Molecular mechanisms of severe acute respiratory syndrome (SARS)

Severe acute respiratory syndrome (SARS) is a new infectious disease caused by a novel coronavirus that leads to deleterious pulmonary pathological features. Due to its high morbidity and mortality and widespread occurrence, SARS has evolved as an important respiratory disease which may be encountered everywhere in the world. The virus was identified as the causative agent of SARS due to the efforts of a WHO-led laboratory network. The potential mutability of the SARS-CoV genome may lead to new SARS outbreaks and several regions of the viral genomes open reading frames have been identified which may contribute to the severe virulence of the virus. With regard to the pathogenesis of SARS, several mechanisms involving both direct effects on target cells and indirect effects via the immune system may exist. Vaccination would offer the most attractive approach to prevent new epidemics of SARS, but the development of vaccines is difficult due to missing data on the role of immune system-virus interactions and the potential mutability of the virus. Even in a situation of no new infections, SARS remains a major health hazard, as new epidemics may arise. Therefore, further experimental and clinical research is required to control the disease

Coronavirus Gene 7 Counteracts Host Defenses and Modulates Virus Virulence

Transmissible gastroenteritis virus (TGEV) genome contains three accessory genes: 3a, 3b and 7. Gene 7 is only present in members of coronavirus genus a1, and encodes a hydrophobic protein of 78 aa. To study gene 7 function, a recombinant TGEV virus lacking gene 7 was engineered (rTGEV-Δ7). Both the mutant and the parental (rTGEV-wt) viruses showed the same growth and viral RNA accumulation kinetics in tissue cultures. Nevertheless, cells infected with rTGEV-Δ7 virus showed an increased cytopathic effect caused by an enhanced apoptosis mediated by caspase activation. Macromolecular synthesis analysis showed that rTGEV-Δ7 virus infection led to host translational shut-off and increased cellular RNA degradation compared with rTGEV-wt infection. An increase of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation and an enhanced nuclease, most likely RNase L, activity were observed in rTGEV-Δ7 virus infected cells. These results suggested that the removal of gene 7 promoted an intensified dsRNA-activated host antiviral response. In protein 7 a conserved sequence motif that potentially mediates binding to protein phosphatase 1 catalytic subunit (PP1c), a key regulator of the cell antiviral defenses, was identified. We postulated that TGEV protein 7 may counteract host antiviral response by its association with PP1c. In fact, pull-down assays demonstrated the interaction between TGEV protein 7, but not a protein 7 mutant lacking PP1c binding motif, with PP1. Moreover, the interaction between protein 7 and PP1 was required, during the infection, for eIF2α dephosphorylation and inhibition of cell RNA degradation. Inoculation of newborn piglets with rTGEV-Δ7 and rTGEV-wt viruses showed that rTGEV-Δ7 virus presented accelerated growth kinetics and pathology compared with the parental virus. Overall, the results indicated that gene 7 counteracted host cell defenses, and modified TGEV persistence increasing TGEV survival. Therefore, the acquisition of gene 7 by the TGEV genome most likely has provided a selective advantage to the virus

Literatuuroverzicht van het bewijs voor een mogelijk verband tussen de ziekte van Crohn en blootstelling aan Mycobacterium avium ssp. Paratuberculosis

