The Prevalence of Gingival Dendritic Cell Subsets in Periodontal Patients.

As the most potent cells activating and polarizing naive T cells, dendritic cells (DCs) are of major importance in the induction of immunity and tolerance. DCs are a heterogeneous population of antigen-presenting cells that are widely distributed in lymphoid and nonlymphoid tissues. Murine studies have highlighted the important role of oral DCs and Langerhans cells (LCs) in orchestrating the physiological homeostasis of the oral mucosa. DCs are also critically involved in pathological conditions such as periodontal diseases, in which gingival DCs appear to have special localization and function. While the characterization of human DCs in health and disease has been extensively investigated in various tissues, this topic was rarely studied in human gingiva. Here, we employed an up-to-date approach to characterize by flow cytometry the gingival DCs of 27 healthy subjects and 21 periodontal patients. Four distinct subsets of mononuclear phagocytes were identified in healthy gingiva: conventional DC type 1 (cDC1), cDC2, plasmacytoid DCs (pDCs), and LCs. In periodontitis patients, the frequencies of gingival LCs and pDCs were dysregulated, as LCs decreased, whereas pDCs increased in the diseased gingiva. This shift in the prevalence of DCs was accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1ß, interferon (IFN)-α, and IFN-γ, while the anti-inflammatory cytokine IL-10 was suppressed. We further found that smoking, a known risk factor of periodontitis, specifically reduces gingival LCs in healthy individuals, indicating a possible role of LCs in the elevated severity of periodontitis in smokers. Collectively, this work reveals the various DC subsets residing in the human gingiva and the impact of periodontitis, as well as smoking, on the prevalence of each subset. Our findings provide a foundation toward understanding the role of human DCs in orchestrating physiological oral immunity and set the stage for the evaluation and modulation of shifts in immunity associated with periodontitis.

Periodontitis and Cardiovascular Diseases. Consensus Report.

Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and Methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations. Results and Conclusions: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices.

Niche Specific Microbiota-Dependent and Independent Bone Loss around Dental Implants and Teeth.

Oral mucosal homeostasis is achieved by complex immunologic mechanisms, orchestrating host immunity to adapt to the physiologic functions of the various specialized niches in the oral cavity. Dental implants introduce a novel mucosal niche to the immune system to deal with. Nevertheless, the immune mechanisms engaged toward implants and whether they have broader effects are not well defined. Using a murine model, we found an accumulation of neutrophils and RANKL-expressing T and B lymphocytes in the implant-surrounding mucosa, accompanied by local bone loss. Surprisingly, the presence of implants had an impact on remote periodontal sites, as elevated inflammation and accelerated bone loss were detected in intact distant teeth. This was due to microbial dysbiosis induced by the implants, since antibiotic treatment prevented bone loss around teeth. However, antibiotic treatment failed to prevent the loss of implant-supporting bone, highlighting the distinct mechanisms mediating bone loss at each site. Further analysis revealed that implants induced chronic lymphocyte activation and increased mRNA expression of IFN-α and accumulation of IFN-α-producing plasmacytoid dendritic cells, which we previously reported as bone-destructive immune responses. Collectively, this study demonstrates that implants have a strong and broad impact on oral mucosal homeostasis, inducing periodontal bone loss in a niche-specific manner that is both microbiota dependent and independent.

Association of dental and maxillary sinus pathologies with ear, nose, and throat symptoms.

OBJECTIVES: To investigate the correlation between cone-beam computerized tomography (CBCT) findings in the maxillary sinus, ear-nose-throat (ENT) symptoms and dental pathologies in asymptomatic patients. MATERIALS AND METHODS: A total 81 patients were referred for CBCT and filled a standard ENT visual analog scale (VAS) questionnaire. CBCT images were analyzed for sinus ostium obstruction, Schneiderian membrane thickening, sinus floor turbidity, and the presence of polyps. Dental pathologies were evaluated with the aid of CBCT images, periapical X-rays, and clinical examination. A possible correlation between the CBCT findings and the ENT/dental parameters was examined by applying Student's t test and the chi-squared test. RESULTS: Despite being asymptomatic, most of the 81 patients reported ENT symptoms in the questionnaire, thereby indicating that these symptoms were mainly subclinical. A significant correlation was found between the presence of polyps in the sinus and a decrease in smell/taste. Obstruction of the sinus meatus was associated with coughing; turbidity was associated with ear congestion. Thickening of the Schneiderian membrane showed an association with both coughing and ear congestion. The mean number of missing posterior teeth correlated with postnasal drip and nasal congestion. Periapical pathology was associated with nasal discharge/runny nose. CONCLUSION: The results emphasize the need to evaluate ENT symptoms when radiographic findings are identified in CBCT.

