Probiotic-educated Tregs are more potent than naïve Tregs for immune tolerance in stressed new-born mice.

When new-born mice are subjected to acute maternal separation stress, cow-milk based formula feeding, and brief recurrent hypoxia with cold stress, they develop gut inflammation similar to the phenotype of neonatal necrotizing enterocolitis, characterised by an increase in gut mucosal effector T (Teffs) and reduced Foxp3+ regulatory T (Tregs) cells. The imbalance can be prevented by probiotic Limosilactobacillus reuteri DSM 17938 (LR 17938). We hypothesised that LR 17938 could potentiate a tolerogenic function of Tregs. To analyse whether LR 17938 can educate Tregs to improve their tolerogenic potency during neonatal stress, we isolated T cells (Tregs and Teffs) from 'donor' mice fed with either LR 17938 (107 cfu) or control media. The cells were adoptively transferred (AT) by intraperitoneal injection (5 × 105 cells/mouse) to new-born (d5) recipient mice. Mice were then separated from their dams, fed formula by gavage, and exposed to hypoxia and cold stress (NeoStress) for 4 days. We analysed the percentage of Tregs in CD4+T helper cells in the intestine (INT) and mesenteric lymph nodes (MLN) of recipient mice. We found that: (1) the percentage of Tregs in the INT and MLN following NeoStress were significantly reduced compared to dam-fed unstressed mice; (2) AT of either naïve Tregs or LR-educated Tregs to mice with Neostress increased the percentage of Tregs in the INT and MLN compared to the percentage in NeoStress mice without Treg treatment; however, LR-educated Tregs increased the Tregs significantly more than naïve Tregs; and (3) AT of LR-educated Tregs reduced pro-inflammatory CD44+Foxp3-NonTregs and inflammatory CX3CR1+ dendritic cells in the intestinal mucosa of NeoStress mice. In conclusion, adoptive transfer of Tregs promotes the generation of and/or migration of endogenous Tregs in the intestinal mucosa of recipient mice. Importantly, probiotic-educated Tregs are more potent than naïve Tregs to enhance immune tolerance following neonatal stress.

High Pressure Quenched Glasses: unique structures and properties.

Zr-based metallic glasses are prepared by quenching supercooled liquid under pressure. These glasses are stable in ambient conditions after decompression. The High Pressure Quenched glasses have a distinct structure and properties. The pair distribution function shows redistribution of the Zr-Zr interatomic distances and their shift towards smaller values. These glasses exhibit higher density, hardness, elastic modulus, and yield stress. Upon heating at ambient pressure, they show volume expansion and distinct relaxation behavior, reaching an equilibrated state above the glass transition. These experimental results are consistent with an idea of pressure-induced low to high density liquid transition in the supercooled melt.

Curie-Weiss behavior of liquid structure and ideal glass state.

We present the results of a structural study of metallic alloy liquids from high temperature through the glass transition. We use high energy X-ray scattering and electro-static levitation in combination with molecular dynamics simulation and show that the height of the first peak of the structure function, S(Q) - 1, follows the Curie-Weiss law. The structural coherence length is proportional to the height of the first peak, and we suggest that its increase with cooling may be related to the rapid increase in viscosity. The Curie temperature is negative, implying an analogy with spin-glass. The Curie-Weiss behavior provides a pathway to an ideal glass state, a state with long-range correlation without lattice periodicity, which is characterized by highly diverse local structures, reminiscent of spin-glass.

Treatment of latent tuberculous infection among health care workers at a tertiary hospital in Korea.

