Microbial ecology and predicted metabolic pathways in various oral environments from patients with acute endodontic infections.

AIM: To assess in a cross-sectional clinical study the effect of antibiotics on the diversity, structure and metabolic pathways of bacterial communities in various oral environments in patients with acute primary infections. METHODOLOGY: Samples of saliva (SA), supragingival biofilm (SB) and from the pulp cavity (PC) were collected from teeth with acute primary infections and then grouped according to previous use of antibiotics (NoAtb = no antibiotics [n = 6]; Atb = antibiotics [n = 6]). DNA sequencing was conducted using MiSeq (Illumina, San Diego, CA, USA). The V1-V3 hyper-variable region of the 16S rRNA gene was amplified. A custom Mothur pipeline was used for 16S rRNA processing. Subsequent analyses of the sequence dataset were performed in R (using vegan, phyloseq and ggplot2 packages) or QIIME. RESULTS: Twelve patients aged from 22 to 56 years were recruited. Participants in the Atb group had taken the beta-lactamics amoxicillin (5/6) or cephalexin (1/6) for 2-3 days. A total of 332 bacterial taxa (OTUs) were identified, belonging to 120 genera, 60 families and nine phyla. Firmicutes (41%) and Bacteroidetes (38%) were the most abundant phyla in all samples. Taxa clustered significantly by oral site (PCoA analysis; P < 0.05, ANOSIM). Use of antibiotics had little effect on this clustering. However, SA, SB and PC had different degrees of richness, diversity and evenness. The greatest diversity was observed in SB samples and the least diversity was observed in PC samples. Metabolic prediction identified 163 pathways and previous use of antibiotics had a major effect on the estimated functional clustering in SA and PC samples. CONCLUSION: The ecological niche had a strong influence on the bacterial content of samples from various oral sites. Previous exposure to antibiotics may exert an effect on the phylogenetic composition of SA. Metabolic pathways appear to be modulated by antimicrobial agents in SA and PC samples. The dynamics of host/microbial interactions in the apical region and the functional ecology of the infected pulp cavity should be revisited.

Startle modulation by heat pain with varying threat levels in chronic pain patients and pain-free controls.

BACKGROUND: Empirical evidence suggests that affective responses to pain are changed in chronic pain. The investigation of startle responses to pain might contribute to clarifying whether such alterations also expand to motivational defensive reactions. We aimed at comparing startle responses to tonic heat pain with high threat (HT) or low threat (LT) in patients with chronic musculoskeletal pain and controls. As pain-related anxiety and catastrophizing are typically elevated in chronic pain, we expected to find stronger startle responses in patients specifically under experimental HT. METHODS: Patients with chronic musculoskeletal, preferentially, back pain (N = 19) and matched pain-free controls (N = 19) underwent two pain-related threat conditions (high and low) in balanced order. Only, in the HT condition, 50% of the trials were announced to include a short further noxious temperature increase at the end. Startle responses to loud tones were always assessed prior to a potential temperature increase in the phase of anticipation and were recorded by surface electromyogram. RESULTS: Surprisingly, we observed no differences in startle responses and ratings of emotional and pain responses between patients and controls despite significantly higher pain-related anxiety and catastrophizing in the patients. Overall, startle was potentiated in the HT condition, but only in participants who started with this condition. CONCLUSION: Our results suggest that, in general, patients with pain are not more responsive emotionally to experimental threat manipulations despite elevated pain anxiety and catastrophizing. Instead, exaggerated responses in patients might be triggered only by individual concerns relating to pain, which are not sufficiently mirrored by our threat paradigm.

High energy proton induced radiation damage of rare earth permanent magnet quadrupoles.

Permanent magnet quadrupoles (PMQs) are an alternative to common electromagnetic quadrupoles especially for fixed rigidity beam transport scenarios at particle accelerators. Using those magnets for experimental setups can result in certain scenarios, in which a PMQ itself may be exposed to a large amount of primary and secondary particles with a broad energy spectrum, interacting with the magnetic material and affecting its magnetic properties. One specific scenario is proton microscopy, where a proton beam traverses an object and a collimator in which a part of the beam is scattered and deflected into PMQs used as part of a diagnostic system. During the commissioning of the PRIOR (Proton Microscope for Facility for Antiproton and Ion Research) high energy proton microscope facility prototype at Gesellschaft für Schwerionenforschung in 2014, a significant reduction of the image quality was observed which was partially attributed to the demagnetization of the used PMQ lenses and the corresponding decrease of the field quality. In order to study this phenomenon, Monte Carlo simulations were carried out and spare units manufactured from the same magnetic material-single wedges and a fully assembled PMQ module-were deliberately irradiated by a 3.6 GeV intense proton beam. The performed investigations have shown that in proton radiography applications the above described scattering may result in a high irradiation dose in the PMQ magnets. This did not only decrease the overall magnetic strength of the PMQs but also caused a significant degradation of the field quality of an assembled PMQ module by increasing the parasitic multipole field harmonics which effectively makes PMQs impractical for proton radiography applications or similar scenarios.

