Hiroyuki Moriuchi

Exposure to bacterial products renders macrophages highly susceptible to T-tropic HIV-1.

Microbial coinfections variably influence HIV-1 infection through immune activation or direct interaction of microorganisms with HIV-1 or its target cells. In this study, we investigated whether exposure of macrophages to bacterial products impacts the susceptibility of these cells to HIV-1 of different cellular tropisms. We demonstrate that () macrophages exposed to bacterial cell wall components such as lipopolysaccharide (LPS) (Gram-negative rods), lipoteichoic acid (Gram-positive cocci), and lipoarabinomannan (Mycobacteria) become highly susceptible to T cell (T)-tropic HIV-1 (which otherwise poorly replicate in macrophages) and variably susceptible to macrophage (M)-tropic HIV-1; () LPS-stimulated macrophages secrete a number of soluble factors (i.e., chemokines, interferon, and proinflammatory cytokines) that variably affect HIV infection of macrophages, depending on the virus phenotype in question; and () LPS-stimulated macrophages express CCR5 (a major coreceptor for M-tropic HIV-1) at lower levels and CXCR4 (a major coreceptor for T-tropic HIV-1) at higher levels compared with unstimulated macrophages. We hypothesize that a more favorable environment for T-tropic HIV-1 and a less favorable or even unfavorable environment for M-tropic HIV-1 secondary to exposure of macrophages to those bacterial products may accerelate a transition from M- to T-tropic viral phenotype, which is indicative of disease progression.

Spontaneous In Vivo Reversion of an Inherited Mutation in the Wiskott-Aldrich Syndrome

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease, arising from mutations of the WAS-protein (WASP) gene. Previously, we have reported that mononuclear cells from WAS patients showed lack/reduced of the intracellular WASP (WASPdim) by flow cytometric analysis, and analysis of WASP by flow cytometry (FCM-WASP) was useful for WAS diagnosis. In this study, we report a WAS patient who showed the unique pattern of FCM-WASP. The patient had the small population of normal expression of WASP (WASPbright) mononuclear cells together with the major WASPdim population. The WASPbright cells were detected in T cells, not in B cells or in monocytes. Surprisingly, the molecular studies of the WASPbright cells revealed that the inherited mutation of WASP gene was reversed to normal. His mother was proved as a WAS carrier, and HLA studies and microsatellite polymorphic studies proved that the WASPbright cells were derived from the patient himself. Therefore, we concluded that the WASPbright cells were resulted from spontaneous in vivo reversion of the inherited mutation. Furthermore, the scanning electron microscopic studies indicated that WASP-positive cells from the patient restored the dense microvillus surface projections that were hardly observed in the WASPdim cells. This case might have significant implications regarding the prospects of the future gene therapy for WAS patients.

Comparison of kangaroo care and standard care: behavioral organization, development, and temperament in healthy, low-birth-weight infants through 1 year.

OBJECTIVE: To determine whether Kangaroo Care (KC) for healthy, low-birth-weight (LBW) infants can promote better behavioral and developmental outcomes.STUDY DESIGN: In this historical control study, 26 infants in the KC group (GA: 34.3±2.5 weeks, BW: 1833.9±167.6 g) and 27 infants in the comparison group who received the standard medical–nursing care (34.6±2.3 weeks, 1850.9±156.7 g) were analyzed by the Neonatal Behavioral Assessment Scale (NBAS) at 40 weeks of postmenstrual age, the Bayley Scales of Infant Development and the Careys Infant Temperament Questionnaire (ITQ) at 6 and 12 months corrected ages.RESULTS: KC infants had significantly higher NBAS scores in Orientation, State Regulation, and Supplementary items; lower Intensity scores and higher Mood scores at 6 months on the ITQ; and higher Bayley Scales score at 12 months.CONCLUSION: KC effectively promoted neonatal behavioral organization and enhanced developmental outcome over the first year of life for LBW infants.

