bluuebunny/crossref_metadata_2025 huggingface dataset:
An Open-Label Exploratory Study with Memantine: Correlation between Proton Magnetic Resonance Spectroscopy and Cognition in Patients with Mild to Moderate Alzheimer’s Disease
Authors: Gordon Marc L. , Kingsley Peter B. , Goldberg Terry E. , Koppel Jeremy , Christen Erica , Keehlisen Lynda , Kohn Nina , Davies Peter
Published: August 2012

Aim: To characterize progression of Alzheimer’s disease (AD) using proton magnetic resonance spectroscopy (1H MRS). Methods: Eleven subjects with mild to moderate AD underwent neurocognitive testing and single-voxel 1H MRS from the precuneus and posterior cingulate region at baseline, after 24 weeks of monotherapy with a cholinesterase inhibitor, and after another 24 weeks of combination therapy with open-label memantine and a cholinesterase inhibitor. Baseline metabolites [N-acetylaspartate (NAA), myo-inositol (mI), choline (Cho), and creatine (Cr)] and their ratios in AD subjects were compared with those of an age-matched control group of 28 cognitively normal subjects. Results: AD subjects had significantly higher mI/Cr and lower NAA, NAA/Cr, NAA/Cho, and NAA/mI. Baseline Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores significantly correlated with NAA/Cr, mI/Cr, and NAA/mI. There was an increase in mI and a decrease in NAA/mI, but no significant change in other metabolites or ratios, or neurocognitive measures, when memantine was added to a cholinesterase inhibitor. Conclusion: Metabolite ratios significantly differed between AD and control subjects. Baseline metabolite ratios correlated with function (ADCS-ADL). There was an increase in mI and a decrease in NAA/mI, but no changes in other metabolites, ratios, or cognitive measures, when memantine was added to a cholinesterase inhibitor.
Matrix Metalloproteinase Inhibitor COL-3 Prevents the Development of Paclitaxel-Induced Hyperalgesia in Mice
Authors: Parvathy Subramanian S. , Masocha Willias
Published: August 2012

Objective: To study the potential of chemically modified tetracycline-3 (COL-3), a potent matrix metalloproteinase (MMP) inhibitor, to protect against the development of paclitaxel-induced painful neuropathy and its immunomodulatory effects. Materials and Methods: The reaction latency to thermal stimuli (hot plate test) of female BALB/c mice was recorded before and after treatment with paclitaxel (2 mg/kg i.p.), paclitaxel plus COL-3 (4, 20 or 40 mg/kg p.o.) or their vehicles for 5 consecutive days. Gene transcripts of CD11b (marker for microglia), 5 cytokines (IFN-γ, IL-1β, IL-6, IL-10 and TNF-α) and 3 chemokines (CCL2, CXCL10 and CX3CL1) were quantified by real-time PCR in the brains, spinal cords and spleens of mice sacrificed on day 7 after treatment. Results: Treatment with paclitaxel reduced the reaction latency time to thermal stimuli (thermal hyperalgesia) for 4 weeks, with maximum effect on days 7 and 10. The coadministration of paclitaxel with COL-3 40 mg/kg, but not lower doses, prevented the development of paclitaxel-induced thermal hyperalgesia. Treatment with paclitaxel alone or coadministration with COL-3 increased CD11b transcript levels in the brain but not in the spinal cord. Treatment with paclitaxel reduced IL-6 transcript levels in the spinal cord but did not alter the transcript levels of other cytokines or chemokines in the brain, spinal cord or spleen. The coadministration of COL-3 with paclitaxel significantly increased the transcript levels of IL-6 in the spleen and decreased CX3CL1 transcripts in the brain in comparison to treatment with paclitaxel alone. Conclusion: Our results indicate that the MMP inhibitor COL-3 protected against paclitaxel-induced thermal hyperalgesia and, thus, could be useful in the prevention of chemotherapy-induced painful neuropathy.
Synthetic Biology and Personalized Medicine
Authors: Jain K.K.
Published: August 2012

Synthetic biology, application of synthetic chemistry to biology, is a broad term that covers the engineering of biological systems with structures and functions not found in nature to process information, manipulate chemicals, produce energy, maintain cell environment and enhance human health. Synthetic biology devices contribute not only to improve our understanding of disease mechanisms, but also provide novel diagnostic tools. Methods based on synthetic biology enable the design of novel strategies for the treatment of cancer, immune diseases metabolic disorders and infectious diseases as well as the production of cheap drugs. The potential of synthetic genome, using an expanded genetic code that is designed for specific drug synthesis as well as delivery and activation of the drug in vivo by a pathological signal, was already pointed out during a lecture delivered at Kuwait University in 2005. Of two approaches to synthetic biology, top-down and bottom-up, the latter is more relevant to the development of personalized medicines as it provides more flexibility in constructing a partially synthetic cell from basic building blocks for a desired task.
Sirtuins and Pyridine Nucleotides
Authors: Abdellatif Maha
Published: August 2012

