The Contactless Vital Sensing System Precisely Reflects R-R Interval in Electrocardiograms of Healthy Subjects.

BACKGROUND: The aim of the present study was to investigate the validity of the contactless vital sensing system that we previously developed. METHODS: A total of 111 healthy Japanese subjects were recruited from the University of Occupational and Environmental Health and the Panasonic Corporation AVC Networks Company. All subjects underwent an evaluation using the contactless vital sensing system and electrocardiography (ECG). We compared the R-R interval obtained using the new contactless sensing system to that obtained using ECG. RESULTS: A very strong correlation was observed between the instruments. CONCLUSIONS: This result confirms the validity of the new contactless sensing system in evaluating healthy subjects.

Universal varicella vaccine immunization in Japan.

In 1974, Japanese scientists developed a live attenuated varicella vaccine based on the Oka strain. The efficacy of the vaccine for the prevention of varicella has been primarily demonstrated in studies conducted in the United States following the adoption of universal immunization using the Oka strain varicella vaccine in 1996. Although the vaccine was developed by Japanese scientists, until recently, the vaccine has been administered on a voluntary basis in Japan resulting in a vaccine coverage rate of approximately 40%. Therefore, Japan initiated universal immunization using the Oka strain varicella vaccine in November 2014. Given the transition from voluntary to universal immunization in Japan, it will also be important to monitor the epidemiology of varicella and herpes zoster. The efficacy and safety of co-administration of the varicella vaccine and measles, mumps, and rubella vaccine have been demonstrated in many countries; however, there was no data from Japan. In order to adopt the practice of universal immunization using the Oka strain varicella vaccine in Japan, data demonstrating the efficacy and safety of co-administration of varicella vaccine and measles and rubella (MR) vaccine were required. Additionally, we needed to elucidate the appropriate time interval between the first and second administrations of the vaccine. It is also important to differentiate between wild type and Oka vaccine type strains in herpes zoster patient with past history of varicella vaccine. Thus, there are many factors to consider regarding the adoption of universal immunization in Japan to control varicella zoster virus (VZV) infections.

Pathogenesis of Severe Neutropenia in Patients With Primary Human Herpesvirus 6B Infection.

BACKGROUND: Although myelosuppression caused by human herpesvirus 6B (HHV-6B) reactivation in transplant recipients has been extensively investigated, the pathophysiological mechanisms of severe neutropenia in primary HHV-6B infection remain unclear. PROCEDURE: Fifty-four patients with primary HHV-6B infection were evaluated. Hematological examinations and blood sampling were conducted on days 1-4 (pre) and 5-10 (post) after the onset of illness. Severe neutropenia was defined as a neutrophil count less than 500 cells/µL. Patient characteristics, clinical data, and cytokines and chemokines levels were compared between the patients with (n = 16) and without (n = 38) severe neutropenia. RESULTS: Severe neutropenia was detected in samples that were collected between days 5 and 10 after illness. Significantly lower platelet counts (pre, P = 0.048; post, P = 0.032) and regulated on activation, normal T cell expressed and secreted levels (post, P = 0.007) were detected in the patients with neutropenia. Aspartate aminotransferase levels (P = 0.008), and interferon γ-inducible protein-10 (P < 0.0001), monocyte chemoattractant protein-1 (P = 0.005), and monokine induced by interferon γ (P = 0.011) levels were significantly higher in post samples collected from the patients with neutropenia. No differences were observed in any patient characteristics and serum cytokines levels. No bacterial infections were detected during the observation period. CONCLUSIONS: Chemokines may play an important role in the pathogenesis of severe neutropenia in patients with primary HHV-6B infection.

Direct detection of human herpesvirus 6B by the LAMP method using newly developed dry-reagents.

The reliability of the HHV-6B LAMP using the dry-reagent method was evaluated using serum samples obtained from febrile children. The sensitivity of the original and dry-reagent methods was 10 copies/reaction and 100 copies/reaction, respectively. The dry-reagent LAMP method was highly sensitive (94.0%) and specific (96.0%) for the detection of HHV-6B.

