Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Long-term Survival of Straumann Dental Implants with TPS Surfaces: A Retrospective Study with a Follow-up of 12 to 23 Years.

PURPOSE: The aim of this study was to evaluate the long-term dental implant survival rates of Straumann dental implants in a university hospital environment over 12 to 23 years. MATERIALS AND METHODS: A total of 388 Straumann dental implants with titanium-sprayed surfaces (TPS) were inserted in 92 patients between 1988 and 1999 in the Department of Oral and Maxillofacial Surgery of the University Hospital Schleswig-Holstein in Kiel, and they were reevaluated with standardized clinical and radiological exams. Kaplan-Meier analyses were performed for individual factors. Cox proportional hazard regression analysis was used to detect the factors influencing long-term implant failure. RESULTS: The long-term implant survival rate was 88.03% after an observation time of 12.2 to 23.5 years. Cox regression revealed statistically significant influences of the International Team for Implantology (ITI) implantation type (p = .00354) and tobacco smoking (p = .01264) on implant failure. A proportion 82.8% of the patients with implant losses had a medical history of periodontitis. Peri-implantitis was diagnosed in 9.7% of the remaining implants in the long-term survey. CONCLUSIONS: This study emphasized the long-term rehabilitation capabilities of Straumann dental implants in complex cases. The survival rates after several years constitute important information for patients, as well as for clinicians, in deciding about different concepts of tooth replacement. Patient-related and technical factors - determined before implant placement - could help to predict the risk of implant loss.

Stromal markers AKR1C1 and AKR1C2 are prognostic factors in primary human breast cancer.

BACKGROUND: Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo-keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. METHODS: Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. RESULTS: AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. CONCLUSION: It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.

Reconstruction of the orbital floor with polydioxanone: a long-term clinical survey of up to 12 years.

Fractures of the orbital floor are common in injured patients, who often require operation to prevent complications and, among other materials, polydioxanone is widely used. The aim of this study was to evaluate the long-term outcomes of fractures of the orbital floor that had been reconstructed with polydioxanone foil. A total of 101 patients (73 men and 28 women) who had reconstruction of the orbital floor for defects of 2cm(2) or smaller with polydioxanone implants, over a mean (SD) time period of 8 (2) years were evaluated. Sensitivity of the infraorbital nerve, ocular motility, and diplopia were evaluated and correlated with perioperative values. Persistent hyperaesthesia was found in 15 patients, whereas in another 15 the hyperaesthesia recovered completely over time. Three patients had double vision during follow-up. Twenty patients with preoperative diplopia had no persistent double vision postoperatively, and 15 patients with disturbed ocular motility recovered completely. Two patients had persistently disturbed motility, and one patient had enophthalmos. There was a significant association between hyperaesthesia preoperatively and postoperatively (p= 0.005). In most patients reconstruction of the orbital floor with polydioxanone was successful. Long-term complications such as diplopia, compromised bulbar motility, and hyperaesthesia of the cheek were seen in a few cases, but might not have been solely related to the use of polydioxanone.

Stem Cell Transplantation for Pulpal Regeneration: A Systematic Review.

For treating pulpal pathological conditions, pulpal regeneration through transplanted stem/progenitor cells might be an alternative to conventional root canal treatment. A number of animal studies demonstrated beneficial effects of stem/progenitor cell transplantation for pulp-dentin complex regeneration, that is, pulpal tissue, neural, vascular, and dentinal regeneration. We systematically reviewed animal studies investigating stem/progenitor cell-mediated pulp-dentin complex regeneration. Studies quantitatively comparing pulp-dentin complex regeneration after transplantation of stem/progenitor cells versus no stem/progenitor cell transplantation controls in intraoral in vivo teeth animal models were analyzed. The following outcomes were investigated: regenerated pulp area per root canal total area, capillaries per total surface, regenerated dentinal area per total defect area, and nerves per total surface. PubMed and EMBASE were screened for studies published until July 2014. Cross-referencing and hand searching were used to identify further articles. Standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated using random-effects meta-analysis. To assess possible bias, SYRCLE's risk of bias tool for animal studies was used. From 1364 screened articles, five studies (representing 64 animals) were included in the quantitative analysis. Risk of bias of all studies was high. Stem/progenitor cell-transplanted pulps showed significantly larger regenerated pulp area per root canal total area (SMD [95% CI]: 2.28 [0.35-4.21]) and regenerated dentin area per root canal total area (SMD: 6.91 [5.39-8.43]) compared with no stem/progenitor cell transplantation controls. Only one study reported on capillaries per or nerves per total surface and found both significantly increased in stem/progenitor cell-transplanted pulps compared with controls. Stem/progenitor cell transplantation seems to enhance pulp-dentin complex regeneration in animal models. Due to limited data quantity and quality, current evidence levels are insufficient for further conclusions.

