Inactivation of human norovirus by chlorous acid water, a novel chlorine-based disinfectant.

INTRODUCTION: Human norovirus (HuNoV) is a leading cause of infectious gastroenteritis. Since HuNoV shows resistance to alcohol, chlorine-based sanitizers are applied to decontaminate the virus on environmental surfaces. Chlorous acid water (CA) has been recently approved as a novel chlorine-based disinfectant categorized as a Type 2 OTC medicine in Japan. In this study, we aimed to evaluate the capability of CA to inactivate HuNoV. METHODS: HuNoV (genogroups GII.2 and GII.4) was exposed to the test disinfectants including CA and sodium hypochlorite (NaClO), and the residual RNA copy was measured by reverse transcription quantitative PCR (RT-qPCR) after pretreatment with RNase. In addition, the log10 reduction of HuNoV RNA copy number by CA and NaClO was compared in the presence of bovine serum albumin (BSA), sheep red blood cells (SRBC), polypeptone, meat extract or amino acids to evaluate the stability of these disinfectants under organic-matter-rich conditions. RESULTS: In the absence of organic substances, CA with 200 ppm free available chlorine provided >3.0 log10 reduction in the HuNoV RNA copy number within 5 min. Even under high organic matter load (0.3% each of BSA and SRBC or 0.5% polypeptone), 200 ppm CA achieved >3.0 log10 reduction in HuNoV RNA copy number while less than 1.0 log10 reduction was observed with 1,000 ppm sodium hypochlorite (NaClO) in the presence of 0.5% polypeptone. CA reacted with only cysteine, histidine and glutathione while NaClO reacted with all of the amino acids tested. CONCLUSIONS: CA is an effective disinfectant to inactivate HuNoV under organic-matter-rich conditions.

Effects of polypharmacy on the prevalence of adverse drug events resulting in outpatient visits and hospitalization.

A high proportion of hospitalizations is attributable to the prevalence of adverse drug events. This retrospective study included outpatients and inpatients to determine the prevalence of adverse drug events and if polypharmacy increases it. The prevalence, classification, and causality of adverse drug events were assessed based on medical records, laboratory values, and other data. Multivariate analysis (multiple logistic regression analysis) was performed with the presence or absence of adverse drug events at the time of the visit as the dependent variable and items for which the P-value was <0.25 in the univariate analysis as independent variables. The prevalence of adverse drug events was 13.0%, 10.9%, and 16.0% among all patients, the outpatient group, and the inpatient group, respectively. Multivariate analysis showed that polypharmacy (≥5 drugs) significantly increased the risk of adverse drug events in all patients. The prevalence of adverse drug events significantly increased with each additional drug used. We expect that minimizing the number of medications through moderation of the number of prescription drugs and elimination of polypharmacy will reduce the number of outpatient visits and hospitalizations due to adverse drug events.

Secondary prevention of diabetes through workplace health screening.

BACKGROUND: Workplace health screening offers a unique opportunity to assess individuals for type 2 diabetes mellitus. AIMS: To evaluate the association between workplace diabetes screening, subsequent diagnosis and changes in fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and body mass index (BMI) among individuals who screened positive for diabetes. METHODS: Employees without a prior diagnosis of diabetes participated in workplace health screening by 45 employers throughout the USA. Individuals screened positive for diabetes based on standard criteria (≥126 mg/dL FPG or ≥6.5% [48 mmol/mol] HbA1c). Diabetes diagnoses were identified after screening using claims-based ICD9-CM diagnosis codes. Discrete-time survival analysis estimated the monthly rate of new diabetes cases after screening, relative to the time period before screening. Paired t-tests evaluated 1-year changes in blood glucose measures and BMI among individuals with positive screenings. RESULTS: Of 22790 participating individuals, 900 (4%) screened positive for diabetes. A significantly greater rate of new diabetes diagnoses was observed during the first month after screening, compared to the 3-month period before screening (odds ratio [OR] 2.65, 95% confidence intervals [CIs] 2.02-3.47). Among 538 individuals with diabetes who returned for workplace screening 1 year later, significant improvements were observed in BMI (mean ± SD = -0.63 ± 2.56 kg/m2, P < 0.001) and FPG levels (mean ± SD = -9.3 ± 66.5 mg/dL, P < 0.01). CONCLUSIONS: Workplace screening was associated with a reduction in the number of undiagnosed employees with diabetes and significant improvement in FPG and BMI at 1-year follow-up.

