C. Mallard | University of Gothenburg (original) (raw)

Papers by C. Mallard

Placenta, 2006

Toll-like receptor 4 (TLR-4) mediates Gram-negative bacterial-induced inflammatory responses, inc... more Toll-like receptor 4 (TLR-4) mediates Gram-negative bacterial-induced inflammatory responses, including production of pro-inflammatory cytokines. Maternal infection and inflammation play an important role in preterm birth and neonatal brain damage. The localization of placental TLR-4 as well as changes during normal gestation are critical issues in understanding the role of toll-like receptors in defending the placento-fetal unit from maternal infection. We therefore investigated, by immunohistochemistry (IHC) and Western blot, the subcellular localization of TLR-4 in first trimester and term human placenta. In both term placenta (n=4) and first trimester placenta villous samples (n=5), immunoreactivity for TLR-4 was found in the cytoplasm of the syncytiotrophoblast, with darker staining in some areas of the maternal facing plasma membrane (MVM). In addition, TLR-4 was found to be expressed in the first trimester cytotrophoblast cells. Using Western blot analysis, TLR-4 was identified in both placental homogenates and isolated MVM and the fetal facing basal membrane (BM). TLR-4 expression in MVM was significantly higher in term (n=9) as compared to first trimester (n=2) samples. We have shown for the first time that the subcellular localization of TLR-4 in term placenta is preferentially in the MVM compared to BM. The MVM is continuously bathed in maternal blood, suggesting that from this vantage point TLR-4 can initiate a rapid response to maternal bacterial infection.

European Journal of Neuroscience, 2005

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, diff... more Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and ⁄ or IGF-I on the serine ⁄ threonine kinases Akt and glycogen synthase kinase 3b (GSK3b) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3b (pGSK3b) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3b remained low 4 h after HI. Administration of IGF-I (50 lg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3b decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3b in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3-and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3b, may explain the attenuated activation of caspases and reduction of injury in the immature brain.

J Immunolgy, 2005

... Olsson, A (author) Brodin, E (author) Hokfelt, T (author) Eriksson, Kristina, 1962-(author) s... more ... Olsson, A (author) Brodin, E (author) Hokfelt, T (author) Eriksson, Kristina, 1962-(author) show less... University of Gothenburg Sahlgrenska Academy. Institute of Medical Microbiology/ Immunology. ... Olsson, A Brodin, E Hokfelt, T show more... Eriksson, Kristi ... show less... ...

Brain Research Reviews, 2000

This paper summarises the available information on MRI-determined hippocampal morphometry in firs... more This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an Ž . illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice 1.5 mm Ž . study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi right y9%, left y11% in first Ž . episode patients that were of a similar magnitude to those found in chronic patients right y10%, left y11% but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses. Consideration is given to the implications of these findings, including the possible role of early and later neurodevelopmental influences. We present animal data Ž . showing that chronic placental insufficiency, as elicited by uterine artery ligation can give rise to substantial reduction 31% in hippocampal volumes and reflect on other potentially relevant pathophysiological mechanisms, including those that may occur during the early phases of psychotic illnesses, including their prodromes. Greater attention needs to be paid to the study of early phase psychosis in order to obtain a clearer understanding of the nature and time course of neurobiological changes associated with it. Although there is a growing literature on first episode psychosis, there is a striking dearth of information on the neurobiology of the prodrome. q

Journal of Neuroinflammation, 2011

Background: Hypoxic-ischemic (HI) brain injury remains a major problem in newborns, resulting in ... more Background: Hypoxic-ischemic (HI) brain injury remains a major problem in newborns, resulting in increased risk of neurological disorders. Neonatal HI triggers a broad inflammatory reaction in the brain, including activation of the innate immune system. Toll-like receptors (TLRs), which are key components of the innate immune system, are believed to play a role in adult cerebral ischemic injury. The expression of TLRs in the neonatal brain and their regulation after HI is unknown. Methods: Wild type C57BL/6, TLR 1 knockout (KO) and TLR 2 KO mice were subjected to HI at postnatal day 9 and sacrificed 30 min, 6 h, 24 h or 5 days after HI. TLR mRNA expression was determined by RT-qPCR and protein and cell type localisation by immunohistochemistry (IHC). To evaluate brain injury, infarct volume was measured in the injured hemisphere.

