Efficient parameterization of cardiac action potential models using a genetic algorithm.

Finding appropriate values for parameters in mathematical models of cardiac cells is a challenging task. Here, we show that it is possible to obtain good parameterizations in as little as 30-40 s when as many as 27 parameters are fit simultaneously using a genetic algorithm and two flexible phenomenological models of cardiac action potentials. We demonstrate how our implementation works by considering cases of "model recovery" in which we attempt to find parameter values that match model-derived action potential data from several cycle lengths. We assess performance by evaluating the parameter values obtained, action potentials at fit and non-fit cycle lengths, and bifurcation plots for fidelity to the truth as well as consistency across different runs of the algorithm. We also fit the models to action potentials recorded experimentally using microelectrodes and analyze performance. We find that our implementation can efficiently obtain model parameterizations that are in good agreement with the dynamics exhibited by the underlying systems that are included in the fitting process. However, the parameter values obtained in good parameterizations can exhibit a significant amount of variability, raising issues of parameter identifiability and sensitivity. Along similar lines, we also find that the two models differ in terms of the ease of obtaining parameterizations that reproduce model dynamics accurately, most likely reflecting different levels of parameter identifiability for the two models.

The association between clinical periodontal parameters and free haem concentration within the gingival crevicular fluid: a pilot study.

OBJECTIVES: To investigate the concentration of local free haem in gingival crevicular fluid at periodontally healthy compared with diseased sites in relation to clinical periodontal parameters. The second objective is to investigate for any correlation between smoking and haem concentration. MATERIAL AND METHODS: Clinical parameters were recorded for two healthy and two diseased sites from 22 patients with untreated periodontitis. Gingival crevicular fluid samples were collected from the same sites. Haem assay analysis was undertaken to determine haem concentration at these sites. RESULTS: Gingival crevicular fluid haem concentration was higher at periodontally diseased sites compared to healthy sites (mean 46.6 ± 70.6 nM in healthy vs. 1116.6 ± 2007.0 nM in diseased sites, p < 0.001) and positively correlated with probing pocket depth, attachment level and radiographic bone loss. Gingival crevicular fluid haem concentration was higher in non-smokers compared with smokers. However, no significant difference in correlation between haem concentration and clinical parameters were seen between smokers and non-smokers (p > 0.3). CONCLUSION: The higher concentration of gingival crevicular fluid haem at diseased compared with healthy sites indicates that there is an association between increased levels of local free haem and periodontal disease. This may be through the pro-inflammatory actions of free haem. Further study on a larger scale is required to determine the influence of smoking between haem concentration and clinical parameters.

Gingival crevicular fluid proteomes in health, gingivitis and chronic periodontitis.

OBJECTIVE: The aim of this study was to compare the proteome composition of gingival crevicular fluid obtained from healthy periodontium, gingivitis and chronic periodontitis affected sites. BACKGROUND: Owing to its site-specific nature, gingival crevicular fluid is ideal for studying biological processes that occur during periodontal health and disease progression. However, few studies have been conducted into the gingival crevicular fluid proteome due to the small volumes obtained. METHODS: Fifteen males were chosen for each of three different groups, healthy periodontium, gingivitis and chronic periodontitis. They were categorized based on clinical measurements including probing depth, bleeding on probing, plaque index, radiographic bone level, modified gingival index and smoking status. Gingival crevicular fluid was collected from each patient, pooled into healthy, gingivitis and chronic periodontitis groups and their proteome analyzed by gel electrophoresis and liquid chromatography electrospray ionization ion trap tandem mass spectrometry. RESULTS: One hundred and twenty-one proteins in total were identified, and two-thirds of these were identified in all three conditions. Forty-two proteins were considered to have changed in abundance. Of note, cystatin B and cystatin S decreased in abundance from health to gingivitis and further in chronic periodontitis. Complement proteins demonstrated an increase from health to gingivitis followed by a decrease in chronic periodontitis. Immunoglobulins, keratin proteins, fibronectin, lactotransferrin precursor, 14-3-3 protein zeta/delta, neutrophil defensin 3 and alpha-actinin exhibited fluctuations in levels. CONCLUSION: The gingival crevicular fluid proteome in each clinical condition was different and its analysis may assist us in understanding periodontal pathogenesis.

