A cephalometric study of class II malocclusions treated with mandibular surgery

INTRODUCTION:

Class II malocclusion is often associated with retrognathic mandible. Some of these problems require surgical correction. The purposes of this study were to investigate treatment outcomes in patients with Class II malocclusions whose treatment included mandibular advancement surgery and to identify predictors of good outcomes.
METHODS:

Pretreatment and posttreatment cephalometric radiographs of 90 patients treated with mandibular advancement surgery by 57 consultant orthodontists in the United Kingdom before September 1998 were digitized, and cephalometric landmarks were identified. Paired samples t tests were used to compare the pretreatment and posttreatment cephalometric values for each patient. For each cephalometric variable, the proportion of patients falling within the ideal range was identified. Multiple logistic regression analysis was performed to identify predictors of achieving ideal range outcomes for the key skeletal (ANB and SNB angles), dental (overjet and overbite), and soft-tissue (Holdaway angle) measurements.
RESULTS:

An overjet within the ideal range of 1 to 4 mm was achieved in 72% of patients and was more likely with larger initial ANB angles. Horizontal correction of the incisor relationship was achieved by a combination of 75% skeletal movement and 25% dentoalveolar change. An ideal posttreatment ANB angle was achieved in 42% of patients and was more likely in females and those with larger pretreatment ANB angles. Ideal soft-tissue Holdaway angles (7 degrees to 14 degrees ) were achieved in 49% of patients and were more likely in females and those with smaller initial SNA angles. Mandibular incisor decompensation was incomplete in 28% of patients and was more likely in females and patients with greater pretreatment mandibular incisor proclination. Correction of increased overbite was generally successful, although anterior open bites were found in 16% of patients at the end of treatment. These patients were more likely to have had initial open bites.
CONCLUSIONS:

Mandibular surgery had a good success rate in normalizing the main dental and skeletal relationships. Less ideal soft-tissue profile outcomes were associated with larger pretreatment SNA-angle values, larger final mandibular incisor inclinations, and smaller final maxillary incisor inclinations. The use of mandibular surgery to correct anterior open bite was associated with poor outcomes.

Long-term occlusal and soft-tissue profile outcomes after treatment of Class II Division 1 malocclusion with fixed appliances

Introduction: Our objective was to determine which factors were predictive of good long-term outcomes after fixed appliance treatment of Class II Division 1 malocclusion. Methods: Two hundred seven patients with Class II Division 1 malocclusion were examined in early adulthood at a mean of 4.6 years after treatment with fixed appliances. The peer assessment rating index was used to evaluate dental alignment and occlusal relationships. The soft-tissue profile was assessed with the Holdaway angle. Results: Logistic regression identified 3 pretreatment variables that were predictive of a good facial profile (Holdaway angle) at recall: the lower lip to E-plane distance (P

Cloning and characterization of the mouse homologue of the human dendritic cell maturation marker CD208/DC-LAMP

DC-LAMP, a member of the lysosomal-associated membrane protein (LAMP) family, is specifically expressed by human dendritic cells (DC) upon activation and therefore serves as marker of human DC maturation. DC-LAMP is detected first in activated human DC within MHC class II molecules-containing compartments just before the translocation of MHC class II-peptide complexes to the cell surface, suggesting a possible involvement in this process. The present study describes the cloning and characterization of mouse DC-LAMP, whose predicted protein sequence is over 50% identical to the human counterpart. The mouse DC-LAMP gene spans over 25 kb and shares syntenic chromosomal localization (16B2-B4 and 3q26) and conserved organization with the human DC-LAMP gene. Analysis of mouse DC-LAMP mRNA and protein revealed the expression in lung peripheral cells, but also its unexpected absence from mouse lymphoid organs and from mouse DC activated either in vitro or in vivo. In conclusion, mouse DC-LAMP is not a marker of mature mouse DC and this observation raises new questions regarding the role of human DC-LAMP in human DC.

