CagA antigen of Helicobacter pylori and coronary instability: insight from a clinico-pathological study and a meta-analysis of 4241 cases

BackgroundCytotoxin-associated gene-A (CagA) antigen is expressed by some virulent strains of Helicobacter pylori (H. pylori). The role of CagA antigen in coronary instability is unknown. We performed a clinico-pathological study and a meta-analysis in the attempt to shed new light on this complex issue.MethodsIn the clinico-pathological study, 38 patients with unstable angina (UA), 25 patients with stable angina (SA), 21 patients with normal coronary arteries (NCA) and 50 age and sex matched healthy volunteers were enrolled. Serology for CagA was assessed in all patients. Specimens of atherosclerotic plaques were obtained from all patients by directional coronary atherectomy, and prepared for immunohistochemistry using anti-CagA monoclonal antibodies. The meta-analysis includes 9 studies assessing the association between seropositivity to CagA strains and acute coronary events.ResultsThe titre of anti-CagA antibodies was significantly higher in patients with unstable angina (161 ± 90 RU/ml) compared to those with stable angina (83 ± 59 RU/ml p < 0.02), NCA (47.3 ± 29 RU/ml p < 0.01) and healthy controls (73 ± 69 p < 0.02). Anti-CagA antibodies recognized antigens localized inside coronary atherosclerotic plaques in all specimens from both stable and unstable patients. In the meta-analysis, seropositivity to CagA was significantly associated with the occurrence of acute coronary events with an odds ratio (OR) of 1.34 (95% CI, 1.15–1.58, p = 0.0003).ConclusionsTaken together these findings suggest that in a subset of patients with unstable angina, an intense immune response against CagA-positive H. pylori strains might be critical to precipitate coronary instability mediated by antigen mimicry between CagA antigen and a protein contained in coronary atherosclerotic plaques.     

Infectious bursal disease virus is an icosahedral polyploid dsRNA virus

Viruses are a paradigm of the economy of genome resources, reflected in their multiplication strategy and for their own structure. Although there is enormous structural diversity, the viral genome is always enclosed within a proteinaceous coat, and most virus species are haploid; the only exception to this rule are the highly pleomorphic enveloped viruses. We performed an in-depth characterization of infectious bursal disease virus (IBDV), a non-enveloped icosahedral dsRNA virus with a bisegmented genome. Up to 6 natural populations can be purified, which share a similar protein composition but show higher sedimentation coefficients as particle density increases. Stoichiometry analysis of their genome indicated that these biophysical differences correlate with the copy number of dsRNA segments inside the viral capsid. This is a demonstration of a functional polyploid icosahedral dsRNA virus. We show that IBDV particles with greater genome copy number have higher infectivity rates. Our results show an unprecedented replicative strategy for dsRNA viruses and suggest that birnaviruses are living viral entities encompassing numerous functional and structural characteristics of positive and negative ssRNA viruses.     

Inhibition of aac(6′)-Ib-mediated amikacin resistance by nuclease-resistant external guide sequences in bacteria

Inhibition of bacterial gene expression by RNase P-directed cleavage is a promising strategy for the development of antibiotics and pharmacological agents that prevent expression of antibiotic resistance. The rise in multiresistant bacteria harboring AAC(6′)-Ib has seriously limited the effectiveness of amikacin and other aminoglycosides. We have recently shown that recombinant plasmids coding for external guide sequences (EGS), short antisense oligoribonucleotides (ORN) that elicit RNase P-mediated cleavage of a target mRNA, induce inhibition of expression of aac(6′)-Ib and concomitantly induce a significant decrease in the levels of resistance to amikacin. However, since ORN are rapidly degraded by nucleases, development of a viable RNase P-based antisense technology requires the design of nuclease-resistant RNA analog EGSs. We have assayed a variety of ORN analogs of which selected LNA/DNA co-oligomers elicited RNase P-mediated cleavage of mRNA in vitro. Although we found an ideal configuration of LNA/DNA residues, there seems not to be a correlation between number of LNA substitutions and level of activity. Exogenous administration of as low as 50 nM of an LNA/DNA co-oligomer to the hyperpermeable E. coli AS19 harboring the aac(6′)-Ib inhibited growth in the presence of amikacin. Our experiments strongly suggest an RNase P-mediated mechanism in the observed antisense effect.     

Rituximab Treatment of Adult Patients with Steroid-Resistant Focal Segmental Glomerulosclerosis