Comparison of clinical and cone beam computed tomography measurements to diagnose furcation involvement.

AIM: This study aimed to determine the degree of discrepancy between clinical measurement of furcation involvement (FI) and cone beam computed tomography image analysis of multirooted teeth. METHODS: FI measurements obtained from clinical records were compared to CBCT images of the same teeth to determine the degree of discrepancy between CBCT FI grading and clinical FI grading. RESULTS: Of the hundred and fifty-four sites analysed, 22% of FI measurements from probing and CBCT were in agreement. Fifty-eight percent of clinical FI recordings were overestimated, and 20% were underestimated when compared to CBCT analysis. CONCLUSION: Clinical recording of FI is both over and underestimated compared to CBCT analysis. This was highest for probing recording grade I furcation involvement where it was highly overestimated. The occurrence of over and under estimation of FI will affect the assignment of prognosis to multirooted teeth, which can influence treatment planning for periodontal therapy and may result in inappropriate treatment.

Blurring the boundaries: decays of multiparticle isomers at the proton drip line.

A multiparticle spin-trap isomer has been discovered in the proton-unbound nucleus (73)(158)Ta85 . The isomer mainly decays by γ-ray emission with a half-life of 6.1(1) µs. Analysis of the γ-ray data shows that the isomer lies 2668 keV above the known 9+ state and has a spin 10ℏ higher and negative parity. This 19- isomer also has an 8644(11) keV, 1.4(2)% α-decay branch that populates the 9+ state in (154)Lu. No proton-decay branch from the isomer was identified, despite the isomer being unbound to proton emission by 3261(14) keV. This remarkable stability against proton emission is compared with theoretical predictions, and the implications for the extent of observable nuclides are considered.

Mass spectrometric analysis of gingival crevicular fluid biomarkers can predict periodontal disease progression.

BACKGROUND AND OBJECTIVE: Gingival crevicular fluid has been suggested as a possible source of biomarkers for periodontal disease progression. This paper describes a technique for the analysis of gingival crevicular fluid from individual sites using mass spectrometry. It explores the novel use of mass spectrometry to examine the relationship between the relative amounts of proteins and peptides in gingival crevicular fluid and their relationship with clinical indices and periodontal attachment loss in periodontal maintenance patients. The aim of this paper was to assess whether the mass spectrometric analysis of gingival crevicular fluid may allow for the site-specific prediction of periodontal disease progression. MATERIAL AND METHODS: Forty-one periodontal maintenance subjects were followed over 12 mo, with clinical measurements taken at baseline and every 3 mo thereafter. Gingival crevicular fluid was collected from subjects at each visit and was analysed using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Samples were classified based upon pocket depth, modified gingival index (MGI), plaque index and attachment loss, and were analysed within these groups. A genetic algorithm was used to create a model based on pattern analysis to predict sites undergoing attachment loss. RESULTS: Three hundred and eighty-five gingival crevicular fluid samples were analysed. Twenty-five sites under observation in 14 patients exhibited attachment loss of > 2 mm over the 12-mo period. The clinical indices pocket depth, MGI, plaque levels and bleeding on probing served as poor discriminators of gingival crevicular fluid mass spectra. Models generated from the gingival crevicular fluid mass spectra could predict attachment loss at a site with a high specificity (97% recognition capability and 67% cross-validation). CONCLUSIONS: Gingival crevicular fluid mass spectra could be used to predict sites with attachment loss. The use of algorithm-generated models based on gingival crevicular fluid mass spectra may provide utility in the diagnosis of periodontal disease.

