Does the use of a piezoelectric saw improve neurosensory recovery following sagittal split osteotomy?

Neurosensory disturbance of the inferior alveolar nerve (IAN) is an adverse effect associated with sagittal split osteotomies (SSO). The purpose of this work was to evaluate neurosensory recovery of the IAN when SSOs were performed with piezoelectric (PZ) versus reciprocating (RP) saws. This was a prospective split-mouth study of patients undergoing bilateral SSO using a PZ saw on one side and an RP saw on the other. The primary outcome of interest was neurosensory recovery, as assessed using the functional sensory recovery (FSR) scale defined by the UK Medical Research Council. Descriptive, bivariate, and regression statistics were computed. Twenty patients (40 SSOs) with a mean age of 19.9 ± 3.2 years were included. The mean mandibular movement did not differ significantly (P = 0.50) between the PZ and RP groups. All patients achieved FSR within 1 year of surgery (range 34-249 days). The median time to FSR overall was comparable between the PZ and RP groups (94.5 days and 101.5 days, respectively; P = 0.20). However, at the time FSR was achieved, PZ SSO sites were more likely to have higher neurosensory scores when compared to RP SSO sites (hazard ratio 2.3, 95% confidence interval 1.1-4.9, P = 0.04).

Two-point nasomaxillary fixation of the Le Fort I osteotomy: assessment of stability at one year postoperative.

The purpose was to assess maxillary position among patients undergoing Le Fort I maxillary advancement with internal fixation placed only at the nasomaxillary buttresses. This was a retrospective study of patients undergoing a Le Fort I osteotomy for maxillary advancement, with internal fixation placed only at the nasomaxillary buttresses. Demographic and cephalometric measures were recorded. The outcome of interest was the change in maxillary position between immediately postoperative (T1), 6 weeks postoperative (T2), and 1 year postoperative (T3). Fifty-eight patients were included as study subjects (32 male, 26 female; mean age 18.4±1.8 years). Twenty-five subjects (43.1%) had a diagnosis of cleft lip and palate. Forty-three subjects (74.1%) had bimaxillary surgery, 16 (27.6%) had bone grafts, and 18 (31.0%) had segmental maxillary osteotomies. At T3, there were no subjects with non-union, malunion, malocclusion, or relapse requiring repeat surgery. Mean linear changes between T1 and T3 were ≤1mm. Mean angular changes between T1 and T3 were <1°. There was no significant difference in stability in multi-segment maxillary osteotomies (P= 0.22) or with bone grafting (P= 0.31). In conclusion, anterior fixation alone in the Le Fort I osteotomy results in a stable maxillary position at 1 year postoperative.

Is alteration of the occlusal plane stable with isolated nasomaxillary fixation of the Le Fort I osteotomy?

The purpose of this work was to evaluate the stability of maxillary position in the setting of occlusal plane rotations in bimaxillary surgery with rigid fixation of the mandible and bilateral nasomaxillary fixation at the Le Fort I level. This was a retrospective assessment of patients undergoing bimaxillary surgery for the correction of dentofacial deformities with occlusal plane alterations. Demographic measures assessed included age, sex, history of craniofacial anomaly, segmental maxillary osteotomy, and maxillary bone grafting. Cephalometric measures assessed included occlusal plane rotation (clockwise (CWR) or counterclockwise (CCWR)), angular measurements of maxillary and mandibular position (SNA, SNB, and ANB), and occlusal plane angle (occlusal plane to corrected Frankfort horizontal); these were assessed preoperatively (T0) and immediately (T1), 6 weeks (T2), and 1year postoperative (T3). Descriptive and bivariate statistics were computed; P≤0.05 was considered significant. Thirty-six patients were included as study subjects (mean age 18.6±1.8 years; 17 (47.2%) female); 27 (75%) had a primary diagnosis of craniofacial anomaly. Eleven patients (30.6%) had segmental maxillary osteotomies; 10 patients (27.8%) had simultaneous maxillary bone grafting. Twelve patients underwent CCWR; 24 patients underwent CWR. No patient required repeat surgery for malocclusion or relapse; there were no malunions or non-unions during follow-up. For CCWR patients, the mean occlusal plane change from preoperative to postoperative was 5.8±2.8°, remaining stable at 1 year postoperative (ΔT3-T1 1.6±1.0°, P>0.05). For CWR patients, the mean occlusal plane rotation was 4.5 ± 2.2°, remaining stable at 1 year postoperative (ΔT3-T1 1.1±0.9°, P>0.05). In patients undergoing bimaxillary surgery for occlusal plane rotation, two-point fixation of the Le Fort I osteotomy resulted in a stable maxillary position at 1 year postoperative.

Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder whose pathology involves multiple immune cell types, including B and T lymphocytes as well as myeloid cells. While it is clear that autoantibody-producing B cells, as well as CD4+ T cell help, are key contributors to disease, little is known regarding the role of innate lymphoid cells such as natural killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multi-color flow cytometry in a large cohort of SLE patients. While the overall percentage of NK cells was similar or slightly decreased compared to healthy controls, a subset of patients displayed a high frequency of NK cells expressing the proliferation marker, Ki67, which was not found in healthy donors. Although expression of Ki67 on NK cells correlated with Ki67 on other immune cell subsets, the frequency of Ki67 on NK cells was considerably higher. Increased frequencies of Ki67+ NK cells correlated strongly with clinical severity and active nephritis and was also related to low NK cell numbers, but not overall leukopenia. Proteomic and functional data indicate that the cytokine interleukin-15 promotes the induction of Ki67 on NK cells. These results suggest a role for NK cells in regulating the immune-mediated pathology of SLE as well as reveal a possible target for therapeutic intervention.

Treatment planning concepts for the ageing patient.

There is an ageing imperative in Australia as in many other industrialized nations, and these populations are extremely heterogeneous. In young adults, the factors which influence decision making for oral health care are whether the patient has the will, the time or the finances to pay for care, while for clinicians, the decisions are whether they have the skill and the resources to carry out the treatment plan. For older adults, the decision making includes all of the previous identified factors, but they are now complicated by the patient's medical and medication problems, the side effects of the medications they are taking, their cognitive status as well as the cumulative effects of a lifetime of physiological, traumatic and iatrogenic effects on the dentition and the oral cavity. The decision-making process which has evolved has been called many names, from cost-effective care to minimal invasive dentistry to rational dental care. Fundamentally, they are similar. Rational dental care has been defined as the process of decision making, which develops a treatment plan that is in the best interest of the patient after evaluating all of the modifying factors. This article will discuss the various concepts, and the strengths and weaknesses of some of these systems. It will also illustrate some of the clinical problems as there is very little evidence-based data to support any of these concepts. However, treatment planning is still an art, which can only be carried out for an individual and not a group, and the result must serve the needs of the patient and enhance the quality of his or her life.

T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site.

BACKGROUND: Development of neutralizing anti-factor (F)VIII antibodies ('inhibitors') is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. OBJECTIVES: The aim of the present study was to identify T-cell epitopes in FVIII and characterize T-cell responses in two unrelated hemophilia A subjects sharing F8-R593C and HLA-DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T-cell epitope. PATIENTS/METHODS: The binding affinities of peptides for recombinant HLA-DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide-loaded tetramers. RESULTS: The inhibitor subjects, but not HLA-matched controls, had high-avidity HLA-DRB1*1101-restricted T-cell responses against FVIII(589-608), which contains the hemophilic missense site. Antigen-specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII(592-603). FVIII(589-608) bound with physiologically relevant (micromolar) IC(50) values to recombinant DR0101, DR1101 and DR1501 proteins. CONCLUSIONS: Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild-type R593 influences inhibitor risk in this hemophilia A sub-population.