Repertoire of HLA-DR1-restricted CD4 T cell responses to capsular Caf1 antigen of Y. pestis HLA-transgenic mice

Yersinia pestis is the causative agent of plague, a rapidly fatal infectious disease that has not been eradicated worldwide. The capsular Caf1 protein of Y. pestis is a protective antigen under development as a recombinant vaccine. However, little is known about the specificity of human T cell responses for Caf1. We characterized CD4 T cell epitopes of Caf1 in 'humanized'-HLA-DR1 transgenic mice lacking endogenous MHC class II molecules. Mice were immunized with Caf1 or each of a complete set of overlapping synthetic peptides, and CD4 T cell immunity was measured with respect to proliferative and IFNgamma T cell responses and recognition by a panel of T cell hybridomas, as well as direct determination of binding affinities of Caf1 peptides to purified HLA-DR molecules. Although a number of DR1-restricted epitopes were identified following Caf1 immunization, the response was biased towards a single immunodominant epitope near the C-terminus of Caf1. In addition, potential promiscuous epitopes, including the immunodominant epitope, were identified by their ability to bind multiple common HLA alleles, with implications for the generation of multivalent vaccines against plague for use in humans.

Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity

Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

Parasite diversity, patterns of MHC II variation and olfactory based mate choice in diverging three-spined stickleback ecotypes

Ecological speciation has been the subject of intense research in evolutionary biology but the genetic basis of the actual mechanism driving reproductive isolation has rarely been identified. The extreme polymorphism of the major histocompatibility complex (MHC), probably maintained by parasite-mediated selection, has been proposed as a potential driver of population divergence. We performed an integrative field and experimental study using three-spined stickleback river and lake ecotypes. We characterized their parasite load and variation at MHC class II loci. Fish from lakes and rivers harbor contrasting parasite communities and populations possess different MHC allele pools that could be the result of a combined action of genetic drift and parasite-mediated selection. We show that individual MHC class II diversity varies among populations and is lower in river ecotypes. Our results suggest the action of homogenizing selection within habitat type and diverging selection between habitat types. Finally, reproductive isolation was suggested by experimental evidence: in a flow channel design females preferred assortatively the odor of their sympatric male. This demonstrates the role of olfactory cues in maintaining reproductive isolation between diverging fish ecotypes.

A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase

We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4(+) T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.-Robinson, M. W., Alvarado, R., To, J., Hutchinson, A. T., Dowdell, S. N., Lund, M., Turnbull, L., Whitchurch, C. B., O'Brien, B. A., Dalton, J. P., Donnelly, S. A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase.

Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.

Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat(Y136F) mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies. We analyzed whether the Lat(Y136F) pathology constitutes a bona fide autoimmune disorder dependent on TCR specificity. Using adoptive transfer experiments, we demonstrated that the expansion and uncontrolled Th2-effector function of Lat(Y136F) CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3(+) regulatory T cells are present in Lat(Y136F) mice and that pathogenic Lat(Y136F) CD4 T cells were capable of escaping the control of infused wild-type Foxp3(+) regulatory T cells. These results argue against a scenario where the Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat(Y136F) CD4 T cells with the ability to trigger the production of Abs and of autoantibodies in a TCR-independent, quasi-mitogenic fashion. Therefore, despite the presence of autoantibodies causative of severe systemic disease, the pathological conditions observed in Lat(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.

Self-perception of dentofacial attractiveness among patients requiring orthognathic surgery

Objective: To test the hypothesis that the self-perception of dental and facial attractiveness among patients requiring orthognathic surgery is no different from that of control patients.

Materials and Methods: Happiness with dental and facial appearance was assessed using questionnaires completed by 162 patients who required orthognathic treatment and 157 control subjects. Visual analog scale, binary, and open response data were collected. Analysis was carried out using a general linear model, logistic regression, and chi-square tests.