The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to its prominent role in metabolic homeostasis in mammals. The Sir1–4 proteins were first discovered in yeast as nicotinamide adenine dinucleotide (NAD
+
)-dependent deacetylases, which through a gene silencing effect promoted longevity. The subsequent discovery of a homologous sirtuin (Sirt) family of proteins in the mammalian systems soon led to the realization that these molecules have beneficial effects in metabolism- and aging-related diseases. Through their concerted functions in the central nervous system, liver, pancreas, skeletal muscle, and adipose tissue, they regulate the body's metabolism. Sirt1, -6, and -7 exert their functions, predominantly, through a direct effect on nuclear transcription of genes involved in metabolism, whereas Sirt3–5 reside in the mitochondrial matrix and regulate various enzymes involved in the tricarboxylic acid and urea cycles, oxidative phosphorylation, as well as reactive oxygen species production. An interesting aspect of the functionality of sirtuin involves their regulation by the circadian rhythm, which affects their function via cyclically regulating systemic NAD
+
availability, further establishing the link of these proteins to metabolism. In this review, we will discuss the relation of sirtuins to NAD
+
metabolism, their mechanism of function, and their role in metabolism and mitochondrial functions. In addition, we will describe their effects in the cardiovascular and central nervous systems.
Overview of
Pyridine Nucleotides
Review Series
Authors: Nakamura Michinari , Bhatnagar Aruni , Sadoshima Junichi
Published: August 2012

Pyridine nucleotides are abundant soluble coenzymes and they undergo reversible oxidation and reduction in several biological electron-transfer reactions. They are comprised of two mononucleotides, adenosine monophosphate and nicotinamide mononucleotide, and are present as oxidized and reduced nicotinamide adenine dinucleotides in their unphosphorylated (NAD
+
and NADH) and phosphorylated (NADP
+
and NADPH) forms. In the past, pyridine nucleotides were considered to be primarily electron-shuttling agents involved in supporting the activity of enzymes that catalyze oxidation-reduction reactions. However, it has recently been demonstrated that pyridine nucleotides and the balance between the oxidized and reduced forms play a wide variety of pivotal roles in cellular functions as important interfaces, beyond their coenzymatic activity. These include maintenance of redox status, cell survival and death, ion channel regulation, and cell signaling under normal and pathological conditions. Furthermore, targeting pyridine nucleotides could potentially provide therapeutically useful avenues for treating cardiovascular diseases. This review series will highlight the functional significance of pyridine nucleotides and underscore their physiological role in cardiovascular function and their clinical relevance to cardiovascular medicine.
Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults
Authors: Breton Carrie V. , Wang Xinhui , Mack Wendy J. , Berhane Kiros , Lopez Milena , Islam Talat S. , Feng Mei , Lurmann Fred , McConnell Rob , Hodis Howard N. , Künzli Nino , Avol Ed
Published: August 2012

Background—

Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.

Methods and Results—

The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007 to 2009. Participants attended 1 study visit during which blood pressure, heart rate, and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and sociodemographic characteristics, and a 12-hour fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency's Air Quality System database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (±54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12 years) O
3
exposure was associated with a 7.8-μm (95% confidence interval, −0.3–15.9) or 10.1-μm (95% confidence interval, 1.8–18.5) higher CIMT, respectively. Lifetime exposure to O
3
showed similar but nonsignificant associations. No associations were observed for PM
2.5
, PM
10
, or NO
2
, although adjustment for these pollutants strengthened the childhood O
3
associations.

Conclusions—

Childhood exposure to O
3
may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
Maximizing the Population Benefit From Thrombolysis in Acute Ischemic Stroke
Authors: Monks Thomas , Pitt Martin , Stein Ken , James Martin
Published: August 2012

Background and Purpose—

To maximize the benefits of thrombolysis, it is necessary not only to treat more patients, but to deliver treatment as early as possible. The aims of our study were to prospectively evaluate the clinical benefit from reducing delays in the emergency stroke pathway at our district hospital and examine outcomes from scenarios that include extension of the alteplase license.

Methods—

We developed a discrete-event simulation from prospective data for patients with stroke arriving at our large district hospital. We modeled current practice and assessed the impact on stroke outcomes of measures to reduce in-hospital delays to alteplase treatment and of extensions to the European license for alteplase from 3 to 4.5 hours and to people aged >80 years.

Results—

Extension of the time window to 4.5 hours increases the thrombolysis rate by 4%, yielding an additional 2 patients per year with minimal or no disability at 3 months. Time window extension is most effective when combined with a system of prealerts, achieving a thrombolysis rate of 15% and an additional 8 patients per year with minimal or no disability, increasing to 13 patients per year with extension of the license to patients >80 years.

