Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.     

RNF213, a new nuclear marker for acanthomorph phylogeny

We show that RNF213 is a nuclear gene suitable for investigating large scale acanthomorph teleosteans interrelationships. The gene recovers many clades already found by several independent studies of acanthomorph molecular phylogenetics and considered as reliable. Moreover, we performed phylogenetic analyses of three other independent nuclear markers, first separately and then of all possible combinations (Dettaï, A., Lecointre, G., 2004. In search of nothothenioid (Teleostei) relatives. Antarct. Sci. 16 (1), 71–85. URL http://dx.doi.org/10.1017/S0954102004) of the four genes. This was coupled with an assessment of the reliability of clades using the repetition index of Li and Lecointre (Li, B., Lecointre, G., 2008. Formalizing reliability in the taxonomic congruence approach. Article accepted by Zoologica Scripta. URL http://dx.doi.org/10.1111/j.1463-6409.2008.00361.x). This index was improved here to handle the incomplete taxonomic overlap among datasets. The results lead to the identification of new reliable clades within the ‘acanthomorph bush’. Within a clade containing the Atherinomorpha, the Mugiloidei, the Plesiopidae, the Blennioidei, the Gobiesocoidei, the Cichlidae and the Pomacentridae, the Plesiopidae is the sister-group of the Mugiloidei. The Apogonidae are closely related to the Gobioidei. A clade named ‘H’ grouping a number of families close to stromateids and scombrids (Stromateidae, Scombridae, Trichiuridae, Chiasmodontidae, Nomeidae, Bramidae, Centrolophidae) is related to another clade named ‘E’ (Aulostomidae, Macrorhamphosidae, Dactylopteridae). The Sciaenidae is closely related to the Haemulidae. Within clade ‘X’ (Dettaï, A., Lecointre, G., 2004. In search of nothothenioid (Teleostei) relatives. Antarct. Sci. 16 (1), 71–85. URL http://dx.doi.org/10.1017/S0954102004), the Cottoidei, the Zoarcoidei, the Gasterosteidae, the Triglidae, the Scorpaenidae, the Sebastidae, the Synanceiidae, and the Congiopodidae form a clade. Within clade ‘L’ (Chen, W.-J., Bonillo, C., Lecointre, G., 2003. Repeatability of clades as a criterion of reliability: a case study for molecular phylogeny of Acanthomorpha (Teleostei) with larger number of taxa. Mol. Phylogenet. Evol. 26, 262–288; Dettaï, A., Lecointre, G., 2004. In search of nothothenioid (Teleostei) relatives. Antarct. Sci. 16 (1), 71–85. URL http://dx.doi.org/10.1017/S0954102004) grouping carangoids with flatfishes and other families (Centropomidae, Menidae, Sphyraenidae, Polynemidae, Echeneidae, Toxotidae, Xiphiidae), carangids are the stem-group of echeneids and coryphaenids, and sphyraenids are the sister-group to the Carangoidei. The Howellidae, the Epigonidae and the Lateolabracidae are closely related. We propose names for most of the clades repeatedly found in acanthomorph phylogenetic studies of various teams of the past decade.     

Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment

A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist–induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA–mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIP_L and not cFLIP_S interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor–mediated cell death.     

“When I Was Circumcised I Was Taught Certain Things”: Risk Compensation and Protective Sexual Behavior among Circumcised Men in Kisumu,Kenya

Background

Male circumcision has been shown to reduce the transmission of HIV from women to men through vaginal sex by approximately 60%. There is concern that men may engage in risk compensation after becoming circumcised, diminishing the benefits of male circumcision.

Methods and Findings

We conducted qualitative interviews with 30 sexually active circumcised men in Kisumu, Kenya from March to November 2008. Most respondents reported no behavior change or increasing protective sexual behaviors including increasing condom use and reducing the number of sexual partners. A minority of men reported engaging in higher risk behaviors either not using condoms or increasing the number of sex partners. Circumcised respondents described being able to perform more rounds of sex, easier condom use, and fewer cuts on the penis during sex.

Conclusions

Results illustrate that information about MC''s protection against HIV has disseminated into the larger community and MC accompanied by counseling and HIV testing can foster positive behavior change and maintain sexual behavior.     

Plasmid vector-linked maturation of natural killer (NK) cells is coupled to antigen-dependent NK cell activation during DNA-based immunization in mice

Plasmid DNA vaccines serve in a wide array of applications ranging from prophylactic vaccines to potential therapeutic tools against infectious diseases and cancer. In this study, we analyzed the mechanisms underlying the activation of natural killer (NK) cells and their potential role in adaptive immunity during DNA-based immunization against hepatitis B virus surface antigen in mice. We observed that the mature Mac-1(+) CD27(-) NK cell subset increased in the liver of mice early after DNA injection, whereas the number of the less mature Mac-1(+) CD27(+) NK cells in the liver and spleen was significantly reduced. This effect was attributed to bacterial sequences present in the plasmid backbone rather than to the encoded antigen and was not observed in immunized MyD88-deficient mice. The activation of NK cells by plasmid-DNA injection was associated with an increase in their effector functions that depended on the expressed antigen. Maturation of NK cells was abrogated in the absence of T cells, suggesting that cross talk exists between NK cells and antigen-specific T cells. Taken together, our data unravel the mechanics of plasmid vector-induced maturation of NK cells and plasmid-encoded antigen-dependent activation of NK cells required for a crucial role of NK cells in DNA vaccine-induced immunogenicity.     

Conductance and block of hair-cell mechanotransducer channels in transmembrane channel–like protein mutants

Transmembrane channel–like (TMC) proteins TMC1 and TMC2 are crucial to the function of the mechanotransducer (MT) channel of inner ear hair cells, but their precise function has been controversial. To provide more insight, we characterized single MT channels in cochlear hair cells from wild-type mice and mice with mutations in Tmc1, Tmc2, or both. Channels were recorded in whole-cell mode after tip link destruction with BAPTA or after attenuating the MT current with GsMTx-4, a peptide toxin we found to block the channels with high affinity. In both cases, the MT channels in outer hair cells (OHCs) of wild-type mice displayed a tonotopic gradient in conductance, with channels from the cochlear base having a conductance (110 pS) nearly twice that of those at the apex (62 pS). This gradient was absent, with channels at both cochlear locations having similar small conductances, with two different Tmc1 mutations. The conductance of MT channels in inner hair cells was invariant with cochlear location but, as in OHCs, was reduced in either Tmc1 mutant. The gradient of OHC conductance also disappeared in Tmc1/Tmc2 double mutants, in which a mechanically sensitive current could be activated by anomalous negative displacements of the hair bundle. This “reversed stimulus–polarity” current was seen with two different Tmc1/Tmc2 double mutants, and with Tmc1/Tmc2/Tmc3 triple mutants, and had a pharmacological sensitivity comparable to that of native MT currents for most antagonists, except dihydrostreptomycin, for which the affinity was less, and for curare, which exhibited incomplete block. The existence in the Tmc1/Tmc2 double mutants of MT channels with most properties resembling those of wild-type channels indicates that proteins other than TMCs must be part of the channel pore. We suggest that an external vestibule of the MT channel may partly account for the channel’s large unitary conductance, high Ca²⁺ permeability, and pharmacological profile, and that this vestibule is disrupted in Tmc mutants.