Copy numbers of telomeric repeat sequences of human herpesvirus 6B in clinical isolates: possibility of mixed infections.

In order to determine whether mixed infections of human herpesvirus 6B (HHV-6B) occur in immunocompetent and immunocompromised individuals, we examined the copy numbers of telomeric repeat sequences (TRS) of clinical isolates. In clinical isolates obtained from patients with exanthem subitum caused by primary HHV-6B infection, PCR products with HHV-6B TRS ranging between 400 and 800 bp were amplified. PCR products of various sizes were amplified in four clinical isolates from drug-induced hypersensitivity syndrome (DIHS) patients and 15 isolates from hematopoietic stem cell transplant (HSCT) recipients with HHV-6B reactivation. Based on the sequence analysis of the PCR products, the copy numbers of TRS in DIHS and HSCT patients were between 42 and 82 and 22 and >90, respectively. For two of the HSCT recipients, HHV-6B TRS PCR products of different sizes were detected in several isolates from each patient, which suggests mixed HHV-6B infections. In two of the posttransplant HHV-6B encephalitis patients, the sizes of the TRS nested PCR products amplified from the reactivated virus detected in the central nervous system differed from those of the virus detected in initial isolates from peripheral blood mononuclear cells. Taken together, these results suggest that PCR analysis of TRS copy number is a reliable tool for the discrimination of HHV-6B clinical isolates. Additionally, mixed HHV-6B infections occurred in HSCT recipients, and in some cases, compartmentalization of the HHV-6B strains to the central nervous system versus the blood compartment occurred in posttransplant HHV-6B encephalitis patients.

Nationwide survey of rotavirus-associated encephalopathy and sudden unexpected death in Japan.

BACKGROUND: Rotavirus can cause severe complications such as encephalopathy/encephalitis and sudden unexpected death. The incidence of rotavirus-associated encephalopathy/encephalitis or sudden unexpected death remains unknown. To clarify the clinical features of rotavirus-associated encephalitis/encephalopathy and sudden unexpected death, we conducted a nationwide survey in Japan. METHOD: A two-part questionnaire was designed to determine the number of the cases and the clinical features of severe cases of rotavirus infection, including encephalitis/encephalopathy and sudden unexpected death, between 2009 and 2011. RESULT: Of the 1365 questionnaires sent to hospitals, 963 (70.5%) were returned and eligible for analysis. We determined 58 cases of rotavirus-associated encephalitis/encephalopathy and 7 cases of sudden unexpected death. These patients were diagnosed with rotavirus infection by immunochromatography. Although 36/58 (62.1%) encephalitis/encephalopathy patients had no sequelae, 15/58 (25.9%) patients had neurological sequelae, and 7/58 (12.1%) patients had fatal outcomes. Pleocytosis was observed in 9/40 (22.5%) patients and cerebrospinal fluid protein levels were elevated in only 4/40 (10%) patients. Elevated lactate dehydrogenase (LDH) (>500 IU/L) or acidemia (pH<7.15) were related to a poor prognosis. CONCLUSION: We estimate that annual cases of rotavirus-associated encephalitis/encephalopathy and sudden unexpected death were 44.0 and 4.9 cases in Japan, respectively. Elevated LDH (>500 IU/L) or acidemia (pH<7.15) were related to a poor prognosis of the encephalitis/encephalopathy.

