Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation.

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. However, functional roles of local brain circadian clocks in memory performance remains unclear. Here, we show that hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8-12, independently of retention delay, encoding time and Zeitgeber entrainment cue. This altered retrieval profile was associated with downregulation of hippocampal Dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Consistently, pharmacological activation of cAMP-signals or D1/5Rs rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation.

Risk factors for neurological complications in complete hemolytic uremic syndrome caused by Escherichia coli O157.

BACKGROUND: The aim of the present study was to investigate the predictive parameters for encephalopathy in complete hemolytic uremic syndrome (HUS) in a large outbreak of O157: H7 infection in 1996. METHODS: A total of 182 inpatients, 71 of whom had complete HUS, including 12 patients with neurological complications, and 46 colitis patients were studied. Presenting signs and symptoms (n = 115) and laboratory data (n = 69) were analyzed using monovariate and multivariate analysis. RESULTS: After adjusting for age and gender, logistic regression showed that presenting symptoms such as bloody diarrhea (odds ratio [OR] = 7.39), proteinuria (OR = 6.16), hematuria (OR = 8.31), oliguria (OR = 17.4) and a pale face (OR = 10.7) were useful for predicting complete HUS. Also, increased white blood cell counts >12,000 microL/mL (OR = 10.0) and C-reactive protein >1.5 mg/dL (OR = 7.39) at the onset of infection, were useful as predictive laboratory parameters. To predict neurological complications in complete HUS patients, the average daily increase of lactate dehydrase >1200 IU/L per day (OR = 26.3) and creatinine >0.5 mg/dL per day (OR = 12) were found to be useful on multivariate logistic regression. CONCLUSION: There are useful predictive clinical factors for neurological complications in complete HUS.

Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA.

We obtained 7,566 peripheral blood mononuclear cell (PBMC) samples from 2,332 individuals and screened them for human herpesvirus infection. We identified five individuals who persistently harbored high copy numbers of human herpesvirus 6 (HHV-6) DNA in their PBMCs. HHV-6 DNA was also detected in other somatic tissues of these individuals. Five additional cases were identified among their family members. For two of these families, chromosomally integrated HHV-6 DNA (CIHHV-6) was detected in the PBMCs by fluorescence in situ hybridization. The prevalence of CIHHV-6 among all the subjects was 0.21%. The HHV-6 DNA was variant B in four families and variant A in one family. Antibodies to immediate early antigen and glycoprotein B were detected in 57 and 14% of individuals with CIHHV-6 and in 0 and 60% of healthy volunteers without CIHHV-6, respectively. HHV-6 could not be isolated from PBMCs with CIHHV-6. These cases shared no clinical features, and included three healthy individuals. Our data suggest that CIHHV-6 is rare but detectable in the general population and that hereditary transmission is one of the routes of HHV-6 transmission.

[Multicenter study of occipital lobe epilepsy in childhood: clinical characteristics].

We investigated the clinical characteristics of 54 patients with childhood onset occipital lobe epilepsy (OLE). There were 25 patients of symptomatic OLE (cortical dysplasia, post encephalitis or encephalopathy, brain tumor and so on), and 29 cases of cryptogenic OLE. Eighteen patients had positive visual symptoms such as flash light, bright spots and sparks of light, 23 patients had negative ones such as scotoma, hemianopia and amaurosis and 10 patients had other complicated visual symptoms such as change of the shape or colors. Young children complained of simple visual phenomena. The youngest patient who could explain visual symptom was 3 years old. All 3 patients with visual field defects had cortical dysplasia in occipital lobe. Ictal SPECT study showed wide hyperperfusion areas in the temporo-parieto-occipital lobe in most of patients with abnormal MRI findings. CBZ and VPA were prescribed in most cases, and were effective in 65% and 60% of the patients, respectively. Seizure prognosis was relatively good. Seizures disappeared in 56% of the patients with symptomatic OLE and 79% of those with cryptogenic OLE.

Enhancement of immunity against VZV by giving live varicella vaccine to the elderly assessed by VZV skin test and IAHA, gpELISA antibody assay.