Results: Orthognathic patients were less happy with their dental appearance than were controls. Class II patients and women had lower happiness scores for their dental appearance. Among orthognathic patients, the "shape" and "prominence" of their teeth were the most frequent causes of concern. Older subjects, women, and orthognathic patients were less happy with their facial appearance. Class III orthognathic patients, older subjects, and women were more likely to have looked at their own face in profile. A greater proportion of Class II subjects than Class III subjects wished to change their appearance.

Conclusions: The hypothesis is rejected. The findings indicate that women and patients requiring orthognathic surgery had lower levels of happiness with their dentofacial appearance. Although Class II patients exhibited the lowest levels of happiness with their dental appearance, there was some evidence that concerns and awareness about their facial profile were more pronounced among the Class III patients.

Induction of Distinct Neurologic Disease Manifestations during Relapsing Fever Requires T Lymphocytes.

Relapsing fever borreliosis is a multisystemic infection characterized primarily by bacteremia but can extend to the CNS. The incidence of CNS disease manifestations in humans depends on the infecting relapsing fever Borrelia species. In the murine model of Borrelia hermsii infection we found high incidence of distinct signs of CNS disease that ranged from a flaccid tail to complete paralysis of hind limbs. Infiltration of large number of T cells into the spinal cord of B. hermsii-infected mice and the upregulation of MHC class II and CD80 on infiltrating macrophages and on microglial cells suggested a role for T cell and Ag-presenting cell interactions in this pathogenesis. Indeed, B. hermsii infection did not induce CNS disease manifestations in T cell-deficient mice (TCR-ß × d-/-), although it resulted in bacteremia comparable to wild-type (Wt) level. Moreover, the infiltration of immune cells into the spinal cord of TCR-ß × d-/- mice was reduced and the resident microglial cells were not activated. Histopathological analysis of lumbar sections of the spinal cord confirmed severe inflammation in Wt but not in TCR-ß × d-/- mice. Induction of CNS disease was dependent on the B. hermsii strain as well as on the ability of the host to control bacteremia. Mice that are impaired in controlling B. hermsii, such as CD14-/- mice, exhibited more severe CNS disease than Wt mice. This study demonstrates that distinct neurologic disease manifestations develop during relapsing fever and that T cells play a critical role in the induction of neuropathogenesis.

Llama antibody fragments have good potential for application as HIV-1 topical microbicides

There is an urgent global need for preventative strategies against HIV-1 infections. Llama heavy-chain antibody fragments (VHH) are a class of molecules recently described as potent cross-clade HIV-1 entry inhibitors. We studied the potential of a VHH-based microbicide in an application-oriented fashion. We show that VHH can be inexpensively produced in high amounts in the GRAS organism S. cerevisiae, resulting in very pure, and endotoxin free product. VHH are very stable under conditions they might encounter during transport, storage or use by women. We developed active formulations of VHH in aqueous gel and compressed and lyophilized tablets for controlled release from an intra vaginal device. The release profile of the VHH from e.g. a vaginal ring suggests sufficient bioavailability and protective concentration of the molecule at the mucosal site at the moment of the infection. The ex vivo penetration kinetics through human tissues show that the VHH diffuse into the mucosal layer and open the possibility to create a second defense layer either by blocking the HIV receptor binding sites or by blocking the receptors of immune cells in the mucosa. In conclusion, our data show that VHH have

The emerging relevance of the cysteine protease Cathepsin S in disease

Cathepsin S is a lysosomal cysteine protease that has been shown to play a key role in MHC class II antigen presentation. Consequently, it has been extensively evaluated as a therapeutic target in autoimmune diseases, such as rheumatoid arthritis and psoriasis. Additionally, clinical and mechanistic evidence is emerging, revealing its inappropriate expression and secretion in a wide range of disease states including atherosclerosis and tumourigenesis. This review covers the known role and consequences of cathepsin S activity in these pathological disorders, highlighting various studies that have demonstrated its utility as a therapeutic target. This review also examines challenges that exist towards the development of agents that specifically target this protease and discusses the studies to date that have applied cathepsin S inhibitors in disease models.