High-energy proton imaging for biomedical applications.

The charged particle community is looking for techniques exploiting proton interactions instead of X-ray absorption for creating images of human tissue. Due to multiple Coulomb scattering inside the measured object it has shown to be highly non-trivial to achieve sufficient spatial resolution. We present imaging of biological tissue with a proton microscope. This device relies on magnetic optics, distinguishing it from most published proton imaging methods. For these methods reducing the data acquisition time to a clinically acceptable level has turned out to be challenging. In a proton microscope, data acquisition and processing are much simpler. This device even allows imaging in real time. The primary medical application will be image guidance in proton radiosurgery. Proton images demonstrating the potential for this application are presented. Tomographic reconstructions are included to raise awareness of the possibility of high-resolution proton tomography using magneto-optics.

Commissioning of the PRIOR proton microscope.

Recently, a new high energy proton microscopy facility PRIOR (Proton Microscope for FAIR Facility for Anti-proton and Ion Research) has been designed, constructed, and successfully commissioned at GSI Helmholtzzentrum für Schwerionenforschung (Darmstadt, Germany). As a result of the experiments with 3.5-4.5 GeV proton beams delivered by the heavy ion synchrotron SIS-18 of GSI, 30 µm spatial and 10 ns temporal resolutions of the proton microscope have been demonstrated. A new pulsed power setup for studying properties of matter under extremes has been developed for the dynamic commissioning of the PRIOR facility. This paper describes the PRIOR setup as well as the results of the first static and dynamic proton radiography experiments performed at GSI.

No effect of the cyclooxygenase-2 inhibitor etoricoxib on pre-emptive and post-operative analgesia in visceral surgery: results of a randomized controlled trial.

BACKGROUND: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design. METHODS: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection. RESULTS: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups. CONCLUSIONS: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery.

[Painful ischemic neuropathy]. / Schmerzhafte ischämische Neuropathie.

Chronic ischemia in patients with peripheral arterial disease (PAD) represents a common medical problem. Neuropathic changes and pain caused by chronic ischemia are often found in the lower extremities of these patients. Pain in patients with chronic critical limb ischemia fulfill the criteria of neuropathic pain. Diagnostic tools besides medical history and examination are questionnaires, quantitative sensory testing (QST) and measuring intraepidermal nerve fiber density (IENFD) when indicated. A pharmacological approach with non-opioids and opioids as well as antidepressive and anticonvulsive drugs (according to the recommendations for the therapy of neuropathic pain) seems to be indicated for treating painful ischemic neuropathy. Spinal cord stimulation (SCS) provides the best evidence for invasive procedures in treating chronic ischemic pain.

Search for solar axions by the CERN axion solar telescope with 3He buffer gas: closing the hot dark matter gap.

The CERN Axion Solar Telescope has finished its search for solar axions with (3)He buffer gas, covering the search range 0.64 eV ≲ ma ≲ 1.17 eV. This closes the gap to the cosmological hot dark matter limit and actually overlaps with it. From the absence of excess x rays when the magnet was pointing to the Sun we set a typical upper limit on the axion-photon coupling of gaγ ≲ 3.3 × 10(-10) GeV(-1) at 95% C.L., with the exact value depending on the pressure setting. Future direct solar axion searches will focus on increasing the sensitivity to smaller values of gaγ, for example by the currently discussed next generation helioscope International AXion Observatory.

[Update on preemptive analgesia : options and limits of preoperative pain therapy]. / Update zur präemptiven Analgesie : Möglichkeiten und Grenzen der präoperativen Schmerztherapie.

BACKGROUND: Wall created the term preemptive analgesia in 1988 and in doing so set in motion a movement to prevent acute and chronic postsurgical pain. The concept of preemptive analgesia implies the administration of analgesic drugs or an intervention before a surgical procedure. A preemptive analgesic approach can comprise non-steroidal anti-inflammatory drugs (NSAID) and cyclo-oxygenase-2 inhibitors (coxibs) used to decrease the production of prostaglandins, local anesthetics (e.g. epidural) to reduce nociceptive input to the spinal cord as well as opioids, N-methyl-D-aspartate (NMDA) antagonists, antidepressants and anticonvulsants, all of which have an inhibitory influence on the central nervous system. AIM: The aim of this article is to present the current possibilities and limits of preoperative pain therapy. MATERIAL AND METHODS: Since 2002 several meta-analyses on the effectiveness of preemptive analgesia have been published which came to varying conclusions on the supportive use of preemptive analgesia. The S3 guidelines on current perioperative pain management developed by the German Interdisciplinary Association for Pain Management (DIVS) specify the preemptive analgesic interventions found to be effective and will be discussed in detail in this article. Furthermore, the results of a current meta-analysis which follows the principle of preventive analgesia will be presented and which have not yet been considered in the S3 guidelines. RESULTS: Preemptive analgesia can reduce acute postoperative pain; however, minimizing the development of chronic pain conditions can only be successful in combination with intraoperative and postoperative pain therapy as well as social and psychological support when indicated (preventive analgesia). CONCLUSION: Reduction of chronic postoperative pain is an important medical function which is also justified from socioeconomic perspectives. Future studies should combine several procedures for perioperative pain therapy in order to do justice to the multifactorial aspects of pain chronification and should also be planned over a sufficiently long observation time period.