Mycobacterium avium ssp. paratuberculosis (Map) wordt door veel onderzoekers beschouwd als mogelijke verwekker van de ziekte van Crohn (morbus Crohn, MC) bij de mens. Dit is vooral gebaseerd op klinische en pathologische overeenkomsten tussen MC en de ziekte Paratuberculose bij runderen (herkauwers), die zonder twijfel veroorzaakt wordt door Map, en de aangetoonde aanwezigheid van Map bij een deel van de patienten met MC. Echter, evenzoveel onderzoekers zijn van mening dat Map niet de verwekker is van MC omdat Paratuberculose en MC ook verschillen in een aantal kenmerken. Map kan bijvoorbeeld niet worden aangetoond bij alle MC patienten. Verder kan Map vaak wel worden aangetoond bij een aanzienlijk deel van de onderzochte gezonde personen. Omdat Map niettemin een ziekteverwekker is die via melk, vlees, water en andere levensmiddelen de consument kan bereiken, bestaat er ernstige bezorgdheid over het mogelijke risico van dit Map-besmet voedsel voor het ontstaan van MC bij de consument. In dit rapport wordt een antwoord gegeven op de vraag 'is het verband tussen de verwekker van Paratuberculose, Mycobacterium avium ssp. paratuberculosis, en de ziekte van Crohn overtuigend bewezen?' De huidige wetenschappelijke kennis over MC wordt beschreven, waarbij het accent wordt gelegd op de informatie die direct of indirect betrekking heeft op, of een indicatie kan zijn voor een mogelijke relatie tussen MC en Map.Crohn's Disease is characterized by a severe, non-specific, chronic inflammation of the intestinal wall. The inflammation of CD most commonly affects the last part of the ileum, and often includes the colon and sigmoid. CD is a Th1 disease characterized by the production of pro-inflammatory cytokines like TNF- , which is responsible for development of the lesions, and by the production of IFN-? and Il-2. CD is a multi-factorial disease; based on epidemiological and geographical observations, several genetic (familial, racial) and environmental (geographic, hygienic) factors (especially microbial) have been associated with the disease. Mutations in the human CARD15 gene and differential expression of Toll-like receptors (TLRs) 2, 3 and 4 have been associated with CD. CARD15 and TLRs are part of the body's innate defence system against bacteria. They activate the immune system after recognizing specific bacterial components. Presence of intestinal bacteria seems to be a prerequisite for CD; the disease cannot develop or perpetuate without the presence of an intestinal flora. One of the bacteria that has been frequently associated with CD is Mycobacterium avium subspecies paratuberculosis (Map). Map causes a severe chronic intestinal disease in ruminants, Paratuberculosis. CD and Paratuberculosis share several clinical, immunological and histo-pathological characteristics. Map is present in many dairy herds and probably can be transmitted to humans via foodstuff. Many investigators have tried to prove, or controvert a common aetiology for CD and Paratuberculosis, and have applied several detection methods to accomplish this. Unfortunately, the quest for Map using PCR and culture methods, and the studies on the immune responses against Map in CD patients, have yet not resulted in conclusive data to support or discount the hypothesis that Map is the etiologic agent of CD. The fact that Map can be found in a high percentage of apparently healthy individuals, and that CD patients have significantly higher immune responses against several food antigens compared to healthy individuals, raises the question whether Map is a common passer-by of the human intestinal tract, or that a particular cofactor (a genetic aberration) is needed before Map can cause disease. The current hypothesis about the patho-physiology of CD is that in a genetic susceptible host, the intestinal flora triggers an aberrant immune response that results in a chronic intestinal inflammation and a damaged (leaky) intestinal mucosal barrier. Although a multi-factorial cause for CD is expected, the possibility, however, that an infectious agent like Map can play a key role in the causation of even a sub-set of CD patients remains, and clearly needs to be taken seriously.VW

Literatuuroverzicht van het bewijs voor een mogelijk verband tussen de ziekte van Crohn en blootstelling aan Mycobacterium avium ssp. Paratuberculosis