Preservation of crestal bone by implant design. A comparative study in minipigs.

OBJECTIVES: To compare crestal bone modeling at three bone level design implants; Astra Tech Osseospeed(™) Implant (AOI), Straumann(®) Bone Level Implant (SBLI) and NobelReplace(™) Tapered Groovy Implant (NBTI). MATERIALS AND METHODS: In 12 minipigs one implant of each design was placed on each side of the mandible with submerged healing. The implant platform was placed at the level of the crest (Group 0), and 1 mm above the crest (Group + 1 mm). In addition, one Straumann(®) Tissue Level Implant STLI was placed as a control on each side of the mandible. At 4 weeks, six animals were sacrificed. In the remaining six animals healing abutments were connected until 12 weeks. Clinical, radiographic, and histologic analyses were made. ANOVA and Mann-Whitney U-tests were used to evaluate differences in bone levels between implant designs. RESULTS: At 4 weeks there was no statistically significant difference in bone changes between implant designs. At 12 weeks implants in Group + 1 mm had minimal bone changes with no differences between implant designs. In Group 0, the AOI and SBLI preserved more crestal bone than NBTI (P < 0.01). Mean distance from the implant platform to the buccal bone was -0.1 ± 0.2 mm for AOI, -0.3 ± 0.3 mm for SBLI, and -1.0 ± 0.3 mm for NBTI. Mean radiographic bone levels from the implant platform were -0.1 ± 0.4 mm for AOI, 0.0 ± 0.3 mm for SBLI and -0.9 ± 0.8 mm for NBTI. CONCLUSION: Greater bone preservation was observed for the AOI and SBLI compared with the NBTI.

Evidence for a smooth onset of deformation in the neutron-rich Kr isotopes.

The neutron-rich nuclei 94,96Kr were studied via projectile Coulomb excitation at the REX-ISOLDE facility at CERN. Level energies of the first excited 2(+) states and their absolute E2 transition strengths to the ground state are determined and discussed in the context of the E(2(1)(+)) and B(E2;2(1)(+)→0(1)(+)) systematics of the krypton chain. Contrary to previously published results no sudden onset of deformation is observed. This experimental result is supported by a new proton-neutron interacting boson model calculation based on the constrained Hartree-Fock-Bogoliubov approach using the microscopic Gogny-D1M energy density functional.

Nuclear isomers in superheavy elements as stepping stones towards the island of stability.

A long-standing prediction of nuclear models is the emergence of a region of long-lived, or even stable, superheavy elements beyond the actinides. These nuclei owe their enhanced stability to closed shells in the structure of both protons and neutrons. However, theoretical approaches to date do not yield consistent predictions of the precise limits of the 'island of stability'; experimental studies are therefore crucial. The bulk of experimental effort so far has been focused on the direct creation of superheavy elements in heavy ion fusion reactions, leading to the production of elements up to proton number Z = 118 (refs 4, 5). Recently, it has become possible to make detailed spectroscopic studies of nuclei beyond fermium (Z = 100), with the aim of understanding the underlying single-particle structure of superheavy elements. Here we report such a study of the nobelium isotope 254No, with 102 protons and 152 neutrons--the heaviest nucleus studied in this manner to date. We find three excited structures, two of which are isomeric (metastable). One of these structures is firmly assigned to a two-proton excitation. These states are highly significant as their location is sensitive to single-particle levels above the gap in shell energies predicted at Z = 114, and thus provide a microscopic benchmark for nuclear models of the superheavy elements.

Left-to-right distribution of periodontal disease.

