Approximal plaque pH lowering after sugar intake in a periodontally infected dentition.

OBJECTIVES: The aim of this study was to evaluate the effect of periodontal inflammation on the approximal plaque pH after a sucrose rinse. MATERIALS AND METHODS: Thirty-two periodontitis patients (aged 38-72 years; 9M/23F) were included. All patients were in need of periodontal surgery. Two non-adjacent interdental spaces, one healthy (no bleeding on probing [BoP] and probing pocket depth [PPD] < 4 mm) and one periodontally diseased (BoP and PPD ≥5 mm) were selected. Before and after surgery, the approximal plaque pH was measured before and after 2, 5 and 10 min after a 1-min rinse with sucrose solution. RESULTS: In periodontally diseased interdental spaces, a significant pH drop was seen 5 min after rinsing. In healthy spaces and after surgery, a significant pH drop was seen after 2 min. A multilevel regression analysis showed that greater probing pocket depths were significantly associated with pH change measured 5 min after rinsing (p < .05). Further on, the approximal pH drop after a sucrose rinse tended to be delayed in dentitions with ≥10% of PPD ≥5 mm (p = .052). CONCLUSIONS: The results suggest that an ongoing periodontal inflammation could temporarily neutralize acidic metabolic products after a sugar challenge. This may further suggest that plaque pH measured after a sugar rinse might be used to identify an ongoing periodontal disease.

The mechanism of Hsp90-induced oligomerizaton of Tau.

Aggregation of the microtubule-associated protein Tau is a hallmark of Alzheimer's disease with Tau oligomers suspected as the most toxic agent. Tau is a client of the molecular chaperone Hsp90, although it is unclear whether and how the chaperone massages the structure of intrinsically disordered Tau. Using electron paramagnetic resonance, we extract structural information from the very broad conformational ensemble of Tau: Tau in solution is highly dynamic and polymorphic, although "paper clip"-shaped by long-range contacts. Interaction with Hsp90 promotes an open Tau conformation, which we identify as the molecular basis for the formation of small Tau oligomers by exposure of the aggregation-prone repeat domain to other Tau molecules. At the same time, formation of Tau fibrils is inhibited. We therefore provide the nanometer-scale zoom into chaperoning an amyloid client, highlighting formation of oligomers as the consequence of this biologically relevant interaction.

Screening for infectious diseases among asylum seekers newly arrived in Germany in 2015: a systematic single-centre analysis.

OBJECTIVES: During the migrant crisis in 2015, Germany was the largest single recipient of new asylum seekers in Europe. The German asylum law requires a screening examination for certain infectious diseases in asylum seekers upon arrival. The aim of this work was to analyse the rate of certain infectious diseases among asylum seekers screened at a reception centre in Southern Germany. STUDY DESIGN: Retrospective medical record review. METHODS: Medical records of 2602 asylum seekers screened by a local public health authority in Germany in 2015 were systematically analysed. RESULTS: The majority of screened subjects came from Afghanistan and Syria. The mean age was 22.1 (±12.0) years. The majority of subjects were male (75.4%). Most individuals were of normal weight or overweight, more subjects were obese than underweight. A total of 78 (3.9%) individuals were infected with hepatitis B and eight (0.4%) with HIV. In 31 cases, chest radiographs suggested active tuberculosis (1.6%), which was confirmed in four cases (0.2%). The physical examination uncovered 44 (1.7%) cases of scabies, nine (0.3%) cases of lice, eight (0.3%) of upper respiratory tract infections, two (0.1%) of varicella and 13 (0.5%) of other skin infections. CONCLUSIONS: In the majority of subjects none of the screened infectious diseases were found. No evidence was found that the overall prevalence of certain infectious diseases screened for in the present analysis was considerably higher than in previous migration studies.

Dynamics of Fukuoka Criteria and Patient Management in Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMNs) During Follow-Up.