The FASEB Journal, 2013

Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI),... more Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.-Järlestedt, K., Rousset, C. I., Ståhlberg, A., Sourkova, H., Atkins, A. L., Thornton, C., Barnum, S. R., Wetsel, R. A., Dragunow, M., Pekny, M., Mallard, C., Hagberg, H., Pekna, M. Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxicischemic brain injury. FASEB J. 27, 3797-3804 (2013

Neuroscience, 2000

Intrauterine growth restriction is a risk factor for neurological and behavioural deficits in chi... more Intrauterine growth restriction is a risk factor for neurological and behavioural deficits in children although the precise underlying biological correlate for this is unclear. The present study shows that animals with intrauterine growth restriction, induced by a period of reduced placental blood flow during the second half of pregnancy, demonstrate reduced numbers of neurons in the hippocampus and the cerebellum in conjunction with retarded dendritic and axonal growth within these structures.

Journal of Neuropathology and Experimental Neurology, 1999

Journal of Child Neurology, 2005

European Journal of Neuroscience, 2005

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, diff... more Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and ⁄ or IGF-I on the serine ⁄ threonine kinases Akt and glycogen synthase kinase 3b (GSK3b) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3b (pGSK3b) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3b remained low 4 h after HI. Administration of IGF-I (50 lg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3b decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3b in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3-and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3b, may explain the attenuated activation of caspases and reduction of injury in the immature brain.

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 1998

It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth... more It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth, but the effects of more sustained hypoxemia are less well understood. We have used fetal sheep in a series of studies aimed at determining the effects of prolonged hypoxemia, induced by placental insufficiency of differing severity and duration, on fetal brain structure. Restriction of placental, and hence fetal, growth by carunclectomy caused impaired development of neural processes and connections in the hippocampus, cerebellum, and visual cortex; neuronal migration and neuronal numbers did not appear to be affected. Twenty days of placental insufficiency during late gestation induced by umbilicoplacental embolisation also caused abnormalities in brain structure; the cerebellum, which develops late in gestation, was particularly affected. In the cortex, there was evidence of white matter lesions, an increase in the size of capillaries and a proliferation of astroglia. We also examined the effects of shorter periods of hypoxemia (6-12 hr) near mid-gestation on brain structure; fetuses were allowed to recover for 7 or 35 days after the hypoxemic challenge. The major changes were mild focal damage in the cortical white matter, a reduction in the number of Purkinje cells, a delay in the growth of neural processes in the cerebellum and proliferation of blood vessels. The hippocampus was also affected, in particular the areal density of pyramidal cells was reduced. The use of several classes of pharmacological agents with the potential to protect neurons from hypoxemic injury is discussed in relation to the developing brain. comp biochem physiol 119A;3:653-660, 1998.

Brain Research Reviews, 2000

This paper summarises the available information on MRI-determined hippocampal morphometry in firs... more This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an Ž . illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice 1.5 mm Ž . study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi right y9%, left y11% in first Ž . episode patients that were of a similar magnitude to those found in chronic patients right y10%, left y11% but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses. Consideration is given to the implications of these findings, including the possible role of early and later neurodevelopmental influences. We present animal data Ž . showing that chronic placental insufficiency, as elicited by uterine artery ligation can give rise to substantial reduction 31% in hippocampal volumes and reflect on other potentially relevant pathophysiological mechanisms, including those that may occur during the early phases of psychotic illnesses, including their prodromes. Greater attention needs to be paid to the study of early phase psychosis in order to obtain a clearer understanding of the nature and time course of neurobiological changes associated with it. Although there is a growing literature on first episode psychosis, there is a striking dearth of information on the neurobiology of the prodrome. q

The Journal of infectious diseases, Jan 15, 2015

Staphylococcus epidermidis (SE) causes late-onset sepsis in preterms. SE activates host response... more Staphylococcus epidermidis (SE) causes late-onset sepsis in preterms. SE activates host responses in part via Toll-like receptor-2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking. Wild-type (WT) and TLR2-deficient (TLR2-/-) mice were injected intravenously with SE at postnatal day (PND)1 prior to measuring plasma and brain cytokines/chemokines, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome. SE bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2-/- mice demonstrated delayed SE clearance from blood, spleen and liver. SE increased white blood cells in CSF, IL-6, IL-12p40, CCL2 and CXCL1 concentrations in plasma, CCL2 in brain, and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 as well as TLR2-independent white matter injury by PND14. SE bacteremia, in the absence of bacterial entry in...