AIM: Symmetry is a property established in many human biological systems and it is reasonable to expect that it may also exist in the mouth. The objective of this study was to examine whether there is a similar left-to-right distribution in periodontal disease. METHOD: Records of 197 patients from the Periodontics department of The Royal Dental Hospital of Melbourne were analysed. The clinical parameters recorded were pocket probing depth, recession, bleeding on probing, mobility and furcation involvement. RESULTS: The average age of our sample group was 47.5 years old, with 34.5% men and 65.5% women. The results demonstrated significant left-to-right distribution with all the periodontal indices recorded. CONCLUSION: The findings support previous studies that show that a similar left-to-right distribution exists in the population studied.

Microbiome profiles of non-responding and responding paired periodontitis sites within the same participants following non-surgical treatment.

Aim: Periodontitis is a site-specific, chronic disease treated by non-surgical debridement of subgingival plaque. We aimed to determine the microbiome of sites that did not respond to this treatment (NR) compared with paired good responding (GR) sites before and after treatment. Materials and methods: In a longitudinal cohort study, clinical parameters of disease and biological samples were taken prior to and 3 months after treatment. Twelve NR sites from six participants were paired with GR sites within the same participant. Subgingival plaque samples were subjected to bacterial community analysis using 16S rRNA gene sequencing. Results: There were no significant differences in clinical parameters and microbial communities at baseline between GR and NR sites. Bacterial communities in deep pockets were dominated by a small number of species, notably Porphyromonas gingivalis and Treponema denticola. In NR sites three months after treatment there was no significant change in bacterial composition whilst there was a collapse in the abundance of pathobionts in GR sites. Conclusion: NR sites were not identifiable prior to treatment by clinical or microbiological parameters. Treatment failed to disrupt pathogenic bacterial community in NR sites. Targeted suppression of particular species should be considered to initiate community collapse and aid disease resolution.

Early onset of ground state deformation in neutron deficient polonium isotopes.

In-source resonant ionization laser spectroscopy of the even-A polonium isotopes (192-210,216,218)Po has been performed using the 6p(3)7s (5)S(2) to 6p(3)7p (5)P(2) (λ=843.38 nm) transition in the polonium atom (Po-I) at the CERN ISOLDE facility. The comparison of the measured isotope shifts in (200-210)Po with a previous data set allows us to test for the first time recent large-scale atomic calculations that are essential to extract the changes in the mean-square charge radius of the atomic nucleus. When going to lighter masses, a surprisingly large and early departure from sphericity is observed, which is only partly reproduced by beyond mean field calculations.

Pattern of cigarette smoking effect on periodontal pocketing and attachment loss: a retrospective study.

AIM: The aim of the present retrospective study was to evaluate the local effects of smoking on periodontium and to assess the patterns of periodontitis (pocket depths and attachment loss) in smokers and non-smokers. METHODS: In this study, records of 126 non-smokers and 51 smokers (≥ 5 cigarettes/day) periodontitis patients were evaluated and probing pocket depth (PPD), clinical attachment level (CAL) and bleeding on probing (BOP) data were collected from clinical patients records. Patients' data were subject to two sample t-tests to assess the difference between the groups and to analysis of variance using the generalized linear model to seek associations between smoking and site positions, age and clinical parameters. RESULTS: The difference between CAL of smokers and non-smokers was greatest at the anterior maxillary palatal sites (P = 0.002) and reached 1 mm. When the effect of different site positions as well as smoking as a between subject variable and age as a co-variate on the attachment level measurements were assessed using analysis of variance, significant effects for smoking, jaw (lower versus upper) and anterior-posterior position as well as age were detected. No significant interactions were found between smoking and any of the three position variables. CONCLUSION: Lack of interaction between smoking and any of the three position variables indicates that the destructive effects of smoking on the periodontal tissues maybe mainly from systemic side-effects and almost independent of the site position within the mouth, although some additional local effects may be present in areas such as anterior palatal sites.

Dentists' preferences in implant maintenance and hygiene instruction.