Determinants of platelet-leukocyte aggregation and platelet activation in stroke.

BACKGROUND: Platelet-leukocyte aggregation (PLA) and platelet activation are found to be on the higher side in ischemic stroke patients. The correlation of PLA with clinical features has not been intensively investigated and the influence of genetic factors on PLA is still unexplored. The interaction of platelets with leukocytes is mainly determined by the proteins encoded by six genes: P-Selectin (SELP encodes CD62P) on the thrombocyte binding to P-Selectin-Glycoprotein-Ligand-1 (PSGL1) on the leukocyte, intracellular-adhesion-molecule 2 (ICAM2) interacting with Integrin alpha M (ITGAM) and Glycoprotein 1b-alpha (GP1BA) binding to Integrin alpha L (ITGAL). METHODS: Seventy-nine patients with acute ischemic stroke and 151 controls without vascular disease from a single German center were enrolled. A neurologist and a neuroradiologist ascertained clinical and radiological features. PLA and platelet activation were analyzed using flow cytometry with various antibodies. Coding as well as tagging SNPs in six genes determining PLA were genotyped. Three groups of parameters were correlated with each other: (i) clinical and radiological parameters, (ii) laboratory parameters, (iii) genetic parameters. For the comparisons, robust nonparametric statistical tests were applicable. RESULTS: PLA and platelet activation were higher in ischemic stroke patients compared to controls. Both, anticoagulant and antiplatelet treatment in the patient group affected platelet activation but not PLA. PLA correlated weakly with measures of stroke severity but not with thrombus length or stroke etiology. The association of SNP rs2228315 in the P-Selectin Glycoprotein Ligand-1-gene (PSGL1) with ischemic stroke and platelet activation was significant before correction for multiple testing while a trend was observed for the association with PLA. Regression analysis revealed that (i) platelet activation was an independent determinant of stroke, (ii) that PLA correlated with stroke, sex, age and platelet activation and (iii) that platelet activation correlated only with stroke. None of the SNPs survived in the regression analysis for stroke, PLA or platelet activation as dependent variables. CONCLUSIONS: The most important result of our study is that PLA and platelet activation are independent of other vascular risk factors correlated with stroke in our sample. In addition, we identified the missense SNP rs2228315 in the PSGL1-gene as a candidate polymorphism for ischemic stroke-related PLA. Association between this SNP and stroke as well as coronary artery disease has also been shown by two other studies.

No shortcut solution to the problem of Y-STR match probability calculation.

Match probability calculation is deemed much more intricate for lineage genetic markers, including Y-chromosomal short tandem repeats (Y-STRs), than for autosomal markers. This is because, owing to the lack of recombination, strong interdependence between markers is likely, which implies that haplotype frequency estimates cannot simply be obtained through the multiplication of allele frequency estimates. As yet, however, the practical relevance of this problem has not been studied in much detail using real data. In fact, such scrutiny appears well warranted because the high mutation rates of Y-STRs and the possibility of backward mutation should have worked against the statistical association of Y-STRs. We examined haplotype data of 21 markers included in the PowerPlex(®)Y23 set (PPY23, Promega Corporation, Madison, WI) originating from six different populations (four European and two Asian). Assessing the conditional entropies of the markers, given different subsets of markers from the same panel, we demonstrate that the PowerPlex(®)Y23 set cannot be decomposed into smaller marker subsets that would be (conditionally) independent. Nevertheless, in all six populations, >94% of the joint entropy of the 21 markers is explained by the seven most rapidly mutating markers. Although this result might render a reduction in marker number a sensible option for practical casework, the partial haplotypes would still be almost as diverse as the full haplotypes. Therefore, match probability calculation remains difficult and calls for the improvement of currently available methods of haplotype frequency estimation.

Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis.

BACKGROUND: Genetic studies demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between coronary artery disease (CAD) and periodontitis. We aimed to identify further shared genetic risk factors to better understand conjoint disease mechanisms. METHODS AND RESULTS: In-depth genotyping of 46 published CAD risk loci of genome-wide significance in the worldwide largest case-control sample of the severe early-onset phenotype aggressive periodontitis (AgP) with the Illumina Immunochip (600 German AgP cases, 1448 controls) and the Affymetrix 500K array set (283 German AgP cases and 972 controls) highlighted ANRIL as the major risk gene and revealed further associations with AgP for the gene PLASMINOGEN (PLG; rs4252120: P=5.9×10(-5); odds ratio, 1.27; 95% confidence interval, 1.3-1.4 [adjusted for smoking and sex]; 818 cases; 5309 controls). Subsequent combined analyses of several genome-wide data sets of CAD and AgP suggested TGFBRAP1 to be associated with AgP (rs2679895: P=0.0016; odds ratio, 1.27 [95% confidence interval, 1.1-1.5]; 703 cases; 2.143 controls) and CAD (P=0.0003; odds ratio, 0.84 [95% confidence interval, 0.8-0.9]; n=4117 cases; 5824 controls). The study further provides evidence that in addition to PLG, the currently known shared susceptibility loci of CAD and periodontitis, ANRIL and CAMTA1/VAMP3, are subjected to transforming growth factor-ß regulation. CONCLUSIONS: PLG is the third replicated shared genetic risk factor of atherosclerosis and periodontitis. All known shared risk genes of CAD and periodontitis are members of transforming growth factor-ß signaling.

Immunohistological expression of human ß-defensin-1 and human ß-defensin-2 in exacerbation of acute and secondary chronic osteomyelitis of the mandible.

BACKGROUND: The majority of patients diagnosed with osteomyelitis of the jaw have severe complaints. Unfortunately, the pathogenesis still remains unclear. Human ß-defensins expressed in epithelial and bone tissues as a part of the innate immunity may be involved in disease development. In this study, we hypothesize that expression levels of human ß-defensin-1 and -2 in the acute and secondary chronic osteomyelitis may be altered in comparison with healthy bone and with bisphosphonate-associated necrosis as well as irradiation from a previous study. METHODS: Bone samples were collected during surgical debridement in a total of eight patients suffering from acute or secondary chronic osteomyelitis of the jaw. Expression levels of hBD-1 and -2 were quantified and related to non-stained cells. Ratios were compared by one-way ANOVA and multiple tests by Holm-Bonferroni. RESULTS: Multiple testing revealed no significant differences for expression levels of human ß-defensin-1 between all groups, whereas labeling index of human ß-defensin-2 was significantly different between specimens of bisphosphonate-associated osteonecrosis of the jaws and all other groups. No significant difference occurred between samples of floride osteomyelitis and healthy bone for expression of hBD-1 and -2. CONCLUSIONS: Although the affected patients showed all clinical signs of acute inflammation, expression levels in acute and secondary chronic osteomyelitis in the jaws did not reveal statistically significant differences compared with healthy bone samples. The weak immunological host response in terms of a putative genetically predisposition should be further discussed as pathogenesis factor for osteomyelitis in the future.

A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis.

AIM: Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis (RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis. MATERIALS AND METHODS: Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped in a German case-control sample of aggressive periodontitis (AgP), using Immunochip genotyping arrays (Illumina, 600 cases, 1440 controls) and Affymetrix 500 K Genotyping Arrays (280 cases and 983 controls). Significant associations were replicated in 168 Dutch AgP cases and 679 controls and adjusted for the confounders smoking and sex. RESULTS: Variants at IRF5 and PRDM1 showed association with AgP. Upon covariate adjustment for smoking and sex, the most strongly associated variant at IRF5 was the rare variant rs62481981 (ppooled  = 0.0012, odds ratio [OR] = 3.1, 95% confidence interval [95% CI] = 1.6-6.1; 801 cases, 1476 controls).Within PRDM1 it was rs6923419 (ppooled  = 0.004, OR = 0.7, 95% CI = 0.6-0.9; 833 cases, 1440 controls). The associations lost significance after correction for multiple testing in the replication. Both genes are implicated in beta-interferon signalling and are also genome-wide associated with SLE and inflammatory bowel disease. CONCLUSION: The study gives no definite evidence for a pathogenic genetic link of periodontitis and RA but suggests IRF5 and PRDM1 as shared susceptibility factors.