Conclusions—

If implemented alone, extension of the time window for alteplase has only a modest additional population disability benefit, but this benefit can be increased 5-fold if time window extension is combined with substantial reductions to in-hospital delays.
Relationship Between Electrical Brain Responses to Motor Imagery and Motor Impairment in Stroke
Authors: Kaiser Vera , Daly Ian , Pichiorri Floriana , Mattia Donatella , Müller-Putz Gernot R. , Neuper Christa
Published: August 2012

Background and Purpose—

New strategies like motor imagery based brain–computer interfaces, which use brain signals such as event-related desynchronization (ERD) or event-related synchronization (ERS) for motor rehabilitation after a stroke, are undergoing investigation. However, little is known about the relationship between ERD and ERS patterns and the degree of stroke impairment. The aim of this work was to clarify this relationship.

Methods—

EEG during motor imagery and execution were measured in 29 patients with first-ever monolateral stroke causing any degree of motor deficit in the upper limb. The strength and laterality of the ERD or ERS patterns were correlated with the scores of the European Stroke Scale, the Medical Research Council, and the Modified Ashworth Scale.

Results—

Mean age of the patients was 58±15 years; mean time from the incident was 4±4 months. Stroke lesions were cortical (n=8), subcortical (n=11), or mixed (n=10), attributable to either an ischemic event (n=26) or a hemorrhage (n=3), affecting the right (n=16) or left (n=13) hemisphere. Higher impairment was related to stronger ERD in the unaffected hemisphere and higher spasticity was related to stronger ERD in the affected hemisphere. Both were related to a relatively stronger ERS in the affected hemisphere.

Conclusion—

The results of this study may have implications for the design of potential poststroke rehabilitation interventions based on brain–computer interface technologies that use neurophysiological signals like ERD or ERS as neural substrates for the mutual interaction between brain and machine and, ultimately, help stroke patients to regain motor control.
Characterization of the Thermal Structure inside an Urban Canyon: Field Measurements and Validation of a Simple Model
Authors: Giovannini Lorenzo , Zardi Dino , de Franceschi Massimiliano
Published: August 2012

The results of measurement campaigns are analyzed to investigate the thermal structure in an urban canyon and to validate a simplified model simulating the air and surface temperatures from surface energy budgets. Starting from measurements at roof-top level, the model provides time series of air and surface temperatures, as well as surface fluxes. Two campaigns were carried out in summer 2007 and in winter 2008/09 in a street of the city of Trento (Italy). Temperature sensors were placed at various levels near the walls flanking the canyon and on a traffic light in the street center. Furthermore, the atmosphere above the mean roof-top level was monitored by a weather station on top of a tower located nearby. Air temperatures near the walls, being strongly influenced by direct solar radiation, display considerable contrasts between the opposite sides of the canyon. On the other hand, when solar radiation is weak or absent, the temperature field remains mostly homogeneous. Moreover, air temperature inside the canyon is generally higher than above roof level, with larger differences during summertime. Air temperatures from the above street measurements are well simulated by the model in both seasons. Furthermore, the modeled surface temperatures are tested against a dataset of wall surface temperatures from the Advanced Tools for Rational Energy Use Towards Sustainability–Photocatalytic Innovative Coverings Applications for Depollution (ATREUS–PICADA) experiment, and a very good agreement is found. Results suggest that the model is a reliable and convenient tool for simplified assessment of climatic conditions occurring in urban canyons under various weather situations.
Energy Dispersion in African Easterly Waves
Authors: Diaz Michael , Aiyyer Anantha
Published: August 2012

The existence of an upstream (eastward) group velocity for African easterly waves (AEWs) is shown based on single-point lag regressions using gridded reanalysis data from 1990 to 2010. The eastward energy dispersion is consistent with the direction of ageostrophic geopotential flux vectors. A local eddy kinetic energy (EKE) budget reveals that, early in the life cycle of AEWs, growth rate due to geopotential flux convergence exceeds baroclinic and barotropic growth rates. Later in the life cycle, EKE decay due to geopotential flux divergence cancels or exceeds baroclinic and barotropic growth. A potential vorticity (PV) budget is used to diagnose tendencies related to group propagation. Although both upstream and downstream group speeds are possible because of the reversal in the mean meridional PV gradient, upstream propagation associated with the positive poleward PV gradient dominates wave packet evolution. Analogous to the concept of downstream development of midlatitude baroclinic waves, new AEWs develop preferentially upstream of the older ones, thus providing a mechanism for seeding new waves. It is suggested that these results are also relevant to AEW intermittency and storm-track structure.
A New Look at the Physics of Rossby Waves: A Mechanical–Coriolis Oscillation
Authors: Cai Ming , Huang Bohua
Published: August 2012

