Longitudinal data on telomere length in leukocytes from newborn baboons support a marked drop in stem cell turnover around 1 year of age

Stem cells of various tissues are typically defined as multipotent cells with 'self-renewal' properties. Despite the increasing interest in stem cells, surprisingly little is known about the number of times stem cells can or do divide over a lifetime. Based on telomere-length measurements of hematopoietic cells, we previously proposed that the self-renewal capacity of hematopoietic stem cells is limited by progressive telomere attrition and that such cells divide very rapidly during the first year of life. Recent studies of patients with aplastic anemia resulting from inherited mutations in telomerase genes support the notion that the replicative potential of hematopoietic stem cells is directly related to telomere length, which is indirectly related to telomerase levels. To revisit conclusions about stem cell turnover based on cross-sectional studies of telomere length, we performed a longitudinal study of telomere length in leukocytes from newborn baboons. All four individual animals studied showed a rapid decline in telomere length (approximately 2-3 kb) in granulocytes and lymphocytes in the first year after birth. After 50-70 weeks the telomere length appeared to stabilize in all cell types. These observations suggest that hematopoietic stem cells, after an initial phase of rapid expansion, switch at around 1 year of age to a different functional mode characterized by a markedly decreased turnover rate.

Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalis

INTRODUCTION: Periodontitis is a common infectious disease to which Porphyromonas gingivalis has been closely linked, in which the attachment tissues of the teeth and their alveolar bone housing are destroyed. We conducted a study to determine if immunization using a purified antigen could alter the onset and progression of the disease. METHODS: Using the ligature-induced model of periodontitis in Macaca fascicularis, we immunized five animals with cysteine protease purified from P. gingivalis and used an additional five animals as controls. Alveolar bone loss was measured by digital subtraction radiography. RESULTS: Immunization induced high titers of specific immunoglobuin G serum antibodies that were opsonic. Total bacterial load, levels of P. gingivalis in subgingival plaque and levels of prostaglandin E(2) in gingival crevicular fluid were significantly reduced. Onset and progression of alveolar bone loss was inhibited by approximately 50%. No manifestations of toxicity were observed. CONCLUSIONS: Immunization using a purified protein antigen from P. gingivalis inhibits alveolar bone destruction in a ligature-induced periodontitis model in M. fascicularis.

The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review

BACKGROUND: Genetically transmitted traits such as cytokine gene polymorphisms may accentuate the host inflammatory response to the bacterial challenge and influence susceptibility to periodontitis. OBJECTIVE: To systematically review the evidence of an association between the interleukin-1 (IL-1) composite genotype, i.e. presence of the allele 2 in the gene clusters IL-1A-889 and in IL-1B +3953, and periodontitis progression and/or treatment outcomes. Material and Methods: Based on the focused question, a search was conducted for longitudinal clinical trials comparing progression of periodontitis and/or treatment outcomes in IL-1 genotype-positive (carrying allele 2) and IL-1 genotype-negative (not carrying allele 2) subjects. A search in the National Library of Medicine computerized bibliographic database MEDLINE and a manual search were performed. Selection of publications, extraction of data and validity assessment were made independently by two reviewers. RESULTS: The search provided 122 titles of which 11 longitudinal publications were included. The heterogeneity of the data prevented the performance of a meta-analysis. While findings from some publications rejected a possible role of IL-1 composite genotype on progression of periodontitis after various therapies, other reported a prognostic value for disease progression of the positive IL-1 genotype status. When assessed on a multivariate risk assessment model, several publications concluded that the assessment of the IL-1 composite genotype in conjunction with other covariates (e.g. smoking and presence of specific bacteria) may provide additional information on disease progression. The small sample size of the available publications, however, requires caution in the interpretation of the results. CONCLUSION: Based on these findings, (i) there is insufficient evidence to establish if a positive IL-1 genotype status contributes to progression of periodontitis and/or treatment outcomes. Therefore, (ii) results obtained with commercially available tests should be interpreted with caution.

