Effectiveness of Meningococcal C Conjugate Vaccine in Salvador,Brazil: A Case-Control Study

Background

During a citywide epidemic of serogroup C meningococcal disease in Salvador in 2010, Brazil, the state government initiated mass vaccination targeting two age groups with high attack rates: individuals aged <5 years and 10–24 years. More than 600,000 doses of meningococcal serogroup C conjugate vaccines were administered. We performed a case-control study to evaluate vaccine uptake, document vaccine effectiveness and identify reasons for non-vaccination.

Methods and Findings

Population-based surveillance identified patients with laboratory-confirmed invasive meningococcal C (MenC) disease during 2010. Information on MenC vaccination was obtained from case patients and age-matched individuals from the same neighborhoods. MenC vaccine effectiveness was estimated based on the exact odds ratios obtained by conditional logistic regression analysis. Of 51 laboratory-confirmed cases of serogroup C meningococcal disease among patients <5 and 10–24 years of age 50 were included in the study and matched with 240 controls. Overall case-fatality was 25%. MenC vaccine coverage among controls increased from 7.1% to 70.2% after initiation of the vaccination campaign. None of the 50 case patients but 70 (29.2%) of the 240 control individuals, including 59 (70.2%) of 84 matched with cases from the period after MenC vaccination, had received at least one MenC vaccine dose. Overall effectiveness of MenC was 98% with a lower 95% exact confidence limit of 89%.

Conclusions

MenC vaccines administered during the meningococcal epidemic were highly effective, suggesting that rapid vaccine uptake through campaigns contributed to control of meningococcal disease.     

Semaphorin-1a is required for Aedes aegypti embryonic nerve cord development

Although mosquito genome projects have uncovered orthologues of many known developmental regulatory genes, extremely little is known about mosquito development. In this study, the role of semaphorin-1a (sema1a) was investigated during vector mosquito embryonic ventral nerve cord development. Expression of sema1a and the plexin A (plexA) receptor are detected in the embryonic ventral nerve cords of Aedes aegypti (dengue vector) and Anopheles gambiae (malaria vector), suggesting that Sema1a signaling may regulate mosquito nervous system development. Analysis of sema1a function was investigated through siRNA-mediated knockdown in A. aegypti embryos. Knockdown of sema1a during A. aegypti development results in a number of nerve cord phenotypes, including thinning, breakage, and occasional fusion of the longitudinal connectives, thin or absent commissures, and general distortion of the nerve cord. Although analysis of Drosophila melanogaster sema1a loss-of-function mutants uncovered many similar phenotypes, aspects of the longitudinal phenotypes differed between D. melanogaster and A. aegypti. The results of this investigation suggest that Sema1a is required for development of the insect ventral nerve cord, but that the developmental roles of this guidance molecule have diverged in dipteran insects.     

Recovery rates of bottlenose dolphin (Tursiops truncatus) carcasses estimated from stranding and survival rate data

Recovery of cetacean carcasses provides data on levels of human‐caused mortality, but represents only a minimum count of impacts. Counts of stranded carcasses are negatively biased by factors that include at‐sea scavenging, sinking, drift away from land, stranding in locations where detection is unlikely, and natural removal from beaches due to wave and tidal action prior to detection. We estimate the fraction of carcasses recovered for a population of coastal bottlenose dolphins (Tursiops truncatus), using abundance and survival rate data to estimate annual deaths in the population. Observed stranding numbers are compared to expected deaths to estimate the fraction of carcasses recovered. For the California coastal population of bottlenose dolphins, we estimate the fraction of carcasses recovered to be 0.25 (95% CI = 0.20–0.33). During a 12 yr period, 327 animals (95% CI = 253–413) were expected to have died and been available for recovery, but only 83 carcasses attributed to this population were documented. Given the coastal habits of California coastal bottlenose dolphins, it is likely that carcass recovery rates of this population greatly exceed recovery rates of more pelagic dolphin species in the region.     

A Novel Adeno-Associated Viral Variant for Efficient and Selective Intravitreal Transduction of Rat Müller Cells

Background

The pathologies of numerous retinal degenerative diseases can be attributed to a multitude of genetic factors, and individualized treatment options for afflicted patients are limited and cost-inefficient. In light of the shared neurodegenerative phenotype among these disorders, a safe and broad-based neuroprotective approach would be desirable to overcome these obstacles. As a result, gene delivery of secretable-neuroprotective factors to Müller cells, a type of retinal glia that contacts all classes of retinal neurons, represents an ideal approach to mediate protection of the entire retina through a simple and innocuous intraocular, or intravitreal, injection of an efficient vehicle such as an adeno-associated viral vector (AAV). Although several naturally occurring AAV variants have been isolated with a variety of tropisms, or cellular specificities, these vectors inefficiently infect Müller cells via intravitreal injection.

