The effect of enamel matrix derivative (Emdogain) on bone formation: a systematic review

This systematic review focused on the question, if and to what extent enamel matrix derivative (Emdogain) [EMD]) promotes the regeneration of bone. The influence of combinations with other biomaterials was additionally evaluated. Twenty histomorphometric studies were included in this systematic review. Main results of the reviewed articles were (i) guide tissue regeneration (GTR) of infrabony defects seems to result in a higher degree of bone regeneration compared to treatment with EMD; (ii) combined therapy (GTR + EMD) of infrabony defects might not lead to better results than GTR therapy alone; (iii) there seems to be no additional benefit of combined therapy (GTR + EMD) in furcation defects over GTR therapy alone; (iv) EMD seems to lead to more bone regeneration of infrabony defects compared to open flap debridement; (v) however, EMD application might result in more bone formation when applied in supporting defects compared to nonsupporting defects; and (vi) EMD does not seem to promote external jaw/parietal bone formation in the titanium capsule model. The results of one study that suggest that EMD increases the initial growth of trabecular bone around endosseous implants by new bone induction need to be confirmed by additional research.     

DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

Human Vγ9Vδ2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway‐derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying Vγ9Vδ2 T‐cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in γδ T‐cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule‐1 (DNAM‐1) and CD96 were expressed by Vγ9Vδ2 T cells. The ligands Nectin‐like‐5 specific of both DNAM‐1 and CD96, and also Nectin‐2, an additional ligand of DNAM‐1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb‐mediated masking experiments that cytotoxicity against HCC cells as well as IFN‐γ production in γδ T cells were dependent on DNAM‐1. Our experiments indicated that Nectin‐like‐5 but not Nectin‐2 was involved in DNAM‐1‐dependent γδ T‐cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb‐mediated blockade that DNAM‐1 and NKG2D could cooperate in the cell lysis of HCC.     

Role of Teichoic Acid Choline Moieties in the Virulence of Streptococcus pneumoniae

In recent reports it was shown that genetically modified choline-free strains of Streptococcus pneumoniae (D39Cho⁻licA64 and D39ChiplicB31) expressing the type II capsular polysaccharide were virtually avirulent in the murine sepsis model, in sharp contrast to the isogenic and highly virulent strains D39Cho⁻ and D39Chip, which have retained the choline residues at their surface. We now demonstrate that this choline-associated virulence is independent of Toll-like receptor 2 recognition. Also, despite the lack of virulence, choline-free strains of S. pneumoniae were able to activate splenic dendritic cells, induce secretion of proinflammatory cytokines, and produce specific protective immunity against subsequent challenge. However, after this transient engagement of the immune system the choline-free bacteria were rapidly cleared from the blood, while the isogenic virulent strain D39Cho⁻ continued to grow, accompanied by prolonged expression of cytokines, eventually killing the experimental animals. The critical contribution of choline residues to the virulence potential of pneumococci appears to be the role that these amino alcohol residues play in a pneumococcal immune evasion strategy, the mechanism of which is unknown at the present time.A unique characteristic of the species Streptococcus pneumoniae is its auxotrophic requirement for choline (14). The bacterium takes up choline from the growth medium and incorporates this amino alcohol into the cell wall teichoic acid (2, 18) and the membrane-anchored glycolipid lipoteichoic acid polymers (1) that are located on the pneumococcal cell surface (7). A choline-independent strain, R6Cho⁻, capable of growing in choline-free medium acquired heterologous genetic elements during transformation of the S. pneumoniae strain R6 with DNA from Streptococcus oralis (10, 17), a streptococcal species that contains choline in its cell wall but does not require choline for growth (9). The choline independence of another, recently isolated mutant, R6Chip, is based on a single point mutation in the tacF gene, which encodes a teichoic acid flippase (4). However, these mutant strains were still able to utilize environmental choline. In order to prevent this, mutant derivatives of R6Cho⁻ and R6Chip were prepared in which genes in the lic1 operon responsible for the cellular uptake and metabolism of choline were inactivated (11). Such mutants, for instance, R6Cho⁻licA64, were able to maintain a choline-free phenotype in the choline-containing in vivo environment. R6Cho⁻licA64 grew in long autolysis-defective chains both in choline-containing and choline-free medium, and D39Cho⁻licA64, a derivative of the strain expressing capsular polysaccharide II, could grow both in vitro and also in vivo in a murine model of pneumococcal infection (11).In a previous study it was demonstrated that the choline-free strains D39Cho⁻licA64 and D39ChiplicB31, expressing the polysaccharide capsular type II, were virtually avirulent in the mouse model of sepsis (4, 11). Nevertheless, following intraperitoneal inoculation, D39Cho⁻licA64 was able to invade the bloodstream and replicate for a limited time, after which the bacteria were cleared from the blood. The purpose of the study described here was to determine to what extent these avirulent strains have the capacity to engage the host immune system during their transient period of growth within the host.     