The presence of the latitudinal variation of the Coriolis parameter serves as a mechanical barrier that causes a mass convergence for the poleward geostrophic flow and divergence for the equatorward flow, just as a sloped bottom terrain does to a crossover flow. Part of the mass convergence causes pressure to rise along the uphill pathway, while the remaining part is detoured to cross isobars out of the pathway. This mechanically excited cross-isobar flow, being unbalanced geostrophically, is subject to a “half-cycle” Coriolis force that only turns it to the direction parallel to isobars without continuing to turn it farther back to its opposite direction because the geostrophic balance is reestablished once the flow becomes parallel to isobars. Such oscillation, involving a barrier-induced mass convergence, a mechanical deflection, and a half-cycle Coriolis deflection, is referred to as a mechanical–Coriolis oscillation with a “barrier-induced half-cycle Coriolis force” as its restoring force. Through a complete cycle of the mechanical–Coriolis oscillation, a new geostrophically balanced flow pattern emerges to the left of the existing flow when facing the uphill (downhill) direction of the barrier in the Northern (Southern) Hemisphere. The β barrier is always sloped toward the pole in both hemispheres, responsible for the westward propagation of Rossby waves. The β-induced mechanical–Coriolis oscillation frequency can be succinctly expressed as , where , and λ is the angle of a sloped surface along which the unbalanced flow crosses isobars, α is the angle of isobars with the barrier’s slope, and k is the wavenumber along the direction of the barrier’s contours.
Attribution of Decadal Variability in Tropical Cyclone Passage Frequency over the Western North Pacific: A New Approach Emphasizing the Genesis Location of Cyclones
Authors: Yokoi Satoru , Takayabu Yukari N.
Published: August 2012

Variability in tropical cyclone (TC) activity is a matter of direct concern for affected populations. On interannual and longer time scales, variability in TC passage frequency can be associated with total TC frequency over the concerned ocean basin [basinwide frequency (BF)], the spatial distribution of TC genesis in the basin [genesis distribution (GD)], and the preferable track (PT) that can be considered as a function of genesis locations. To facilitate investigation of mechanisms responsible for the variability, the authors propose an approach of decomposing anomalies in the passage frequency into contributions of variability in BF, GD, and PT, which is named the Integration of Statistics on TC Activity by Genesis Location (ISTAGL) analysis. Application of this approach to TC best track data in the western North Pacific (WNP) basin reveals that overall distribution of the passage frequency trends over the 1961–2010 period is mainly due to the PT trends. On decadal time scales, passage frequency variability in midlatitudes is primarily due to PT variability, while the BF and GD also play roles in the subtropics. The authors further discuss decadal variability over the East China Sea in detail. The authors demonstrate that northward shift of the PT for TCs generated around the Philippines Sea and westward shift for TCs generated in the eastern part of the WNP contribute the variability with almost equal degree. The relationships between these PT shifts and anomalies in environmental circulation fields are also discussed.
The Atmospheric Response to Three Decades of Observed Arctic Sea Ice Loss
Authors: Screen James A. , Simmonds Ian , Deser Clara , Tomas Robert
Published: August 2012

Arctic sea ice is declining at an increasing rate with potentially important repercussions. To understand better the atmospheric changes that may have occurred in response to Arctic sea ice loss, this study presents results from atmospheric general circulation model (AGCM) experiments in which the only time-varying forcings prescribed were observed variations in Arctic sea ice and accompanying changes in Arctic sea surface temperatures from 1979 to 2009. Two independent AGCMs are utilized in order to assess the robustness of the response across different models. The results suggest that the atmospheric impacts of Arctic sea ice loss have been manifested most strongly within the maritime and coastal Arctic and in the lowermost atmosphere. Sea ice loss has driven increased energy transfer from the ocean to the atmosphere, enhanced warming and moistening of the lower troposphere, decreased the strength of the surface temperature inversion, and increased lower-tropospheric thickness; all of these changes are most pronounced in autumn and early winter (September–December). The early winter (November–December) atmospheric circulation response resembles the negative phase of the North Atlantic Oscillation (NAO); however, the NAO-type response is quite weak and is often masked by intrinsic (unforced) atmospheric variability. Some evidence of a late winter (March–April) polar stratospheric cooling response to sea ice loss is also found, which may have important implications for polar stratospheric ozone concentrations. The attribution and quantification of other aspects of the possible atmospheric response are hindered by model sensitivities and large intrinsic variability. The potential remote responses to Arctic sea ice change are currently hard to confirm and remain uncertain.
The Sensitivity of the Arctic Ocean Sea Ice Thickness and Its Dependence on the Surface Albedo Parameterization
Authors: Björk Göran , Stranne Christian , Borenäs Karin
Published: August 2012

In this study, the response of sea ice thickness to changes in the external forcing is investigated and particularly how this response depends on the surface albedo formulation by means of a one-dimensional coupled ocean–ice–atmosphere model. The main focus is on the thickness response to the atmospheric heat advection Fwall, solar radiation FSW, and amount of snow precipitation Sprec. Different albedo parameterization schemes [ECHAM5, CSIRO, and Community Climate System Model, version 3 (CCSM3)] representing albedos commonly used in global climate models are compared together with more simplified schemes. Using different albedo schemes with the same external forcing produces large differences in ice thickness. The ice thickness response is similar for all realistic albedo schemes with a nearly linear decrease with increasing Fwall in the perennial ice regime and with a steplike transition into seasonal ice when Fwall exceeds a certain threshold. This transition occurs at an annual-mean ice thickness of 1.7–2.0 m. Latitudinal differences in solar insolation generally leads to increasing ice thickness toward the North Pole. The snow response varies significantly depending on which albedo scheme is used. The ECHAM5 scheme yields thinner ice with Sprec, the CSIRO scheme gives ice thickness nearly independent of Sprec, and with the CCSM3 scheme the ice thickness decreases with Sprec. A general result is that the modeled ice cover is rather sensitive to positive perturbations of the external heat supply when it is close to the transition such that just a small increase of, for example, Fwall can force the ice cover into the seasonal regime.
Integration of Climate and Weather Information for Improving 15-Day-Ahead Accumulated Precipitation Forecasts
Authors: Wang Hui , Sankarasubramanian A. , Ranjithan Ranji S.
Published: August 2012