BACKGROUND: This study investigated the preferences of dentists in Australia in providing professional implant maintenance and implant-specific oral hygiene instructions (OHI). METHODS: General dentists were surveyed online about their preferences in peri-implant diagnostics, maintenance provision, armamentarium used, and implant OHI techniques and frequency. RESULTS: Most of the 303 respondents (96%) provided maintenance services; 87.6% reviewed implants regularly while 10.7% only performed diagnostics after detecting clinical signs/symptoms. Supragingival prosthesis cleaning was performed by 77.9% of respondents, 35.0% performed subgingival debridement, 41.9% treated peri-implant mucositis and 18.2% treated peri-implantitis. About 15% did not treat nor refer peri-implant disease, including significantly more non-implant providers and dentists without implant training. Maintenance armamentarium commonly included floss (76.3%), prophylaxis (73.9%), plastic curettes (43.3%) and stainless-steel ultrasonics (38.0%). Brushing (86.5%), flossing (73.9%) and interdental brush use (68.3%) were most commonly recommended. Implant OHI was repeated routinely by 57.4% of dentists who provided it. Dentists with greater implant training and experience were more likely to perform reviews and complex maintenance procedures. CONCLUSIONS: Peri-implant diagnostics performed, treatments provided and armamentarium varied among dentists. Implant providers and those with higher levels of training had more preventative approaches to implant OHI. Possible shortcomings in disease management and OHI reinforcement were identified.

Unimapper: An Online Interactive Analyzer/Visualizer of Optical Mapping Experimental Data.

Time series of spatially-extended two-dimensional recordings are the cornerstone of basic and clinical cardiac electrophysiology. The data source may be either multipolar catheters, multi-electrode arrays, optical mapping with the help of voltage and calcium-sensitive fluorescent dyes, or the output of simulation studies. The resulting data cubes (usually two spatial and one temporal dimension) are shared either as movie files or, after additional processing, various graphs and tables. However, such data products can only convey a limited view of the data. It will be beneficial if the data consumers can interactively process the data, explore different processing options and change its visualization. This paper presents the Unified Electrophysiology Mapping Framework (Unimapper) to facilitate the exchange of electrophysiology data. Its pedigree includes a Java-based optical mapping application. The core of Unimapper is a website and a collection of JavaScript utility functions for data import and visualization (including multi-channel visualization for simultaneous voltage/calcium mapping), basic image processing (e.g., smoothing), basic signal processing (e.g., signal detrending), and advanced processing (e.g., phase calculation using the Hilbert transform). Additionally, Unimapper can optionally use graphics processing units (GPUs) for computationally intensive operations. The Unimapper ecosystem also includes utility libraries for commonly used scientific programming languages (MATLAB, Python, and Julia) that allow the data producers to convert images and recorded signals into a standard format readable by Unimapper. Unimapper can act as a nexus to share electrophysiology data - whether recorded experimentally, clinically or generated by simulation - and enhance communication and collaboration among researchers.

Orbital dependent nucleonic pairing in the lightest known isotopes of tin.

By studying the (109)Xe→(105)Te→(101)Sn superallowed α-decay chain, we observe low-lying states in (101)Sn, the one-neutron system outside doubly magic (100)Sn. We find that the spins of the ground state (J=7/2) and first excited state (J=5/2) in (101)Sn are reversed with respect to the traditional level ordering postulated for (103)Sn and the heavier tin isotopes. Through simple arguments and state-of-the-art shell-model calculations we explain this unexpected switch in terms of a transition from the single-particle regime to the collective mode in which orbital-dependent pairing correlations dominate.

Examination of 'lipotoxicity' in skeletal muscle of high-fat fed and ob/ob mice.