Methodology/Principal Findings

We have previously applied directed evolution to create several novel AAV variants capable of efficient infection of both rat and human astrocytes through iterative selection of a panel of highly diverse AAV libraries. Here, in vivo and in vitro characterization of these isolated variants identifies a previously unreported AAV variant ShH10, closely related to AAV serotype 6 (AAV6), capable of efficient, selective Müller cell infection through intravitreal injection. Importantly, this new variant shows significantly improved transduction relative to AAV2 (>60%) and AAV6.

Conclusions/Significance

Our findings demonstrate that AAV is a highly versatile vector capable of powerful shifts in tropism from minor sequence changes. This isolated variant represents a new therapeutic vector to treat retinal degenerative diseases through secretion of neuroprotective factors from Müller cells as well as provides new opportunities to study their biological functions in the retina.     

Immunolocalisation and expression of proteoglycan 4 (cartilage superficial zone proteoglycan) in tendon.

Cartilage superficial zone protein/proteoglycan (SZP) or proteoglycan 4 (PRG4), has been demonstrated to have the potential for several distinct biological functions including cytoprotection, lubrication and matrix binding. In the present study, we have examined both the immunolocalisation and the mRNA expression pattern of PRG4 in tissue harvested from the compressed and tensional regions of young and mature bovine tendons. Immunohistochemical analyses, utilizing monoclonal antibody 3-A-4 which recognizes a conformational-dependent epitope on native PRG4, demonstrated that PRG4 is present predominantly at the surface of fibrocartilaginous regions of tendon, with the intensity of immunoreactivity in this region increasing with age. RT-PCR analyses revealed that the expression of PRG4 mRNA can be modulated by exposure to cytokines and growth factors. In addition, analyses of human pathological tendon revealed that PRG4 may also be expressed as an alternatively spliced form lacking exons which encode part of the N-terminal matrix-binding and cell-proliferative domain; however, it remains to be determined whether such splice variants are a feature of human tendon, regardless of disease state. Taken together, these data indicate that PRG4 may play an important cytoprotective role by preventing cellular adhesion to the tendon surface as well as providing lubrication during normal tendon function, in a manner complimentary to cartilage PRG4. Structural modifications to SZP, together with a reduction in synthesis during tendon inflammation with injury and disease may account for the formation of tendon adhesions and contribute to the overall dysfunction of the tissue.     

Primary antibody-forming cells and secondary B cells are generated from separate precursor cell subpopulations

Two precursor cell subpopulations have been isolated from the spleen cells of nonimmune mice. The major B cell subpopulation binds high levels of the J11D monoclonal antibody and, upon T cell-dependent antigenic stimulation, gives rise to primary antibody-forming cell clones but not secondary B cells. A minority of the 10%-14% of Ia+ precursors that bind low levels of J11D (J11Dlo) also generate antibody-forming cell clones after primary stimulation. However, over 70% of J11Dlo precursors yield no primary antibody-forming cell clones but instead give rise to secondarily responsive B cells. The existence of a distinct precursor cell subpopulation that is responsible for the generation of B cell memory is further evidenced by the distribution of variable region clonotypes among J11Dlo primary precursors, which resembles the clonotype patterns of secondary B cells, and by the accumulation of somatic mutations in their clonal progeny.     

Functional characterization of the N-terminal domain of subunit H (Vma13p) of the yeast vacuolar ATPase

The yeast Saccharomyces cerevisiae vacuolar H(+)-ATPase (V-ATPase) is a multisubunit complex responsible for acidifying intracellular organelles and is highly regulated. One of the regulatory subunits, subunit H, is encoded by the VMA13 gene in yeast and is composed of two domains, the N-terminal domain (amino acids (aa) 1-352) and the C-terminal domain (aa 353-478). The N-terminal domain is required for the activation of the complex, whereas the C-terminal domain is required for coupling ATP hydrolysis to proton translocation (Liu, M., Tarsio, M., Charsky, C. M., and Kane, P. M. (2005) J. Biol. Chem. 280, 36978-36985). Experiments with epitope-tagged copies of Vma13p revealed that there is only one copy of Vma13p/subunit H per V-ATPase complex. Analysis of the N-terminal domain shows that the first 179 amino acids are not required for the activation and full function of the V-ATPase complex and that the minimal region of Vma13p/subunit H capable of activating the V-ATPase is aa 180-353 of the N-terminal domain. Subunit H is expressed as two splice variants in mammals, and deletion of 18 amino acids in yeast Vma13p corresponding to the mammalian subunit H beta isoform results in reduced V-ATPase activity and significantly lower coupling of ATPase hydrolysis to proton translocation. Intriguingly, the yeast Vma13p mimicking the mammalian subunit H beta isoform is functionally equivalent to Vma13p lacking the entire C-terminal domain. These results suggest that the mammalian V-ATPase complexes with subunit H splice variant SFD-alpha or SFD-beta are likely to have different activities and may perform distinct cellular functions.