Placenta, 2006

Toll-like receptor 4 (TLR-4) mediates Gram-negative bacterial-induced inflammatory responses, inc... more Toll-like receptor 4 (TLR-4) mediates Gram-negative bacterial-induced inflammatory responses, including production of pro-inflammatory cytokines. Maternal infection and inflammation play an important role in preterm birth and neonatal brain damage. The localization of placental TLR-4 as well as changes during normal gestation are critical issues in understanding the role of toll-like receptors in defending the placento-fetal unit from maternal infection. We therefore investigated, by immunohistochemistry (IHC) and Western blot, the subcellular localization of TLR-4 in first trimester and term human placenta. In both term placenta (n=4) and first trimester placenta villous samples (n=5), immunoreactivity for TLR-4 was found in the cytoplasm of the syncytiotrophoblast, with darker staining in some areas of the maternal facing plasma membrane (MVM). In addition, TLR-4 was found to be expressed in the first trimester cytotrophoblast cells. Using Western blot analysis, TLR-4 was identified in both placental homogenates and isolated MVM and the fetal facing basal membrane (BM). TLR-4 expression in MVM was significantly higher in term (n=9) as compared to first trimester (n=2) samples. We have shown for the first time that the subcellular localization of TLR-4 in term placenta is preferentially in the MVM compared to BM. The MVM is continuously bathed in maternal blood, suggesting that from this vantage point TLR-4 can initiate a rapid response to maternal bacterial infection.

European Journal of Neuroscience, 2005

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, diff... more Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and ⁄ or IGF-I on the serine ⁄ threonine kinases Akt and glycogen synthase kinase 3b (GSK3b) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3b (pGSK3b) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3b remained low 4 h after HI. Administration of IGF-I (50 lg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3b decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3b in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3-and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3b, may explain the attenuated activation of caspases and reduction of injury in the immature brain.

J Immunolgy, 2005

... Olsson, A (author) Brodin, E (author) Hokfelt, T (author) Eriksson, Kristina, 1962-(author) s... more ... Olsson, A (author) Brodin, E (author) Hokfelt, T (author) Eriksson, Kristina, 1962-(author) show less... University of Gothenburg Sahlgrenska Academy. Institute of Medical Microbiology/ Immunology. ... Olsson, A Brodin, E Hokfelt, T show more... Eriksson, Kristi ... show less... ...

Brain Research Reviews, 2000

This paper summarises the available information on MRI-determined hippocampal morphometry in firs... more This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an Ž . illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice 1.5 mm Ž . study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi right y9%, left y11% in first Ž . episode patients that were of a similar magnitude to those found in chronic patients right y10%, left y11% but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses. Consideration is given to the implications of these findings, including the possible role of early and later neurodevelopmental influences. We present animal data Ž . showing that chronic placental insufficiency, as elicited by uterine artery ligation can give rise to substantial reduction 31% in hippocampal volumes and reflect on other potentially relevant pathophysiological mechanisms, including those that may occur during the early phases of psychotic illnesses, including their prodromes. Greater attention needs to be paid to the study of early phase psychosis in order to obtain a clearer understanding of the nature and time course of neurobiological changes associated with it. Although there is a growing literature on first episode psychosis, there is a striking dearth of information on the neurobiology of the prodrome. q

Journal of Neuroinflammation, 2011

Background: Hypoxic-ischemic (HI) brain injury remains a major problem in newborns, resulting in ... more Background: Hypoxic-ischemic (HI) brain injury remains a major problem in newborns, resulting in increased risk of neurological disorders. Neonatal HI triggers a broad inflammatory reaction in the brain, including activation of the innate immune system. Toll-like receptors (TLRs), which are key components of the innate immune system, are believed to play a role in adult cerebral ischemic injury. The expression of TLRs in the neonatal brain and their regulation after HI is unknown. Methods: Wild type C57BL/6, TLR 1 knockout (KO) and TLR 2 KO mice were subjected to HI at postnatal day 9 and sacrificed 30 min, 6 h, 24 h or 5 days after HI. TLR mRNA expression was determined by RT-qPCR and protein and cell type localisation by immunohistochemistry (IHC). To evaluate brain injury, infarct volume was measured in the injured hemisphere.