OBJECTIVE: To evaluate the acceptance of, adherence to, and outcomes of latent tuberculous infection (LTBI) treatment among health care workers (HCWs). DESIGN: This was a retrospective study in a tertiary hospital in Korea. From May to August 2017, 2190 HCWs simultaneously underwent a tuberculin skin test (TST) and interferon-gamma release assay (IGRA). LTBI was diagnosed if the TST induration was 10 mm or IGRA results were positive. RESULTS: Of 2190 HCWs tested, 1006 (45.9%) were diagnosed with LTBI. Of these, 655 (65.1%) HCWs visited out-patient clinics, 234 (35.7%) of whom were advised treatment by physicians. Among these, 120 (51.3%) accepted the physicians' recommendations. In general, HCWs who were older, male and smoked were less likely to visit out-patient clinics. Sixty (50%) HCWs received 3 months of isoniazid plus rifampicin (3HR) and 57 (47.5%) HCWs received 4 months of rifampicin (4R). The proportion of HCWs with 2 side effects (3HR 20% vs. 4R 7.0%, P = 0.041) and drug stoppage rate (3HR 20% vs. 4R 5.3%, P = 0.017) were higher in the 3HR group than in the 4R group. Of the 120 HCWs, 78 (65%) completed LTBI treatment. CONCLUSION: Overall, the acceptance and completion rate for LTBI treatment was not adequate. For effective LTBI management in HCWs, further programmatic strategies are needed.

Reliability and validity of the Korean-language version of the Communication Function Classification System in children with cerebral palsy.

PURPOSE: The Communication Function Classification System (CFCS) and Viking Speech Scale (VSS) are useful systems for describing the broad communication function and speech intelligibility, respectively, of children with cerebral palsy (CP). The aims of this study were to determine the reliability and validity of the Korean version of the CFCS and also to investigate the association between the CFCS and the VSS and other functional classifications for children with CP. MATERIALS AND METHODS: Participants were 50 children with CP (33 males, 17 females; mean age 7.2 years, range 4-16 years) recruited from a rehabilitation hospital. We analysed the interrater and intrarater reliabilities of the Korean version of the CFCS and VSS between parents, a physiatrist, and a speech-language pathologist (SLP). The social function domain of the Paediatric Evaluation of Disability Inventory was assessed to examine the concurrent validity of the CFCS and VSS. RESULTS: The intrarater reliabilities of the CFCS and VSS were excellent in a physiatrist (ƙ = 0.92, ƙ = 0.94, respectively) and an SLP (ƙ = 0.98, ƙ = 0.98) and very good in parents (ƙ = 0.87, ƙ = 0.89). The interrater reliability of the CFCS and VSS was very good between the physiatrist and SLP (ƙ = 0.87, ƙ = 0.89) and good between parents and the SLP (ƙ = 0.63, ƙ = 0.78) and between parents and the physiatrist (ƙ = 0.61, ƙ = 0.76). The CFCS and VSS were strongly related with the social function domain of Paediatric Evaluation of Disability Inventory. In addition, we found very strong associations between the VSS and CFCS. CONCLUSIONS: The Korean version of the CFCS is a valid and reliable tool to classify communication ability and is strongly associated with the VSS, a reliable tool to classify speech intelligibility.

Renal outcome after kidney-transplantation in Korean patients with lupus nephritis.

We investigated renal outcome of kidney-transplantation in 19 Korean recipients with biopsy-proven lupus nephritis and compared it with 18 Korean age- and gender-matched recipients without lupus nephritis who were diagnosed with end-stage renal disease caused by renal diseases other than lupus nephritis in a single centre. We reviewed histological findings of kidneys and calculated cumulative dose of immunosuppressive agents. We assessed renal flare of systemic lupus erythematosus, recurrence of lupus nephritis and graft failure as prognosis. The mean age of recipients with lupus nephritis was 43.5 years and all patients were female. Six patients had class III, 10 had class IV and three had class V. There were no meaningful differences in demographic data, renal replacement modality, cumulative doses of immunosuppressants and prognosis between recipients with and without lupus nephritis. Eight patients experienced renal flare of systemic lupus erythematosus, but there were no cases of recurrence of lupus nephritis or graft failure in recipients with lupus nephritis. Kidney-recipients with class IV lupus nephritis exhibited a lower cumulative renal flare of systemic lupus erythematosus free survival rate than those with class III lupus nephritis. In conclusion, renal outcome of kidney-transplantation in patients with lupus nephritis is similar to that in those without lupus nephritis, and class IV was associated with renal flare of systemic lupus erythematosus.

Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition.