Maternal body mass index and gestational weight gain and their association with perinatal outcomes in Viet Nam

OBJECTIVE To examine the association between gestational weight gain and maternal body mass index (BMI) among Vietnamese women and the risk of delivering an infant too small or too large for gestational age. METHODS A prospective health-facility-based study of 2989 pregnant Vietnamese women was conducted in the city of Nha Trang in 2007-2008. Cubic logistic regression was used to investigate the association of interest. Infants were classified into weight-for-gestational-age categories according to weight centiles for the Asian population. Gestational age was based on the date of last menstrual period and adjusted by the results of first-trimester ultrasound. FINDINGS BMI was low (< 18.5), normal (18.5-22.9) and high (≥ 23.0) in 26.1%, 65.4% and 8.5% of the women, respectively. In each of these BMI categories, the percentage of women who delivered infants too small for gestational age was 18.1, 10.0 and 9.4, respectively, and the mean gestational weight gain was 12.5 kg (standard deviation, SD: ± 3.6), 12.2 kg (SD: ± 3.8) and 11.5 kg (SD: ± 4.7), respectively. Among women with low BMI, the risk of delivering an infant too small for gestational age ranged from approximately 40% if the gestational weight gain was < 5 kg to 20% if it was 5-10 kg. CONCLUSION Having a low BMI, commonly found in Viet Nam, puts women at risk of delivering an infant too small for gestational age, especially when total maternal gestational weight gain is < 10 kg.

The calming effect of a maternal breast milk odor on the human newborn infant

We examined the effects of the odors from mothers milk, other mothers milk and formula milk on pain responses in newborns undergoing routine heelsticks. Forty-eight healthy infants were assigned to four groups, an own mothers breast milk odor group (Own MM), another mothers breast milk odor group (Other MM), a formula milk odor group (Formula M) and a control group. To assess infant distress in response to the heelsticks, their crying, grimacing and motor activities were recorded during the experiment as behavioral indices of the pain response. After the heelstick, the behavioral indices of the Own MM group were lower than those of other groups. By contrast, the Other MM and Formula M groups showed no significant changes compared with the Control group. We also measured salivary cortisol concentration as a biochemical index in Control and Own MM infants before and after heelstick. After the heelstick, the level of salivary cortisol was significantly increased in Control infants, but not in Own MM infants. These results suggest that pain is relieved in human newborns when they are exposed to odors from their mothers milk.

A Milk Protein Lactoferrin Enhances Human T Cell Leukemia Virus Type I and Suppresses HIV-1 Infection

Human T cell leukemia virus type I (HTLV-I) and HIV-1, causative agents of adult T cell leukemia/lymphoma and AIDS, respectively, are transmitted vertically via breast milk. Here we demonstrate that lactoferrin, a milk protein that has a variety of antimicrobial and immunomodulatory activities, facilitates replication of HTLV-I in lymphocytes derived from asymptomatic HTLV-I carriers and transmission to cord blood lymphocytes in vitro. Transient expression assays revealed that lactoferrin can transactivate HTLV-I long terminal repeat promoter. In contrast, lactoferrin inhibits HIV-1 replication, at least in part, at the level of viral fusion/entry. These results suggest that lactoferrin may have different effects on vertical transmission of the two milk-borne retroviruses.

Role of varicella-zoster virus in stroke syndromes

Stroke syndromes of childhood are very rare and develop idiopathically or secondary to primary cerebrovascular disease or a variety of medical conditions. The causative role of varicella-zoster virus (VZV) infection in vasculopathy in the central nervous system (CNS) has been described in both immunocompetent and immunocompromised hosts; both varicella (primary infection) and herpes zoster (reactivation) have been associated with this disorder. 3 Contralateral hemiparesis usually results from infarction of the ipsilateral middle cerebral artery several weeks after the onset of herpes zoster ophthalmicus (HZO). We report a 12year-old girl who developed right facial palsy and left hemiparesis 9 months after an episode of HZO on the right side and review the previously reported cases of VZV-associated stroke syndromes.