Association between meteorological factors and reported cases of hand, foot, and mouth disease from 2000 to 2015 in Japan.

The purpose of this study was to clarify the association between hand, foot, and mouth disease (HFMD) epidemics and meteorological conditions. We used HFMD surveillance data of all 47 prefectures in Japan from January 2000 to December 2015. Spectral analysis was performed using the maximum entropy method (MEM) for temperature-, relative humidity-, and total rainfall-dependent incidence data. Using MEM-estimated periods, long-term oscillatory trends were calculated using the least squares fitting (LSF) method. The temperature and relative humidity thresholds of HFMD data were estimated from the LSF curves. The average temperature data indicated a lower threshold at 12 °C and a higher threshold at 30 °C for risk of HFMD infection. Maximum and minimum temperature data indicated a lower threshold at 6 °C and a higher threshold at 35 °C, suggesting a need for HFMD control measures at temperatures between 6 and 35 °C. Based on our findings, we recommend the use of maximum and minimum temperatures rather than the average temperature, to estimate the temperature threshold of HFMD infections. The results obtained might aid in the prediction of epidemics and preparation for the effect of climatic changes on HFMD epidemiology.

Improvement of a three-dimensional measurement system for the evaluation of foot edema.

BACKGROUND/AIMS: This study investigated the accuracy and usefulness of a newly improved three-dimensional measurement system for measuring the volume and circumference at the foot as well as at the calf and ankle. METHODS: Regarding the newly improved device, halogen light was projected from four directions instead of the conventional two directions. The circumference and volume were measured in the morning and evening with and without elastic stockings in 23 healthy subjects. RESULTS: The average circumference at the foot calculated using the 'average method', in which the circumference of the foot was measured in 10 places every 1 mm and the values were averaged, significantly increased in the evening compared with in the morning. When stockings were applied, the significant differences in the circumference or volume between the morning and evening disappeared at all sites of the leg. CONCLUSION: The newly improved three-dimensional measurement system incorporating the halogen light from four directions, in which the foot circumference was calculated using an 'average method', was reliable and useful for evaluating edema at the foot as well as at the calf and ankle. The beneficial effect of elastic stockings on edema prevention was observed at all sites of the leg.

Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study.

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

Aromatic interaction of hydantoin compounds leads to virucidal activities.

Virus inactivation or disinfection is the first line of protection against virus infection. Here, we report for the first time the virus inactivation (virucidal) activities of hydantoin and its derivative, 1-methylhydantoin against enveloped herpes simplex virus type-1. These hydantoin compounds showed favorable interaction with aromatic amino acids, similarly to arginine hydrochloride also exhibiting aromatic interaction and virucidal activities on the same virus. Among them, 1-methylhydantoin demonstrated a greater virucidal activity. Solubility measurements in organic solvents and salting-out salt solutions showed that 1-methylhydantoin is more hydrophobic than others, suggesting that the hydrophobic nature and aromatic interaction play a role in interaction with viral proteins and thereby virucidal activity.

Arginine as a synergistic virucidal agent.

Development of effective and environmentally friendly disinfectants, or virucidal agents, should help prevent the spread of infectious diseases through human contact with contaminated surfaces. These agents may also be used, if non-toxic to cells and tissues, as chemotherapeutic agents against infectious diseases. We have shown that arginine has a synergistic effect with a variety of virucidal conditions, namely acidic pH and high temperature, on virus inactivation. All of these treatments are effective, however, at the expense of toxicity. The ability of arginine to lower the effective threshold of these parameters may reduce the occurrence of potential toxic side effects. While it is clear that arginine can be safely used, the mechanism of its virus inactivation has not yet been elucidated. Here we examine the damages that viruses suffer from various physical and chemical stresses and their relations to virus inactivation and aggregation. Based on the relationship between the stress-induced structural damages and the infectivity of a virus, we will propose several plausible mechanisms describing the effects of arginine on virus inactivation using the current knowledge of aqueous arginine solution properties.

Antiviral and Virucidal Activities of Umesu Phenolics on Influenza Viruses.