Reciprocal interactions between cancer cells and the tumor microenvironment drive multiple clinically significant behaviors including dormancy, invasion, and metastasis as well as therapy resistance. These microenvironment-dependent phenotypes share typical characteristics with cancer stem cells (CSC). However, it is poorly understood how metabolic stress in the confined tumor microenvironment contributes to the emergence and maintenance of CSC-like phenotypes. Here, we demonstrate that chronic metabolic stress (CMS) in a long-term nutrient deprivation induces a Wnt-dependent phenoconversion of non-stem cancer cells toward stem-like state and this is reflected in the transcriptome analysis. Addition of Wnt3a as well as transfection of dominant-negative Tcf4 establishes an obligatory role for the Wnt pathway in the acquisition of CSC-like characteristics in response to metabolic stress. Furthermore, systematic characterization for multiple single cell-derived clones and negative enrichment of CD44+/ESA+ stem-like cancer cells, all of which recapitulate stem-like cancer characteristics, suggest stochastic adaptation rather than selection of pre-existing subclones. Finally, CMS in the tumor microenvironment can drive a CSC-like phenoconversion of non-stem cancer cells through stochastic state transition dependent on the Wnt pathway. These findings contribute to an understanding of the metabolic stress-driven dynamic transition of non-stem cancer cells to a stem-like state in the tumor metabolic microenvironment.

Progress of PTSD symptoms following birth: a prospective study in mothers of high-risk infants.

OBJECTIVE: To understand how postpartum posttraumatic stress disorder (PTSD) symptoms in mothers of high-risk infants progress and identify what factors predict postpartum PTSD. STUDY DESIGN: We prospectively obtained self-reported psychological data from neonatal intensive care unit discharged infants' mothers (NICU mothers) at the infants' corrected ages of 1 (T0), 3 (T1) and 12 months (T2) and mothers of healthy infants (controls). Maternal sociodemographic and infant-related factors were also investigated. RESULT: PTSD was present in 25 and 9% of NICU mothers and controls, respectively. We identified four PTSD patterns: none, persistent, delayed and recovered. The postpartum PTSD course was associated with trait anxiety. Whether the infant was the first child who predicted PTSD at year 1 (adjusted odds ratio=7.62, 95% confidence interval=1.07 to 54.52). CONCLUSION: Mothers of high-risk infants can develop early or late PTSD, and its course can be influenced by factors besides medical status. We therefore recommend regular screenings of postpartum PTSD.

Establishment of a rat model for canine necrotizing meningoencephalitis (NME).

The pathogenesis of necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME) is still uncertain, although they are considered immune-mediated diseases. The purpose of the present study is to generate a rodent model(s) of these diseases. Rats were injected with rat cerebral or cerebellar homogenate. Rats injected with cerebral homogenate (Cbr) exhibited vacuolar or malacic changes mainly in the cerebral cortex. CD3-positive T cells and Iba-1-positive and CD163-negative microglia infiltrated and activated around the lesions. IgG deposited in the glial fibrillary acid protein (GFAP)-positive glia limitans from the early phase, and CD3-positive T cells attached to GFAP-positive astrocytes. Autoantibodies against GFAP were detected in the sera. These pathological features of Cbr rats were consistent with those of canine NME. In contrast, rats injected with cerebral homogenate (Cbe) exhibited demyelinating lesions with inflammatory reactions in the cerebellum, brainstem, and spinal cord. The presence of demyelination and autoantibodies against myelin proteins in Cbe rats was similar to murine experimental autoimmune encephalitis and differed from NME, NLE, and GME. All the present findings indicate that autoantibodies together with microglia and T cells may play a major role in the pathogenesis of idiopathic canine meningoencephalomyelitis.

Acute calcium deposits in the hand and wrist; comparison of acute calcium peritendinitis and acute calcium periarthritis.

Acute calcium deposits are characterized by acute pain and a radiographic finding of amorphous calcification. A prospective, observational study was carried out on 30 consecutive patients undergoing conservative treatment for acute calcium deposits of the hand and wrist. Thirteen patients presented with acute calcific peritendinitis (Group A), and the other 17 with acute calcific periarthritis (Group B). All patients were followed for more than 12 months (mean 29 months). The average age at onset and recurrence rate of acute calcific peritendinitis were both significantly greater than for acute calcific periarthritis.

Th1-, Th2-, and Th17-related cytokine and chemokine receptor mRNA and protein expression in the brain tissues, T cells, and macrophages of dogs with necrotizing and granulomatous meningoencephalitis.

Necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME) are idiopathic inflammatory diseases in the central nervous system (CNS) of dogs. In our previous study, the proportion of inflammatory cells, except for CD3-positive T cells, were not different in parenchymal and perivascular lesions in the brain. However, breed specificities, clinical courses, and specific lesions were distinct among these diseases. Thus, similarities and differences in the pathologies of these diseases have been implied. In this study, the messenger RNA (mRNA) and/or protein expression levels of cytokines and chemokine receptors were investigated in NME (n = 2), NLE (n = 4), and GME (n = 2) cases, and their relationship in the formation of specific lesions was discussed. The mRNA and protein expression levels of interferon (IFN)-γ and interleukin (IL)-17 were marked in NME and GME, respectively. The mRNA expression levels of CXCR3 and CCR2 were also marked in NME and GME, respectively. The results of double-labeling immunofluorescence, used to identify cells producing IL-17 in these lesions, showed that most CD163-positive macrophages/microglia but fewer CD3-positive T cells were IL-17 positive in GME. These results indicate that IFN-γ plays a key role in NME lesions and that the macrophages/microglia that infiltrate brain lesions producing IL-17 are more important in GME than T cells.

Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: a multicenter randomized controlled trial.

BACKGROUND AND PURPOSE: We investigated the effect of celecoxib, a selective inhibitor of cyclo-oxygenase 2, in patients with intracerebral hemorrhage (ICH). METHODS: We conducted a multicenter, randomized, controlled, and open with blinded end-point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end-point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut-off value, 20%). RESULTS: The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end-point analysis using cut-off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end-points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow-up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058). CONCLUSIONS: In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.

Expression of p53, p27 and Jab1 protein in epithelial ovarian tumors.

OBJECTIVE: The study aimed to investigate expression of p53, p27 and Jun activation domain-binding protein 1 (Jab1) proteins in epithelial ovarian tumors and the values of these factors as discriminating markers for the transformation of borderline tumors to cancers. METHODS: Forty-seven cases of paraffin-embedded tissues of epithelial ovarian tumors including 22 cases of benign ovarian tumors, nine cases of borderline tumors, and 16 cases of invasive cancers were used to evaluate expression of p53, p27 and Jab1 proteins by immunohistochemical methods. RESULTS: p53 protein was expressed in 13.6% of the benign tumors, 44.4% of the borderline tumors and 62.5% of the malignant tumors and p27 protein was expressed in 95.5% of the benign tumors, 66.7% of the borderline tumors, and 37.5% of the malignant tumors. Expression of Jab1 protein was observed in 22.7% of the benign tumors, 77.8% of the borderline tumors and 62.5% of the malignant tumors. Expressions of p53, p27 and Jab1 proteins in malignant tumors were all higher than in benign tumors and the expression of p27 protein in malignant tumors was lower than in benign tumors (p < 0.05). Expression of Jab1 protein in borderline tumors was significantly higher than in benign tumors (p < 0.05). CONCLUSIONS: Expression of p53, p27 and Jab1 proteins can be used to discriminate between benign and malignant tumors in epithelial ovarian tumors.

Interleukin-13/-4-induced oxidative stress contributes to death of hippocampal neurons in aß1-42-treated hippocampus in vivo.

AIMS: The present study examined whether Aß(1-42) can induce endogenous expression of interleukin-13 (IL-13) or (IL-4) within activated microglia in the rat hippocampus in vivo. We further investigated whether these cytokines mediate ROS/RNS generation through activation of NADPH oxidase and/or inducible nitric oxide synthase (iNOS), and thus contribute to the degeneration of hippocampal neurons in vivo. RESULTS: Here, we show that IL-13 and IL-4, endogenously expressed in Aß(1-42)-activated microglia in hippocampus in vivo, contribute to degeneration of hippocampal neurons in vivo. Neutralization of IL-13 and IL-4 protected hippocampal neurons in vivo against neurotoxicity by inhibiting activation of microglial NADPH oxidase and iNOS, resulting in attenuation of ROS generation and oxidative damage of protein, lipid and DNA. INNOVATION: To our knowledge, this is the first study to demonstrate the possible involvement of endogenously expressed IL-13 and/or IL-4 in activated microglia after Aß(1-42) injection in the degeneration of hippocampal neurons in vivo. The current findings suggest that the deleterious effects of microglia-derived endogenous IL-13 and/or IL-4 are involved in oxidative stress-mediated neurodegenerative diseases, such as AD. CONCLUSION: We carefully hypothesize that IL-13 and IL-4, well-known as anti-inflammatory cytokines might serve as neurotoxic mediators by enhancing microglia-derived oxidative stress in Aß(1-42)-treated hippocampus in vivo.