Cytokine and chemokine responses in the blood and cerebrospinal fluid of patients with human herpesvirus 6B-associated acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion has become increasingly common among various types of human herpesvirus 6B (HHV-6B) encephalitis at the time of primary viral infection. The aim of the present study is to explore the pathophysiology of HHV-6B-associated acute encephalopathy with biphasic seizures and late reduced diffusion. Five cytokines and five chemokines were measured in serum and cerebrospinal fluid (CSF) obtained from 12 HHV-6B-associated acute encephalopathy with biphasic seizures and late reduced diffusion patients and 19 control exanthem subitum (without complications) patients. Serum interleukin (IL)-10 (P = 0.007) and IL-8 (P = 0.025) were significantly higher in the patients with the disease than controls. Serum IL-1ß (P = 0.034) and monocyte chemoattractant protein (MCP)-1 (P = 0.002) were significantly higher in the controls than patients with the disease. In patients with the disease, IL-10 (P = 0.012), regulated on activation normal T cell expressed and secreted (RANTES; P = 0.001), and monokine induced by interferon γ (MIG; P = 0.001) were significantly higher in serum than CSF, meanwhile IL-6 (P = 0.034), IL-8 (P = 0.034), and MCP-1 (P = 0.001) were significantly higher in CSF than serum. Additionally, serum IL-10 was significantly higher in the disease patients with sequelae than those without sequelae (P = 0.016). Several cytokines and chemokines may be associated with the pathogenesis of acute encephalopathy with biphasic seizures and late reduced diffusion. Moreover, the regulation of cytokine networks appears to be different between peripheral blood (systemic) and central nervous system.

Cycling probe technology to quantify and discriminate between wild-type varicella-zoster virus and Oka vaccine strains.

Rapid differentiation between wild-type varicella zoster virus (VZV) and Oka-vaccine (vOka) strains is important for monitoring side reactions of varicella vaccination. To develop a high-throughput molecular diagnostic method for the differentiation of wild-type VZV and vOka strains based on cycling probe technology. The primers were designed to amplify common sequences spanning a single nucleotide polymorphism (SNP) in gene 62 of VZV. DNA-RNA chimeric probes (cycling probes) were designed to detect the SNP at nucleotide 105705. The cycling probe real-time PCR assays for VZV wild-type and vOka strains specifically amplified plasmids containing target sequences that ranged between 10 and 1×10(6) copies per reaction. The inter- and intra-assay coefficients of variation were less than 5%. After initial validation studies, the clinical reliability of this method was evaluated using 38 swab samples that were collected from patients suspected of being zoster. Compared to the loop mediated isothermal amplification method, which is defined as the gold standard, cycling probe real-time PCR was highly sensitive and specific. The cycling probe real-time PCR technology is a reliable tool for differentiating between wild-type VZV and vOka strains in clinical samples.

Rhabdomyolysis in an infant with primary human herpesvirus 6 infection.

We report here the first case of rhabdomyolysis at the time of primary human herpesvirus 6 infection. The patient was a previously healthy 1-year-old girl who developed rhabdomyolysis 4 days after the onset of the primary human herpesvirus 6 infection. No other etiologic agent that might cause rhabdomyolysis was identified.

Cytokine and chemokine responses in pediatric patients with severe pneumonia associated with pandemic A/H1N1/2009 influenza virus.

Severe pneumonia and leukocytosis are characteristic, frequently observed, clinical findings in pediatric patients with pandemic A/H1N1/2009 influenza virus infection. The aim of this study was to elucidate the role of cytokines and chemokines in complicating pneumonia and leukocytosis in patients with pandemic A/H1N1/2009 influenza virus infection. Forty-seven patients with pandemic A/H1N1/2009 influenza virus infection were enrolled in this study. Expression of interleukin (IL)-10 (P = 0.027) and IL-5 (P = 0.014) was significantly greater in patients with pneumonia than in those without pneumonia. Additionally, serum concentrations of interferon-γ (P = 0.009), tumor necrosis factor-α (P = 0.01), IL-4 (P = 0.024), and IL-2 (P = 0.012) were significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without neutrophilic leukocytosis. Of the five serum chemokine concentrations assessed, only IL-8 was significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without leukocytosis (P = 0.001). These cytokines and chemokines may play important roles in the pathogenesis of childhood pneumonia associated with A/H1N1/2009 influenza virus infection.

Correlation between serum matrix metalloproteinase and antigenemia levels in patients infected with rotavirus.