Vaccination with recombinant RgpA peptide protects against Porphyromonas gingivalis-induced bone loss.

OBJECTIVE: Following Porphyromonas gingivalis infection in mice, the efficacy of vaccination by recombinant and native RgpA in modulating the early local anti-inflammatory and immune responses and periodontal bone loss were examined. MATERIAL AND METHODS: Using the subcutaneous chamber model, exudates were analyzed for cytokines after treatment with native RgpA and adjuvant (test), or adjuvant and saline alone (controls). Mice were also immunized with recombinant RgpA after being orally infected with P. gingivalis. After 6 wk, serum was examined for anti-P. gingivalis IgG1 and IgG2a titers and for alveolar bone resorption. RESULTS: Immunization with native RgpA shifted the immune response toward an anti-inflammatory response as demonstrated by decreased proinflammatory cytokine IL-1ß production and greater anti-inflammatory cytokine IL-4 in chamber exudates. Systemically, immunization with recombinant RgpA peptide prevented alveolar bone loss by 50%, similar to immunization with heat-killed whole bacteria. Furthermore, recombinant RgpA shifted the humoral response toward high IgG1 and low IgG2a titers, representing an in vivo anti-inflammatory response. CONCLUSIONS: The present study demonstrates the potential of RgpA to shift the early local immune response toward an anti-inflammatory response while vaccination with recRgpA protected against P. gingivalis-induced periodontitis.

Implant dentistry in postgraduate university education. Present conditions, potential, limitations and future trends.

INTRODUCTION: In recent years, opportunities for postgraduate university education in implant dentistry have increased significantly, with an increase in both the number but also the complexity of available postgraduate programmes. However, there appears to be a lack of standards directing the learning outcomes of such programmes. METHODS: A scientific literature search was conducted for publications reporting on university programmes within implant dentistry, including description of programmes and evaluation of learning outcomes. A separate Internet search was conducted to collect information on existing university programmes as presented on university websites. RESULTS: Implant dentistry has reached a critical mass of an independent, multidisciplinary and vibrant domain of science, which combines knowledge and discovery from many clinical and basic sciences. Many university programmes conclude with a master's or equivalent degree, but there appears to be a great diversity with regard to duration and learning objectives, as well as targeted skills and competences. The importance of implant dentistry has also increased within established specialist training programmes. There was little indication, however, that the comprehensive aspects of implant dentistry are present in all specialist training programmes where implants are being covered. CONCLUSIONS: Although universities should maintain the options of designing academic programmes as they best see fit, it is imperative for them to introduce some form of transparent and comparable criteria, which will allow the profession and the public to relate the degree and academic credentials to the actual skills and competences of the degree holder. With regard to established specialist training programmes, the interdisciplinary and comprehensive nature of implant dentistry needs to be emphasised, covering both surgical and restorative aspects. Finally, implant dentistry is not, at present, a dental specialty. The profession has not reached a consensus as to whether the introduction of a new recognised specialist field is either necessary or desired.

[The pathogenesis of periodontal disease: a paradigm shift].

Periodontitis is a family of related diseases that differ in etiology, natural history, disease progression and response to therapy, but have a common underlying chain of events, thatareinfluenced by disease modifiers. The clinical manifestations observed are a result of the complex interplay of these factors. The pathogenesis of human periodontitis was placed on a rational footing for the first time by Page & Schroeder in 1976 and the general principles and the overall conclusions reached in that article are still largely acceptable today. Still, an enormous amount has been learned about all aspects of human periodontitis, including its pathogenesis, since 1976. A critical evaluation of the literature regarding the complex relationship between the microbial factor, the host factor and the occurrence of a disease, might be leading us over a surge of a paradigm shift in our understanding the pathogenesis of the disease. It is well acknowledged that while the etiology of periodontitis is bacterial, the pathogenesis is inflammatory. The understanding of regulation of inflammation in periodontitis is far from complete; however, as the understanding of periodontal inflammation increases, the current understanding of the microbiology of periodontitis becomes less clear. While we think we know that bacteria initiate the disease, the role of specific bacteria is still unknown. The current knowledge of the microbiology of periodontitis is based on large cross-sectional and association studies. Periodontitis is seen as the direct consequence of bacterial invasion and is regarded as an infectious disease. It is however, not possible to draw cause and- effect inferences from these studies. One might state that the inflammation precedes the overgrowth of the bacteria. In this scenario, the initiator of the disease might be early, gram-positive colonizers that elicit a profound inflammatory response in the susceptible host. The implication of that paradigm shift outlined above is that periodontitis is an inflammatory disease, and in that case the primary target of pharmacotherapy should be the inflammation, rather than the bacteria. Still, the question to be asked and investigated is whether dampening of the inflammatory response in certain individuals susceptible to periodontitis might prevent development of disease. This is a question yet to be answered.