Skillful medium-range weather forecasts are critical for water resources planning and management. This study aims to improve 15-day-ahead accumulated precipitation forecasts by combining biweekly weather and disaggregated climate forecasts. A combination scheme is developed to combine reforecasts from a numerical weather model and disaggregated climate forecasts from ECHAM4.5 for developing 15-day-ahead precipitation forecasts. Evaluation of the skill of the weather–climate information (WCI)-based biweekly forecasts under leave-five-out cross validation shows that WCI-based forecasts perform better than reforecasts in many grid points over the continental United States. Correlation between rank probability skill score (RPSS) and disaggregated ECHAM4.5 forecast errors reveals that the lower the error in the disaggregated forecasts, the better the performance of WCI forecasts. Weights analysis from the combination scheme also shows that the biweekly WCI forecasts perform better by assigning higher weights to the better-performing candidate forecasts (reforecasts or disaggregated ECHAM4.5 forecasts). Particularly, WCI forecasts perform better during the summer months during which reforecasts have limited skill. Even though the disaggregated climate forecasts do not perform well over many grid points, the primary reason WCI-based forecasts perform better than the reforecasts is due to the reduction in the overconfidence of the reforecasts. Since the disaggregated climate forecasts are better dispersed than the reforecasts, combining them with reforecasts results in reduced uncertainty in predicting the 15-day-ahead accumulated precipitation.
Comparing the Convective Structure and Microphysics in Two Sahelian Mesoscale Convective Systems: Radar Observations and CRM Simulations
Authors: Guy Nick , Zeng Xiping , Rutledge Steven A. , Tao Wei-Kuo
Published: August 2012

Two mesoscale convective systems (MCSs) observed during the African Monsoon Multidisciplinary Analyses (AMMA) experiment are simulated using the three-dimensional (3D) Goddard Cumulus Ensemble model. This study was undertaken to determine the performance of the cloud-resolving model in representing distinct convective and microphysical differences between the two MCSs over a tropical continental location. Simulations are performed using 1-km horizontal grid spacing, a lower limit on current embedded cloud-resolving models within a global multiscale modeling framework. Simulated system convective structure and microphysics are compared to radar observations using contoured frequency-by-altitude diagrams (CFADs), calculated ice and water mass, and identified hydrometeor variables. Vertical distributions of ice hydrometeors indicate underestimation at the mid- and upper levels, partially due to the inability of the model to produce adequate system heights. The abundance of high-reflectivity values below and near the melting level in the simulation led to a broadening of the CFAD distributions. Observed vertical reflectivity profiles show that high reflectivity is present at greater heights than the simulations produced, thought to be a result of using a single-moment microphysics scheme. Relative trends in the population of simulated hydrometeors are in agreement with observations, though a secondary convective burst is not well represented. Despite these biases, the radar-observed differences between the two cases are noticeable in the simulations as well, suggesting that the model has some skill in capturing observed differences between the two MCSs.
Progress Dissecting the Oral Microbiome in Caries and Health
Authors: Burne R.A. , Zeng L. , Ahn S.J. , Palmer S.R. , Liu Y. , Lefebure T. , Stanhope M.J. , Nascimento M.M.
Published: August 2012

Recent rapid advances in “-omics” technologies have yielded new insights into the interaction of the oral microbiome with its host. Associations of species that are usually considered to be acid-tolerant with caries have been confirmed, while some recognized as health-associated are often present in greater proportions in the absence of caries. In addition, some newly identified bacteria have been suggested as potential contributors to the caries process. In spite of this progress, two major challenges remain. The first is that there is a great deal of heterogeneity in the phenotypic capabilities of individual species of oral bacteria. The second is that the most abundant taxa in oral biofilms display remarkable phenotypic plasticity, i.e., the bacteria associated most strongly with health or with caries can morph rapidly in response to alterations in environmental pH, carbohydrate availability and source, and oxygen tension and redox environment. However, new technologic advances coupled with “old-fashioned microbiology” are starting to erode the barriers to a more complete understanding of oral biofilm physiology and ecology, and in doing so are beginning to provide insights for the creation of novel cost-effective caries control therapies.
Fluoride Plus Functionalized β-TCP
Authors: Karlinsey R.L. , Pfarrer A.M.
Published: August 2012