Rotavirus (RV) antigenemia has been reported in patients with gastroenteritis; however, the exact mechanism remains unclear. In order to elucidate the mechanism of RV antigenemia, an association between RV antigenemia and matrix metalloproteinase (MMP) were analyzed. The object of this study was to elucidate the role of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the pathogenesis of RV antigenemia. Forty children admitted to hospital with RV gastroenteritis were enrolled in this study. Paired serum samples were collected at the time of admission and discharge. Enzyme-linked immunosorbent assays (ELISA) were used to detect serum concentrations of viral antigens, MMP-1, -2, -9, -13, TIMP -1, and -2. Cytokines were measured using flow cytometric beads array. RV antigens were significantly higher in serum collected at the time of admission than discharge (P < 0.001). MMP-9 concentrations were significantly higher in serum collected at the time of admission than discharge (P < 0.001). MMP-2 concentrations were significantly lower in serum collected at the time of admission than discharge (P < 0.001). A weak but a significantly positive association (P = 0.034) was observed between RV antigen and MMP-9 in serum collected at the time of admission, and inverse association was observed between RV antigen and MMP-2. In addition, a weak but significantly positive association (P = 0.002) was observed between IL-6 and MMP-9. These data suggest that MMPs may contribute to the pathogenesis of RV antigenemia.

Host factors associated with the kinetics of Epstein-Barr virus DNA load in patients with primary Epstein-Barr virus infection.

The aims of this study were to elucidate the kinetics of Epstein-Barr virus (EBV) DNA load in serially collected peripheral blood mononuclear cells of patients with primary EBV infection, and to determine the correlated host factors. Blood samples were collected from 24 patients with primary EBV infection. EBV DNA copy numbers were measured using real-time polymerase chain reaction. Based on the kinetics of EBV DNA load, the 24 patients were divided into two groups: rapid regression and slow regression. Eighteen of the 24 patients (75%) were included in the slow regression and 6 (25%) in the rapid regression group. No statistically significant differences were observed between the two groups in clinical features and laboratory findings. However, acute phase (3 to 10 days after the onset of the illness) serum samples from six children in the slow regression and four in the rapid regression group revealed significantly higher serum interleukin (IL)-1ß (P= 0.018), IL-12 (P= 0.009), tumor necrosis factor-α (P= 0.019), interferon-inducible protein 10, and monokine induced by interferon γ concentrations in the rapid regression than the slow regression group. On the other hand, sera from six children in the slow regression and four in the rapid regression group in the convalescent phase (14 to 21 days after the onset of the illness) showed no statistically significant differences between the two groups in these biomarker concentrations. Based on this, it was concluded that the kinetics of EBV DNA load can be divided to two different patterns after primary EBV infection, and immune response might be associated with viral clearance.

Spread of herpes simplex virus to the spinal cord is independent of spread to dorsal root ganglia.

Levels of herpes simplex virus 1 (HSV-1) and HSV-2 DNA in dorsal root ganglia (DRG) and spinal cord (SC) were quantified after inoculation of guinea pig genitals and footpads. In genital infection, viral DNA reached SC and DRG simultaneously (at 2 to 3 days after inoculation) but was more abundant in SC than in DRG. After inoculation of footpads, which lack parasympathetic innervation, the viruses spread more efficiently to DRG than to SC. These results show important differences between genital and footpad infections, including independence of spread to DRG and SC, and imply that autonomic neurons may play an important role in the pathogenesis of viral latency after genital inoculation.

Exanthem subitum-associated encephalitis: nationwide survey in Japan.

We sought to clarify clinical features of exanthem subitum associated-encephalitis/encephalopathy, generally caused by primary human herpesvirus-6 infection in Japan. A two-part questionnaire was sent to hospitals between January 2003-December 2004. Of 3357 questionnaires, 2357 (70.2%) were returned, and 2293 (68.3%) were eligible for analysis. Eighty-six cases of exanthem subitum-associated encephalitis/encephalopathy were reported. Seventy-seven (89.5%) of 86 patients were diagnosed with human herpesvirus-6 infection by virologic examination. Although 41 (50.6%) of 81 patients had no sequelae, 38 (46.9%) had neurologic sequelae. Moreover, two fatal cases (2.5%) were reported. Pleocytosis was evident in only 4 (7.5%) of 53 patients, and cerebrospinal fluid protein levels were within normal range (23.4 +/- 14.6 mg/dL S.D.) in all patients. Human herpesvirus-6 DNA was detected in 21 (53.8%) of 39 patients. Abnormal computed tomography findings were a predictor of neurologic sequelae (P = 0.0097). As a consequence of this survey, we estimate that 61.9 cases of exanthem subitum-associated encephalitis occur every year. The disease prognosis was unexpectedly poor.