IL-10 gene transfer attenuates P. gingivalis-induced inflammation.

IL-10 is an anti-inflammatory cytokine secreted by stimulated Th2 lymphocytes that can down-regulate inflammatory responses to bacterial challenge. We hypothesized that local delivery of IL-10 using gene-transfer will down-regulate inflammatory responses. We examined the effect of IL-10 plasmid injection on the local cytokine response. Two weeks after the implantation of chambers, either IL-10 plasmid or vector was injected into the mice. Four days later, they were challenged with an intra-chamber injection of P. gingivalis. The intra-chamber levels of IL-10, IFNgamma, TNFalpha, and IL-1beta were evaluated after 2 and 24 hrs. The results showed that local IL-10 gene delivery elevated the levels of IL-10 at both time periods. It attenuated the levels of IFNgamma (656 +/- 154 to 218 +/- 144 pg/mL) and TNFalpha (23 +/- 2.0 to 12.5 +/- 2.9 ng/mL) at 2 hrs, and of IL-1beta (21.5 +/- 5.7 to 12.4 +/- 3.0 ng/mL) at 24 hrs. The results suggest the possibility of modulating the local inflammatory response to P. gingivalis by direct IL-10 gene transfer.

Use of antimicrobial agents during supportive periodontal therapy.

Individual susceptibility to periodontal breakdown involves an interplay of genes, periodontal pathogens and other modulating factors. Anti-infective treatment, which includes oral hygiene measures, mechanical debridement, pharmacologic intervention and surgery, has been shown to be effective in arresting the progression of periodontal disease. Nevertheless, due to the chronic nature of the disease, susceptible individuals who are not maintained in a supervised recall program subsequent to the active treatment phase, show signs of recurrent destruction. Supportive periodontal therapy (SPT) is an integral part of periodontal treatment for patients with history of periodontitis, and is needed to prevent recurrence of disease in susceptible individuals. To prevent re-infection with periodontal pathogens, SPT includes elimination of dental plaque and bacteria from the oral cavity, thereby preventing the recurrence of pathogens into the gingival area. For individuals at risk of developing periodontitis, SPT should combine self-performed and professional anti-infective therapy, using mechanical and pharmacological means. The existing evidence suggests that the adjunctive use of antimicrobial pharmacologic therapy during SPT may enhance the results of mechanical debridement. The use of antimicrobials varies between patients, and is dependent on risk assessment and longitudinal monitoring of the clinical status of the periodontium.

Interferon-gamma deficiency attenuates local P. gingivalis-induced inflammation.

Infection with the periodontal pathogen Porphyromonas gingivalis causes a strong local inflammatory reaction. Using IFNgamma-deficient mice, we tested the hypothesis that the absence of IFNgamma would result in a reduction of the local pro-inflammatory response to P. gingivalis. Cytokine secretion by macrophages from IFNgamma(-/-) animals was significantly attenuated. Addition of IFNgamma restored cytokine secretion. In vivo injection of P. gingivalis into subcutaneous chambers increased the intra-chamber leukocyte counts and TNFalpha and IL-1beta levels. This increase was significantly lower in the IFNgamma(-/-) mice. Local reconstitution of IFNgamma(-/-) mice at the site of inflammation with the IFNgamma gene increased the levels of TNFalpha and decreased the IL-10 levels. Anti-P. gingivalis IgG1 levels, a marker of Th2 response, were higher in immunized IFNgamma(-/-) than in IFNgamma(+/+) mice. The results suggest that lack of IFNgamma reduced the amplitude of the local pro-inflammatory response without decreasing the humoral protective response. The higher IgG1/IgG2a ratio observed supports the possibility of a Th2-dominant response in IFNgamma-deficient animals.

[Single-stage implants in areas of maxillary sinuses that were augmented with allograft. Case reports].

