUC) for CysC to diagnose SCr-defined AKI and predict persistent AKI. SCr-AKI definition was based on the Kidney Disease: Improving Global Outcomes (≥stage 1: ≥50 % or 26.5 μmol/l SCr rise from baseline; stage 2: SCr doubling); CysC-AKI was based on a modified version using CysC rise. SCr-AKI and CysC-AKI developed in 45 and 48 % treatments, respectively. CysC rise predicted stage 1 (AUC = 0.75, 95 % CI 0.60-0.90) and 2 (AUC = 0.85, 95 % CI 0.75-0.95) SCr-AKI 2 days before SCr-AKI attainment. The best combined sensitivity/specificity for percent CysC rise to predict stage 1 SCr-AKI was with a 44 % CysC rise (sensitivity = 65 %, specificity = 83 %). CysC rise on day of SCr-...
Proceedings of the National Academy of Sciences of the United States of America, 2004
New neurons are generated in adult mammalians and may contribute to repairing the brain after inj... more New neurons are generated in adult mammalians and may contribute to repairing the brain after injury. Here, we show that the number of new neurons in the dentate gyrus of adult rats increased in cerebral ischemic stroke and correlated with activation of the cAMP-response-element-binding protein (CREB). Inhibition of endogenous CREB by expression of a dominant-negative mutant of CREB (CREB-S133A or CREB-R287L) blocked ischemia-induced neurogenesis in the dentate gyrus of adult rats, whereas expression of constitutively active CREB, VP16-CREB, increased the number of new neurons. Thus, our findings provide roles and regulatory mechanisms for CREB in adult neurogenesis and possibly suggest a practical strategy for replacing dead neurons in brain injury. P rogenitor cells in the adult dentate gyrus can proliferate and differentiate into mature neurons when maintained in culture medium containing growth factors in vitro (1) or when grafted into the adult brain in vivo (2), suggesting that residential neuronal progenitors are capable of responding to environmental factors in the adult host (2, 3). Consistent with this hypothesis, several recent studies show that neurogenesis in the dentate gyrus of adults is regulated by stress (4), exercise (5), and learning (6, 7).
Remyelination is the generation of new myelin sheaths after injury facilitated by processes of di... more Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 21, 2015
Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protec... more Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling. When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator, macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B, particular...
Matrix metalloproteinases (MMPs) are expressed in the developing, healthy adult and diseased CNS.... more Matrix metalloproteinases (MMPs) are expressed in the developing, healthy adult and diseased CNS. We emphasize the regulation of neurogenesis and oligodendrogenesis by MMPs during CNS development, and highlight physiological roles of MMPs in the healthy adult CNS, such as in synaptic plasticity, learning and memory. Nonetheless, MMPs as "the good guys" go bad in neurological conditions, likely aided by the sudden and massive upregulation of several MMP members. We stress the necessity of drawing a fine balance in the treatment of neurological diseases, and we suggest that MMP inhibitors do have therapeutic potential early after CNS injury.
Proceedings of the National Academy of Sciences, 2004
New neurons are generated in adult mammalians and may contribute to repairing the brain after inj... more New neurons are generated in adult mammalians and may contribute to repairing the brain after injury. Here, we show that the number of new neurons in the dentate gyrus of adult rats increased in cerebral ischemic stroke and correlated with activation of the cAMP-response-element-binding protein (CREB). Inhibition of endogenous CREB by expression of a dominant-negative mutant of CREB (CREB-S133A or CREB-R287L) blocked ischemia-induced neurogenesis in the dentate gyrus of adult rats, whereas expression of constitutively active CREB, VP16-CREB, increased the number of new neurons. Thus, our findings provide roles and regulatory mechanisms for CREB in adult neurogenesis and possibly suggest a practical strategy for replacing dead neurons in brain injury. P rogenitor cells in the adult dentate gyrus can proliferate and differentiate into mature neurons when maintained in culture medium containing growth factors in vitro (1) or when grafted into the adult brain in vivo (2), suggesting that residential neuronal progenitors are capable of responding to environmental factors in the adult host (2, 3). Consistent with this hypothesis, several recent studies show that neurogenesis in the dentate gyrus of adults is regulated by stress (4), exercise (5), and learning (6, 7).