HLA-DR-restricted T-cell responses to factor VIII epitopes in a mild haemophilia A family with missense substitution A2201P.

An HLA-DRA-DRB1*0101-restricted T-cell epitope in the factor VIII (FVIII) C2 domain occurred in a mild haemophilia A patient with missense substitution FVIII-A2201P. His T cells responded to synthetic peptides FVIII(2186-2205) and FVIII(2194-2213) (J Thromb Haemost 2007; 5: 2399). T cells from family members with genotype FVIII-A2201P were analysed to determine if FVIII-specific T cells occur in individuals with a haemophilic mutation but no clinically significant inhibitor response. Fluorescent MHC class II tetramers corresponding to subjects'HLA-DRB1 types were loaded with 20-mer peptides and utilized to label antigen-specific CD4+ T cells. T-cell responses to peptides spanning the FVIII-C2 sequence were evaluated. T cells recognizing specific peptides were cloned, and antigen specificity was verified by proliferation assays. Plasma and/or purified IgG samples were tested for FVIII inhibitory activity. CD4+ T cells and T-cell clones from two brothers who shared the DRB1*0101 allele responded to FVIII(2194-2213). A haemophilic cousin's HLA-DRA-DRB1*1104-restricted response to FVIII(2202-2221) was detected only when CD4+CD25+ cells were depleted. A great uncle and two obligate carriers had no detectable FVIII-C2-specific T cells. Concentrated IgG from the brother without a clinical inhibitor response showed a low-titre FVIII inhibitor. FVIII-specific T cells and inhibitory IgG were found in a previously infused, haemophilic subject who had a sub-clinical FVIII inhibitor. CD4+CD25+ depleted T cells from a non-infused haemophilic cousin recognized an overlapping FVIII epitope, indicating a latent HLA-DRA-DRB1*1104-restricted T-cell response to FVIII. Specific T-cell responses to FVIII can occur without clinically significant inhibitors.

Valeriana officinalis root extracts have potent anxiolytic effects in laboratory rats.

Valerian root (Valeriana officinalis) is a popular and widely available herbal supplement, primarily used to treat insomnia and anxiety. Until recently, its mechanism of action has remained unknown. Neurobiological research has begun to show that the herb, with its active valerenic acid, interacts with the GABA(A)-ergic system, a mechanism of action similar to the benzodiazepine drugs. This series of experiments sought to corroborate these findings with behavioral measures, compare them to the benzodiazepine diazepam, and to analyze the chemical composition of Valeriana officinalis. Rats were administered either ethanol (1 ml/kg), diazepam (1mg/kg), valerian root extract (3 ml/kg), valerenic acid (3mg/kg), or a solution of valerenic acid and exogenous GABA (75 microg/kg and 3.6 microg/kg, respectively) and assessed for the number of entries and time spent on the open arms of an elevated plus maze. Results showed that there was a significant reduction in anxious behavior when valerian extract or valerenic acid exposed subjects were compared to the ethanol control group. The evidence supports Valeriana officinalis as a potential alternative to the traditional anxiolytics as measured by the elevated plus maze.

Interleukin 21 as a target of intervention in autoimmune disease.

Interleukin 21 (IL21) belongs to a family of cytokines that bind to a composite receptor consisting of a private receptor (IL21R) and the common cytokine receptor gamma chain (gamma(C)). The IL21R is widely distributed on lympho-haematopoietic cells and IL21 impacts a number of cell types, including CD8+ memory T cells, NK cells and subsets of CD4 memory T cells. One essential role of IL21 is the promotion of B-cell activation and differentiation or death during humoral immune responses. Increased IL21 production is characteristic of certain autoimmune diseases and is likely to contribute to autoantibody production as well as pathological features of autoimmune disease. The critical role of IL21 in promoting humoral immune responses makes it an important focus of potential therapeutic interventions in conditions characterised by overproduction of pathogenic autoantibodies.

