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Antiviral effects of pyrrolidine dithiocarbamate on human rhinoviruses.

Human rhinoviruses (HRVs) are the predominant cause of the common cold. The frequency of HRV infections in industrial countries and the lack of effective therapeutical treatment underline the importance of research for new antiviral substances. As viral infections are often accompanied by the generation of oxidative stress inside the infected cells, several redox-active substances were tested as potential antivirals. In the course of these studies it was discovered that pyrrolidine dithiocarbamate (PDTC) is an extremely potent compound against HRV and poliovirus infection in cell culture. Besides the ability to dramatically reduce HRV production by interfering with viral protein expression, PDTC promotes cell survival and abolishes cytopathic effects in infected cells. PDTC also protects cells against poliovirus infection. These effects were highly specific, as several other antioxidants (vitamin C, Trolox, 2-mercaptoethanol, and N-acetyl-L-cysteine) are inactive against HRV infection. Synthesis of HRV proteins and cleavage of eucaryotic initiation factor 4G responsible for host cell shutoff of cellular protein synthesis are severely inhibited in the presence of PDTC.

Antiviral Agents↗

VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds.

Rhinoviruses are the most common infectious agents of humans. They are the principal etiologic agents of afebrile viral upper-respiratory-tract infections (the common cold). Human rhinoviruses (HRVs) comprise a genus within the family Picornaviridae. There are >100 serotypically distinct members of this genus. In order to better understand their phylogenetic relationship, the nucleotide sequence for the major surface protein of the virus capsid, VP1, was determined for all known HRV serotypes and one untyped isolate (HRV-Hanks). Phylogenetic analysis of deduced amino acid sequence data support previous studies subdividing the genus into two species containing all but one HRV serotype (HRV-87). Seventy-five HRV serotypes and HRV-Hanks belong to species HRV-A, and twenty-five HRV serotypes belong to species HRV-B. Located within VP1 is a hydrophobic pocket into which small-molecule antiviral compounds such as pleconaril bind and inhibit functions associated with the virus capsid. Analyses of the amino acids that constitute this pocket indicate that the sequence correlates strongly with virus susceptibility to pleconaril inhibition. Further, amino acid changes observed in reduced susceptibility variant viruses recovered from patients enrolled in clinical trials with pleconaril were distinct from those that confer natural phenotypic resistance to the drug. These observations suggest that it is possible to differentiate rhinoviruses naturally resistant to capsid function inhibitors from those that emerge from susceptible virus populations as a result of antiviral drug selection pressure based on sequence analysis of the drug-binding pocket.

Amino Acid Sequence↗

Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells.

Rhinoviruses (RV) are the major cause of the common cold and acute exacerbations of asthma and chronic obstructive pulmonary disease. Toll-like receptors (TLRs) are a conserved family of receptors that recognize and respond to a variety of pathogen-associated molecular patterns. TLR3 recognizes double-stranded RNA, an important intermediate of many viral life cycles (including RV). The importance of TLR3 in host responses to virus infection is not known. Using BEAS-2B (a human bronchial epithelial cell-line), we demonstrated that RV replication increased the expression of TLR3 mRNA and TLR3 protein on the cell surface. We observed that blocking TLR3 led to a decrease in interleukin-6, CXCL8, and CCL5 in response to poly(IC) but an increase following RV infection. Finally, we demonstrated that TLR3 mediated the antiviral response. This study demonstrates an important functional requirement for TLR3 in the host response against live virus infection and indicates that poly(IC) is not always a good model for studying the biology of live virus infection.

Bronchi↗

Grommets in otitis media with effusion: an individual patient data meta-analysis.