Microbial Quorum-Sensing Molecules Induce Acrosome Loss and Cell Death in Human Spermatozoa

Infertility in men and women is frequently associated with genital contamination by various commensal or uropathogenic microbes. Since many microorganisms are known to release quorum-sensing signals in substantial amounts, we raised the question whether such molecules can directly affect human spermatozoa. Here we show that farnesol and 3-oxododecanoyl-l-homoserine lactone, employed by the opportunistic pathogenic yeast Candida albicans and the gram-negative bacterium Pseudomonas aeruginosa, respectively, induce multiple damage in spermatozoa. A reduction in the motility of spermatozoa coincided in a dose-dependent manner with apoptosis and necrosis at concentrations which were nondeleterious for dendritic cell-like immune cells. Moreover, sublethal doses of both signaling molecules induced premature loss of the acrosome, a cap-like structure of the sperm head which is essential for fertilization. Addressing their mechanism of action, we found that the bacterial molecule, but not the fungal molecule, actively induced the acrosome reaction via a calcium-dependent mechanism. This work uncovers a new facet in the interaction of microorganisms with human gametes and suggests a putative link between microbial communication systems and host infertility.The phenomenon of quorum sensing (QS) has gained intensive attention not only in the study of microbial communication within defined bacterial populations but also in the study of interkingdom signaling and pathogenicity. QS is defined as a means for microorganisms to sense their population density via the release of signaling molecules, to which they in turn respond. Reaching a threshold concentration in a bacterial population, these molecules can coordinately regulate a multitude of different effects, such as bioluminescence, biofilm formation, and virulence gene expression. Different QS molecules, such as the autoinducing peptides or N-acylhomoserine lactones, have been described in the past for many bacterial species (17, 40).A eukaryotic QS system was first evidenced in Candida albicans, a major human fungal pathogen and frequent commensal of the gastrointestinal and genitourinary tracts (10, 23). The isoprenoid alcohol farnesol was shown to inhibit the transition of C. albicans yeast cells to filamentous growth forms, and an opposite effect was recorded for tyrosol, another QS molecule in this fungus (5). Both these molecules are detectable in the supernatants of dense C. albicans yeast cell cultures in micromolar amounts. Recent observations indicate that the effects of farnesol are much more complex, since physiological farnesol concentrations of approximately 35 μM favor stress resistance in C. albicans (38) and even support antagonistic properties on other microbes. For example, farnesol was shown to induce apoptosis in the filamentous fungus Aspergillus nidulans (29) and to inhibit biofilm formation in the bacterial pathogen Staphylococcus aureus (13). There has also been particular interest in the impact of QS molecules on human cells, because evidence suggests implications in immunomodulation and the proliferation of distinct immune and malignant cells (11, 22, 26).Genital infections caused by various microbial pathogens are frequently associated with infertility in men and women worldwide (24). Little attention has been paid, however, to potential direct influences of commensal or pathogenic microorganisms on human gametes, and therefore their interaction with human spermatozoa remains largely elusive. Nevertheless, adverse effects of microbes on sperm could be observed during in vitro coincubation experiments with uropathogenic bacteria and yeasts (12), even in the presence of cell-free supernatants of C. albicans cultures (37). Since QS molecules are expected to be released by microorganisms in substantial amounts in vitro as well as in the human host, we raised for the first time the question whether such molecules can directly affect human spermatozoa. To address this possibility, we monitored the impact of selected QS molecules on sperm parameters which are crucial for fertilization. Here we studied not only the impact of C. albicans farnesol but also that of 3-oxododecanoyl-l-homoserine lactone (3-oxo-C₁₂-HSL), which is employed by the gram-negative, opportunistic pathogenic bacterium Pseudomonas aeruginosa, a frequent inducer of urinary tract infections (34). These studies revealed that distinct microbial QS molecules elicit multiple detrimental effects on human spermatozoa. They not only can impair sperm motility but also can induce spermatozoal cell death and, most notably, at sublethal doses can cause premature acrosome loss, a phenotype which is known to prevent the penetration of the oocyte by the sperm (19).     

Type I interferon receptor signalling is induced during demyelination while its function for myelin damage and repair is redundant

The type I interferons, interferon-beta and alpha (IFN-β, IFN-α), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-β as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair.     

Ataxin-2 associates with rough endoplasmic reticulum

Ataxin-2 is a novel protein, normally with a domain of 22 consecutive glutamine (Q) residues, which may expand beyond a threshold of (Q)₃₂, causing a neurodegenerative disease named Spinocerebellar ataxia type 2 (SCA2). To obtain clues about the functions of ataxin-2, we used fluorescence microscopy and centrifugation fractionation analyses. Immunocytochemical detection in non-neuronal and neuronal cells showed endogenous and transfected ataxin-2 distributed throughout the cytoplasm, with perinuclear preference and a granular appearance. Triple-labelling and confocal microscopy demonstrated co-localisation with the endoplasmic reticulum (ER) markers calreticulin, calnexin and CFP-ER. The pathogenic form of ataxin-2 with an expanded polyQ domain showed the same distribution pattern. Subcellular fractionation of mouse brain homogenates showed endogenous ataxin-2 associated with rough ER (rER) membranes, in a manner dependent on RNA, salt and phosphorylation. Our data are in agreement with recent findings that ataxin-2 directly interacts with poly(A)-binding protein (PABP), thus associating with polyribosomes under normal conditions and being recruited to stress granules under environmental stress. These data, in conjunction with the presence of Lsm domains within ataxin-2, suggest that ataxin-2 is involved in the processing of mRNA and/or the regulation of translation.     

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.