In this study, umesu phenolics were purified from the salt extracts of Japanese apricot (Nanko-mume cultivar of Prunus mume Sieb. et Zucc.). Characterization of umesu phenolics revealed that, when added to the culture media of the infected cells, they inhibited the multiplication of influenza and many other RNA and DNA viruses. In addition to these antiviral activities, the phenolics significantly decreased the plating efficiency of influenza virus, if present in the virus inoculum. More drastic effects were observed in terms of virucidal activity; the infectivity of several strains of influenza viruses decreased less than 0.001 when they were incubated with 4 mg/ml phenolics at 30 ℃ for 5 min. The virucidal activity of phenolics was found to be more remarkable in acidic conditions; however, the activity was not merely a result of the acidity of the phenolics. These results clearly support the antiviral and virucidal activities of the umesu phenolics against influenza viruses and suggest their potential pharmacological usefulness as disinfectants or preventive medicine against superficial infections, such as the respiratory infections.

Antiviral effect of arginine against herpes simplex virus type 1.

We investigated the effects of arginine on the multiplication of herpes simplex virus type 1 (HSV-1) and the potential of arginine as an antiherpetic agent. Arginine suppressed the growth of HSV-1 concentration-dependently. Inhibition of HSV-1 by arginine leveled off at 50-60 mM, although the higher concentration was not suitable as an antiviral agent due to cytotoxicity. 'Time of addition' experiments revealed that arginine was particularly effective when added within 6 h post-infection (h p.i.), suggesting that the reagent sensitive step is in the early stages of the infection. A one-step growth curve of HSV-1 in the presence of 30 mM arginine revealed that: i) the latent period was significantly extended, ii) the rate of formation of progeny infectious virus decreased and iii) the final yield of progeny virus decreased to 1%. The addition of arginine at 8 h p.i., after the completion of viral DNA replication in the virus multiplication, allowed the normal formation of progeny virus in the subsequent 4 h, confirming that arginine does not directly interfere with the formation of progeny infectious virus. In addition, arginine also inhibits several RNA viruses.

Co-operative thermal inactivation of herpes simplex virus and influenza virus by arginine and NaCl.

Elevated temperatures have been used to inactivate viruses for plasma-derived biopharmaceuticals. This paper describes the effects of arginine and NaCl in conjunction with elevated temperature for inactivation of two enveloped viruses, i.e., herpes simplex virus type 1 (HSV-1) and influenza virus type A at neutral pH. In phosphate-buffered saline, a significant inactivation of HSV-1 occurred above 40 degrees C, resulting in less than 10% surviving virus (over 90% virus inactivation) at 50 degrees C. Arginine concentration dependently decreased the temperature required for virus inactivation, leading to temperature shift by almost 17 degrees C at 1.2M. NaCl also decreased the inactivation temperature, but to a considerably lesser extent, indicating that virus inactivation effect of arginine is not simply due to ionic strength. Influenza virus was also inactivated by high temperature, but its responses to arginine and NaCl were different from those on HSV-1, suggesting that virus inactivation mechanism is different between these two viruses, i.e., the effects of these reagents are virus specific.

Protein aggregation suppressor arginine as an effective mouth cleaning agent.

We have tested here whether or not arginine, a well-known aggregation suppressor, is effective in removing bacterial cells, which may present a potential risk of accidental pneumonia infection in aged individuals, from the oral mucosal membranes. This is based on the ability of arginine to suppress protein-protein interaction and surface adsorption and increase the solubility of organic compounds. Twelve student volunteers were subjected to mouthwashes with saline, citrate buffer (pH 3.5), arginine (pH 3.5) and a commercial Listerine. Insignificant effects were observed with saline and citrate buffer, whereas arginine and Listerine mouthwashes led to significant reduction of bacterial cells from the dorsal side of the volunteer's tongue. Arginine also appeared to disrupt biofilms present in the mouth.

Pelvic body composition measurements by quantitative computed tomography: association with recent hip fracture.

INTRODUCTION: Loss of subcutaneous fat, decreased muscle cross-sectional area (CSA) and increased muscle adiposity are related to declining physical function and disability in the elderly, but there is little information about the relationship of these tissue changes to hip fracture. Thus we have compared body composition measures in women with hip fractures to age-matched controls, using quantitative computed tomography (QCT) imaging of the hip to characterize total adiposity, muscle CSA and muscle attenuation coefficient, a measure of adiposity. MATERIALS AND METHODS: 45 Chinese women (mean age 74.71+/-5.94) with hip fractures were compared to 66 healthy control subjects (mean age 70.70+/-4.66). Hip QCT scans were analyzed to compute total adipose CSA as well as CSA and attenuation values of muscle groups in the CT scan field of view, including hip extensors, abductors, adductors and flexors. The total femur areal BMD (aBMD) was estimated from the QCT images. Logistic regression was employed to compare body composition measures between fracture subjects and controls after adjustment for age, height, BMI and aBMD. Receiver-operator curve (ROC) analyses determined whether combinations of aBMD and body composition had higher area under curve (AUC) than aBMD alone. RESULTS AND CONCLUSIONS: Fracture subjects had lower fat CSA (p<0.0001) than controls but had higher muscle adiposity as indicated by lower attenuation in the adductor, abductor and flexor groups (0.00001