With more than 50 years of clinical success, fluoride serves as the gold standard agent for preventing tooth decay. In particular, the action of fluoride facilitates saliva-driven remineralization of demineralized enamel and alters solubility beneficially. Still, tooth decay remains problematic, and one way to address it may be through the development of new mineralizing agents. Laboratory and clinical studies have demonstrated that the combination of fluoride and functionalized β-tricalcium phosphate ( fTCP) produces stronger, more acid-resistant mineral relative to fluoride, native β-TCP, or fTCP alone. In contrast to other calcium-based approaches that seem to rely on high levels of calcium and phosphate to drive remineralization, fTCP is a low-dose system designed to fit within existing topical fluoride preparations. The functionalization of β-TCP with organic and/or inorganic molecules provides a barrier that prevents premature fluoride-calcium interactions and aids in mineralization when applied via common preparations and procedures. While additional clinical studies are warranted, supplementing with fTCP to enhance fluoride-based nucleation activity, with subsequent remineralization driven by dietary and salivary calcium and phosphate, appears to be a promising approach.
Caries Clinical Trial Methods for the Assessment of Oral Care Products in the 21st Century
Authors: Ellwood R.P. , Goma J. , Pretty I.A.
Published: August 2012

Traditionally, caries clinical trials of oral care products have focused on the prevention of caries in children and adolescents at the “cavitation” level. Because of a general reduction in caries incidence and the use of positive control comparators, studies have grown both in size and duration to improve statistical power. Currently, they tend to be of 2 to 3 years’ duration, with up to 2,000 high-risk individuals per group. During the past decade, there has been a shift in emphasis from a restorative approach to the treatment of dental caries to a therapeutic approach focused on the remineralization of early caries lesions. However, caries clinical trials of oral care products have not often reflected this paradigm change. This manuscript reviews alternative caries clinical trial methods for oral care products. It is concluded that methods focused on the detection and monitoring of enamel caries and root caries, by visual approaches such as ICDAS and instrumental methods such as QLF, Diagnodent, and Electrical Caries Monitors, provide viable alternatives to traditional methods. In particular, such approaches more accurately reflect the modes of action of many therapeutic agents and formulations and may reduce the cost and duration of product innovation.
Probiotics for Caries Prevention and Control
Authors: Twetman S. , Keller M.K.
Published: August 2012

Modulation of the microbiota for restoring and maintaining health is a growing issue in medical science. A search for relevant clinical trials on the use of probiotic bacteria as a potential and clinically applicable anti-caries measure was performed. According to predetermined criteria, papers were selected and key data on study design, sample size, intervention, duration, and results were extracted. Two animal and 19 human studies were retrieved. Most studies were short-term and restricted to microbiological endpoints, and only 3 human studies reported a caries endpoint. A high degree of heterogeneity among the included investigations hampered the analysis. Significant reductions of mutans streptococci in saliva or plaque following daily intake of probiotic lactobacilli or bifidobacteria were reported in 12 out of 19 papers, whereas 3 reported an increase of lactobacilli. Three caries trials in preschool children and the elderly demonstrated prevented fractions of between 21% and 75% following regular intakes of milk supplemented with L. rhamnosus. No adverse effects or potential risks were reported. The currently available literature does not exclude the possibility that probiotic bacteria can interfere with the oral biofilm, but any clinical recommendation would be premature. Large-scale clinical studies with orally derived specific anti-caries candidates are still lacking.
Next-generation Sequencing Approaches to Understanding the Oral Microbiome
Authors: Zaura E.
Published: August 2012

Until recently, the focus in dental research has been on studying a small fraction of the oral microbiome—so-called opportunistic pathogens. With the advent of next-generation sequencing (NGS) technologies, researchers now have the tools that allow for profiling of the microbiomes and metagenomes at unprecedented depths. The major advantages of NGS are the high throughput and the fact that specific taxa do not need to be targeted. The relatively low cost and the availability of sequencing facilities have contributed to nearly exponential growth of NGS datasets. The quality and interpretation of the NGS data could be undermined at numerous steps—from sample collection, storage, and DNA extraction to PCR bias, sequencing errors, choice of algorithms for data processing, and statistical analyses. Making sense out of this data deluge is and will be the major challenge. The community analyses based on systems ecology principles will bring us closer to an understanding of the underlying forces that facilitate the stability (or imbalance) of the microbiome. The next logical step will take us beyond the microbiome. The integration of bacterial, viral, fungal “meta-omes” such as the meta-transcriptome, meta-proteome, and meta-metabolome, together with the host as a major co-factor, should be the ultimate goal in unraveling the complexity of the oral interactome.
Clinical Efficacy and Effects of Xylitol Wipes on Bacterial Virulence
Authors: Zhan L. , Featherstone J.D.B. , Lo J. , Krupansky C. , Hoang N. , DenBesten P. , Huynh T.
Published: August 2012