Public health issues in geriatric dentistry in the United States.

The aging United States population living in the new millennium has dental needs that are very different and more complex than those experienced by previous older adult cohorts during the twentieth century. The type of dental care to be provided for older Americans goes way beyond emergency care, extractions and denture care. Dental caries is still clearly a public health problem for subgroups of older Americans, such as those of lower socioeconomic status, with dementia, who are homebound and who are institutionalized. These are also the subgroups experiencing greater barriers to accessing dental care. Stakeholders, including dental professionals and the dental benefits industry, need to work together to develop innovative dental financing programs that will increase older Americans access to dental care.

T-cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide.

BACKGROUND: Antibodies that neutralize factor (F) VIII activity, clinically referred to as 'inhibitors', complicate the treatment of hemophilia A patients; current tolerance and bypass strategies are extremely costly and sometimes ineffective. The development of inhibitors requires T-cell help. OBJECTIVES: We characterized T-cell responses of a subject with mild hemophilia A with missense genotype A2201P for one year following his initial inhibitor response, with the goals of defining the primary epitope(s) and its (their) MHC Class II restriction. We investigated the possible involvement of regulatory T cells in modulating immune responses. PATIENTS/METHODS: The subject developed high-titer FVIII-neutralizing antibodies (250 BU mL(-1)) that declined over time to 8 BU ml(-1). His clotting activity was initially impaired (3%) but returned to baseline (8-10%) within four weeks. MHC Class II tetramers were used to analyze his CD4 T cells, which were stimulated with peptides spanning the C2 domain. Responses of total and CD25-depleted CD4 cells to sequences containing A2201 (native), P2201 (hemophilic), and other predicted T-cell epitopes were evaluated. RESULTS AND CONCLUSIONS: An HLA-DRA-DRB1*0101 restricted T-cell epitope containing the wild-type A2201 sequence was identified. Interestingly, peptides containing A2201 were recognized by CD4 T cells at all time points, whereas a P2201 peptide was recognized only near the initial peak response. The responsiveness of CD25-depleted CD4 cells to an A2201 peptide was enhanced 11 and 19 weeks following inhibitor detection, suggesting the possible involvement of CD4+CD25+ regulatory T cells in modulating immune responses. Patient-derived T-cell clones proliferated in response to C2 protein and to peptides containing A2201 but not P2201.

Autoantibody epitopes to the smaller isoform of glutamate decarboxylase do not differ in Swedish and Japanese type 1 diabetes patients and may be associated with high-risk human leucocyte antigen class II alleles.

Type 1 diabetes (T1D) is an autoimmune disease with a strong human leucocyte antigen (HLA) class II association. Depending on geographic locations, the disease-associated HLA class II alleles vary. We evaluated the beta cell-specific autoimmunity reflected in autoantibodies directed to the smaller isoform of glutamate decarboxylase (GAD65) in Japanese and Swedish T1D patients. GAD65Ab epitope specificities were assessed using GAD65-specific recombinant Fab. GAD65Ab epitope specificities did not differ between Swedish and Japanese patients. Only recognition of the MICA-4-defined middle epitope was significantly stronger in the Japanese T1D patient group compared to the Swedish T1D patients (P = 0.001). Binding to the b96.11-defined middle epitope was substantial in both groups and showed significant associations with high-risk HLA class II haplotypes. In the Japanese T1D group the association was with haplotype DRB1*0802-DQB1*0302 (P = 0.0008), while in the Swedish T1D patients binding to the b96.11-defined epitope as associated with the presence of high-risk HLA genotypes DR3-DQB1*0201 and/or DR4-DQB1*0302 (P = 0.02). A significant association between reduction in binding in the presence of recombinant Fab (rFab) DPD and high-risk allele DQB1*0201 was found (P = 0.008) in the Swedish T1D patients only. We hypothesize that epitope-specific autoantibodies effect the peptide presentation on HLA class II molecules by modulating antigen uptake and processing. Molecular modelling of the high-risk HLA class II molecules will be necessary to test whether these different molecules present similar peptide-binding specificities.