Analysis of rotavirus antigenemia and extraintestinal manifestations in children with rotavirus gastroenteritis.

OBJECTIVE: This study was conducted to examine the association between rotavirus antigenemia and clinical features, particularly extraintestinal manifestations, and the association between serum cytokine levels and rotavirus antigen quantity. METHODS: Sixty hospitalized children who received a diagnosis of acute rotavirus gastroenteritis were enrolled in this study. Paired serum samples were collected from the 60 children when admitted to and discharged from the hospital. Associations among viral antigen levels and fever, elevated transaminase levels, and seizures were evaluated to determine whether antigenemia correlated with disease severity. Viral antigen was measured by using an in-house enzyme-linked immunosorbent assay that detected VP6 antigen. A flow-cytometric bead array was used to measure serum cytokine levels. RESULTS: Rotavirus antigen levels were significantly higher in serum collected at the time of hospital admission than at the time of discharge. Serum rotavirus antigen levels peaked on day 2 of the illness (2.02 +/- 0.73), followed by a gradual decrease in antigen levels to nearly undetectable levels by day 6. The quantity of rotavirus antigen was significantly higher in serum collected from patients with fever than those without fever. The presence or absence of elevated transaminase levels and seizures was not associated with serum rotavirus antigen levels. A weak but significantly positive association was observed between interleukin 8 levels and antigenemia. A weak but significantly negative association was observed between interleukin 10 levels and antigenemia. CONCLUSIONS: Rotavirus antigenemia is frequently observed in a patient's serum during the acute phase, and viral antigen levels change dramatically during the acute phase of the illness. Because patients with fever had higher rotavirus antigen levels, antigenemia severity might contribute to fever. The host immune response plays an important role in controlling antigenemia levels.

Human herpesvirus 6 infection in adult living related liver transplant recipients.

To analyze human herpesvirus 6 (HHV-6) infection in adult living related liver transplantation, we performed a virological analysis, including viral isolation, serological assay, and real-time polymerase chain reaction, of serially collected blood samples from 67 recipients. In addition, cytokine levels were measured to determine their role in viral reactivation. HHV-6 was isolated from only 4 recipients (6.0%), and viral DNA was detected in 15 (22.4%) of the 67 recipients. A significant increase in HHV-6 immunoglobulin G antibody titers was observed in 19 (28.4%) of the 67 recipients. Finally, 26 recipients (38.8%) had HHV-6 reactivation 2-6 weeks after transplantation. HHV-6 associated clinical features were analyzed in the 17 recipients presenting with either viremia or DNAemia. Two recipients with viremia and 3 recipients with DNAemia had unexplained fever at the time of viral infection. An increase in aminotransferase levels was observed in 2 recipients with viremia and 3 recipients with DNAemia. Recipients with liver cirrhosis caused by hepatitis B virus or hepatitis C virus infection as the underlying disease were more likely to have HHV-6 infection (P = 0.025). Mortality at the last follow-up in recipients with HHV-6 reactivation was significantly higher than in those without viral reactivation (P = 0.0118). Plasma interleukin-6 levels were significantly higher in the recipients with HHV-6 viremia than in the recipients without viremia at 4 weeks post-transplant (P = 0.0411). Moreover, tumor necrosis factor alpha levels were also higher in recipients with HHV-6 viremia (P < 0.0001) or reactivation (P = 0.0011) than in recipients without viremia or reactivation 4 weeks post-transplant.

Direct detection of human herpesvirus 6 DNA in serum by the loop-mediated isothermal amplification method.