The aim of the study was to investigate whether xylitol-wipe use in young children prevented caries by affecting bacterial virulence. In a double-blinded randomized controlled clinical trial, 44 mother-child pairs were randomized to xylitol-wipe or placebo-wipe groups. Salivary mutans streptococci levels were enumerated at baseline, 6 months, and one year. Ten mutans streptococci colonies were isolated and genotyped from each saliva sample. Genotype-colonization stability, xylitol sensitivity, and biofilm formation of these isolates were studied. Despite a significant reduction in new caries at one year in the xylitol-wipe group, no significant differences were found between the two groups in levels of mutans streptococci. Children in the xylitol-wipe group had significantly fewer retained genotypes (p = 0.06) and more transient genotypes of mutans streptococci (p = 0.05) than those in the placebo-wipe group. At one year, there was no significant difference in the prevalence of xylitol-resistant genotypes or in biofilm formation ability of mutans streptococci isolates between the two groups. The mechanism of the caries-preventive effect of xylitol-wipe use may be related to the stability of mutans streptococci colonization. Further studies with genomic characterization methods are needed to determine specific gene(s) that account for the caries-preventive effect of xylitol.
Strategic Protein Target Analysis for Developing Drugs to Stop Dental Caries
Authors: Horst J.A. , Pieper U. , Sali A. , Zhan L. , Chopra G. , Samudrala R. , Featherstone J.D.B.
Published: August 2012

Dental caries is the most common disease to cause irreversible damage in humans. Several therapeutic agents are available to treat or prevent dental caries, but none besides fluoride has significantly influenced the disease burden globally. Etiologic mechanisms of the mutans group streptococci and specific Lactobacillus species have been characterized to various degrees of detail, from identification of physiologic processes to specific proteins. Here, we analyze the entire Streptococcus mutans proteome for potential drug targets by investigating their uniqueness with respect to non-cariogenic dental plaque bacteria, quality of protein structure models, and the likelihood of finding a drug for the active site. Our results suggest specific targets for rational drug discovery, including 15 known virulence factors, 16 proteins for which crystallographic structures are available, and 84 previously uncharacterized proteins, with various levels of similarity to homologs in dental plaque bacteria. This analysis provides a map to streamline the process of clinical development of effective multispecies pharmacologic interventions for dental caries.
Targeted Antimicrobial Treatment to Re-establish a Healthy Microbial Flora for Long-term Protection
Authors: Eckert R. , Sullivan R. , Shi W.
Published: August 2012

Streptococcus mutans has been implicated as the major acid-producing (cariogenic) bacterium. Dietary sugars and other factors may cause an imbalance of oral microflora that enables S. mutans to become dominant in the multi-species biofilms on the tooth surface, which could lead to dental caries. The application of broad-spectrum antimicrobials often results in re-colonization and re-dominance of S. mutans within oral flora, while in contrast, therapies capable of selective elimination of S. mutans from oral microbial communities may help to re-establish the normal flora and provide long-term protection. C16G2, a novel synthetic antimicrobial peptide with specificity for S. mutans, was found to have robust killing efficacy and selectivity for S. mutans in vitro. A subsequent pilot human study found that a single application of C16G2 in the oral cavity (formulated in a mouthrinse vehicle) was associated with a reduction in plaque and salivary S. mutans, lactic acid production, and enamel demineralization during the entire 4-day testing period. C16G2 is now being developed as a new anticaries drug.
Remineralization Models
Authors: Cochrane N.J. , Zero D.T. , Reynolds E.C.
Published: August 2012

During the ICNARA 2 conference, a workshop was held on remineralization models. The group considered the role of remineralization models, whether there was one ideal in situ model design, what essential features should be incorporated into an in situ model, other alternative models, and what new methods for measuring remineralization were on the horizon. This paper summarizes the discussion. In situ and other caries models can be used as a surrogate for caries clinical trials but only when data exist to validate the model. In situ model design should be flexible to allow for investigation of different aspects of the caries process; however, several essential features were identified that should be incorporated into the study design. A range of other caries models was discussed, including the study of non-cavitated lesions, lesions post-orthodontic therapy, plaque retention models to form more standardized lesions, and the study of root caries lesions. Numerous new methods for quantifying remineralization were discussed, but it was considered that these require validation before they can be used in clinical trials.
Remineralization Agents – New and Effective or Just Marketing Hype?
Authors: Lynch R.J.M. , Smith S.R.
Published: August 2012

This is a review of the need for better remineralization and of the status of calcium-based remineralizing agents for use in anti-caries toothpastes. Use of fluoride toothpastes has markedly reduced caries. However, the decline may be over or in reverse. There is a limit to what fluoride alone can do; complementary agents are needed. Using plaque as a reservoir for calcium-based agents holds promise. Plaque fluid is already supersaturated with respect to relevant calcium phosphates at neutral pH; extra calcium may lead to surface-blocking and sub-optimal lesion consolidation. However, at cariogenic pH, lesions may be more porous to the ingress of mineral, leading to fuller consolidation, and controlled release of calcium should reduce undersaturation with respect to enamel and accelerate deposition of fluorhydroxyapatite. Clinical data to validate in vitro screening models are scarce. Direct progression to in situ models may often be appropriate. The spectrum of lesion types, from softening to relatively advanced subsurface, and lesion activity should be considered. Far from being ‘marketing hype’, progress with calcium-based remineralizing agents is both encouraging and scientifically sound. Clinical evidence exists for the efficacy of some agents, but further unequivocal clinical data are needed before these agents might be considered ‘effective’ when delivered from toothpaste.
Novel Anticaries and Remineralizing Agents
Authors: ten Cate J.M.
Published: August 2012