AMPA receptor channels (Hollmann et al., 1991; Hume et al., 1991). Nearly 100% of GluR2 mRNA is e... more AMPA receptor channels (Hollmann et al., 1991; Hume et al., 1991). Nearly 100% of GluR2 mRNA is edited at the so-called Q/R site at codon 607, where an arginine (R) codon replaces the genomic glutamine (Q) codon (Sommer et al., 1991; Verdoorn et al., 1991; Burnashev et
ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca 2+... more ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca 2+ entry through AMPA receptor channels. Here, we show that forebrain ischemia in adult rats selectively reduces expression of ADAR2 enzyme and, hence, disrupts RNA Q/R site editing of GluR2 subunit in vulnerable neurons. Recovery of GluR2 Q/R site editing by expression of exogenous ADAR2b gene or a constitutively active CREB, VP16-CREB, which induces expression of endogenous ADAR2, protects vulnerable neurons in the rat hippocampus from forebrain ischemic insult. Generation of a stable ADAR2 gene silencing by delivering small interfering RNA (siRNA) inhibits GluR2 Q/R site editing, leading to degeneration of ischemia-insensitive neurons. Direct introduction of the Q/R site edited GluR2 gene, GluR2(R 607 ), rescues ADAR2 degeneration. Thus, ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons in the rat hippocampus to forebrain ischemia.
The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its no... more The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its normal physiology. Alterations to the ECM occur after neural injury (for example, in multiple sclerosis, spinal cord injury or Alzheimer's disease) and can have drastic consequences. Of note, injury-induced changes in chondroitin sulphate proteoglycans (CSPGs)--a family of ECM proteoglycans--can lead to the inhibition of myelin repair. Here, we highlight the pathophysiological roles of the brain's ECM, particularly those of CSPGs, after neural insults and discuss how the ECM can be targeted to promote remyelination.
Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of funct... more Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of function related to the poor regeneration of injured axons. Injured axons encounter several barriers to regeneration, such as the glial scar at the injury site. The glial scar contains extracellular matrix (ECM) macromolecules deposited by reactive astrocytes in response to injury. The scar ECM is rich in chondroitin sulfate proteoglycans (CSPGs), macromolecules that inhibit axonal growth. CSPGs consist of a core protein with attachment sites for glycosaminoglycan (GAG) chains. An extensive literature demonstrates that enzymatic removal of the GAG chains by chondroitinase ABC permits some axonal regrowth; however, the remaining intact core proteins also possess inhibitory domains. Because metalloproteinases can degrade core proteins of CSPGs, we have evaluated five matrix metalloproteinases (MMPs) and a related protease-a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4)-for their capacity to overcome CSPG inhibition of neuritic growth in culture. The metalloproteinases were selected for their known expression after CNS injuries. Of the MMPs, MMP-3, -7 and -8 reduced or abolished inhibition of neurite outgrowth on a purified CSPG substrate and on an astrocyte-derived ECM. ADAMTS-4 also attenuated CSPG inhibition of neurites and had the additional benefits of neither degrading laminin nor causing neurotoxicity. The efficacy of ADAMTS-4 matched that of blocking the EGFR signaling previously reported to mediate CSPG inhibition. These findings highlight ADAMTS-4 as a superior protease for overcoming CSPG inhibition of axonal regeneration in the CNS.
Objective: Failure of remyelination is a critical impediment to recovery in multiple sclerosis (M... more Objective: Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination. Methods: We evaluated the expression of CSPGs in lysolecithin-injected mouse spinal cord, an animal model of demyelination and spontaneous remyelination. The functional impact of CSPGs on OPCs and remyelination was investigated using cultured adult murine and human OPCs and by treating demyelinated mice with xyloside to reduce the CSPG deposition that occurred following injury. Results: Early and robust upregulation of CSPGs following lysolecithin-induced demyelination was cleared during remyelination. In culture, CSPGs anchored onto the substratum reduced the adhesion of mouse and human OPCs and their subsequent morphological differentiation into process-bearing oligodendrocytes. Soluble CSPGs added to already adherent OPCs reduced the development of processes, whereas the acquisition of mature myelin proteins was unimpeded. Stripe assays of alternating CSPG and control substrata confirmed the nonpermissive nature of CSPGs for OPC adhesion and morphological differentiation. Enzymatic degradation of CSPGs with chondroitinase ABC was sufficient to overcome CSPG-dependent inhibition of human oligodendrocytes. Finally, in vivo xyloside treatment to reduce CSPG synthesis in lysolecithin-demyelinated mice increased numbers of OPCs and oligodendrocytes in lesions, and culminated in improved remyelination. Interpretation: These results identify CSPGs as a nonpermissive substrate for OPCs and oligodendrocytes, and as a prominent impediment to remyelination. The data suggest the requirement for the neutralization of CSPGs for repair after demyelination. ANN NEUROL 2012;72:419-432 View this article online at wileyonlinelibrary.com.