BACKGROUND Pancreatic intraductal papillary mucinous neoplasms (IPMNs) present a clinical challenge. Evidence-based guidelines are lacking. The so-called "Fukuoka criteria" were developed to assess the risk of malignancy in IPMNs upon imaging. However, little is known about their diagnostic value and the natural course of IPMNs. Thus, the aim of this study was the assessment of Fukuoka criteria and patient management in pancreatic IPMNs -during follow-up. MATERIAL AND METHODS IPMNs were identified via retrospective survey of endoscopic ultrasound (EUS) examinations. Fukuoka criteria were assessed on EUS findings and additional imaging (CT, MRI, ultrasound). Patients' symptoms and comorbidities were recorded. Dynamics of Fukuoka criteria and patient management were compared at first presentation and during follow-up. RESULTS We screened 1324 EUS examinations. Sixty-five patients (male/female, 14/37; mean age, 68.8 years; range, 48-85 years) with IPMNs were identified (57 branch duct (BD-)IPMNs, 3 main duct (MD-) IPMNs, 5 mixed-type (MT)-IPMNs). Seven patients received surgical resection (4 BD-IPMNs, 2 MD-IPMNs, 1 MT-IPMN). Nine BD-IPMNs had neither surgery nor follow-up. Fifty-one patients (44 BD-IPMNs, 2 MD-IPMNs, 5 MT-IPMNs) underwent follow-up (mean duration, 18.7 months; range, 3-139 months). There were 15/51 patients who were initially Fukuoka-positive. One MD-IPMN, 4/5 MT-IPMNs, and 13/44 BD-IPMNs showed progressive changes but were not resected due to patients' refusal or comorbidities. Four BD-IPMNs converted to Fukuoka-positive. CONCLUSIONS Evidence-based guidelines for non-invasive dignity assessment of IPMNs are lacking. In our study, MD-IPMNs displayed greater dynamics than BD-IPMNs and MT-IPMNs concerning Fukuoka criteria. Prospective long-term studies are needed to clarify prognostic significance of the single Fukuoka criteria and sensible duration of follow-up.

Population equations for degree-heterogenous neural networks.

We develop a statistical framework for studying recurrent networks with broad distributions of the number of synaptic links per neuron. We treat each group of neurons with equal input degree as one population and derive a system of equations determining the population-averaged firing rates. The derivation rests on an assumption of a large number of neurons and, additionally, an assumption of a large number of synapses per neuron. For the case of binary neurons, analytical solutions can be constructed, which correspond to steps in the activity versus degree space. We apply this theory to networks with degree-correlated topology and show that complex, multi-stable regimes can result for increasing correlations. Our work is motivated by the recent finding of subnetworks of highly active neurons and the fact that these neurons tend to be connected to each other with higher probability.

Calcium waves in a grid of clustered channels with synchronous IP3 binding and unbinding.

Calcium signals in cells occur at multiple spatial scales and variable temporal duration. However, a physical explanation for transitions between long-lasting global oscillations and localized short-term elevations (puffs) of cytoplasmic Ca2+ is still lacking. Here we introduce a phenomenological, coarse-grained model for the calcium variable, which is represented by ordinary differential equations. Due to its small number of parameters, and its simplicity, this model allows us to numerically study the interplay of multi-scale calcium concentrations with stochastic ion channel gating dynamics even in larger systems. We apply this model to a single cluster of inositol trisphosphate (IP 3) receptor channels and find further evidence for the results presented in earlier work: a single cluster may be capable of producing different calcium release types, where long-lasting events are accompanied by unbinding of IP 3 from the receptor (Rückl et al., PLoS Comput. Biol. 11, e1003965 (2015)). Finally, we show the practicability of the model in a grid of 64 clusters which is computationally intractable with previous high-resolution models. Here long-lasting events can lead to synchronized oscillations and waves, while short events stay localized. The frequency of calcium releases as well as their coherence can thereby be regulated by the amplitude of IP 3 stimulation. Finally the model allows for a new explanation of oscillating [IP 3], which is not based on metabolic production and degradation of IP 3.