Comprehensive immunohistochemical studies on canine necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME).

In dogs, there are several idiopathic meningoencephalitides, such as necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME). Although they are often assumed to be immune mediated, the etiology of these diseases remains elusive. In this study, the histopathology of the lesions caused by these conditions and the inflammatory cell populations produced in response to them were examined among dogs affected with GME, NME, or NLE to understand their pathogeneses. The brain tissues of dogs with NME (n = 25), NLE (n = 5), or GME (n = 9) were used. The inflammatory cells were identified by immunohistochemistry using antibodies against CD3, IgG, CD20, CD79acy, and CD163. In NME and NLE, malacic changes were located in the cerebral cortex, as well as the cerebral white matter and thalamus, respectively. The distribution of the brain lesions in NME and NLE was breed specific. In GME, granulomatous lesions that were mostly composed of epithelioid macrophages were observed in the cerebral white matter, cerebellum, and brainstem. Although the proportions of IgG-, CD20-, and CD79acy-positive cells (B cells) were not significantly different among the GME, NME, and NLE lesions, that of CD3-positive cells (T cells) was increased in GME. In NME and NLE, CD163-positive cells (macrophages) had diffusely infiltrated the cerebral cortex and white matter, respectively. However, in GME, CD163-positive cells accumulated around the blood vessels in the cerebral and cerebellar white matter. The distributions of these lesions were quite different among GME, NME, and NLE, whereas there were no marked differences in the proportions of inflammatory cells.

Childhood obesity in ambulatory children and adolescents with spastic cerebral palsy in Korea.

OBJECTIVE: Childhood obesity is an emerging health issue in Korea. We investigated the prevalence of obesity and its trend over time in ambulatory Korean children with CP. METHODS: We retrospectively reviewed the medical records of 1,397 children with CP between 1995 and 2008. The data were grouped into 4 time periods (1995-1997, 1998-2002, 2003-2004 and 2005-2008). The prevalence of obesity over each period and its relationship to gender, birth weight, age, and gross motor function classification system were investigated. RESULTS: The percentage of obese children was 5.8%, overweight children 11.2%, and underweight children 10.4%. The prevalence of obesity significantly increased from the first time period to the third time period. The prevalence of obesity found in our study was significantly lower than the report from the U.S.A. during same time period between 1994 and 2004 (p<0.05). The prevalence of obesity significantly decreased with age as well. CONCLUSIONS: The prevalence of obesity in our subjects significantly increased and has reached a plateau in recent years. Compared to the prevalence of childhood obesity in ambulatory individuals with CP in the U.S.A. study, the prevalence in our study was significantly lower.

IL-32γ inhibits cancer cell growth through inactivation of NF-κB and STAT3 signals.

Several studies have shown physiological functions of interleukin (IL)-32, a novel cytokine. However, the role of IL-32 in cancer development has not been reported. In this study, we showed that IL-32γ inhibited tumor growth in IL-32γ-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32γ-transfected colon cancer cells (SW620). The inhibitory effect of IL-32γ on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-κB (NF-κB) and of signal transducer and activator of transcription 3 (STAT3). The expression of antiapoptotic, cell proliferation and tumor-promoting genes (bcl-2, X-chromosome inhibitor of apoptosis protein (IAP), cellular IAP and cellular FADD-like IL-1ß-converting enzyme-inhibitory protein, cyclin D), cyclin-dependent kinase 4, cycolooxygenase-2 and inducible nitric oxide synthase was decreased, whereas the expression of apoptotic target genes (caspase-3 and -9, bax) increased. In tumor, spleen and blood, the number of cytotoxic CD8(+) T cells and CD57(+) natural killer cells and the levels of IL-10 increased, but that of tumor necrosis factor-α (TNF-α), IL-1ß and IL-6 decreased. We also found that forced overexpression of IL-32γ inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-κB and STAT3 in vitro. In addition, when IL-32γ was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32γ antibody, IL-32γ-induced colon cancer cell growth inhibition, the IL-32γ-induced decrease of TNF-α, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-κB and STAT3 augmented IL-32γ-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32γ in cancer development.