Demineralized freezed dried bone allograft (DFDBA) is known as a bone inductive material, and used widely in periodontal and bone regeneration procedures. DFDBA can also be used for sinus floor augmentation prior or with implant placement. The present manuscript described cases of single-stage implants that were used successfully in areas where the maxillary sinus was augmented with DFDBA simultaneously with implant placement (Case 1) or in a second procedure, 18 months following grafting of the sinus (Case 2). These cases demonstrated the ability to use single-stage implants in the augmented maxillary sinus, in a separated or simultaneous procedure.

Genetic polymorphism of the tumor necrosis factor (TNF)-alpha promoter region in families with localized early-onset periodontitis.

Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine that is able to induce tissue destruction and bone resorption. A G-to-A polymorphism at the -308 position of the TNF-alpha promoter region was suggested to influence TNF-alpha production. We had previously shown that monocytes of patients with localized early-onset periodontitis (EOP) secrete high levels of TNF-alpha compared to matched controls. The aim of the present study was to investigate the possible link between the -308 polymorphism in the TNF-alpha gene and EOP. Genomic DNA was extracted from the blood of 64 individuals from 11 nuclear families with EOP. The TNF-alpha polymorphism at -308 was assessed using allele-specific polymerase chain reaction. 77% of the tested adolescents were found to have the G/G genotype, and 23% had the A/G genotype. In the diseased subjects, 81% were with G/G genotype and 19% with A/G genotype. The healthy children had 74% G/G genotype, while 26% had A/G genotype. The differences between the disease group and the healthy group were not statistically significant. In summary, the present results could not demonstrate any link between EOP and genetic polymorphism in the -308 position of the TNF-alpha promoter.

[Preliminary results of short-term follow-up after MIS screw-type implants with rough surface].

The present article describes the preliminary results of a short-term follow up retrospective study of 104 external hex, screw-type MIS implants with rough surface that were consecutively implanted in 34 patients. The implants were followed up between 1 to 3 years. 49 implants were placed in the maxilla and 55 in the mandible. Bone regenerative procedures were carried out simultaneously in the time of implant placement in 21 of the implants. A total of 6 implants failed (5.7%) during the observation period, all in the first year after implant placement. Two implants failed in the same diabetic patient, and one in a heavy smoker. Two of the failed implants were placed together with bone regenerative procedures, and another one was with no initial stability at the time of implant placement. This short-term follow up report has shown that the success rate of MIS screw-type implants with rough surface is similar to the success rate reported for other implant systems. However, long-term follow up is needed to verify the long-term success MIS implant system.

Immunization to Porphyromonas gingivalis enhances the local pro-inflammatory response to subcutaneous bacterial challenge.

BACKGROUND, AIMS: Human and animal studies have suggested that immunization to P. gingivalis might be beneficial for controlling periodontitis, by the induction of protective antibody response. The present study was designed to examine the effect of immunization on the local cellular, cytokine and antibody response to P. gingivalis in mice. METHODS: Subcutaneous chambers were implanted in 3 groups of mice. 2 groups were then immunized with P. gingivalis in either incomplete Freund's (IFA) or an Alum-based adjuvant. The 3rd group served as the control. At baseline, all mice were challenged with an intra-chamber injection of P. gingivalis. Chamber exudates were sampled at baseline, 1 and 7 days post-challenge, following by determination of leukocyte counts and the cytokines TNF-alpha, IFNgamma (pro-inflammatory) and IL-10 (anti-inflammatory). IgG levels to P. gingivalis were analyzed in both the exudates and serum. RESULTS: Leukocyte accumulation increased in the chambers over the study period and was more marked in the immunized groups. P. gingivalis challenge induced the expression of the tested cytokines in all groups. Levels of IFNgamma showed a significantly greater increase in the immunized groups on day 1 post-challenge. By day 7, the levels in the controls had reached those of the immunized groups. IL-10 levels were significantly higher in the control group compared to the immunized groups on day 1 and by day 7 they were reduced significantly in all groups to barely detectable levels. While there were no significant differences in TNF-alpha levels between IFA and control groups, they were significantly higher in the Alum group on day 0 and 7. Both immunization protocols induced anti-P. gingivalis IgG. The Alum group achieved the highest antibody levels, which were due to the increased expression of IgG1, a marker of a Th2-response. CONCLUSIONS: The results suggest that immunization to P. gingivalis results in enhanced expression of pro-inflammatory, tissue-destructive cytokines in the inflammatory site. The nature of the adjuvant used for immunization allows manipulation of the T-cell response, and alum was more effective in reducing the inflammatory response than IFA.