Perception of dry mouth in a sample of community-dwelling older adults in Japan.

The purpose of this study was to examine the prevalence of perceived dry mouth among a group of independently-living elderly persons in Japan, and to determine its association with general disease, medication, and dental status, as well as its effect on oral function. The study population consisted of participants of the Senior Citizens' College. The subjective sensations of oral dryness on waking and while eating a meal were measured by a questionnaire. The number of usable questionnaires was 1003 or 77.9%. The mean age of the subjects was 66.3 +/- 4.2 years, and 53.0% were male. More than one-third (37.8%) of the subjects reported oral dryness on waking. Only 9.1% of them noticed a subjective feeling of dry mouth during eating. Persons who had at least one of these symptoms made up 41.0%. A multiple stepwise logistic regression analysis indicated the following results: Perception of dry mouth on waking was more frequent among males (p < 0.001), persons who had a low BMI (p < 0.05), and those taking two or more prescribed drugs (p < 0.01). Sensation of dry mouth when eating was more frequent among subjects with a low BMI (p < 0.001) and those who wore a denture in the maxillary arch (p < 0.05). Perception of dry mouth when eating was associated with self-assessed chewing ability (p < 0.01) and dissatisfaction with speaking clearly (p < 0.05), as well as dental status. However, dissatisfaction with tasting a meal had a significant relationship with the reports of mouth dryness on waking (p < 0.01). Our findings suggest that a substantially higher percentage of persons have the perception of dry mouth on waking than when eating, which was associated with medications, being male, and having a low BMI. This perception may influence oral function, especially the reported dissatisfaction with tasting foods.

A critical role for lymphotoxin-beta receptor in the development of diabetes in nonobese diabetic mice.

To assess the role of lymphotoxin-beta receptor (LTbetaR) in diabetes pathogenesis, we expressed an LTbetaR-Fc fusion protein in nonobese diabetic (NOD) mice. The fusion protein was expressed in the embryo, reached high levels for the first 2 wk after birth, and then declined progressively with age. High expression of LTbetaR-Fc blocked diabetes development but not insulitis. After the decline in chimeric protein concentration, mice became diabetic with kinetics similar to the controls. Early expression of fusion protein resulted in disrupted splenic architecture. However, primary follicles and follicular dendritic cells, but not marginal zones, developed in aged mice. Hence, LTbetaR signaling is required for diabetes development and regulates follicular and marginal zone structures via qualitatively or quantitatively distinct mechanisms.

In vitro evaluation of fluoride-releasing restorative materials for sealing the root canals of overdenture abutments.

PURPOSE: The purpose of this study was to evaluate the ability of newer fluoride-releasing restorative materials to protect the root surface from acid attack. MATERIALS AND METHODS: The materials used were glass-ionomer cement (GIC), resin-modified glass-ionomer cement (RM-GIC), and a compomer (Comp). A composite resin (CR) was used as the control. The restored teeth were stored in deionized, distilled water for 14 days and subjected to 300 thermocycles (55 degrees C and 5 degrees C). The teeth were cycled in a demineralizing solution (pH 5.0 or 4.0) for 6 hours and in a remineralizing solution (pH 7.0) for 17 hours for 10 days. The depths of lesions created by acid challenge were measured at the interface of the tooth and the restorative material and then at a distance of 50, 100, and 300 microns from the tooth-restoration margin using polarized light microscopy and contact microradiography. RESULTS: At pH 4.0, there was significant difference in the depth at the interface between the tooth and the restorative material (P < .001). The GIC and RM-GIC were protective, and the lesion depths were significantly shallower than for Comp or CR. The protective effect varied depending on the distance from the interface of the tooth and the restorative material. At pH 5.0, the GIC and RM-GIC had no lesions at the interface, while the Comp and the CR had lesions (P < .001). CONCLUSION: Fluoride-releasing glass-ionomer cement seems to be an appropriate material to seal the root canals of overdenture abutments, because it has an inhibiting effect on demineralization at the cavity wall in vitro.