Background and objectives: Isolated case reports have shown a beneficial effect of rituximab on pediatric patients with primary FSGS, but there is no information about rituximab treatment of FSGS in adults.Design, setting, participants, & measurements: All patients who had biopsy-proven FSGS and were treated with rituximab in Spain were identified, independent of their positive or negative response, among the nephrology departments that belong to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Their characteristics and outcome after rituximab treatment were studied.Results: Eight patients were identified. Rituximab failed to improve nephrotic syndrome in five of eight patients, who continued to show massive proteinuria and exhibited a rapidly deteriorating renal function in two cases. Among the remaining three patients, two of them showed an improvement of renal function and a remarkable proteinuria reduction and one experienced a beneficial but transitory effect after rituximab. There were no differences in clinical or laboratory characteristics or in the CD20 B lymphocyte count after rituximab between these three patients and the five who had a negative response. The only difference was in the regimen of rituximab administration: Whereas the five patients with a negative response received only four weekly consecutive infusions of 375 mg/m², the three remaining patients received additional doses of rituximab.Conclusions: Only a minority (three of eight) of patients in our series of adult patients with FSGS showed a positive influence of rituximab. More studies are necessary to characterize further the optimal dosages and the mechanisms of action of rituximab in FSGS.The treatment of idiopathic steroid-resistant FSGS remains a worrying challenge for nephrologists. Cyclosporine has demonstrated a beneficial effect in some prospective, randomized studies, inducing partial or complete remission in a majority of treated patients (1); however, relapses are common after cyclosporine withdrawal, and the risk for chronic nephrotoxicity when the drug is maintained for long periods remains an important concern. Some observational studies have suggested a beneficial effect of tacrolimus, mycophenolate, sirolimus, ACTH, or plasmapheresis on some patients, but prospective, controlled studies are lacking.Rituximab is a mAb directed against the cell surface antigen CD20 of B lymphocytes. It is an effective therapy for non-Hodgkin''s lymphoma and other B cell malignancies (2). Several reports of successful use of rituximab in systemic diseases and immune-mediated renal disorders have been published, including membranous glomerulonephritis, lupus nephritis, vasculitis, mixed cryoglobulinemia, and thrombotic thrombocytopenic purpura (3,4).Some case reports have suggested that rituximab could be effective to resolve recurrent nephrotic syndrome after renal transplantation in patients whose primary renal disease was FSGS (5–9). The potential usefulness of rituximab has also been explored in patients with steroid-dependent or steroid-resistant forms of nephrotic syndrome. Several case reports and observational studies strongly suggest that rituximab could be an effective treatment for steroid-dependent nephrotic syndrome because the great majority of treated patients (most of them children) have experienced long-lasting periods of remission without steroids or other immunosuppressive drugs (10–12). Nevertheless, no prospective, randomized trials have been performed to compare the efficacy of this treatment with other available therapies for steroid-dependent nephrotic syndrome. Regarding steroid-resistant nephrotic syndrome, a few case reports of children with biopsy-proven FSGS and one adult with minimal-change disease in whom rituximab induced a complete or partial remission of nephrotic syndrome have been reported (13–16). As far as we know, no studies about rituximab treatment of adult patients with steroid-resistant nephrotic syndrome as a result of FSGS in their native kidneys have been published. Moreover, in the absence of prospective, controlled trials, anecdotal case reports tend to publish preferably patients with a positive response to innovative treatments. For all of these reasons, we collected the experience with rituximab-treated patients with FSGS among the nephrology departments that belong to the Spanish Group for the study of Glomerular Diseases (GLOSEN).     

Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia

We report the case of a child with clinical and haematological features indicative of juvenile myelomonocytic leukaemia (JMML). The patient showed dysmorphic features: high forehead, bilateral epicanthal folds, long eyebrows, low nasal bridge and slightly low-set ears. A 38G>A (G13D) mutation in exon 1 of the NRAS gene was first demonstrated on peripheral blood cells, and then confirmed on granulocyte-macrophage colony-forming units. The same mutation was also found in buccal swab, hair bulbs, endothelial cells, skin fibroblasts. This case suggests for the first time that constitutional mutations of NRAS may be responsible for development of a myeloproliferative/myelodysplastic disorder in children.     

Latin American position on the current status of hormone therapy during the menopausal transition and thereafter

OBJECTIVE: Data from placebo-controlled, randomized clinical trials conducted during the past few years resulted in critical re-evaluation of the overall health benefits of hormone therapy (HT) in women during the menopausal transition and thereafter. These data stimulated vigorous debate among experts and produced several position papers by North American and European authorities providing guidance on the use of HT. It is well known that cultural, geographic and ethnic differences influence the acceptance and risk perception of HT. Therefore, it was considered essential to present a position specifically relevant to Latin American countries. METHODS: A Latin American Expert Panel, convening in Salvador, Bahia, Brazil, obtained consensus on recommendations for HT that incorporated the findings of the most recently published reports. The panelists' opinions were surveyed by means of the Likert scale along five categories ranging from complete agreement to complete disagreement. RESULTS: The Panel presented 13 recommendations and considered three additional issues relevant to HT use. There was consensus that HT during the perimenopause and thereafter is warranted in Latin American women in particular for the management of vasomotor symptoms. HT may also be an option for osteoporosis prevention in women at significant risk, after evaluation of risks/benefits and after consideration of alternative therapies. HT should be individualized and prescribed at the lowest effective dose. CONCLUSIONS: The Panel concluded that HT remains a safe and effective treatment option for peri- and postmenopausal Latin American women.     

Thermal Behavior,Structure and Morphology of Propene/Higher 1‐Olefin Copolymers

Summary: Propene‐based random copolymers, synthesized with two isospecific methylaluminoxane‐activated ansa‐zirconocenes and containing even and odd carbon‐numbered higher 1‐olefins, were investigated by DSC and WAXD. Nature and amount of co‐units affect primary and secondary crystallization as well as melting behavior; their role is discussed in the light of microstructural features of the macromolecular chains. The specific role of 1‐olefin comonomers in the development of the γ‐polymorph was assessed by crystallizing selected samples at relatively high temperatures. A good agreement between the fraction of γ‐phase calculated from the deconvolution of the DSC melting endotherms and from WAXD analysis was found. The γ‐phase content nicely correlates with the average length of the isotactic sequences. In the WAXD patterns of some propene/1‐butene copolymers a new reflection at 2θ ? 10°, likely corresponding to the newly discovered trigonal modification of isotactic polypropene, was found.

Room temperature WAXD of copolymer M‐PBu7.5 after isothermal crystallization at two different temperatures.