Effect of periconceptional nutrition on the growth, behaviour and survival of the neonatal lamb.

Periconceptional nutrition (PCN) can influence foetal hypothalamo-pituitary adrenal (HPA) axis function and alter cortisol secretion with possible consequences for maturation and growth of major organs, gestation length and behaviour. We examined effects of PCN on phenotype and survival of the neonatal lamb in 466 Merino ewes allocated to treatments providing 70%, 100% and 150% respectively, of maintenance requirements for 17 days prior and 6 days after insemination. Gestation length and birth weight for lambs in PCN treatment groups was similar (P > 0.05) but low PCN decreased the size of the neonate (crown-rump-length and metacarpal length P < 0.05). A subset of lambs euthanased at 5 days of age further showed that low PCN decreased the amount of peri-renal fat (P < 0.05) and increased liver mass (P < 0.05) while high PCN increased neck thymus and ovary mass (P < 0.05). Neonatal lambs from low PCN ewes returned faster to their mothers after release (P < 0.05) and contacted the udder in the shortest time (P < 0.05). Significant interactions between PCN treatment and sex (P < 0.05) and between PCN treatment and ewe age (P < 0.05) were also observed for time lambs took to follow the ewe. Survival of lambs was similar but potential differences may have been masked by favourable weather conditions. In conclusion, this study provides evidence of significant changes in lamb growth and development dependent on PCN and, for the first time, links these changes with significant changes in behaviour of the neonate. The impact of these effects on lamb survival and potential reproductive capacity of female offspring remains to be determined.

Impact of acoustic radiation force impulse imaging in clinical practice of patients after orthotopic liver transplantation.

BACKGROUND: Acoustic radiation force impulse (ARFI) elastography is a reliable diagnostic device for quantitative non-invasive assessment of liver fibrosis in patients with chronic liver disease. The aim of our prospective study was to evaluate the impact of ARFI in patients after orthotopic liver transplantation (OLT). Therefore, we compared ARFI shear wave velocities with clinical features, non-invasive markers, and the histology of patients following OLT. MATERIAL AND METHODS: Post-transplant patients underwent a clinical examination and blood samples were taken. B-mode and Doppler ultrasound (US) of the portal vein and the hepatic artery were performed. Subsequently, a minimum of 10 valid ARFI values were measured in the left and right liver lobe. Liver biopsy was performed if indicated. RESULTS: Between May 2012 and May 2014, 58 Patients after OLT were included in the prospective study. Laboratory markers and aspartate aminotransferase-to-platelet ratio index (APRI) correlated with ARFI values (r=0.44, p<0.001). The histological (n=22) fibrosis score (Ludwig) was significantly correlated with the ARFI of the biopsy site (r=0.55, p=0.008). The mean shear-wave velocities were significantly increased in advanced fibrosis (F≤2 1.57±0.57 m/s; F≥3 2.85±0.66 m/s; p<0.001), obstructive cholestasis and active viral hepatitis. The area under the receiver operating characteristic (AUROC) curves for the accuracy of ARFI were 74% (F≥1), 73% (F≥2), 93% (F≥3), and 80% (=F4). CONCLUSIONS: ARFI elastography correlates well with laboratory values and with noninvasive and invasive markers of fibrosis in patients after OLT. In this regard, elevated ARFI-velocities should be interpreted with caution in the context of obstructive cholestasis and active viral disease.

Excitability in a stochastic differential equation model for calcium puffs.

Calcium dynamics are essential to a multitude of cellular processes. For many cell types, localized discharges of calcium through small clusters of intracellular channels are building blocks for all spatially extended calcium signals. Because of the large noise amplitude, the validity of noise-approximating model equations for this system has been questioned. Here we revisit the master equations for local calcium release, examine the multiple scales of calcium concentrations in the cluster domain, and derive adapted stochastic differential equations. We show by comparison of discrete and continuous trajectories that the Langevin equations can be made consistent with the master equations even for very small channel numbers. In its deterministic limit, the model reveals that excitability, a dynamical phenomenon observed in many natural systems, is at the core of calcium puffs. The model also predicts a bifurcation from transient to sustained release which may link local and global calcium signals in cells.