SLC23A1 polymorphism rs6596473 in the vitamin C transporter SVCT1 is associated with aggressive periodontitis.

AIM: Identification of variants within genes SLC23A1 and SLC23A2 coding for vitamin C transporter proteins associated with aggressive (AgP) and chronic periodontitis (CP). MATERIAL AND METHODS: Employment of three independent case-control samples of AgP (I. 283 cases, 979 controls; II. 417 cases, 1912 controls; III. 164 cases, 357 controls) and one sample of CP (1359 cases, 1296 controls). RESULTS: Stage 1: Among the tested single-nucleotide polymorphisms (SNPs), the rare allele (RA) of rs6596473 in SLC23A1 showed nominal significant association with AgP (p = 0.026, odds ratio [OR] 1.26, and a highly similar minor allele frequency between different control panels. Stage 2: rs6596473 showed no significant association with AgP in the replication with the German and Dutch case-control samples. After pooling the German AgP populations (674 cases, 2891 controls) to significantly increase the statistical power (SP = 0.81), rs6596473 RA showed significant association with AgP prior to and upon adjustment with the covariates smoking and gender with padj  = 0.005, OR = 1.35. Stage 3: RA of rs6596473 showed no significant association with severe CP. CONCLUSION: SNP rs6596473 of SLC23A1 is suggested to be associated with AgP. These results add to previous reports that vitamin C plays a role in the pathogenesis of periodontitis.

Impact of patient-prosthesis mismatch following aortic valve replacement on short-term survival: a retrospective single center analysis of 632 consecutive patients with isolated stented biological aortic valve replacement.

OBJECTIVES: The impact of patient-prosthesis mismatch (PPM) after aortic valve replacement (AVR) on short-term and long-term mortality remains controversial. The objective of this study was to evaluate the incidence and severity of PPM and its impact on short-term survival in a large cohort of patients treated with isolated stented biological AVR in a single institution. METHODS: We analyzed retrospectively data of 632 consecutive patients with aortic stenosis undergoing isolated stented biological AVR between January 2007 and February 2012 at our institution. PPM was defined as an indexed effective orifice area ≤ 0.85 cm(2)/m(2). Statistical analyses were performed to identify influencing variables on valve size implanted. RESULTS: Of the 632 patients investigated, 46% were females and mean age was 71.9 ± 10.4 years. PPM was observed in 93.8% (593 of 632 patients). In 71% of the patients, moderate (0.65-0.85 cm(2)/m(2)) PPM was present and in 22.8% severe (< 0.65 cm(2)/m(2)) PPM was present. The 30-day mortality was 1.4% (9 of 632 patients) with all being females. PPM was not associated with increased 30-day mortality. Multiple regression analyses demonstrated the usefulness of sex, height, body mass index, and body surface area as simultaneous predictors of the valve size implanted (R(2)= 0.39). CONCLUSION: PPM had no discernable impact on short-term survival, although it was present in 93.8% of our patients following isolated stented biological AVR.

Estimating trace-suspect match probabilities for singleton Y-STR haplotypes using coalescent theory.