AIMS: To identify subgroups of children with otitis media with effusion (OME) that might benefit more than others from treatment with ventilation tubes. METHODS: An individual patient data (IPD) meta-analysis on seven randomised controlled trials (n = 1234 children in all), focusing on interactions between treatment and baseline characteristics--hearing level (HL), history of acute otitis media, common colds, attending day-care, gender, age, socioeconomic status, siblings, season, passive smoking, and history of breast feeding. Outcome measures that could be studied were mean time spent with effusion (n = 557), mean hearing levels (n = 557 in studies that randomised children, and n = 180 in studies that randomised ears), and language development (n = 381). RESULTS: In the trials that treated both ears the only significant interaction was between day-care and surgery, occurring where mean hearing level was the outcome measure. None of the other baseline variables showed an interaction effect with treatment that would justify subgrouping. In the trials that treated only one ear, the baseline hearing level showed a significant but not pervasive interaction with treatment-that is, only with a cut-off of 25 dB HL. CONCLUSIONS: The effects of conventional ventilation tubes in children studied so far are small and limited in duration. Observation (watchful waiting) therefore seems to be an adequate management strategy for most children with OME. Ventilation tubes might be used in young children that grow up in an environment with a high infection load (for example, children attending day-care), or in older children with a hearing level of 25 dB HL or greater in both ears persisting for at least 12 weeks.

Child↗

Is there a moral obligation not to infect others?

The emergence of HIV infection and AIDS has refocused concern on the obligations surrounding the carrying and transmission of communicable diseases. This article asks three related questions: Is there a general duty not to spread contagion? Are there special obligations not to communicate disease in the workplace? And does the mode of transmission of the disease affect the ethics of transmission and, if so, how and to what extent? There seems to be a strong prima facie obligation not to harm others by making them ill where this is avoidable, and this obligation not to communicate disease applies as much to relatively trivial diseases like the common cold as it does to HIV disease. The reasonableness of expecting people to live up to this obligation, however, depends on society reciprocating the obligation in the form of providing protection and compensation.

Communicable Diseases↗

Nasal cancers, symptoms and upper airway function in woodworkers.

In 186 cases of nasal cancer diagnosed over the decade 1965-74, in a population of 2-0 million, 114 of 157 ectodermal tumours were found in men. Adenocarcinoma was found in 17 patients, two women and 15 men; 12 of these had a history of occupational exposure to wood dust in the furniture industry. The period of latency was from 28 to 57 years. Among the remaining 99 tumours in men there was occupational exposure to wood dust in 10 cases. Wood dust concentrations in the breathing zone, respiratory symptoms and upper airway function were studied in 68 workers in the furniture industry. The dust concentrations affecting 63% of the workers were higher than 5 mg/m3 (TLV). Middle ear inflammation and common colds were more frequent at high dust concentrations, and the number of workers with nasal mucostasis was directly proportional to the wood dust concentration.

Adenocarcinoma↗

Impact of exposure to insulation wool on lung function and cough in Swedish construction workers.

OBJECTIVES: To investigate whether application of insulation wool adversely affects lung volumes and increases the occurrence of symptoms of airway irritation. METHODS: Data from nationwide health check ups in 1981-93 of male construction workers born in 1955 or later were used to investigate cross sectional (n = 96,004) and longitudinal (n = 26,298) associations between lung volumes, vital capacity (VC), and forced expiratory volume in one second (FEV1) and exposure to insulation wool by combining a job exposure matrix (JEM) and self reported exposure. Data on 12 month prevalence of persistent cough not associated with the common cold was available for the period 1989-92. Potential confounding from smoking, exposure to asbestos, silica, and isocyanates, was considered in the analyses. RESULTS: For those in the highest exposure category (self reported duration of exposure of > or = 11 years, and high exposure according to the JEM) VC was on average 2.5 cl lower (95% CI -6.5 to 1.5) than in those with no exposure. The corresponding figures for FEV1 was -2.4 cl (95% CI -6.1 to 1.3). In the longitudinal analyses, the yearly change in VC between the first and last spirometry for those in the highest exposure category was 0.50 cl (95% CI -0.97 to 1.98) less than in the unexposed category. The corresponding figure for FEV1 was 0.89 cl (95% CI - 0.70 to 2.06). High exposure to insulation wool, asbestos, or silica, during the 12 months preceding the check up was associated with increased odds ratios (ORs) for persistent cough of the same magnitude as current smoking. CONCLUSIONS: The results indicate no effects on VC or FEV1 from exposure to insulation wool. Recent exposure to insulation wool, asbestos, and silica was associated with an increased prevalence of persistent cough.

Adult↗

Chromium (VI) induced oxidative damage to DNA: increase of urinary 8-hydroxydeoxyguanosine concentrations (8-OHdG) among electroplating workers.