The interactions of human neutrophils with the constituents of an experimental dental biofilm.

Despite the antibacterial properties of neutrophils, their ability to prevent colonization of the dental biofilm by pathogenic bacteria is limited. The present study examined the ability of human neutrophils to attach to an experimental dental biofilm and tested their antibacterial functions following adhesion. Neutrophil adhesion was greatest to hydroxyapatite (HA) in the absence of biofilm. Among the biofilms, glucosyltransferase or fructosyltransferase adsorbed onto saliva-coated HA showed the highest adhesion of cells. The adhesion of neutrophils was directly related to their initial concentration in the solution and to the duration of incubation. Plasma was found to reduce neutrophil attachment significantly, while stimulation of the cells had no effect. Stimulation of attached neutrophils induced superoxide secretion with levels significantly lower than that secreted by suspended cells. The presence of neutrophils on the biofilm reduced the number and the viability of Streptococcus mutans attached to the beads. The present findings suggest that neutrophils are able to attach to dental biofilms and that the attached neutrophils retained their antibacterial activity.

Experimental stress suppresses recruitment of macrophages but enhanced their P. gingivalis LPS-stimulated secretion of nitric oxide.

BACKGROUND: Epidemiological studies have suggested that stress can alter the onset and progression of periodontal disease. However, the mechanisms involved are not clear. The present study was designed to examine whether the functional response of mouse macrophages stimulated by Porphyromonas gingivalis lipopolysaccharide (LPS) is affected by experimental stress, and to investigate the role of corticosterone (CS) in the stress-related effects. METHODS: Two models of stress were used: emotional (isolation) and physical (cold). We measured thioglycollate-induced macrophage recruitment in vivo, and LPS-induced nitric oxide (NO) secretion by the macrophages in vitro. Two groups of mice were exposed to the stress conditions: isolation or cold. A third group was injected daily with CS, and a fourth group was used as a control (no stress). After 3 days of stress conditions, thioglycollate was injected into the peritoneal cavity. Four days later, peritoneal macrophages were isolated, counted, and cultured. The secretion of NO by the cultured cells was evaluated with and without P. gingivalis LPS stimulation. RESULTS: The number of cells in the peritoneal lavage of stressed mice was significantly reduced in comparison to macrophages isolated from non-stressed animals. The number of macrophages from CS-treated mice did not differ from controls. NO secretion from unstimulated macrophages did not differ between the stressed and control groups. Stimulation of the macrophages with P. gingivalis LPS significantly enhanced NO secretion by macrophages from the control and stressed animals, but not by the CS-treated group. NO levels secreted by P. gingivalis-stimulated cells from the two stressed groups were significantly higher than the levels secreted by controls, and the isolation group released significantly higher levels than the cold group. Stimulation of the macrophages with P. gingivalis LPS and interferon (IFN)-gamma resulted in enhanced NO secretion in the 4 groups compared to LPS alone, with no significant differences between the groups. CONCLUSIONS: The results suggest that experimental stress modulates the response of macrophages to inflammatory stimulants, and that CS is not the sole mediator involved. The presence of IFN-gamma in the culture may mask the functional differences induced by stress. The stress-induced upregulation of NO secretion might be involved in the accelerated periodontal destruction in stressed subjects.

Repeat bacterial challenge in a subcutaneous chamber model results in augmented tumour necrosis factor-alpha and interferon-gamma response, and suppression of interleukin-10.