To compare the characteristics of symptoms of hypoglycemia in children and in adults with type 1 ... more To compare the characteristics of symptoms of hypoglycemia in children and in adults with type 1 diabetes. Adults with diabetes and parents of children with diabetes who were participants were asked to call a phone system to report episodes of hypoglycemia (presence of symptoms and a blood glucose <4.0 mmol/L). For each episode, blood glucose reading and a scoring of 28 symptoms on a 7-point scale (1 = not present, 7 = very intense) were collected. Sixty six children (49.2% males, mean age = 12.1±2.4 years, mean age at diagnosis = 7.5±2.9 years) and 53 adults (41.2% males, mean age 38.7±14.5 years, mean age at diagnosis = 17.5±12.9 years) with type 1 diabetes participated. The most common symptoms in adults were hunger, sweating, trembling and weakness. The most common symptoms in children were weakness, trembling and hunger. The 2 most discriminating variables between children and adults were sleepiness and tiredness, which were more common in children (p<0.01). In a comparat...
The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidi... more The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidisciplinary expertise and knowledge of both local ultrasonography practices and the local malignancy rates for a given fine-needle aspiration (FNA) result. Even in such a multidisciplinary setting, FNA cytology has the inherent limitation that indeterminate cytology results cannot distinguish between follicular adenomas, follicular thyroid carcinomas or follicular variant papillary thyroid carcinomas. Accumulating evidence suggests that this limitation can be overcome by using molecular diagnostic approaches. In this Review, we present the advantages and disadvantages of the different molecular diagnostic methodologies, which can be divided into two approaches: those that 'rule out' malignancy (to reduce the overtreatment of benign nodules) and those that 'rule in' malignancy (to optimize surgical planning). We identify microRNA classifiers as potential additional markers ...
Pediatric nephrology (Berlin, Germany), Jan 14, 2016
Serum cystatin C (CysC) is a more accurate glomerular filtration rate marker than serum creatinin... more Serum cystatin C (CysC) is a more accurate glomerular filtration rate marker than serum creatinine (SCr) and may rise more quickly with acute kidney injury (AKI). We performed a prospective cohort study of 81 non-critically ill children during 110 aminoglycoside (AG) treatments. We calculated area under the curve (AUC) for CysC to diagnose SCr-defined AKI and predict persistent AKI. SCr-AKI definition was based on the Kidney Disease: Improving Global Outcomes (≥stage 1: ≥50 % or 26.5 μmol/l SCr rise from baseline; stage 2: SCr doubling); CysC-AKI was based on a modified version using CysC rise. SCr-AKI and CysC-AKI developed in 45 and 48 % treatments, respectively. CysC rise predicted stage 1 (AUC = 0.75, 95 % CI 0.60-0.90) and 2 (AUC = 0.85, 95 % CI 0.75-0.95) SCr-AKI 2 days before SCr-AKI attainment. The best combined sensitivity/specificity for percent CysC rise to predict stage 1 SCr-AKI was with a 44 % CysC rise (sensitivity = 65 %, specificity = 83 %). CysC rise on day of SCr-...
Proceedings of the National Academy of Sciences of the United States of America, 2004
New neurons are generated in adult mammalians and may contribute to repairing the brain after inj... more New neurons are generated in adult mammalians and may contribute to repairing the brain after injury. Here, we show that the number of new neurons in the dentate gyrus of adult rats increased in cerebral ischemic stroke and correlated with activation of the cAMP-response-element-binding protein (CREB). Inhibition of endogenous CREB by expression of a dominant-negative mutant of CREB (CREB-S133A or CREB-R287L) blocked ischemia-induced neurogenesis in the dentate gyrus of adult rats, whereas expression of constitutively active CREB, VP16-CREB, increased the number of new neurons. Thus, our findings provide roles and regulatory mechanisms for CREB in adult neurogenesis and possibly suggest a practical strategy for replacing dead neurons in brain injury. P rogenitor cells in the adult dentate gyrus can proliferate and differentiate into mature neurons when maintained in culture medium containing growth factors in vitro (1) or when grafted into the adult brain in vivo (2), suggesting that residential neuronal progenitors are capable of responding to environmental factors in the adult host (2, 3). Consistent with this hypothesis, several recent studies show that neurogenesis in the dentate gyrus of adults is regulated by stress (4), exercise (5), and learning (6, 7).