AIMS: To investigate the concentration of urinary 8-hydroxydeoxyguanosine (8-OHdG) among electroplating workers in Taiwan. METHODS: Fifty workers were selected from five chromium (Cr) electroplating plants in central Taiwan. The 20 control subjects were office workers with no previous exposure to Cr. Urinary 8-OHdG concentrations were determined using high performance liquid chromatography with electrochemical detection. RESULTS: Urinary 8-OHdG concentrations among Cr workers (1149.5 pmol/kg/day) were higher than those in the control group (730.2 pmol/kg/day). There was a positive correlation between urinary 8-OHdG concentrations and urinary Cr concentration (r = 0.447, p < 0.01), and urinary 8-OHdG correlated positively with airborne Cr concentration (r = 0.285). Using multiple regression analysis, the factors that affected urinary 8-OHdG concentrations were alcohol, the common cold, and high urinary Cr concentration. There was a high correlation of urinary 8-OHdG with both smoking and drinking, but multiple regression analysis showed that smoking was not a significant factor. Age and gender were also non-significant factors. CONCLUSION: 8-OHdG, which is an indicator of oxidative DNA damage, was a sensitive biomarker for Cr exposure.

8-Hydroxy-2'-Deoxyguanosine↗

An investigation of the immune response of patients suffering from anorexia nervosa.

Patients suffering from anorexia nervosa rarely appear to develop the common cold or influenza. This study examines the immunological response of fifteen female anorexia nervosa patients of both the vomiting and carbohydrate-abstaining type and compares them with a control population matched for age and occupation. Both anorectics and control populations received the admune influenza vaccine. Initially both groups had similar haemagglutination inhibition titres against the three different viral antigens: A/HK; A/PC; A/Eng. However, the anorectics showed over a 2-month period a higher titre of antibody especially to the Hong Kong virus: this was sigignificant. Cellular immune responses were measured using a tuberculin and a macrophage inhibition test, no significant difference between the two groups was obderved. These results which support the clinical findings are discussed.

Adolescent↗

A defective type 1 response to rhinovirus in atopic asthma.

BACKGROUND: Rhinoviruses (RVs) are the most frequent precipitants of the common cold and asthma exacerbations, but little is known about the immune response to these viruses and its potential implications in the pathogenesis of asthma. METHODS: Peripheral blood mononuclear cells (PBMC) from patients with atopic asthma and normal subjects were exposed to live or inactivated RV preparations. Levels of interferon (IFN)gamma and interleukins IL-12, IL-10, IL-4, IL-5 and IL-13 were evaluated in the culture supernatants with specific immunoassays. RESULTS: Exposure of PBMC to RVs induced the production of IFNgamma, IL-12, IL-10, and IL-13. Cells from asthmatic subjects produced significantly lower levels of IFNgamma and IL-12 and higher levels of IL-10 than normal subjects. IL-4 was induced only in the asthmatic group, while the IFNgamma/IL-4 ratio was more than three times lower in the asthmatic group. CONCLUSIONS: This evidence suggests that the immune response to RVs is not uniquely of a type 1 phenotype, as previously suggested. The type 1 response is defective in atopic asthmatic individuals, with a shift towards a type 2 phenotype in a way similar, but not identical, to their aberrant response to allergens. A defective type 1 immune response to RVs may be implicated in the pathogenesis of virus induced exacerbations of asthma.

Adult↗

Retrospective survey on therapeutic efficacy of Qigong in Korea.