Event-related potentials reflect spectral differences in speech and non-speech stimuli in children and adults.

OBJECTIVE: Event-related brain potentials (ERP) may provide tools for examining normal and abnormal language development. To clarify functional significance of auditory ERPs, we examined ERP indices of spectral differences in speech and non-speech sounds. METHODS: Three Spectral Items (BA, DA, GA) were presented as three Stimulus Types: syllables, non-phonetics, and consonant-vowel transitions (CVT). Fourteen 7- to 10-year-old children and 14 adults were presented with equiprobable Spectral Item sequences blocked by Stimulus Type. RESULTS: Spectral Item effect appeared as P1, P2, N2, and N4 amplitude variations. The P2 was sensitive to all Stimulus Types in both groups. In adults, the P1 was also sensitive to transitions while the N4 was sensitive to syllables. In children, only the 50-ms CVT stimuli elicited N2 and N4 spectral effects. In both groups, non-phonetic stimuli elicited larger N1-P2 amplitudes while speech stimuli elicited larger N2-N4 amplitudes. CONCLUSIONS: Auditory feature processing is reflected by P1-P2 and N2-N4 peaks and matures earlier than supra-sensory integrative mechanisms, reflected by N1-P2 peaks. Auditory P2 appears to pertain to both processing types. SIGNIFICANCE: These results delineate an orderly processing organization whereby direct feature mapping occurs earlier in processing and, in part, serves sound detection whereas relational mapping occurs later in processing and serves sound identification.

Antiviral effects of ascorbic and dehydroascorbic acids in vitro.

In the present study, ascorbic acid weakly inhibited the multiplication of viruses of three different families: herpes simplex virus type 1 (HSV-1), influenza virus type A and poliovirus type 1. Dehydroascorbic acid, an oxidized form of ascorbic acid and hence without reducing ability, showed much stronger antiviral activity than ascorbic acid, indicating that the antiviral activity of ascorbic acid is due to factors other than an antioxidant mechanism. Moreover, addition of 1 mM Fe3+, which oxidizes ascorbic acid to dehydroascorbic acid and also enhances the formation of hydroxyl radicals by ascorbic acid in the culture media, strongly enhanced the antiviral activity of ascorbic acid to a level significantly stronger than that of dehydroascorbic acid. Although both ascorbic acid and dehydroascorbic acid showed some cytotoxicity, the degree of cytotoxicity of the former was 10-fold higher than the latter, suggesting that the observed antiviral activity of ascorbic acid with and without ferric ion is, at least in part, a secondary result of the cytotoxic effect of the reagent, most likely due to the free radicals. However, the possibility that oxidation of ascorbic acid also contributed to the antiviral effects of ascorbic acid exists, in particular in the presence of ferric ion, since dehydroascorbic acid exhibited a very strong antiviral activity. Characterization of the mode of antiviral action of dehydroascorbic acid revealed that the addition of the reagent even at 11 h post infection almost completely inhibited the formation of progeny infectious virus in the infected cells, indicating that the reagent inhibits HSV-1 multiplication probably at the assembly process of progeny virus particles after the completion of viral DNA replication.

Solubility enhancement of gluten and organic compounds by arginine.

Arginine suppresses protein-protein and protein-surface interactions and thus is expected to increase the solubility of the proteins. We have examined here the effects of arginine on the solubility of a highly insoluble protein, gluten, and two organic compounds, octyl-gallate and coumarin, which have low to moderate aqueous solubilities. Arginine significantly increased the solubility of these molecules concentration dependently, while a weak salting-out salt, NaCl, decreased it. The observed ability of arginine to salt-in these compounds can be explained from its binding to aromatic groups and protein surface. Such solubilizing action of arginine may be used to enhance the solubility of poorly soluble organic drug substances.