Excess lipid accumulation resulting from an elevated supply of plasma fatty acids is linked to the pathogenesis of the metabolic syndrome and heart disease. The term 'lipotoxicity' was coined to describe how lipid accumulation leads to cellular dysfunction and death in non-adipose tissues including the heart, pancreas and liver. While lipotoxicity has been shown in cultured skeletal muscle cells, the degree of lipotoxicity in vivo and the functional consequences are unresolved. We studied three models of fatty acid overload in male mice: 5 h Intralipid((R)) and heparin infusion, prolonged high fat feeding (HFF) and genetic obesity induced by leptin deficiency (ob/ob mice). Markers of apoptosis, proteolysis and autophagy were assessed as readouts of lipotoxicity. The Intralipid((R)) infusion increased caspase 3 activity in skeletal muscle, demonstrating that enhancing fatty acid flux activates pro-apoptotic pathways. HFF and genetic obesity increased tissue lipid content but did not influence apoptosis. Gene array analysis revealed that HFF reduced the expression of 31 pro-apoptotic genes. Markers of autophagy (LC3beta and beclin-1 expression) were unaffected by HFF and were associated with enhanced Bcl(2) protein expression. Proteolytic activity was similarly unaffected by HFF or in ob/ob mice. Thus, contrary to our previous findings in muscle culture in vitro and in other non-adipose tissues in vivo, lipid overload did not induce apoptosis, autophagy or proteolysis in skeletal muscle. A broad transcriptional suppression of pro-apoptotic proteins may explain this resistance to lipid-induced cell death in skeletal muscle.

Progression of chronic periodontitis can be predicted by the levels of Porphyromonas gingivalis and Treponema denticola in subgingival plaque.

INTRODUCTION: Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth associated with bacteria. Diagnosis is achieved retrospectively by clinical observation of attachment loss. Predicting disease progression would allow for targeted preventive therapy. The aim of this study was to monitor disease progression in patients on a maintenance program and determine the levels of specific bacteria in subgingival plaque samples and then examine the ability of the clinical parameters of disease and levels of specific bacteria in the plaque samples to predict disease progression. METHODS: During a 12-month longitudinal study of 41 subjects, 25 sites in 21 subjects experienced disease progression indicated by at least 2 mm of clinical attachment loss. Real-time polymerase chain reaction was used to determine the levels of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in subgingival plaque samples. RESULTS: No clinical parameters were able to predict periodontal disease progression. In sites undergoing imminent periodontal disease progression within the next 3 months, significant partial correlations were found between P. gingivalis and T. forsythia (r = 0.55, P < 0.001) and T. denticola and T. forsythia (r = 0.43, P = 0.04). The odds of a site undergoing imminent periodontal disease progression increased with increasing levels of P. gingivalis and T. denticola. CONCLUSION: Monitoring the proportions of P. gingivalis and T. denticola in subgingival plaque has the potential to help identify sites at significant risk for progression of periodontitis, which would assist in the targeted treatment of disease.

Implant education patterns and clinical practice of general dentists in Australia.

BACKGROUND: This study aimed to understand trends in dentists' implant training attendance and correlation to treatment provision. Implant-specific oral hygiene instruction coverage in training programs was investigated. METHODS: A cross-sectional web-survey of dentists registered in Australia was conducted. Respondents were asked about their background, implant training history and treatment provision. Results were analysed by implant provision characteristics and graduation decade. RESULTS: Three hundred and three responses from general dental practitioners (GDPs) were received and analysed. The highest implant training levels attained post-graduation were postgraduate non-specialist qualification (7.9% of respondents), continuing professional development (CPD) (73.6%) versus none (18.5%), with differences between implant providers and non-providers (P < 0.001), different graduation decades (P < 0.001) and those restoring implants or performing surgery as well (P < 0.001). University-based CPD was attended less than dental association/society or implant company CPD. Non-providers were significantly less likely to recall implant oral hygiene instruction sources (P < 0.001). Most GDPs (74.9%) provided implant services, with younger GDPs beginning earlier after graduation. About 16% of respondents did not provide implants once established career-wise. CONCLUSIONS: Dentists might be providing implant treatments increasingly earlier in their careers. Respondents with more training were significantly more likely to perform more complex procedures, while implant training attendance trends varied by graduation decade.