Qigong is a complementary intervention for preventing and curing disease, and protecting and improving health through regulation of body and mind. Recently, we have been studying the psychoneuroimmunological effects of Qigong on the promotion of health. However, there are not many studies on the therapeutic efficacy of Qigong on various symptoms in Korea, hence the need to survey the clinical efficacy of Qigong. To evaluate the impact of Qigong in health care we categorized its effectiveness on the basis of ten years of subjects' memoranda. Among the 768 subjects, the motivation for doing Qigong was mostly to attend to health problems (81.5%), and males were more likely to use Qigong than females. The most improved symptoms were associated with psychological and musculoskeletal problems. Furthermore 66.9% of subjects reported improvements of perceived physical health and 40.3% of perceived psychological health. Other symptoms reduced by Qigong were pain (43.1%), fatigue (22.1%), and insomnia (8.7%). Wound healing was also surveyed (n = 332), and 84% of respondents reported improvement in recovery time, 66.6% reported reduced inflammation after Qigong and 50.3% reported no scarring as compared to before. In addition, 59.9% of respondents reported an increase in resistance to the common cold after four months of Qigong. The limitation of the study is that it is a retrospective survey on the basis of trainees' experiences of Qigong. Although this may constitute a potential bias, the study despite its limitations does provide precious empirical evidence of the effectiveness of Qigong.

Adolescent↗

Antiviral effect of gingyo-san, a traditional Chinese herbal medicine, on influenza A2 virus infection in mice.

Gingyo-san is a crude drug containing extracts from 7 medicinal plants and fermented soybeans in a specific ratio. It has been used clinically in China as a therapeutic agent for the common cold. In the present study, we examined the antiviral effect of this agent on influenza virus infection in mice. Gingyo-san and its components were administered orally to mice 1 day before, then 1 and 4 days after the inhalation of a mouse-adopted strain of influenza A2 (H2N2) virus. After infection with a 10 LD50 of the virus, 100% of mice treated with 10 mg/kg of the agent survived as compared with a 0% survival of control mice treated with saline. Also, the mean survival days were increased and consolidation scores were decreased in treated mice as compared with those of control mice. Two components contained in the agent, extracts from Glycyrrhizae radix and Arctii fructus, expressed antiviral activities in mice infected with influenza virus. However, in vitro growth of influenza virus in MDCK cells or viability of the virus was not affected by these extracts or Gingyo-san. From these results Gingyo-san was shown to be an antiviral agent in mice infected with a lethal amount of a mouse-adopted strain of influenza A2 virus.

Animals↗

Zinc and the risk for infectious disease.

Zinc is an essential micronutrient for human growth, development, and immune function. Zinc deficiency impairs overall immune function and resistance to infection. Mild to moderate zinc deficiency can be best detected through a positive response to supplementation trials. Zinc supplementation has been shown to have a positive effect on the incidence of diarrhea (18% reduction, 95% CI: 7-28%) and pneumonia (41% reduction, 95% CI: 17-59%), and might lead to a decrease in the incidence of malaria. Zinc has also proven to decrease the duration of diarrhea by 15% (95% CI: 5-24%). Maternal zinc supplementation may lead to a decrease in infant infections. Studies assessing the role of zinc supplementation among persons with HIV, tuberculosis, and the common cold have not been conclusive. Two studies have shown zinc supplementation to decrease child mortality by more than 50%. Zinc clearly has an important role in infant and childhood infectious diseases; programs to increase the intake of zinc among deficient populations are needed.

Animals↗

Rhinoviruses as pathogens of the lower respiratory tract.

Rhinoviruses (RVs) are the most common upper respiratory pathogens, inducing the majority of common colds worldwide. RV-related morbidity, although significant cumulatively, has been considered trivial for the individual patient. However, recent strong epidemiological associations of RVs with asthma exacerbations, including severe episodes requiring hospitalization, indicate that RV infections can result in serious disease. Current evidence supports the possibility that RVs infect the lower airways, inducing a local inflammatory response. Such evidence suggests that the role of RVs in other lower respiratory diseases, such as pneumonia, bronchitis, bronchiolitis and cystic fibrosis, should be re-examined with polymerase chain reaction-based methodologies, which are considerably more sensitive than traditional, cell culture-based techniques. The mechanisms through which RVs induce lower airway disease are studied to understand the relative contributions of the epithelial, neurogenic and immune components in the antiviral response, and to permit the design and implementation of specific treatments.

Asthma↗

Clinicocytological correlation in establishing the aetiology of chronic rhinitis.