The enhancement of immunity against varicella-zoster vaccine (VZV) by subcutaneous injection of a live varicella vaccine was assessed by the VZV skin test for cell-mediated immunity (CMI), and immunoadherence hemagglutination assay (IAHA) and gpELISA antibody assays in the elderly people of 50-79 years of age. A total of 127 subjects were examined: 79 aged 50-59, 25 aged 60-69, and 25 aged 70-79. All were seropositive by the gpELISA assay (one was seronegative in the IAHA antibody assay). In contrast, a notable decline was observed in the VZV skin test with increasing age. Negative reaction was observed in 16/79 (20.2%) of the subjects in their 50s, 12/25 (48.0%) in their 60s and 14/25 (56.0%) in the 70s. After the vaccination, the results of the VZV skin test changed from negative to positive in 15/16 (91.8%) of subjects in their 50s, 11/12 (91.7%) in their 60s and 12/14 (85.7%) in their 70s. The mean antibody titer in the IAHA and the gpELISA increased approximately two-fold after the vaccination in each group. Immunity to VZV in 35 elderly subjects who were vaccinated previously was followed up for 4 years. All were positive by the VZV skin test after the previous vaccination. After 4 years, 31 (88.6%) were positive by the skin test, 4 were negative and became positive after revaccination. Although this study was uncontrolled open study, the results suggest that administering live varicella vaccine to the elderly is effective for enhancing immunity, particularly CMI to VZV.

Human herpesvirus 6B infection of the large intestine of patients with diarrhea.

Four patients had severe diarrhea after undergoing stem cell transplantation. Human herpesvirus 6B (HHV-6B) DNA was detected in large intestine tissue specimens and in peripheral blood mononuclear cells. In situ hybridization was positive for HHV-6B DNA in the nuclei of goblet cells and, sometimes, in the histiocytes in the submucous region of the large intestine, which suggests that HHV-6B may infect and reactivate in these cells.

Shift of serum osteocalcin components between cord blood and blood at day 5 of life.

Vitamin K deficiency is a relatively common condition in neonates. However, the role of vitamin K in neonatal bone metabolism remains to be determined. Osteocalcin (OC) is the most abundant noncollagenous protein in bone, and is regulated to be gamma-carboxylated by vitamin K. In this study, we measured gamma-carboxylated osteocalcin (Gla-OC) and non- or undercarboxylated osteocalcin (Glu-OC) separately, and examined the effects of vitamin K on osteocalcin metabolism. Eighteen full-term healthy neonates were enrolled in this study. In the cord and d-5 blood samples, the OC levels were determined by three different methods to examine the intact OC by immunoradiometric assay (IRMA), Gla-OC, and Glu-OC. Serum vitamin K fractions, hepaplastin test, and type 1 procollagen carboxyl extension peptide were also determined. Urine samples were also collected from the first voiding and on d 5 to determine urinary pyridinoline, deoxypyridinoline, and gamma-carboxylated glutamic acid. Serum levels of phylloquinone (PK) and menaquinone (MK)-4 increased on d 5 following vitamin K administration and increased intake in breast milk and/or formula. The OC levels determined by IRMA did not change between cord and d-5 blood samples, but the Gla-OC level increased remarkably and Glu-OC reduced to a negligible level. OC in cord blood is mainly Glu-OC, and Glu-OC is replaced with Gla-OC within 5 d of life after vitamin K supplement. The IRMA assay fails to distinguish Gla-OC from Glu-OC and caution is needed to estimate bone turnover with this method in the perinatal period.

High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients.

Human herpesvirus 6 (HHV-6) infection in recipients of cord blood stem cell transplants (CBSCTs) was estimated by semiquantitative and real-time quantitative polymerase chain reaction (PCR) and reverse-transcription PCR. Of the CBSCT recipients, 7 (70%) of 10 had active HHV-6 infection after transplantation, and all 7 were inferred from their age to have already had a primary infection. Because HHV-6 DNA is seldom detected in cord blood, these cases were considered likely to represent reactivation. In contrast, the 3 patients without HHV-6 infection were all believed to be naive regarding HHV-6 primary infection because of their age and the results of PCR assays given before the transplantation procedure. The incidence of HHV-6 infection after transplantation was significantly higher (P <.05) than after bone marrow (BM) transplantation and peripheral blood stem cell (PBSC) transplantation, when recipients without primary HHV-6 infection prior to transplantation were excluded (CBSCT, 100%; BMT/PBSCT, 56.3%). Real-time PCR revealed a higher level of viral DNA in the peripheral blood mononuclear cells from CBSCT recipients than from BMT/PBSCT recipients or patients with exanthem subitum (P <.05). HHV-6 mRNA of the U79/80 gene was also detected by reverse-transcription PCR in all analyzed patients with HHV-6 infection. Its detection was correlated with the emergence of viral DNA in the plasma and symptoms such as fever and rash. Thus, HHV-6 infection was more frequent and the viral load was higher in CBSCT recipients with prior primary infection.