Mutation and Gene Copy Number Analyses of Six Pituitary Transcription Factor Genes in 71 Patients with Combined Pituitary Hormone Deficiency: Identification of a Single Patient with LHX4 Deletion

CONTEXT Mutations of multiple transcription factor genes involved in pituitary development have been identified in a minor portion of patients with combined pituitary hormone deficiency (CPHD). However, copy number aberrations involving such genes have been poorly investigated in patients with CPHD. OBJECTIVE We aimed to report the results of mutation and gene copy number analyses in patients with CPHD. SUBJECTS AND METHODS Seventy-one Japanese patients with CPHD were examined for mutations and gene copy number aberrations affecting POU1F1, PROP1, HESX1, LHX3, LHX4, and SOX3 by PCR-direct sequencing and multiplex ligation-dependent probe amplification. When a deletion was indicated, it was further studied by fluorescence in situ hybridization, oligoarray comparative genomic hybridization, and serial sequencing for long PCR products encompassing the deletion junction. RESULTS We identified a de novo heterozygous 522,009-bp deletion involving LHX4 in a patient with CPHD (GH, TSH, PRL, LH, and FSH deficiencies), anterior pituitary hypoplasia, ectopic posterior pituitary, and underdeveloped sella turcica. We also identified five novel heterozygous missense substitutions (p.V201I and p.H387P in LHX4, p.T63M and p.A322T in LHX3, and p.V53L in SOX3) that were assessed as rare variants by sequencing analyses for control subjects and available parents and by functional studies and in silico analyses. CONCLUSIONS The results imply the rarity of abnormalities affecting the six genes in patients with CPHD and the significance of the gene copy number analysis in such patients.

Cathepsin G, a Neutrophil-Derived Serine Protease, Increases Susceptibility of Macrophages to Acute Human Immunodeficiency Virus Type 1 Infection

ABSTRACT Neutrophils dominate acute inflammatory responses that generally evolve into chronic inflammatory reactions mediated by monocyte/macrophages and lymphocytes. The latter cell types also serve as major targets for human immunodeficiency virus type 1 (HIV-1). In this study we have investigated the role of neutrophil products, particularly cathepsin G, in HIV infection. Cathepsin G induced chemotaxis and production of proinflammatory cytokines by macrophages but not CD4+ T cells. Pretreatment with cathepsin G markedly increased susceptibility of macrophages but not CD4+ T cells to acute HIV-1 infection. When macrophages were exposed to pertussis toxin prior to cathepsin G treatment, the cathepsin G-mediated effect was almost abrogated, suggesting that enhancement of HIV-1 replication by cathepsin G requires Gi protein-mediated signal transduction. Although prolonged exposure to cathepsin G suppressed HIV infection of macrophages, serine protease inhibitors, which are exuded from the bloodstream later during inflammatory processes, neutralized the inhibitory effect. Neutrophil extracts or supernatants from neutrophil cultures, which contain cathepsin G, had effects similar to purified cathepsin G. Thus, cathepsin G, and possibly other neutrophil-derived serine proteases, may have multiple activities in HIV-1 infection of macrophages, including chemoattraction of monocyte/macrophages (HIV-1 targets) to inflamed tissue, activation of target cells, and increase in their susceptibility to acute HIV-1 infection.

Severe postnatal cytomegalovirus infection in a very premature infant.

Several studies have reported that postnatally acquired cytomegalovirus (CMV) infection can cause sepsis-like syndrome in premature infants. We here report a 622-gram birth weight male infant of 23 weeks’ gestation who had sepsis-like syndrome and pneumonia. Substantial CMV loads were detected in peripheral blood cells, plasma, and urine when the patient was in crisis, but was decreased in parallel to clinical improvement without using ganciclovir. CMV DNA was not detected from his umbilical cord or Guthrie card, even by highly sensitive real-time PCR. Molecular profiles were indistinguishable between the CMV strain isolated from his urine and that from maternal breast milk, indicating postnatal acquisition of CMV through breast milk. Although he had transient hearing impairment, his neurodevelopmental outcome of 30 months of corrected age was normal. Further accumulation of clinical and virological data in postnatal CMV infection is necessary for evaluating the severity and selecting patients requiring antiviral therapy.