Estimation of match probabilities for singleton haplotypes of lineage markers, i.e. for haplotypes observed only once in a reference database augmented by a suspect profile, is an important problem in forensic genetics. We compared the performance of four estimators of singleton match probabilities for Y-STRs, namely the count estimate, both with and without Brenner's so-called 'kappa correction', the surveying estimate, and a previously proposed, but rarely used, coalescent-based approach implemented in the BATWING software. Extensive simulation with BATWING of the underlying population history, haplotype evolution and subsequent database sampling revealed that the coalescent-based approach is characterized by lower bias and lower mean squared error than the uncorrected count estimator and the surveying estimator. Moreover, in contrast to the two count estimators, both the surveying and the coalescent-based approach exhibited a good correlation between the estimated and true match probabilities. However, although its overall performance is thus better than that of any other recognized method, the coalescent-based estimator is still computation-intense on the verge of general impracticability. Its application in forensic practice therefore will have to be limited to small reference databases, or to isolated cases of particular interest, until more powerful algorithms for coalescent simulation have become available.

Influence of the drill material and method of cooling on the development of intrabony temperature during preparation of the site of an implant.

Our aim was to evaluate the intrabony friction heat produced by implant drills, using different drill materials and methods of cooling. Four pilot drills and 4 form drills were used. The following combinations of drill material and cooling supply were tested: steel and external cooling; steel and internal cooling; steel coated with zirconium nitride and external cooling; and zirconium oxide and external cooling. The handpiece that supported the drill was fixed in a lifting device. Specimens of bovine ribs were fixed below the handpiece, and the drill speed was set to 1200 rpm. The vertical force was adjusted to 1 kg for pilot drills and 0.5 kg for implant drills. Intrabony temperature during drilling was measured at depths of 4, 8, and 12 mm parallel to the drill, and the depth was limited to 13 mm. There were no significant differences in heat generation between the drill materials (p>.05), but the differences between groups with internal or external cooling supplies were significant (p≤.05). The method of cooling affected the development of the intrabony temperature during preparation of the site of the implant, but the drill material seemed to play no particular role.

Empirical evaluation reveals best fit of a logistic mutation model for human Y-chromosomal microsatellites.

The rate of microsatellite mutation is dependent upon both the allele length and the repeat motif, but the exact nature of this relationship is still unknown. We analyzed data on the inheritance of human Y-chromosomal microsatellites in father-son duos, taken from 24 published reports and comprising 15,285 directly observable meioses. At the six microsatellites analyzed (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393), a total of 162 mutations were observed. For each locus, we employed a maximum-likelihood approach to evaluate one of several single-step mutation models on the basis of the data. For five of the six loci considered, a novel logistic mutation model was found to provide the best fit according to Akaike's information criterion. This implies that the mutation probability at the loci increases (nonlinearly) with allele length at a rate that differs between upward and downward mutations. For DYS392, the best fit was provided by a linear model in which upward and downward mutation probabilities increase equally with allele length. This is the first study to empirically compare different microsatellite mutation models in a locus-specific fashion.

A Markov chain description of the stepwise mutation model: local and global behaviour of the allele process.

The stepwise mutation model (SMM) is a simple, widely used model to describe the evolutionary behaviour of microsatellites. We apply a Markov chain description of the SMM and derive the marginal and joint properties of this process. In addition to the standard SMM, we also consider the normalised allele process. In contrast to the standard process, the normalised process converges to a stationary distribution. We show that the marginal stationary distribution is unimodal. The standard and normalised processes capture the global and the local behaviour of the SMM, respectively.

Histological detection of minimal metastatic disease in inguinal non-sentinel lymph nodes in penile cancer.

UNLABELLED: The aim of this study was to detect lymphatic spread by serial step-section technique in non-sentinel lymph nodes (NSLNs), which were earlier assessed as negative by histological examination. PATIENTS AND METHODS: Inguinal dissection specimens of 13 men with penile cancer were investigated. The LNs were sectioned at multiple levels (150 mum-intervals) and then H&E- and immuno-stained for cytokeratin (Lu-5). RESULTS: 196 LNs of 13 men were examined. In 2 out of 13 patients (15%) previously ranked as pN0, minimal lymph node involvement was detected by serial step sections and both immunohistochemistry and H&E staining. Both patients have had an uneventful follow-up of currently 62 and 16 months. CONCLUSION: Conventional histological examination of NSLNs fails to detect lymphatic spread in penile cancer. Step-section technique at 3 section levels, rather than immunohistochemistry, helps to safely detect minimal metastatic disease. The prognostic relevance is still unclear and has to be investigated in larger cohort studies.