Distinct T cell interactions with HLA class II tetramers characterize a spectrum of TCR affinities in the human antigen-specific T cell response.

The polyclonal nature of T cells expanding in an ongoing immune response results in a range of disparate affinities and activation potential. Recently developed human class II tetramers provide a means to analyze this diversity by direct characterization of the trimolecular TCR-peptide-MHC interaction in live cells. Two HSV-2 VP16(369-379)-specific, DQA1*0102/DQB1*0602 (DQ0602)-restricted T cell clones were compared by means of T cell proliferation assay and HLA-DQ0602 tetramer staining. These two clones were obtained from the same subject, but show different TCR gene usage. Clone 48 was 10-fold more sensitive to VP16(369-379) peptide stimulation than clone 5 as assayed by proliferation assays, correlating with differences in MHC tetramer binding. Clone 48 gave positive staining with the DQ0602/VP16(369-379) tetramer at either 23 or 37 degrees C. Weak staining was also observed at 4 degrees C. Clone 5 showed weaker staining compared with clone 48 at 37 degrees C, and no staining was observed at 23 degrees C or on ice. Receptor internalization was not required for positive staining. Competitive binding indicates that the cell surface TCR of clone 48 has higher affinity for the DQ0602/VP16(369-379) complex than clone 5. The higher binding affinity of clone 48 for the peptide-MHC complex also correlates with a slower dissociation rate compared with clone 5.

Beta 57-Asp plays an essential role in the unique SDS stability of HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC allele associated with protection from insulin-dependent diabetes mellitus.

Studies of the stability of HLA-DQ have revealed a correlation between SDS stability of MHC class II alphabeta dimers and insulin-dependent diabetes mellitus (IDDM) susceptibility. The MHC class II alphabeta dimer encoded by HLA-DQA1*0102/DQB1*0602 (DQ0602), which is a dominant protective allele in IDDM, exhibits the greatest SDS stability among HLA-DQ molecules in EBV-transformed B-lymphoblastoid cells and PBLs. DQ0602 is also uniquely SDS stable in the HLA-DM-deficient cell line, BLS-1. We addressed the molecular mechanism of the stability of DQ0602 in BLS-1. A panel of mutants based on the polymorphic differences between HLA-DQA1*0102/DQB1*0602 and HLA-DQA1*0102/DQB1*0604 were generated and expressed in BLS-1. An Asp at beta57 was found to be critical for SDS stability, whereas Tyr at beta30, Gly at beta70, and Ala at beta86 played secondary roles. Furthermore, the level of class II-associated invariant chain peptide bound to HLA-DQ did not correlate with SDS stability, suggesting that class II-associated invariant chain peptide does not play a direct role in the unique SDS stability of DQ0602. These results support a role for DQB1 codon 57 in HLA-DQ alphabeta dimer stability and IDDM susceptibility.

Active cocaine immunization attenuates the discriminative properties of cocaine.

Anticocaine antibody, resulting from immunization with the cocaine-keyhole-limpet-hemocyanin (KLH) conjugate, weakened the ability of cocaine to act as a discriminative stimulus in rats. Subjects were given extensive training to discriminate 5.0 mg/kg of cocaine from saline prior to immunization. Several weeks following immunization with cocaine-KLH, subjects failed to reliably discriminate cocaine from saline. Nonimmunized control rats retained the ability to discriminate cocaine from saline throughout the experiment. These results further demonstrate that active immunization is effective in blunting cocaine effects. Immunized subjects were able to discriminate 20 mg/kg of cocaine, however, suggesting that anticocaine antibody may be overwhelmed by large cocaine doses.