The FASEB Journal, 2013

Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI),... more Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.-Järlestedt, K., Rousset, C. I., Ståhlberg, A., Sourkova, H., Atkins, A. L., Thornton, C., Barnum, S. R., Wetsel, R. A., Dragunow, M., Pekny, M., Mallard, C., Hagberg, H., Pekna, M. Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxicischemic brain injury. FASEB J. 27, 3797-3804 (2013

Neuroscience, 2000

Intrauterine growth restriction is a risk factor for neurological and behavioural deficits in chi... more Intrauterine growth restriction is a risk factor for neurological and behavioural deficits in children although the precise underlying biological correlate for this is unclear. The present study shows that animals with intrauterine growth restriction, induced by a period of reduced placental blood flow during the second half of pregnancy, demonstrate reduced numbers of neurons in the hippocampus and the cerebellum in conjunction with retarded dendritic and axonal growth within these structures.

Journal of Neuropathology and Experimental Neurology, 1999

Journal of Child Neurology, 2005

European Journal of Neuroscience, 2005

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, diff... more Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and ⁄ or IGF-I on the serine ⁄ threonine kinases Akt and glycogen synthase kinase 3b (GSK3b) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3b (pGSK3b) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3b remained low 4 h after HI. Administration of IGF-I (50 lg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3b decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3b in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3-and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3b, may explain the attenuated activation of caspases and reduction of injury in the immature brain.

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 1998

It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth... more It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth, but the effects of more sustained hypoxemia are less well understood. We have used fetal sheep in a series of studies aimed at determining the effects of prolonged hypoxemia, induced by placental insufficiency of differing severity and duration, on fetal brain structure. Restriction of placental, and hence fetal, growth by carunclectomy caused impaired development of neural processes and connections in the hippocampus, cerebellum, and visual cortex; neuronal migration and neuronal numbers did not appear to be affected. Twenty days of placental insufficiency during late gestation induced by umbilicoplacental embolisation also caused abnormalities in brain structure; the cerebellum, which develops late in gestation, was particularly affected. In the cortex, there was evidence of white matter lesions, an increase in the size of capillaries and a proliferation of astroglia. We also examined the effects of shorter periods of hypoxemia (6-12 hr) near mid-gestation on brain structure; fetuses were allowed to recover for 7 or 35 days after the hypoxemic challenge. The major changes were mild focal damage in the cortical white matter, a reduction in the number of Purkinje cells, a delay in the growth of neural processes in the cerebellum and proliferation of blood vessels. The hippocampus was also affected, in particular the areal density of pyramidal cells was reduced. The use of several classes of pharmacological agents with the potential to protect neurons from hypoxemic injury is discussed in relation to the developing brain. comp biochem physiol 119A;3:653-660, 1998.

Brain Research Reviews, 2000

This paper summarises the available information on MRI-determined hippocampal morphometry in firs... more This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an Ž . illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice 1.5 mm Ž . study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi right y9%, left y11% in first Ž . episode patients that were of a similar magnitude to those found in chronic patients right y10%, left y11% but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses. Consideration is given to the implications of these findings, including the possible role of early and later neurodevelopmental influences. We present animal data Ž . showing that chronic placental insufficiency, as elicited by uterine artery ligation can give rise to substantial reduction 31% in hippocampal volumes and reflect on other potentially relevant pathophysiological mechanisms, including those that may occur during the early phases of psychotic illnesses, including their prodromes. Greater attention needs to be paid to the study of early phase psychosis in order to obtain a clearer understanding of the nature and time course of neurobiological changes associated with it. Although there is a growing literature on first episode psychosis, there is a striking dearth of information on the neurobiology of the prodrome. q

The Journal of infectious diseases, Jan 15, 2015

Staphylococcus epidermidis (SE) causes late-onset sepsis in preterms. SE activates host response... more Staphylococcus epidermidis (SE) causes late-onset sepsis in preterms. SE activates host responses in part via Toll-like receptor-2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking. Wild-type (WT) and TLR2-deficient (TLR2-/-) mice were injected intravenously with SE at postnatal day (PND)1 prior to measuring plasma and brain cytokines/chemokines, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome. SE bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2-/- mice demonstrated delayed SE clearance from blood, spleen and liver. SE increased white blood cells in CSF, IL-6, IL-12p40, CCL2 and CXCL1 concentrations in plasma, CCL2 in brain, and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 as well as TLR2-independent white matter injury by PND14. SE bacteremia, in the absence of bacterial entry in...