Percolation of spatially constrained Erdos-Rényi networks with degree correlations.

Motivated by experiments on activity in neuronal cultures [ J. Soriano, M. Rodríguez Martínez, T. Tlusty and E. Moses Proc. Natl. Acad. Sci. 105 13758 (2008)], we investigate the percolation transition and critical exponents of spatially embedded Erdos-Rényi networks with degree correlations. In our model networks, nodes are randomly distributed in a two-dimensional spatial domain, and the connection probability depends on Euclidian link length by a power law as well as on the degrees of linked nodes. Generally, spatial constraints lead to higher percolation thresholds in the sense that more links are needed to achieve global connectivity. However, degree correlations favor or do not favor percolation depending on the connectivity rules. We employ two construction methods to introduce degree correlations. In the first one, nodes stay homogeneously distributed and are connected via a distance- and degree-dependent probability. We observe that assortativity in the resulting network leads to a decrease of the percolation threshold. In the second construction methods, nodes are first spatially segregated depending on their degree and afterwards connected with a distance-dependent probability. In this segregated model, we find a threshold increase that accompanies the rising assortativity. Additionally, when the network is constructed in a disassortative way, we observe that this property has little effect on the percolation transition.

Pulse transit time and blood pressure during cardiopulmonary exercise tests.

Pulse transit time (PTT), the interval between ventricular electrical activity and peripheral pulse wave, is assumed to be a surrogate marker for blood pressure (BP) changes. The objective of this study was to analyze PTT and its relation to BP during cardiopulmonary exercise tests (CPET). In 20 patients (mean age 51+/-18.4 years), ECG and finger-photoplethysmography were continuously recorded during routine CPETs. PTT was calculated for each R-wave in the ECG and the steepest slope of the corresponding upstroke in the plethysmogram. For each subject, linear and non-linear regression models were used to assess the relation between PTT and upper-arm oscillometric BP in 9 predefined measuring points including measurements at rest, during exercise and during recovery. Mean systolic BP (sBP) and PTT at rest were 128 mm Hg and 366 ms respectively, 197 mm Hg and 289 ms under maximum exercise, and 128 mm Hg and 371 ms during recovery. Linear regression showed a significant, strong negative correlation between PTT and sBP. The correlation between PTT and diastolic BP was rather weak. Bland-Altman plots of sBP values estimated by the regression functions revealed slightly better limits of agreements for the non-linear model (-10.9 to 10.9 mm Hg) than for the linear model (-13.2 to 13.1 mm Hg). These results indicate that PTT is a good potential surrogate measure for sBP during exercise and could easily be implemented in CPET as an additional parameter of cardiovascular reactivity. A non-linear approach might be more effective in estimating BP than linear regression.

Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity.

The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.

Law of mass action, detailed balance, and the modeling of calcium puffs.

Using deterministic-stochastic simulations we show that for intracellular calcium puffs the mixing assumption for reactants does not hold within clusters of receptor channels. Consequently, the law of mass action does not apply and useful definitions of averaged calcium concentrations in the cluster are not obvious. Effective reaction kinetics can be derived, however, by separating concentrations for self-coupling of channels and coupling to different channels, thus eliminating detailed balance in the reaction scheme. A minimal Markovian model can be inferred, describing well calcium puffs in neuronal cells and allowing insight into the functioning of calcium puffs.

Calcium domains around single and clustered IP3 receptors and their modulation by buffers.

