Strategies for preventing influenza: future perspectives in influenza vaccine technology

Prevention of influenza transmission and containment of epidemics and pandemics require effective strategies that can be efficiently and easily addressed to the whole population. Annual vaccination is undoubtedly the most effective way to provide protection against influenza infection. Numbers of vaccines are actually available for yearly immunisation. However, the continuous increasing demand for rapidly available vaccine doses for immunisation of a larger proportion of population represents the stimulus for study and development of more efficient vaccine production technologies, which can guarantee reduction of vaccine manufacture times and better compliance by availability of easier routes of administration. New perspectives in influenza vaccination technology are making their way in the future panorama of influenza prevention strategies.     

Retrocochlear function of the peripheral deafness gene Cacna1d

Hearing impairment represents the most common sensory deficit in humans. Genetic mutations contribute significantly to this disorder. Mostly, only malfunction of the ear is considered. Here, we assessed the role of the peripheral deafness gene Cacna1d, encoding the L-type channel Ca(v)1.3, in downstream processing of acoustic information. To this end, we generated a mouse conditional Cacna1d-eGFP(flex) allele. Upon pairing with Egr2::Cre mice, Ca(v)1.3 was ablated in the auditory brainstem, leaving the inner ear intact. Structural assessment of the superior olivary complex (SOC), an essential auditory brainstem center, revealed a dramatic volume reduction (43-47%) of major nuclei in young adult Egr2::Cre;Cacna1d-eGFP(flex) mice. This volume decline was mainly caused by a reduced cell number (decline by 46-56%). Abnormal formation of the lateral superior olive was already present at P4, demonstrating an essential perinatal role of Ca(v)1.3 in the SOC. Measurements of auditory brainstem responses demonstrated a decreased amplitude in the auditory nerve between 50 and 75 dB stimulation in Egr2::Cre;Cacna1d-eGFP(flex) knockout mice and increased amplitudes in central auditory processing centers. Immunohistochemical studies linked the amplitude changes in the central auditory system to reduced expression of K(v)1.2. No changes were observed for K(v)1.1, KCC2, a determinant of inhibitory neurotransmission, and choline acetyltransferase, a marker of efferent olivocochlear neurons. Together, these analyses identify a crucial retrocochlear role of Ca(v)1.3 and demonstrate that mutations in deafness genes can affect sensory cells and neurons alike. As a corollary, hearing aids have to address central auditory processing deficits as well.     

Prevalence of undiagnosed celiac disease in the parents of preterm and/or small for gestational age infants

OBJECTIVES:  The aim of this study was to estimate the prevalence of undiagnosed celiac disease (CD) in the parents of preterm and/or small for gestational age (SGA) infants.
METHODS:  A sample of 1,714 parents (868 women, 846 men) of 905 preterm (<37 wk of gestational age) and/or SGA (<10th percentile of birthweight) infants consecutively born in Lombardy, Northern Italy, and not diagnosed with CD prior to pregnancy, were tested for CD. Diagnosis was based on antitissue transglutaminase and anti-endomysial antibodies and confirmed by duodenal biopsy.
RESULTS:  The overall prevalence of undiagnosed CD was 0.64% (95% confidence interval [CI] 0.32–1.15%), 0.92% (0.40–1.81%) in women and 0.35% (0.07–1.03%) in men. In the mothers of preterm infants prevalence of CD was 0.39% (0.05–1.39%). In the mothers of SGA infants prevalence of CD was 1.60% (0.64–3.27%), and the observed number of mothers with CD was 2.25 times higher than the expected one in the Italian female population ( P = 0.039). Undiagnosed CD in mothers was associated with an increased risk of SGA birth (odds ratio 6.97, 95% CI 1.11–43.55%).
CONCLUSIONS:  While additional powered studies are needed, the present results suggest that the prevalence of undiagnosed CD in the mothers of SGA infants is higher than in the general female population.     

