[From a pathogen's genome to an effective vaccine: the four-component meningococcal serogroup B vaccine]. / Del genoma de un patógeno a una vacuna efectiva: la vacuna de cuatro componentes frente a los meningococos del serogrupo B.

Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, entails significant mortality and morbidity. Disease incidence is highest in infants <1 year and young children globally. In Europe, N. meningitidis serogroup B is responsible for over 50% of overall IMD cases, whereas the majority of IMD cases in Latin America is caused either by serogroup B or C. The development of an effective vaccine against serogroup B has challenged the researchers for over half a century. Serogroup B capsular polysaccharide was an inappropriate vaccine antigen, and the success of outer membrane vesicle (OMV) vaccines was restricted to homologous bacterial strains. Reverse vaccinology led to the development of a 4-component meningococcal vaccine including three novel antigens, and OMVs (4CMenB). Each vaccine component has a different target. 4CMenB has been authorised based on its immunogenicity and safety data because the low disease incidence precluded formal clinical efficacy studies. Human serum bactericidal antibody (hSBA) assay tests functional antibodies in the serum of vaccinated individuals (i.e. the vaccine immunogenicity), and is the accepted correlate of protection. Vaccine strain coverage has been assessed both through hSBA assays and a more conservative method named Meningococcal Antigen Typing System (MATS). Effectiveness data of 4CMenB have been collected in the field since 2013. The vaccine proved effective in outbreak control in North America, and recent data from the introduction of the vaccine in the United Kingdom infant national immunisation programme reveal a vaccine effectiveness of 82.9% for the first two doses, with an acceptable safety profile.

Incomplete hemolytic-uremic syndrome in Argentinean children with bloody diarrhea.

Argentina has an exceptionally high frequency of hemolytic-uremic syndrome (HUS). We sought to define prospectively the role of verocytotoxins (Shiga-like toxins [SLTs]) in 254 Argentinean children with grossly bloody diarrhea during spring and summer. Free fecal SLTs (I/II) and/or DNA probe-positive isolates were found in 99 (39%) of the children. During the follow-up period, HUS developed in 6 patients (4 with evidence of recent SLT infection based on stool studies); another 14 patients had some, but not all, of the abnormalities seen in typical HUS. The development of HUS or incomplete HUS in these children was significantly associated with recent SLT-Escherichia coli infection (p = 0.024). The high incidence of SLT-associated bloody diarrhea in Argentina explains, at least partially, the unusually high frequency of HUS. Our data indicate that incomplete forms of HUS may be common in patients with SLT-associated bloody diarrhea.

Tumor necrosis factor concentrations in hemolytic uremic syndrome patients and children with bloody diarrhea in Argentina.

Hemolytic uremic syndrome (HUS) is thought to be a vascular endothelial injury disease. The mechanism of injury is unknown although verocytotoxins (Shiga-like toxins (SLTs)) are known to be associated with it. Recent evidence suggests that in vitro treatment of some endothelial cells with tumor necrosis factor alpha (TNF-alpha) dramatically increases their susceptibility to SLTs. We studied 25 children with HUS, 63 children with SLT-positive bloody diarrhea, 62 children with bloody diarrhea not associated with SLTs and 39 children admitted for elective surgery, included as an age- and season-matched control group. The TNF-alpha concentrations were found to be significantly elevated in children with HUS (range, 1 to 95 pg/ml; geometric mean, 32.2 pg/ml) compared with the healthy controls (range, 0 to 53 pg/ml; mean, 12.5 pg/ml; P < 0.001). Because it is hypothesized that TNF-alpha elevation might precede development of HUS, we also studied children with blood diarrhea. The TNF-alpha serum concentrations were significantly higher during the first 10 days after onset of bloody diarrhea than after the first 10 days (P < 0.02). Such elevation could be associated with vascular endothelial glycolipid receptor up-regulation and increased susceptibility to the effects of SLTs.

Effects of sodium nitroprusside on potassium induced contracture in isolated vascular smooth muscle.

The present study investigates the effects of Sodium Nitroprusside (SNP) on isometric developed tension (IDT) and tonic component of K+ induced contracture of rat portal vein. The availability of activator calcium for the contraction was modified by changing the ionic composition of the Krebs Ringer bicarbonate medium (KRB) or by using pharmacological agents such as nifedipine or KCl. In control conditions (KRB media) magnitude of IDT was 10.61 +/- 0.56 mN (n = 13). Addition of increasing concentrations of SNP (non cumulative) diminished IDT in a dose related manner. Tonic component of 60 mM KCl evoked contracture decayed 27.04 +/- 10.9% (n = 6) after 10(-4)M SNP incubation. Relaxant effect of SNP was more pronounced in the presence of nifedipine 10(-10)M (72.35 +/- 7.5% of inhibition, n = 6). The sensitivity of the preparation to SNP was strongly reduced in conditions of diminished Ca+2 efflux (slow sodium media = KRB sucrose). Experiments here presented support the hypothesis that the vasodilator effect of SNP could be attributed to an enhanced Ca+2 efflux from the vessel.

Effects of sodium nitroprusside on potassium induced contracture in isolated vascular smooth muscle.

The present study investigates the effects of Sodium Nitroprusside (SNP) on isometric developed tension (IDT) and tonic component of K+ induced contracture of rat portal vein. The availability of activator calcium for the contraction was modified by changing the ionic composition of the Krebs Ringer bicarbonate medium (KRB) or by using pharmacological agents such as nifedipine or KCl. In control conditions (KRB media) magnitude of IDT was 10.61 +/- 0.56 mN (n = 13). Addition of increasing concentrations of SNP (non cumulative) diminished IDT in a dose related manner. Tonic component of 60 mM KCl evoked contracture decayed 27.04 +/- 10.9

(n = 6) after 10(-4)M SNP incubation. Relaxant effect of SNP was more pronounced in the presence of nifedipine 10(-10)M (72.35 +/- 7.5

of inhibition, n = 6). The sensitivity of the preparation to SNP was strongly reduced in conditions of diminished Ca+2 efflux (slow sodium media = KRB sucrose). Experiments here presented support the hypothesis that the vasodilator effect of SNP could be attributed to an enhanced Ca+2 efflux from the vessel.