Reduced neuronal efficacy in progressive mild cognitive impairment: a prospective fMRI study on visuospatial processing

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimer's disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma

AIM: To compare the plasma levels of endothelin-1 (ET-1) between patients with primary open angle glaucoma with visual field progression despite normal or normalised intraocular pressure and patients with stabile visual fields in a retrospective study. METHODS: The progressive group consisted of 16 primary open angle glaucoma patients and the group with stable visual field consisted of 15 patients. After a 30 minute rest in a supine position, venous blood was obtained for ET-1 dosing. Difference in the plasma level of ET-1 between two groups was compared by means of analysis of covariance (ANCOVA), including age, sex, and mean arterial blood pressure as covariates. RESULTS: ET-1 plasma levels were found to be significantly increased in patients with deteriorating (3.47 (SD 0.75) pg/ml) glaucoma when compared to those with stable (2.59 (SD 0.54) pg/ml) visual fields (p = 0.0007). CONCLUSIONS: Glaucoma patients with visual field progression in spite of normal or normalised intraocular pressure have been found to have increased plasma endothelin-1 levels. It remains to be determined if this is a secondary phenomenon or whether it may have a role in the progression of glaucomatous damage.

Influence of residual pockets on progression of periodontitis and tooth loss: results after 11 years of maintenance

BACKGROUND: Limited evidence exists on the significance of residual probing pocket depth (PPD) as a predictive parameter for periodontal disease progression and tooth loss. AIM: The aim of this study was to investigate the influence of residual PPD >or=5 mm and bleeding on probing (BOP) after active periodontal therapy (APT) on the progression of periodontitis and tooth loss. MATERIAL AND METHODS: In this retrospective cohort, 172 patients were examined after APT and supportive periodontal therapy (SPT) for 3-27 years (mean 11.3 years). Analyses were conducted using information at site, tooth and patient levels. The association of risk factors with tooth loss and progression of periodontitis was investigated using multilevel logistic regression analysis. RESULTS: The number of residual PPD increased during SPT. Compared with PPDor=7 mm 37.9 and 64.2, respectively. At patient level, heavy smoking, initial diagnosis, duration of SPT and PPD>or=6 mm were risk factors for disease progression, while PPD>or=6 mm and BOP>or=30% represented a risk for tooth loss. CONCLUSION: Residual PPD>or=6 mm represent an incomplete periodontal treatment outcome and require further therapy.

Similarities in the Subgingival Microbiota Assessed by a Curet Sampling Method at Sites With Chronic Periodontitis

Background: The goal of this study was to determine whether site-specific differences in the subgingival microbiota could be detected by the checkerboard method in subjects with periodontitis. Methods: Subjects with at least six periodontal pockets with a probing depth (PD) between 5 and 7 mm were enrolled in the study. Subgingival plaque samples were collected with sterile curets by a single-stroke procedure at six selected periodontal sites from 161 subjects (966 subgingival sites). Subgingival bacterial samples were assayed with the checkerboard DNA-DNA hybridization method identifying 37 species. Results: Probing depths of 5, 6, and 7 mm were found at 50% (n = 483), 34% (n = 328), and 16% (n = 155) of sites, respectively. Statistical analysis failed to demonstrate differences in the sum of bacterial counts by tooth type (P = 0.18) or specific location of the sample (P = 0.78). With the exceptions of Campylobacter gracilis (P <0.001) and Actinomyces naeslundii (P <0.001), analysis by general linear model multivariate regression failed to identify subject or sample location factors as explanatory to microbiologic results. A trend of difference in bacterial load by tooth type was found for Prevotella nigrescens (P <0.01). At a cutoff level of >/=1.0 x 10(5), Porphyromonas gingivalis and Tannerella forsythia (previously T. forsythensis) were present at 48.0% to 56.3% and 46.0% to 51.2% of sampled sites, respectively. Conclusions: Given the similarities in the clinical evidence of periodontitis, the presence and levels of 37 species commonly studied in periodontitis are similar, with no differences between molar, premolar, and incisor/cuspid subgingival sites. This may facilitate microbiologic sampling strategies in subjects during periodontal therapy.