Crohn's Disease is characterized by a severe, non-specific, chronic inflammation of the intestinal wall. The inflammation of CD most commonly affects the last part of the ileum, and often includes the colon and sigmoid. CD is a Th1 disease characterized by the production of pro-inflammatory cytokines like TNF- , which is responsible for development of the lesions, and by the production of IFN-? and Il-2. CD is a multi-factorial disease; based on epidemiological and geographical observations, several genetic (familial, racial) and environmental (geographic, hygienic) factors (especially microbial) have been associated with the disease. Mutations in the human CARD15 gene and differential expression of Toll-like receptors (TLRs) 2, 3 and 4 have been associated with CD. CARD15 and TLRs are part of the body's innate defence system against bacteria. They activate the immune system after recognizing specific bacterial components. Presence of intestinal bacteria seems to be a prerequisite for CD; the disease cannot develop or perpetuate without the presence of an intestinal flora. One of the bacteria that has been frequently associated with CD is Mycobacterium avium subspecies paratuberculosis (Map). Map causes a severe chronic intestinal disease in ruminants, Paratuberculosis. CD and Paratuberculosis share several clinical, immunological and histo-pathological characteristics. Map is present in many dairy herds and probably can be transmitted to humans via foodstuff. Many investigators have tried to prove, or controvert a common aetiology for CD and Paratuberculosis, and have applied several detection methods to accomplish this. Unfortunately, the quest for Map using PCR and culture methods, and the studies on the immune responses against Map in CD patients, have yet not resulted in conclusive data to support or discount the hypothesis that Map is the etiologic agent of CD. The fact that Map can be found in a high percentage of apparently healthy individuals, and that CD patients have significantly higher immune responses against several food antigens compared to healthy individuals, raises the question whether Map is a common passer-by of the human intestinal tract, or that a particular cofactor (a genetic aberration) is needed before Map can cause disease. The current hypothesis about the patho-physiology of CD is that in a genetic susceptible host, the intestinal flora triggers an aberrant immune response that results in a chronic intestinal inflammation and a damaged (leaky) intestinal mucosal barrier. Although a multi-factorial cause for CD is expected, the possibility, however, that an infectious agent like Map can play a key role in the causation of even a sub-set of CD patients remains, and clearly needs to be taken seriously.Mycobacterium avium ssp. paratuberculosis (Map) wordt door veel onderzoekers beschouwd als mogelijke verwekker van de ziekte van Crohn (morbus Crohn, MC) bij de mens. Dit is vooral gebaseerd op klinische en pathologische overeenkomsten tussen MC en de ziekte Paratuberculose bij runderen (herkauwers), die zonder twijfel veroorzaakt wordt door Map, en de aangetoonde aanwezigheid van Map bij een deel van de patienten met MC. Echter, evenzoveel onderzoekers zijn van mening dat Map niet de verwekker is van MC omdat Paratuberculose en MC ook verschillen in een aantal kenmerken. Map kan bijvoorbeeld niet worden aangetoond bij alle MC patienten. Verder kan Map vaak wel worden aangetoond bij een aanzienlijk deel van de onderzochte gezonde personen. Omdat Map niettemin een ziekteverwekker is die via melk, vlees, water en andere levensmiddelen de consument kan bereiken, bestaat er ernstige bezorgdheid over het mogelijke risico van dit Map-besmet voedsel voor het ontstaan van MC bij de consument. In dit rapport wordt een antwoord gegeven op de vraag 'is het verband tussen de verwekker van Paratuberculose, Mycobacterium avium ssp. paratuberculosis, en de ziekte van Crohn overtuigend bewezen?' De huidige wetenschappelijke kennis over MC wordt beschreven, waarbij het accent wordt gelegd op de informatie die direct of indirect betrekking heeft op, of een indicatie kan zijn voor een mogelijke relatie tussen MC en Map

The effect of sacral neuromodulation (SNM) during the tined lead procedure (TLP) on nocturia in patients with overactive bladder syndrome (OAB)

1.5Full digital generat a partir de la base topogràfica 1:5 000. Els fulls d'aquesta sèrie corresponen a la divisió 4 x 4 de la malla de distribució del Mapa topográfico nacional de España 1:50 000. Cada full inclou 2 finestres (Mapa índex de la sèrie; Mapa guia). - Projecció Universal Transversa Mercator (UTM), fus 31, sobre el·lipsoide internacional i datum europeu. Equidistància de les corbes de nivell: 5 m.Imatge digital de 90 x 67 cm1:5 000300 PP