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.

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.

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.

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.

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.

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.

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.

Antimicrobial activity and stability of weakly acidified chlorous acid water.

The antimicrobial activity of weakly acidified chlorous acid water (WACAW) against Staphylococcus aureus, non-pathogenic Escherichia coli, enterohemorrhagic E. coli (EHEC O157:H7), Candida albicans, and spore-forming Bacillus and Paenibacillus species was evaluated in vitro. The antiviral activity was also examined using feline calicivirus (FCV). Diluted WACAW (>100 ppm) effectively reduced the number of non-spore-forming bacteria (>4 log10 CFU reductions) within 5 min. Treatment with this sanitizer at 400 ppm for 30 min achieved>5 log10 CFU reductions in spore-forming Bacillus and Paenibacillus species while an equivalent concentration of sodium hypochlorite (NaClO) resulted in only a 0.98 and 2.72 log10 CFU reduction, respectively. The effect of this sanitizer against FCV was equivalent to that of NaClO. Immersion in WACAW (400 ppm) achieved >4 and 2.26 log10 CFU reductions in Campylobacter jejuni and EHEC, respectively, on artificially contaminated broiler carcass pieces. Finally, theantimicrobial activity of this sanitizer was shown to be maintained for at least 28 d when in contact with nonwoven fabric (100% cotton). This study showed that pH control of chlorous acid is expected to modify its antimicrobial activity and stability. WACAW is expected to have applications in various settings such as the food processing and healthcare industries.

Inhibition by caffeic acid of the influenza A virus multiplication in vitro.

Caffeic acid has been shown to inhibit the multiplication of influenza A virus in vitro, whereas caffeine, quinic acid and chlorogenic acid do not. Caffeic acid has also been shown to have antiviral activity against herpes simplex virus (DNA virus) and polio virus (RNA virus). In the present study, a comparison of the one-step growth curve of the influenza virus in the presence of caffeic acid with that in the absence of the reagent showed that an eclipse period of the virus multiplication in the infected cells was not affected by the reagent, while the progeny virus yield was markedly decreased in the presence of caffeic acid. In additional experiments, it was found that the addition of caffeic acid at an early time point post-infection (within 3 h post-infection) was mandatory for extensive antiviral activity, suggesting that a major target of the reagent exists in the early stages of infection. Simultaneously with the decrease in the progeny virus yield, both the virus-induced cytopathic effects and apoptotic nuclear fragmentation were markedly suppressed by the reagent, suggesting that caffeic acid suppresses, at least temporally, the degeneration of the virus-infected cells and that the observed antiviral activity is likely not the secondary result of the cytotoxic effects of the reagent. These results suggest the potential pharmacological use of caffeic acid or its derivatives as an antiviral drug against influenza A virus.

Development of separated elastic stockings.

OBJECTIVES: To investigate the acceptability of newly developed separated elastic stockings, which are divided into two portions at the ankle. METHODS: The difficulty in putting on and taking off stockings was compared between the original or modified separated stockings with various techniques in order to reduce the shift of the stockings and current non-separated stockings in healthy volunteers and patients with lymphoedema by applying both stockings alternately. In the modified model, the shift during daily activities was measured in healthy volunteers and patients with lymphoedema. RESULTS: The two items, 'easier compared with non-separated stockings' and 'much easier', were chosen at rates of 75% and 81% for putting on and taking off stockings for the original separated stockings and 75% and 75% for the modified separated stockings, respectively. Complaints during daily activities with the modified type to the stockings decreased as compared with the original type. The shift of stockings after an average 11-hour application was 1.6 ± 3.0 SD mm (range: 0-10 mm). CONCLUSIONS: Modified separated elastic stockings are easier to put on and take off compared with current non-separated stockings, and they can be used safely because of their low-level shift during daily activities.

Effect of gaiters on muscle pump activity in healthy volunteers.

OBJECTIVES: Exercise of the leg with external limb compression has been reported to be useful for preventing and reducing leg oedema. The aim of this study was to investigate the effects of leg gaiters on calf muscle pump activity. METHODS: Continuous measurements of the interface pressure at the leg during exercise and determination of the femoral venous velocity at the groin during exercise were carried out in healthy volunteers with elastic stockings alone, leg gaiters alone and gaiters over the elastic stockings. RESULTS: The greatest pressure difference between muscle contraction and relaxation during exercise was observed when gaiters were applied over the elastic stockings at the calf. Gaiters alone without elastic stockings led to a significantly greater pressure difference between muscle contraction and relaxation during exercise than elastic stockings alone (P < 0.01). A significantly higher value of the peak flow velocity of the femoral vein was observed with the combined use of gaiters and elastic stockings than the single use of elastic stockings. CONCLUSIONS: Leg gaiters have a beneficial effect of augmenting venous femoral blood flow during calf muscle pump activity in volunteers with a normal valve function of leg veins.

Interface pressure is affected by slippage of bandages at thigh.