Two hundred patients clinically diagnosed as having chronic rhinitis were provisionally grouped into allergic and non-allergic types of rhinitis on the basis of history, clinical examination, X-ray of the paranasal sinuses using the occipitomental view and other relevant investigations like differential and total leucocyte count. Whereas 158 cases were categorized into allergic rhinitis, 13 were diagnosed as suffering from vasomotor rhinitis, 25 from infective rhinitis and 4 patients from atrophic rhinitis. A nasal cytogram performed in all these cases showed allergic rhinitis in 107 cases, vasomotor rhinitis in 30 cases, infective on top of allergic rhinitis in 32 cases, common cold over allergic rhinitis in 3 cases, infective rhinitis in 20 cases, a non-infective non-allergic type in 4 cases and atrophic rhinitis in 4 cases. There was a good clinicocytological correlation; however, 30 patients clinically suspected to be having allergic rhinitis had an infective episode alone or on top of allergic rhinitis. Nasal cytology was thus found useful in modifying the treatment. It is a simple, easy and reliable investigation that can be done routinely in the out-patient department.

Adolescent↗

Vegetable, fruit, and cereal intake and risk of idiopathic pulmonary fibrosis in Japan.

AIMS: There has been little interest in the role of nutrition in prevention of idiopathic pulmonary fibrosis (IPF). We investigated the relationship between dietary intake of vegetables, fruit, cereals, antioxidants, and fiber and the risk of IPF in Japan. METHODS: Included were 104 cases aged 40 years or over who were within 2 years of the diagnosis in accordance with the most recent criteria. Controls aged 40 years or over comprised 56 hospitalized patients diagnosed as having acute bacterial pneumonia and 4 outpatients with common cold. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for age, sex, region, pack-years of smoking, employment status, occupational exposure, saturated fatty acid intake, and body mass index. RESULTS: Consumption of fruit in the second and third quartiles was associated with a statistically significant reduced risk of IPF. Although not statistically significant, a beneficial association between soluble fiber intake and IPF was found. No statistically significant dose-response relationship was observed between intake of green and yellow vegetables, other vegetables, cereals, beta-carotene, vitamins C and E, or insoluble fiber and the risk of IPF. CONCLUSION: Our findings suggest that fruit intake may confer protection against the development of IPF.

Adult↗

Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.

Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress. Supplementation of vitamin C was found to improve components of the human immune system such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Vitamin C contributes to maintaining the redox integrity of cells and thereby protects them against reactive oxygen species generated during the respiratory burst and in the inflammatory response. Likewise, zinc undernutrition or deficiency was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell activity, and the generation of oxidative burst. Therefore, both nutrients play important roles in immune function and the modulation of host resistance to infectious agents, reducing the risk, severity, and duration of infectious diseases. This is of special importance in populations in which insufficient intake of these nutrients is prevalent. In the developing world, this is the case in low- and middle-income countries, but also in subpopulations in industrialized countries, e.g. in the elderly. A large number of randomized controlled intervention trials with intakes of up to 1 g of vitamin C and up to 30 mg of zinc are available. These trials document that adequate intakes of vitamin C and zinc ameliorate symptoms and shorten the duration of respiratory tract infections including the common cold. Furthermore, vitamin C and zinc reduce the incidence and improve the outcome of pneumonia, malaria, and diarrhea infections, especially in children in developing countries.

Antioxidants↗

Rhinoviral infections activate p38MAP-kinases via membrane rafts and RhoA.

Rhinoviral infections belong to the most frequent human infections characterized by common cold, chronic bronchitis, exacerbations of asthma, otitis media and sinusitis. Here, we define molecular mechanisms that mediate infections of human epithelial cells with human rhinovirus strain 14 (RV14). We demonstrate that RV14 activates p38-MAPKinase (p38-K) in a biphasic time course. Early stimulation of p38-K by RV14 was observed a few minutes after initiation of the infection, while the late increase of p38-K activity occurred 7-12 hrs upon infection. The stimulation of p38-K was mediated by the small G-protein RhoA,which was activated by RV14. Transfection of a genetic construct preventing RhoA activation blocked RV14-induced p38-K activation. Further, integrity of cholesterol and sphingolipid-enriched membrane domains was required for RV14-mediated p38-K activation, which was inhibited by destruction of membrane rafts. The data indicate that RV employs a signaling cascade from membrane rafts via the small G-protein RhoA to p38-K to infect human cells.

Blotting, Western↗