Oral administration of Lactobacillus strains from Kimchi inhibits atopic dermatitis in NC / Nga mice.

AIMS: Atopic dermatitis (AD) is marked by elevated levels of immunoglobulin E and skin lesions such as oedema and haemorrhage. Kimchi is a Korean fermented food that contains beneficial bacteria for human health. In this study, Lactobacillus plantarum CJLP55, CJLP56, CJLP133 and CJLP136 isolated from Kimchi were investigated for their capacity to inhibit AD. METHODS AND RESULTS: The three strains, CJLP55, CJLP133 and CJLP136, suppressed AD-like skin lesions, high serum IgE levels and epidermal thickening. The three strains diminished the accumulation of eosinophils and mast cells into topical inflammatory sites and the enlargement of axillary lymph nodes, which are responsible for the dorsal dermatitis. CJLP55, CJLP133 and CJLP136 decreased production of type 2 cytokines such as IL-4 and IL-5 in lymph node cell culture. CJLP133 and CJLP136 increased IFN-γ secretion, while CJLP55 enhanced IL-10 production. CONCLUSIONS: The three strains isolated from Kimchi suppress house-dust mite-induced dermatitis in NC/Nga mouse, a representative animal model of human AD. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggest that lactobacilli isolated from Kimchi inhibit AD, probably by altering the balance of Th1/Th2 ratio or inducing IL-10 production.

Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury.

While intraventricular administration of epidermal growth factor (EGF) expands the proliferation of neural stem/progenitor cells in the subventricular zone (SVZ), overexpression of brain-derived neurotrophic factor (BDNF) is particularly effective in enhancing striatal neurogenesis. We assessed the induction of striatal neurogenesis and consequent functional recovery after chronic infusion of BDNF and EGF in an adult animal model of neonatal hypoxic-ischemic (HI) brain injury. Permanent brain damage was induced in CD-1 (ICR) mice (P7) by applying the ligation of unilateral carotid artery and hypoxic condition. At 6 weeks of age, the mice were randomly assigned to groups receiving a continuous 2-week infusion of one of the following treatments into the ventricle: BDNF, EGF, BDNF/EGF, or phosphate buffered saline (PBS). Two weeks after treatment, immunohistochemical analysis revealed an increase in the number of BrdU(+) cells in the SVZ and striata of BDNF/EGF-treated mice. The number of new neurons co-stained with BrdU and betaIII-tubulin was also significantly increased in the neostriata of BDNF/EGF-treated mice, compared with PBS group. In addition, the newly generated cells were expressed as migrating neuroblasts labeled with PSA-NCAM or doublecortin in the SVZ and the ventricular side of neostriata. The new striatal neurons were also differentiated as mature neurons co-labeled with BrdU(+)/NeuN(+). When evaluated post-surgical 8 weeks, BDNF/EGF-treated mice exhibited significantly longer rotarod latencies at constant speed (48 rpm) and under accelerating condition (4-80 rpm), relative to PBS and untreated controls. In the forelimb-use asymmetry test, BDNF/EGF-treated mice showed significant improvement in the use of the contralateral forelimb. In contrast, this BDNF/EGF-associated functional recovery was abolished in mice receiving a co-infusion of 2% cytosine-b-d-arabinofuranoside (Ara-C), a mitotic inhibitor. Induction of striatal neurogenesis by the intraventricular administration of BDNF and EGF promoted functional recovery in an adult animal model of neonatal HI brain injury. The effect of Ara-C to completely block functional recovery indicates that the effect may be the result of newly generated neurons. Therefore, this treatment may offer a promising strategy for the restoration of motor function for adults with cerebral palsy (CP).