Although the use of fluorides has been successful in reducing dental caries, the need remains to develop and evaluate new approaches and promising products for caries prevention. Comprehensive caries-prevention protocols should encompass fluoride and other agents affecting the de-/remineralization balance but also antimicrobial strategies. Different from the traditional restorative approach, the current opinion is that caries should be detected and monitored in its earliest stages, when a nonsurgical reversal can still be achieved. This paradigm shift has implications for methods of caries diagnosis, the choice of preventative materials and the design of randomized clinical trials. This article summarizes the highlights of a special conference dedicated to the topic of novel anticaries and remineralizing agents (ICNARA 2), and identifies the current consensus and remaining questions on pivotal issues in this field.
Flagellin-PAc Fusion Protein is a High-efficacy Anti-caries Mucosal Vaccine
Authors: Sun Y. , Shi W. , Yang J.Y. , Zhou D.H. , Chen Y.Q. , Zhang Y. , Yang Y. , He B.X. , Zhong M.H. , Li Y.M. , Cao Y. , Xiao Y. , Li W. , Yu J. , Li Y.H. , Fan M.W. , Yan H.M.
Published: August 2012

We previously demonstrated that an anti-caries DNA vaccine intranasally administered with recombinant flagellin protein as a mucosal adjuvant enhanced salivary IgA response and conferred better protection against caries. However, the relatively weak immunogenicity of DNA vaccines and the necessity for a large quantity of antigens remain significant challenges. Here, we fused the flagellin derived from E. coli (KF) and target antigen PAc containing the A-P fragment of PAc from S. mutans (rPAc) to produce a single recombinant protein (KF-rPAc). The abilities of KF-rPAc to induce rPAc-specific mucosal and systemic responses and protective efficiency against caries following intranasal immunization were compared with those of rPAc alone or a mixture of rPAc and KF (KF + rPAc) in rats. Results showed that KF-rPAc promoted significantly higher rPAc-specific antibodies in serum as well as in saliva than did an equivalent dose of rPAc alone or a mixture of KF + rPAc. Intranasal immunization of 8.5 µg KF-rPAc could achieve 64.2% reduction of dental caries in rats. In conclusion, our study demonstrated that flagellin and PAc fusion strategy is promising for anti-caries vaccine development, and KF-rPAc could be used as an anti-caries mucosal vaccine.
SSEA-4 is a Marker of Human Deciduous Periodontal Ligament Stem Cells
Authors: Fukushima H. , Kawanabe N. , Murata S. , Ishihara Y. , Yanagita T. , Balam T.A. , Yamashiro T.
Published: August 2012

Although human deciduous teeth are an ideal source of adult stem cells, no method for identifying deciduous periodontal ligament (D-PDL) stem cells has so far been developed. In the present study, we investigated whether stage-specific embryonic antigen (SSEA)-4 is a marker that could be used to isolate D-PDL stem cells. The isolated D-PDL cells met the minimum criteria for mesenchymal stem cells (MSCs): They showed plastic adherence, specific-surface antigen expression, and multipotent differentiation potential. SSEA-4+ D-PDL cells were detected in vitro and in vivo. A flow cytometric analysis demonstrated that 22.7% of the D-PDL cells were positive for SSEA-4. SSEA-4+ clonal D-PDL cells displayed multilineage differentiation potential: They were able to differentiate into adipocytes, osteoblasts, and chondrocytes in vitro. A clonal assay demonstrated that 61.5% of the SSEA-4+ D-PDL cells had adipogenic, osteogenic, and chondrogenic potential. Our present study demonstrated that SSEA-4+ D-PDL cells are a subset of multipotent stem cells. Hence, SSEA-4 is a specific marker that can be used to identify D-PDL stem cells.
Transition Assessment and Planning for Youth With Severe Intellectual and Developmental Disabilities
Authors: Carter Erik W. , Brock Matthew E. , Trainor Audrey A.
Published: August 2012

Although federal law now mandates age-appropriate transition assessment as a key component of high-quality transition planning, little research exists to guide educators on what they might learn when undertaking this process. In this study, the authors examined teacher and parent assessments of the transition-related strengths and needs of 134 youth with severe intellectual and developmental disabilities who were eligible for the state’s alternate assessment. The perspectives of teachers and parents regarding the transition-related strengths and needs of particular students often diverged in key ways. Students with severe disabilities were perceived as having a range of transition-related strengths across the nine transition domains. Although a number of transition-related needs were identified by teachers, the transition profiles of individual students within this sample were quite heterogeneous. The authors offer recommendations for strengthening the transition assessment and planning process by incorporating multiple perspectives, and present important directions for future research on transition assessment.