A systematic review of the effects of full-mouth debridement with and without antiseptics in patients with chronic periodontitis

OBJECTIVES: To assess the clinical and microbiological effects of full-mouth debridement with (FMD) and without the use of antiseptics [full-mouth scaling and root planing (FMSRP)] in comparison with conventional staged debridement (CSD) in patients with chronic periodontitis after at least 6 months. MATERIAL AND METHODS: The search in MEDLINE (PubMed), covering a period of 1975 to October 2007, and hand searching yielded 207 titles. Forty-two abstracts and 17 full-text articles were screened for inclusion. RESULTS: Twelve articles allowed a direct comparison of FMD with CSD, FMSRP with CSD and FMD with FMSRP. Probing pocket depth reductions were significantly greater (0.2 mm) with FMD and FMSRP compared with CSD. Moreover, a modest reduction in BOP (9%) favoured FMD. Likewise, clinical attachment levels were improved by 0.2-0.4 mm in favour of FMD and FMSRP, respectively. In all comparisons, single-rooted teeth and deep pockets benefitted slightly from FMD and FMSRP. Limited differences in the changes of the subgingival microbiota were noted between the treatment modalities. CONCLUSIONS: Despite the significant differences of modest magnitude, FMD or FMSRP do not provide clinically relevant advantages over CSD. Hence, all three treatment modalities may be recommended for debridement in the initial treatment of patients with chronic periodontitis.

Staphylococcus aureus and other bacteria in untreated periodontitis

Whether the subgingival microbiota differ between individuals with chronic and those with aggressive periodontitis, and whether smoking influences bacterial composition, is controversial. We hypothesized that the subgingival microbiota do not differ between sites in individuals with chronic or aggressive periodontitis, or by smoking status. Bacterial counts and proportional distributions were assessed in 84 individuals with chronic periodontitis and 22 with aggressive periodontitis. No differences in probing pocket depth by periodontal status were found (mean, 0.11 mm; 95% CI, 0.6 to 0.8, p = 0.74). Including Staphylococcus aureus, Parvimonas micra, and Prevotella intermedia, 7/40 species were found at higher levels in those with aggressive periodontitis (p < 0.001). Smokers had higher counts of Tannerella forsythia (p < 0.01). The prevalence of S. aureus in non-smokers with aggressive periodontitis was 60.5%. The null hypothesis was rejected, in that P. intermedia, S. aureus, and S. mutans were robust in diagnosing sites in individuals with aggressive periodontitis. S. aureus, S. sanguinis, and T. forsythia differentiated smoking status.

Cardiovascular disease and periodontitis: an update on the associations and risk

BACKGROUND: Associations between periodontitis and cardiovascular diseases have been recognized. MATERIAL AND METHODS: New literature since the last European Workshop on Periodontology has been reviewed. RESULTS: The lack of reliable epidemiological data on disease prevalence makes an assessment of the associations and risks between periodontitis and cardiovascular diseases difficult. Two recent meta-analysis reports have identified associations between periodontitis and cardiovascular diseases (odds ratios: 1.1-2.2). Different surrogate markers for both disease entities, including serum biomarkers, have been investigated. Brachial artery flow-mediated dilatation, and carotid intima media thickness have in some studies been linked to periodontitis. Studies are needed to confirm early results of improvements of such surrogate markers following periodontal therapy. While intensive periodontal therapy may enhance inflammatory responses and impair vascular functions, studies are needed to assess the outcome of periodontal therapies in subjects with confirmed cardiovascular conditions. Tooth eradication may also reduce the systemic inflammatory burden of individuals with severe periodontitis. The role of confounders remain unclear. CONCLUSIONS: Periodontitis may contribute to cardiovascular disease and stroke in susceptible subjects. Properly powered longitudinal case-control and intervention trials are needed to identify how periodontitis and periodontal interventions may have an impact on cardiovascular diseases.