Human herpesvirus-6 infection in neonates: Not protected by only humoral immunity.

BACKGROUND: Infants are usually protected from various viral infections, including human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7) infections, during the early infantile period by antibodies transferred from their mothers. However, rare cases of exanthem subitum (ES) in neonates have been described in published reports. METHODS: From the infantile patients of febrile illness, HHV-6 and HHV-7 DNA were examined by the polymerase chain reaction method. Antibodies to HHV-6 and HHV-7 were detected by indirect immuno-fluorescence assay and neutralization test. Viral isolation was attempted from the patient's peripheral blood mononuclear cells (PBMC) during the acute phase of febrile illness. RESULTS: Human herpesvirus-6 was verified virologically in two neonates who were clinically diagnosed as ES within the first month of life. Although high copies of HHV-6 DNA were detected in their PBMC during the acute phase, the isolation of HHV-6 from their PBMC was not successful. Neutralizing antibodies to HHV-6 were detected in sera of the acute phase, and those antibodies were considered to be transferred from their mothers. Antibody titers showed fourfold elevation in sera of the convalescent phase. The HHV-6 infection occurred despite the presence of pre-existing maternal antibody. Human herpesvirus-7 and HHV-7 DNA were not detected from their clinical samples. CONCLUSIONS: This observation suggests that HHV-6 infection could not be protected by only humoral immunity.

P wave signal averaged electrocardiography in patients undergoing the Fontan operation.

OBJECTIVES: Supraventricular arrhythmias are one of the most common and fatal sequelae of the Fontan operation. P wave triggered signal averaged electrocardiography was performed in patients undergoing the Fontan operation to evaluate the presence of atrial degeneration, and to clarify which factors affected the development of atrial arrhythmias. METHODS: P wave triggered signal averaged electrocardiography was recorded in 14 patients after the Fontan-type operation (conventional atriopulmonary connection in 5 and total cavopulmonary connection in 9) and 15 healthy controls. The duration and area of the filtered P wave, and the signal magnitudes (M20, M30) at 20 Hz and 30 Hz obtained from the frequency domain analysis of the P wave (M20, M30) were evaluated and compared with the hemodynamic data. RESULTS: The duration and area of the filtered P wave, M20 and M30 in patients after atriopulmonary connection were significantly greater than in those after total cavopulmonary connection and the control subjects (p < 0.05). M20 was significantly greater in patients after total cavopulmonary connection than in the control subjects. Right atrial volume in patients after atriopulmonary connection was significantly (p < 0.001) larger than in patients after total cavopulmonary connection (p < 0.05). There were no significant differences in other indices including atrial pressure between the two groups. CONCLUSIONS: Our results suggest that the substrate for atrial arrhythmias such as atrial myocardial degeneration and fibrosis is frequently present in patients after the Fontan operation, especially after atriopulmonary connection. Thus, the enlarged right atrium may be involved in the presence of a substrate for atrial arrhythmias. The developmental risk for late atrial arrhythmias seems to be present even in patients after total cavopulmonary connection.

Unverricht-Lundborg disease with cystatin B gene abnormalities.

The clinical, neurophysiologic, and genetic findings in two Japanese patients with the Unverricht-Lundborg type of progressive myoclonus epilepsy are described. The cystatin B gene of Patient 1 exhibited expansion of the dodecamer (12-mer) repeat located in the 5' region and a point mutation (G-->A mutation) in exon 2. The cystatin B gene of Patient 2 exhibited homozygous expansion of the dodecamer repeat. Both parents of Patient 2 were heterozygous carriers. The two patients had a similar clinical course, and their symptoms were similar to those of previously reported patients in Finland. They both had a good response to zonisamide and low-dose primidone. We recommend that zonisamide and low-dose primidone should be introduced as the first drugs of choice for the treatment of patients with the Unverricht-Lundborg type of progressive myoclonus epilepsy.

A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome.

A T-to-G transition at nucleotide 9176 (T9176G) in the mitochondrial adenosine triphosphate 6 gene (MTATP6) was detected in two siblings with Leigh syndrome. Heteroplasmy was observed in the mother's leukocytes. The T9176G mutation changes a highly conserved leucine residue to an arginine in subunit 6 of ATPase and is maternally inherited like mutations in the other mitochondrial genes. Another mutation in the same codon (T9176C) has been previously reported in Leigh syndrome. This gives strong support to the relevance of MTATP6 dysfunction in Leigh syndrome and the importance of leucine at that position.