Butyroyl-arginine as a potent virus inactivation agent.

Virus inactivation is a critical step in the manufacturing of recombinant therapeutic proteins, in particular antibodies, using mammalian expression systems. We have shown in the previous paper that arginine is effective in inactivation of herpes simplex virus type 1 (HSV-1) and influenza virus at low temperature under mildly acidic pH, i.e., above pH 4.0; above this pH, conformational changes of most antibodies are negligible. We have here extended virus inactivation study of arginine to other enveloped viruses, such as Sendai virus and Newcastle Disease Virus (NDV), and observed that arginine was ineffective against both viruses under the similar conditions, i.e., on ice and above pH 4.0. However, an arginine derivative, butyroyl-arginine, showed a strong virucidal potency against Sendai virus, leading to a 4log reduction in virus yield at pH 4.0, but not against NDV. In addition, although arginine and butyroyl-arginine were equally effective against influenza virus having a cleaved form of hemagglutinin spike proteins, only butyroyl-arginine was significantly effective against the same virus, but having an uncleaved hemagglutinin spike proteins. Furthermore, butyroyl-arginine was more effective than arginine against HSV-1 at pH 4.5; i.e., it has a broader pH spectrum than does arginine.

Antiviral activities of coffee extracts in vitro.

Both hot water extracts of coffee grinds and instant coffee solutions inhibited the multiplication of herpes simplex virus type 1, a representative enveloped DNA virus, when they were added to the culture medium of the virus-infected cells at a dose of one fifth the concentration suitable for drinking. The antiherpetic activity was independent of the suppliers (companies) of the coffee grinds and of the locations where the coffee beans were produced. Further characterization revealed that there are two different mechanisms, by which the coffee extracts exert inhibitory activities on the virus infection; (1) a direct inactivation of the infectivity of virus particle (i.e., a virucidal activity) and (2) the inhibition of progeny infectious virus formation at the late stage of viral multiplication in the infected cells. Caffeine, but not quinic acid and chlorogenic acid, inhibited the virus multiplication to some extent, but none of them showed the virucidal activity, suggesting that other component(s) in the coffee extracts must play a role in the observed antiviral activity. In addition, the coffee extracts inhibited the multiplication of poliovirus, a non-enveloped RNA virus, but showed no virucidal effect on this virus.

Hearing recovery from deafness caused by bromate intoxication.

OBJECTIVES: Sodium bromate is a strong oxidant, and bromate intoxication can cause irreversible severe-to-profound sensorineural hearing loss. This paper reports the first case in the English literature of bromate-induced hearing loss with hearing recovery measured by formal audiological assessment.Case reportA 72-year-old woman was admitted to hospital with complaints of profound hearing loss, nausea, diarrhoea and anuria after bromate ingestion in a suicide attempt. On admission, pure tone audiometry and auditory brainstem responses showed profound bilateral deafness. Under the diagnosis of bromate-induced acute renal failure and sensorineural hearing loss, continuous haemodiafiltration was performed. When dialysis was discontinued, pure tone audiometry and auditory brainstem responses showed partial threshold recovery from profound deafness. CONCLUSION: Severe-to-profound sensorineural hearing loss is a common symptom of bromate intoxication. Bromate-induced hearing loss may be partially treated, and early application of continuous haemodiafiltration might be useful as a treatment for this intractable condition.

Characterization of Virucidal Activities of Chlorous Acid.

Virucidal effects of chlorous acid on enveloped and non-enveloped viruses were characterized. The virucidal activity was prominent in enveloped viruses. However, among non-enveloped viruses, viruses such as human rhinovirus and feline calicivirus showed a significant sensitivity to the reagent, whereas others such as poliovirus and coxsackievirus showed a weak sensitivity to the reagent, suggesting the presence of 2 classes of sensitivity to the reagent, among non-enveloped viruses. In addition, characterization of the mode of inactivation by the reagent revealed that virus inactivation is strongly dependent on virus species, contaminated proteins, and solvent system composition. Comparison of the cytotoxic effects of chlorous acid with those of sodium hypochlorite or sodium dodecyl sulfate (SDS) revealed that chlorous acid was similar to SDS and remarkably weaker than sodium hypochlorite. These results indicate the unique nature of chlorous acid as a potent virucidal agent with tolerable tissue damage, and reveal the merits and limitations of chlorous acid as a disinfectant in food hygiene and sanitizer in healthcare.