BACKGROUND: A more rapid and easier method is needed for monitoring human herpesvirus 6 (HHV-6) infections. The loop-mediated isothermal amplification method (LAMP) can detect viral DNA with high specificity, efficiency, and speed under isothermal conditions. LAMP requires only simple equipment that is available in hospital laboratories. OBJECTIVES: We evaluated LAMP as a means of detecting HHV-6 DNA directly from patients' sera. RESULTS: The sensitivity of the HHV-6 LAMP protocol without heat denaturation was 1000 copies/tube; with heat denaturation 10 copies/tube were detected. Three hundred serum samples from children with fever were analyzed. Using HHV-6 isolation as a definition of HHV-6 infection, the sensitivity, specificity, positive predictive value, and negative predictive value of the HHV-6 LAMP method without DNA extraction were 95.5%, 95.2%, 94.0%, and 96.4%, respectively. CONCLUSION: Direct detection of HHV-6 DNA in serum with a modified HHV-6 LAMP could be used for rapid diagnosis of exanthem subitum (ES).

How great is willingness to pay for recovery from sequelae after severe traumatic brain injury in Japan?

OBJECTIVE: To evaluate the burden on families with a family member suffering traumatic brain injury sequelae in Japan. DESIGN: Cross-sectional study. METHODS: Family members' burden from the sequelae of traumatic brain injury was estimated by use of willingness-to-pay models and the contingent valuation method. A national survey among 1707 members of the Japan Traumatic Brain Injury Association was conducted by postal questionnaire with open-ended questions. A total of 509 (29.8%) of the family members responded (405 men and 104 women). Mean age of patients with traumatic brain injury was 33.4 (SD 14.3) years and of responding family members 53.3 (SD 14.5) years. RESULTS: Willingness-to-pay for the family member's recovery from sequelae of traumatic brain injury (8,694,502 Japanese yen; 79,134 US dollars/year) was similar to that reported for a family member's survival from incurable terminal disease (8,342,953 Japanese yen; 75,934 US dollars/year). CONCLUSION: The data indicate that family members perceive the burden of a family member with traumatic brain injury sequelae as similar to what would have been caused by an incurable terminal disease.

Effectiveness of a comprehensive day treatment program for rehabilitation of patients with acquired brain injury in Japan.

OBJECTIVE: To assess the effectiveness of a day treatment program with a comprehensive team approach for treating outpatients with acquired brain injury, which is offered by the Kanagawa Rehabilitation Hospital. DESIGN: Non-randomized controlled study. SUBJECTS: Twenty-five program graduates and 12 control patients with acquired brain injury. METHODS: A prospective study using 25 brain-injured patients with cognitive dysfunction who were provided with a comprehensive day treatment program at Kanagawa Rehabilitation Hospital. The 25 enrolled patients had treatment sessions lasting 2-4 hours for 2 days a week over a 3-6-month period. Functional Independence Measure/Functional Assessment Measure (FIM/FAM) and the Community Integration Questionnaire (CIQ) were administered before and after the program to compare outcomes between the 25 program participants and the 12 control patients who did not receive the day treatment program. RESULTS: Significant improvements in speech intelligibility, problem solving, memory, attention and social integration scores in the FIM/FAM and scores in social integration and productive activity in the CIQ were evident in the enrolled subjects. In addition, 9 of the 25 patients returned to work or school. CONCLUSION: These results demonstrate the effectiveness of this program in helping to rehabilitate patients with acquired brain injury.

Examination by near-infrared spectroscopy for evaluation of piano performance as a frontal lobe activation task.

The purpose of this study was to reveal the activation of the frontal lobe in piano performance by the use of near-infrared spectroscopy. Participants wereseven healthy volunteer music college students. The results of the examination showed a tendency towards an increase in total hemoglobin volume over a wider area in the frontal part of the brain during an appropriate piano task compared with an easy piano task or the Keio version of the Wisconsin Card Sorting Test. The results suggest that piano performance is recognized as a frontal lobe-activating task and that performance of an appropriate piano task can be expected to elicit wider activation of the frontal lobe than an easy one.