We study Ca(2+) release through single and clustered IP(3) receptor channels on the ER membrane under presence of buffer proteins. Our computational scheme couples reaction-diffusion equations and a Markovian channel model and allows our investigating the effects of buffer proteins on local calcium concentrations and channel gating. We find transient and stationary elevations of calcium concentrations around active channels and show how they determine release amplitude. Transient calcium domains occur after closing of isolated channels and constitute an important part of the channel's feedback. They cause repeated openings (bursts) and mediate increased release due to Ca(2+) buffering by immobile proteins. Stationary domains occur during prolonged activity of clustered channels, where the spatial proximity of IP(3)Rs produces a distinct [Ca(2+)] scale (0.5-10 microM), which is smaller than channel pore concentrations (>100 microM) but larger than transient levels. While immobile buffer affects transient levels only, mobile buffers in general reduce both transient and stationary domains, giving rise to Ca(2+) evacuation and biphasic modulation of release amplitude. Our findings explain recent experiments in oocytes and provide a general framework for the understanding of calcium signals.

Puff-wave transition in an inhomogeneous model for calcium signals.

In many cell types, calcium ion channels on the endoplasmic reticulum membrane occur in a clustered distribution. The channels generate either localized puffs, each comprising channels of only one cluster, or global calcium waves. In this work we model the calcium system as a two-dimensional lattice of active elements distributed regularly in an otherwise passive space. We address an important feature of the puff-wave transition, which is the difference in lifetime of puffs at a few hundred milliseconds and long-lived global waves with periods of several seconds. We show that such a lifetime difference between puffs and waves can be understood with strongly reduced ordinary differential equations modified by a time-scale factor that takes into account the coupling strength of active and passive regions determined by the Ca2+ diffusion coefficient. Furthermore, we show that the point model can also describe very well the dependence of Ca2+ oscillation characteristics on the cluster-cluster distance in the case of large diffusivity.

An investigation of models of the IP3R channel in Xenopus oocyte.

We consider different models of inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) channels in order to fit nuclear membrane patch clamp data of the stationary open probability, mean open time, and mean close time of channels in the Xenopus oocyte. Our results indicate that rather than to treat the tetrameric IP(3)R as four independent and identical subunits, one should assume sequential binding-unbinding processes of Ca(2+) ions and IP(3) messengers. Our simulations also favor the assumption that a channel opens through a conformational transition from a close state to an active state.

Modeling of the modulation by buffers of Ca2+ release through clusters of IP3 receptors.

Intracellular Ca(2+) release is a versatile second messenger system. It is modeled here by reaction-diffusion equations for the free Ca(2+) and Ca(2+) buffers, with spatially discrete clusters of stochastic IP(3) receptor channels (IP(3)Rs) controlling the release of Ca(2+) from the endoplasmic reticulum. IP(3)Rs are activated by a small rise of the cytosolic Ca(2+) concentration and inhibited by large concentrations. Buffering of cytosolic Ca(2+) shapes global Ca(2+) transients. Here we use a model to investigate the effect of buffers with slow and fast reaction rates on single release spikes. We find that, depending on their diffusion coefficient, fast buffers can either decouple clusters or delay inhibition. Slow buffers have little effect on Ca(2+) release, but affect the time course of the signals from the fluorescent Ca(2+) indicator mainly by competing for Ca(2+). At low [IP(3)], fast buffers suppress fluorescence signals, slow buffers increase the contrast between bulk signals and signals at open clusters, and large concentrations of buffers, either fast or slow, decouple clusters.

Dynamics of excitable elements with time-delayed coupling.

Motivated by recent experiments on intracellular calcium release we study the effects of different types of coupling on the dynamics of arrays of excitable elements. We intend to find a mechanism that produces a sustained activity of the elements following a spike. While instantaneous diffusive coupling does not exhibit this property, we show that, for a coupling term with temporal delay, signals from adjacent elements can serve as mutual excitations and thus prolong the duration of the signal. We propose that time delayed coupling is generated by diffusion between isolated clusters of calcium channels. Our model could thus provide an explanation for two different release modes observed in the Ca2+ system.