[Periodontitis and cardiovascular disease]

The prevalence of periodontitis and cardiovascular disease (CVD) is high. A mixed infectious biofilm etiology of periodontitis is known but not fully established in CVD. Cofactors; smoking habits, stress, ethnicity, genetics, socioeconomics and age contribute to both diseases. The objectives of this report are to summarize factors in regards to CVD and periodontitis that are clinically relevant. The hypothesis behind a relationship between the two conditions can be founded in (I) shared infections etiology, (II) shared inflammatory response, (III) epidemiological and case-control studies, and (IV) periodontal studies demonstrating improvements of CVD markers. Streptococcus species in the S. mitis group, and S. anginosus group have been identified in periodontitis and are known as pathogens in endocarditis possibly transported from the oral cavity to the heart through bacteremia during dental therapies, and tooth brushing. Other periodontal bacteria such as Porphyromonas gingivalis, Fusobacterium nucleatum and Parvimonas micra are beta-lactamase producing and may contribute to antibiotic resistance (extended spectrum beta-lactamases). Other bacteria in CVD and periodontitis include Staphylococcus aureus, and Pseudomonas aeruginosa. Chlamydia pneumoniae and P. gingivalis lipopolyysaccharide capsels share homology and induce heat-shock protein activity and a cascade of proinflammatory cytokines. Associations between periodontitis and CVD have been presented in many studies when controlling for confounders. Other studies have demonstrated that periodontal therapies increase brachial artery flow rate and reduce serum inflammatory cytokine levels. Thus, physicians caring for subjects at CVD risk should consult with dentists/periodontists. Dentists must improve their medical knowledge and also learn to consult with physicians when treating patients at CVD risk.

Effectiveness of selective dorsal rhizotomy in 2 patients with progressive spasticity due to neurodegenerative disease

Selective dorsal rhizotomy at the lumbar level is a neurosurgical procedure, which reduces spasticity in the legs. Its effect has mainly been studied in children with spastic cerebral palsy. Little is known about the outcome of selective dorsal rhizotomy in patients with neurodegenerative disorders. We report the clinical course after selective dorsal rhizotomy in 2 patients with progressive spasticity. Leg spasticity was effectively and persistently reduced in both patients, facilitating care and improving sitting comfort. However, spasticity of the arms and other motor disturbances, such as spontaneous extension spasms and the ataxia, increased gradually in time. Selective dorsal rhizotomy leads to a disappearance of leg spasticity in patients with a neurodegenerative disease. Other motor signs are not influenced and may increase due to the progressive nature of the underlying disease.

Natalizumab: targeting alpha4-integrins in multiple sclerosis

In 1992, it was shown that monoclonal antibodies blocking alpha(4)-integrins prevent the development of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS). As alpha(4)beta(1)-integrin was demonstrated to mediate the attachment of immune-competent cells to inflamed brain endothelium in experimental autoimmune encephalomyelitis, the therapeutic effect was attributed to the inhibition of immune cell extravasation and inflammation in the central nervous system. This novel therapeutic approach was rapidly and successfully translated into the clinic. The humanized anti-alpha(4)-integrin antibody natalizumab demonstrated an unequivocal therapeutic effect in preventing relapses and slowing down the pace of neurological deterioration in patients with relapsing-remitting MS in phase II and phase III clinical trials. The occurrence of 3 cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab led to the voluntary withdrawal of the drug from the market. After a thorough safety evaluation of all patients receiving this drug in past and ongoing studies for MS and Crohn's disease, natalizumab again obtained approval in the US and the European Community. A treatment targeting leukocyte trafficking in MS has now re-entered the clinic. Further thorough evaluation is necessary for a better understanding of the risk-benefit balance of this new treatment option for relapsing MS. In this review, we discuss the basic mechanism of action, key clinical results of clinical trials and the emerging indication of natalizumab in MS.