Remyelination is the generation of new myelin sheaths after injury facilitated by processes of di... more Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 21, 2015
Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protec... more Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling. When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator, macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B, particular...
Matrix metalloproteinases (MMPs) are expressed in the developing, healthy adult and diseased CNS.... more Matrix metalloproteinases (MMPs) are expressed in the developing, healthy adult and diseased CNS. We emphasize the regulation of neurogenesis and oligodendrogenesis by MMPs during CNS development, and highlight physiological roles of MMPs in the healthy adult CNS, such as in synaptic plasticity, learning and memory. Nonetheless, MMPs as &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;the good guys&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; go bad in neurological conditions, likely aided by the sudden and massive upregulation of several MMP members. We stress the necessity of drawing a fine balance in the treatment of neurological diseases, and we suggest that MMP inhibitors do have therapeutic potential early after CNS injury.
Proceedings of the National Academy of Sciences, 2004
New neurons are generated in adult mammalians and may contribute to repairing the brain after inj... more New neurons are generated in adult mammalians and may contribute to repairing the brain after injury. Here, we show that the number of new neurons in the dentate gyrus of adult rats increased in cerebral ischemic stroke and correlated with activation of the cAMP-response-element-binding protein (CREB). Inhibition of endogenous CREB by expression of a dominant-negative mutant of CREB (CREB-S133A or CREB-R287L) blocked ischemia-induced neurogenesis in the dentate gyrus of adult rats, whereas expression of constitutively active CREB, VP16-CREB, increased the number of new neurons. Thus, our findings provide roles and regulatory mechanisms for CREB in adult neurogenesis and possibly suggest a practical strategy for replacing dead neurons in brain injury. P rogenitor cells in the adult dentate gyrus can proliferate and differentiate into mature neurons when maintained in culture medium containing growth factors in vitro (1) or when grafted into the adult brain in vivo (2), suggesting that residential neuronal progenitors are capable of responding to environmental factors in the adult host (2, 3). Consistent with this hypothesis, several recent studies show that neurogenesis in the dentate gyrus of adults is regulated by stress (4), exercise (5), and learning (6, 7).
AMPA receptor channels (Hollmann et al., 1991; Hume et al., 1991). Nearly 100% of GluR2 mRNA is e... more AMPA receptor channels (Hollmann et al., 1991; Hume et al., 1991). Nearly 100% of GluR2 mRNA is edited at the so-called Q/R site at codon 607, where an arginine (R) codon replaces the genomic glutamine (Q) codon (Sommer et al., 1991; Verdoorn et al., 1991; Burnashev et
ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca 2+... more ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca 2+ entry through AMPA receptor channels. Here, we show that forebrain ischemia in adult rats selectively reduces expression of ADAR2 enzyme and, hence, disrupts RNA Q/R site editing of GluR2 subunit in vulnerable neurons. Recovery of GluR2 Q/R site editing by expression of exogenous ADAR2b gene or a constitutively active CREB, VP16-CREB, which induces expression of endogenous ADAR2, protects vulnerable neurons in the rat hippocampus from forebrain ischemic insult. Generation of a stable ADAR2 gene silencing by delivering small interfering RNA (siRNA) inhibits GluR2 Q/R site editing, leading to degeneration of ischemia-insensitive neurons. Direct introduction of the Q/R site edited GluR2 gene, GluR2(R 607 ), rescues ADAR2 degeneration. Thus, ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons in the rat hippocampus to forebrain ischemia.
The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its no... more The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its normal physiology. Alterations to the ECM occur after neural injury (for example, in multiple sclerosis, spinal cord injury or Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease) and can have drastic consequences. Of note, injury-induced changes in chondroitin sulphate proteoglycans (CSPGs)--a family of ECM proteoglycans--can lead to the inhibition of myelin repair. Here, we highlight the pathophysiological roles of the brain&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s ECM, particularly those of CSPGs, after neural insults and discuss how the ECM can be targeted to promote remyelination.
Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of funct... more Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of function related to the poor regeneration of injured axons. Injured axons encounter several barriers to regeneration, such as the glial scar at the injury site. The glial scar contains extracellular matrix (ECM) macromolecules deposited by reactive astrocytes in response to injury. The scar ECM is rich in chondroitin sulfate proteoglycans (CSPGs), macromolecules that inhibit axonal growth. CSPGs consist of a core protein with attachment sites for glycosaminoglycan (GAG) chains. An extensive literature demonstrates that enzymatic removal of the GAG chains by chondroitinase ABC permits some axonal regrowth; however, the remaining intact core proteins also possess inhibitory domains. Because metalloproteinases can degrade core proteins of CSPGs, we have evaluated five matrix metalloproteinases (MMPs) and a related protease-a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4)-for their capacity to overcome CSPG inhibition of neuritic growth in culture. The metalloproteinases were selected for their known expression after CNS injuries. Of the MMPs, MMP-3, -7 and -8 reduced or abolished inhibition of neurite outgrowth on a purified CSPG substrate and on an astrocyte-derived ECM. ADAMTS-4 also attenuated CSPG inhibition of neurites and had the additional benefits of neither degrading laminin nor causing neurotoxicity. The efficacy of ADAMTS-4 matched that of blocking the EGFR signaling previously reported to mediate CSPG inhibition. These findings highlight ADAMTS-4 as a superior protease for overcoming CSPG inhibition of axonal regeneration in the CNS.
Objective: Failure of remyelination is a critical impediment to recovery in multiple sclerosis (M... more Objective: Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination. Methods: We evaluated the expression of CSPGs in lysolecithin-injected mouse spinal cord, an animal model of demyelination and spontaneous remyelination. The functional impact of CSPGs on OPCs and remyelination was investigated using cultured adult murine and human OPCs and by treating demyelinated mice with xyloside to reduce the CSPG deposition that occurred following injury. Results: Early and robust upregulation of CSPGs following lysolecithin-induced demyelination was cleared during remyelination. In culture, CSPGs anchored onto the substratum reduced the adhesion of mouse and human OPCs and their subsequent morphological differentiation into process-bearing oligodendrocytes. Soluble CSPGs added to already adherent OPCs reduced the development of processes, whereas the acquisition of mature myelin proteins was unimpeded. Stripe assays of alternating CSPG and control substrata confirmed the nonpermissive nature of CSPGs for OPC adhesion and morphological differentiation. Enzymatic degradation of CSPGs with chondroitinase ABC was sufficient to overcome CSPG-dependent inhibition of human oligodendrocytes. Finally, in vivo xyloside treatment to reduce CSPG synthesis in lysolecithin-demyelinated mice increased numbers of OPCs and oligodendrocytes in lesions, and culminated in improved remyelination. Interpretation: These results identify CSPGs as a nonpermissive substrate for OPCs and oligodendrocytes, and as a prominent impediment to remyelination. The data suggest the requirement for the neutralization of CSPGs for repair after demyelination. ANN NEUROL 2012;72:419-432 View this article online at wileyonlinelibrary.com.
To compare the characteristics of symptoms of hypoglycemia in children and in adults with type 1 ... more To compare the characteristics of symptoms of hypoglycemia in children and in adults with type 1 diabetes. Adults with diabetes and parents of children with diabetes who were participants were asked to call a phone system to report episodes of hypoglycemia (presence of symptoms and a blood glucose <4.0 mmol/L). For each episode, blood glucose reading and a scoring of 28 symptoms on a 7-point scale (1 = not present, 7 = very intense) were collected. Sixty six children (49.2% males, mean age = 12.1±2.4 years, mean age at diagnosis = 7.5±2.9 years) and 53 adults (41.2% males, mean age 38.7±14.5 years, mean age at diagnosis = 17.5±12.9 years) with type 1 diabetes participated. The most common symptoms in adults were hunger, sweating, trembling and weakness. The most common symptoms in children were weakness, trembling and hunger. The 2 most discriminating variables between children and adults were sleepiness and tiredness, which were more common in children (p<0.01). In a comparat...
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Papers by Lorraine Lau