AIM: Very little is known about how compression bandages lose interface pressure. We hypothesized that the loss of interface pressure is correlated with the slippage of the bandages, and studied the interface pressure and slippage of three bandages over 8 hours. METHODS: Twenty-Seven legs from 27 healthy volunteers were bandaged with short stretch bandages (SS), cohesive short stretch bandages (CS), and long stretch bandages (LS). Pressure sensors were placed above the ankle (B1), below the knee (D), and mid thigh (F). Interface pressures in a sitting position were recorded at the beginning, and 4 and 8 hours later. In 17 legs, the pressure sensor sites were marked, and their heights were measured on standing upright. RESULTS: SS and CS lost interface pressure quickly, but LS maintained pressure better than SS and CS at all sites. There was no pressure difference between SS and CS at the lower leg. However, CS maintained pressure better than SS at the mid thigh (44.6% vs. 54.4% pressure loss at 8 hours, respectively. P=0.037). There was a tendency toward less slippage with CS than SS at the mid thigh. In CS and LS, there was a linear correlation between the slippage of bandages and the interface pressure at the mid thigh (P <.01, in both). CONCLUSION: The interface pressure may be affected by the slippage of bandages at the thigh, but not at the lower leg. Cohesive short stretch bandages may exert their beneficial impact at the thigh.

Arginine inactivates human herpesvirus 2 and inhibits genital herpesvirus infection.

Arginine, among the amino acids, has demonstrated unique properties, including suppression of protein-protein interactions and virus inactivation. We investigated the effects of arginine on the infectivity of human herpesvirus 2 (HHV-2) and the potential application of arginine as a chemotherapeutic agent against genital herpes. Arginine directly inactivated HHV-2 and characterization of the inactivation demonstrated that 1 M arginine at pH 4.3 inactivated the virus more efficiently compared to 0.1 M citrate or 1 M sodium chloride, indicating that neither acidic pH nor ionic strength alone is sufficient for virus inactivation. The effect of arginine was rapid and concentration-dependent. Although virus inactivation was efficient at an acidic pH, arginine inactivated the virus even at a neutral pH, provided that a higher arginine concentration and prolonged incubation time were used. In addition, arginine suppressed the multiplication of HHV-2 under the conditions at which its effect on cell viability was insignificant. Pilot mouse model studies revealed a marked suppression of death by arginine when the mice were infected with HHV-2 through the vaginal route, followed by an intermittent application of acidic arginine by vaginal instillation.

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.

Interface pressure and stiffness in different combinations of compression material.

OBJECTIVES: To compare the interface pressure and stiffness between various combinations of compression material. METHODS: Using a stiffness-determining device, the interface pressure and stiffness were determined in several combinations of five elastic stockings and two elastic bandages. RESULTS: In the double stockings system, the interface pressure increased significantly and the highest stiffness was observed in double short-stretch stockings. When short-stretch bandages were applied over either short- or long-stretch stockings, a significant increase in stiffness was observed at any initial pressure compared with the single use of short-stretch stockings. In double bandage systems, when short-stretch bandages were applied over either short- or long-stretch bandages, the stiffness increased significantly. When long-stretch bandages were used over short-stretch bandages, the stiffness decreased significantly. CONCLUSIONS: The stiffness is changeable according to the combinations of material, such as double stockings, double bandages and the wearing of bandages over stockings. The use of short-stretch bandages as the outside layer produces the highest stiffness at a high initial pressure.

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.

Inhibition of multiplication of herpes simplex virus by caffeic acid.

Hot water extracts of coffee grinds and commercial instant coffee solutions have been shown to exhibit marked antiviral and virucidal activities against herpes simplex virus type 1 (HSV-1). Specifically, it has been shown that caffeine and N-methyl-pyridinium formate inhibit the multiplication of HSV-1 in HEp-2 cells. The present study examined the virological properties and the antiviral activity of caffeic acid against HSV-1. Caffeic acid inhibited the multiplication of HSV-1 in vitro, while chlorogenic acid, a caffeic acid ester with quinic acid, did not. These reagents did not have a direct virucidal effect. The one-step growth curve of HSV-1 showed that the addition of caffeic acid at 8 h post infection (h p.i.) did not significantly affect the formation of progeny viruses. An analysis of the influence of the time of caffeic acid addition, revealed that addition at an early time post infection remarkably inhibited the formation of progeny infectious virus in the infected cells, but its addition after 6 h p.i. (i.e., the time of the completion of viral genome replication) did not efficiently inhibit this process. These results indicate that caffeic acid inhibits HSV-1 multiplication mainly before the completion of viral DNA replication, but not thereafter. Although caffeic acid showed some cytotoxicity by prolonged incubation, the observed antiviral activity is likely not the secondary result of the cytotoxic effect of the reagent, because the inhibition of the virus multiplication was observed before appearance of the notable cytotoxicity.

Effects of electrolytes on virus inactivation by acidic solutions.

Acidic pH is frequently used to inactivate viruses. We have previously shown that arginine synergizes with low pH in enhancing virus inactivation. Considering a potential application of the acid inactivation of viruses for the prevention and treatment of superficial virus infection at body surfaces and fixtures, herein we have examined the effects of various electrolytes on the acid-induced inactivation of the herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), the influenza A virus (IAV) and the poliovirus upon their incubation at 30˚C for 5 min. Eight electrolytes, i.e., phosphate, NaCl, glutamate, aspartate, pyrrolidone carboxylate, citrate, malate and acetate were tested. No detectable inactivation of the poliovirus was observed under the conditions examined, reflecting its acid-resistance. HSV-1 and HSV-2 responded similarly to the acid-treatment and electrolytes. Some electrolytes showed a stronger virus inactivation than others at a given pH and concentration. The effects of the electrolytes were virus-dependent, as IAV responded differently from HSV-1 and HSV-2 to these electrolytes, indicating that certain combinations of the electrolytes and a low pH can exert a more effective virus inactivation than other combinations and that their effects are virus-specific. These results should be useful in designing acidic solvents for the inactivation of viruses at various surfaces.