Early-Transmitted Variants and Their Evolution in a HIV-1 Positive Couple: NGS and Phylogenetic Analyses

We had access to both components of a couple who became infected with human immunodeficiency virus (HIV)-1 through sexual behavior during the early initial phase of infection and before initiation of therapy. We analyzed blood samples obtained at the time of diagnosis and after six months of combined antiretroviral therapy. Next-generation sequencing (NGS) and phylogenetic analyses were used to investigate the transmission and evolution of HIV-1 quasispecies. Phylogenetic analyses were conducted using Bayesian inference methods. Both partners were infected with an HIV-1 B subtype. No evidence of viral recombination was observed. The lowest intrapersonal genetic distances were observed at baseline, before initiation of therapy, and in particular in the V1V2 fragment (distances ranging from 0.102 to 0.148). One HIV-1 single variant was concluded to be dominant in all of the HIV-1 regions analyzed, although some minor variants could be observed. The same tree structure was observed both at baseline and after six months of therapy. These are the first extended phylogenetic analyses performed on both members of a therapy-naïve couple within a few weeks of infection, and in which the effect of antiretroviral therapy on viral evolution was analyzed. Understanding which HIV-1 variants are most likely to be transmitted would allow a better understanding of viral evolution, possibly playing a role in vaccine design and prevention strategies.     

Plasma levels of fibronectin in polymyalgia rheumatica giant cell arteritis

Summary In order to verify whether measurement of plasma fibronectin (Fn) could represent a useful tool in acute-phase-response assessment, Fn was measured in 16 previously untreated patients (group A) affected by polymyalgia rheumatica giant cell arteritis (PMR-GCA), both before, during, and after 45 days of steroid therapy, and its course was compared with the behavior of some acute-phase reactants such as erythrocyte sedimentation rate (ESR), fibrinogen (Fng), and prealbumin (Preal). No difference was detected between the baseline Fn levels found in patients and those registered in a control group composed of 15 sex- and age-matched healthy subjects; no correlation was found with the other acute-phase parameters considered, and no significant variation of plasma Fn levels was registered as a result of the steroid therapy administered. On the contrary, all the other parameters revealed a good degree of correlation and tended progressively and homogeneously towards normalization as a result of the therapy administered.Plasma Fn was also measured in another group of 16 PMR-GCA patients (group B), all of whom had pathological retinal fluoroangiographic findings, and its levels were compared with those of the von Willebrand factor antigen (vWfAg), a biochemical index of vascular damage. While the levels of Fn continued to be the same as those detected in the control group, the values of vWfAg registered in group B proved to be significantly different from those found in another homogeneous control group of 25 healthy subjects. Finally, no correlation could be detected between Fn and vWfAg, and neither of them showed any significant correlation with the ESR. These results indicate that plasma Fn may not be considered to be an acute-phase reactant in PMR-GCA, and that it is not useful for revealing the vascular involvement in PMR-GCA.     

Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome)

A murine monoclonal antibody made against an idiotypic determinant (Id) of surface IgM/IgD lambda molecules on chronic lymphocytic leukemia (CLL) cells of a 71-year-old woman was used for clonal analysis by two- color immunofluorescence. The anti-Id antibody identified IgM+/IgD+/lambda+ B cells as the predominant cell type of her CLL clone. In addition, substantial proportions of the IgG and IgA B cells and most of the IgM plasma cells in her bone marrow and blood were Id+. Six years after diagnosis, the patient died of respiratory failure due to infiltration of lungs by malignant cells. Autopsy revealed a dramatic change in the tumor cell morphology. The lungs, hilar nodes, and liver were infiltrated by a diffuse large cell lymphoma admixed with the leukemic cells. By immunohistologic staining these anaplastic lymphoma cells were IgM+/IgD-/lambda+ B cells expressing the same Id noted earlier on the CLL cells. The immunoglobulin gene rearrangement pattern on Southern blot analysis was also the same in leukemic blood cells and in the tissues involved by the lymphoma. Thus, the combination of antiidiotype and immunoglobulin gene analyses in this patient with Richter's syndrome revealed that a CLL clone, seemingly "frozen" in differentiation, was actually undergoing isotype switching, differentiation into plasma cells, and evolution into a rapidly growing and fetal lymphoma.