The present study compared the effect of a single or a repeat challenge with the Gram-negative pathogen Porphyromonas gingivalis on the local inflammatory response within subcutaneous chamber model in mice. Subcutaneous chambers were implanted 2 weeks prior to the final challenge. The repeat-challenge (REP) group received two intrachamber bacterial injections 14 days apart, while the single-injection group (SIN) received only a single bacterial challenge. Injection of saline was used as the control. The cellular contents of the chamber exudates were used for differential cell counts, and the supernatants were analysed for tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin (IL)-10 levels. Immunoglobulin G1 (IgG1) and IgG2a levels to P. gingivalis in the exudates were also determined. The results showed that the leucocyte counts increased significantly post-challenge, and the REP group showed the highest number of lymphocytes and neutrophils. Both P. gingivalis-challenged groups exhibited significant increase in TNF-alpha and IL-10 levels at day 1 post-challenge. TNF-alpha levels in the chamber exudate were threefold higher in the REP group compared with the SIN group on day 1 post-challenge (P < 0.05). In contrast, IL-10 levels were significantly lower in the REP group 1 day post-challenge compared with the SIN group. The REP group had significantly higher levels of IFN-gamma at baseline, and this difference remained significant 1 day post-challenge. Analysis of antibody levels to P. gingivalis showed that while the control and the SIN groups had no anti-P. gingivalis IgG in the chamber exudate during the 7-day study period, the REP group showed high anti-P. gingivalis IgG levels. In addition, the titres of IgG2a were fivefold higher than the IgG1 titres. The results showed that a repeat local challenge with P. gingivalis augmented the proinflammatory cytokines TNF-alpha and IFN-gamma, while inhibiting the accumulation of the anti-inflammatory cytokine IL-10. This shift towards a T helper 1 (Th1)-dominant response was reflected in the relatively high anti-P. gingivalis IgG2a titres in the local inflammatory environment 7 days post-challenge.

Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C.

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Although autosomal recessive transmission of PLS is evident, a more "complex" autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A--> G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited "identical by descent" from a common ancestor. This finding supports simple autosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6 CTSC codon (2126C-->T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.

Using the PerioChip in treating adult periodontitis: an interim report.

Multicenter clinical trials have established that the adjunctive use of the subgingival controlled release of chlorhexidine, in the form of the PerioChip, significantly reduces pocket probing depth, improves probing attachment levels, and reduces bleeding on probing compared to scaling and root planing alone, for periods up to 9 months. The purpose of the present study was to report on the adjunctive use of the PerioChip for the long-term management of adult periodontitis for 2 years. A total of 836 patients with adult periodontitis from private dental offices were recruited into the trial. This interim report is on the first 72 patients to have completed the 2-year study. Treatments included initial definitive therapy followed by PerioChip placement in pocket sites with a pocket probing depth of > or = 5 mm after 1 month. Subsequently, the patients received routine periodontal maintenance therapy together with the placement of a PerioChip in pockets with pocket probing depths > or = 5 mm every 3 months. Results indicated that there was a continuous decrease in pocket probing depth over the 2 years (1.26 +/- 0.77 mm). This decrease in pocket probing depth was marked over the first 9 to 12 months, and then appeared to be less marked over the next 12 months. At 2 years, 60% of the patients had at least 2 pockets showing a reduction of 2 mm or more, and only 10% of the patients showed no change or increased pocket probing depth. The results indicate that adjunctive PerioChip use is a clinically effective treatment option for dental professionals and their patients for the long-term management of adult periodontitis.

Differentiation of monocytes to macrophages primes cells for lipopolysaccharide stimulation via accumulation of cytoplasmic nuclear factor kappaB.

During infection, circulating blood monocytes migrate from the vasculature to the extravascular compartments where they mature into tissue macrophages. The maturation process prepares the cell to actively participate in the inflammatory and the immune responses, and many transcription factors have been found to be involved. Here we report on a novel role for nuclear factor kappaB (NF-kappaB) in this process. Its accumulation in the cytoplasm of differentiated macrophages is responsible for the enhanced ability of the cell to respond to lipopolysaccharide (LPS) stimulation, as determined by tumor necrosis factor alpha (TNF-alpha) secretion. Differentiation of the human monocytic cell line THP-1 into macrophage-like cells was induced by exposure of the cells to phorbol myristate acetate. DNA-bindable NF-kappaB was not detected in the cytoplasm of undifferentiated THP-1 cells but accumulated in the cytoplasm of the cells following differentiation. No TNF-alpha was detected in the media of resting differentiated and nondifferentiated THP-1 cells. Stimulation with LPS of differentiated cells induced the production of higher levels of TNF-alpha than stimulation of nondifferentiated cells. This hyperresponsiveness to LPS was found in the mRNA and secreted TNF-alpha levels. Furthermore, stimulation with LPS induced the translocation of NF-kappaB from the cytoplasm into the nucleus. This translocation process was more rapid in the differentiated cells than in the nondifferentiated cells, and the resultant accumulated levels of NF-kappaB in the nucleus were higher. The DNA-bindable NF-kappaB was identified as a heterodimer of p65 and p50. The results suggest that NF-kappaB accumulation in the cytoplasm during maturation of monocytes to macrophages primes the cells for enhanced responsiveness to LPS and results in the rapid secretion of inflammatory mediators, such as TNF-alpha, by mature macrophages following LPS challenge.