First biological images with high-energy proton microscopy.

High-energy proton microscopy provides unique capabilities in penetrating radiography including the combination of high spatial resolution and field-of-view, dynamic range of density for measurements, and reconstructing density variations to less than 1% inside volumes and in situ environments. We have recently proposed to exploit this novel proton radiography technique for image-guided stereotactic particle radiosurgery. Results of a first test for imaging biological and tissue-equivalent targets with high-energy (800 MeV) proton microscopy are presented here. Although we used a proton microscope setup at ITEP (Moscow, Russia) optimized for fast dynamic experiments in material research, we could reach a spatial resolution of 150 µm with approximately 10(10) protons per image. The potential of obtaining high-resolution online imaging of the target using a therapeutic proton beam in the GeV energy region suggests that high-energy proton microscopy may be used for image-guided proton radiosurgery.

Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve.

BACKGROUND AND PURPOSE: Amitriptyline is often prescribed as a first-line treatment for neuropathic pain but its precise mode of analgesic action remains uncertain. Amitriptyline is known to inhibit voltage-dependent ion channels and also to act as an antagonist at ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). In the present study, we tested the effect of amitriptyline on nicotinic responses of unmyelinated axons in isolated segments of human peripheral nerve. In particular, a comparison was made between the concentrations of amitriptyline necessary for inhibition of nAChRs and those required for inhibition of the compound C-fibre action potential. EXPERIMENTAL APPROACH: Isolated axon fascicles were prepared from short segments of human sural nerve, and multiple measures of axonal excitability were recorded using computer-controlled threshold tracking software. KEY RESULTS: Amitriptyline (EC(50) 2.6 microM) reduced the nicotine-induced increase in C-fibre excitability but only slightly altered the amplitude and latency to onset of the compound action potential. In contrast, tetrodotoxin produced a clear reduction in the amplitude and a prolongation of action potential onset latency but was without effect on the nicotine-induced increase in axonal excitability. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that low concentrations of amitriptyline suppress the response of human peripheral C-type axons to nicotine by directly inhibiting nAChRs. Blockade of tetrodotoxin-sensitive, voltage-dependent sodium channels does not contribute to this effect. An inhibitory action of amitriptyline on nAChRs in unmyelinated nociceptive axons may be an important component of amitriptyline's therapeutic effect in the treatment of neuropathic pain.

[Correlation between quantitative sensory testing and questionnaires on neuropathic pain for chronic ischemic pain in peripheral arterial disease]. / Zusammenhang von Quantitativer Sensorischer Testung und Fragebögen zu neuropathischen Schmerzen am Beispiel chronischer Ischämieschmerzen bei PAVK.

BACKGROUND: A neuropathic component to chronic ischemic pain in peripheral arterial disease (PAD) has recently been shown using quantitative sensory testing (QST) and pain questionnaires. The aim of this study was to examine correlations between QST and pain questionnaires in patients with chronic ischemic pain. METHODS: A total of 10 patients with severe PAD (Fontaine stages III and IV) without diabetes mellitus answered a questionnaire and were examined with QST. The questionnaire consisted of several validated instruments which were used to examine the intensity of pain, quality of pain and neuropathic pain (VAS, SF-MPQ, S-LANSS, NPSI). RESULTS: The results of the QST confirmed previously published data. Several terms of the SF-MPQ showed a correlation with parameters of the QST, such as Allodynia (QST) which correlated with the term tender (SF-MPQ) (Spearman's correlation coefficient 0.911; p< or =0.001) and the NPSI subscore evoked pain correlated with the QST parameter wind-up ratio (0.683; p=0.042). CONCLUSION: The results suggest that there might be correlations between psychophysical tests (QST) and pain questionnaires. Subjective perceptions of pain might be represented by a certain pattern in the QST. These connections could contribute to further clarify the pathophysiologic mechanisms leading to the perception of pain.

Retigabine reduces the excitability of unmyelinated peripheral human axons.

Enhancement of membrane K(+) conductance may reduce the abnormal excitability of primary afferent nociceptive neurons in neuropathic pain. It has been shown that retigabine, a novel anticonvulsant, activates Kv7 (KCNQ/M) channels in the axonal/nodal membrane of peripheral myelinated axons. In this study, we have tested the effects of retigabine on excitability parameters of C-type nerve fibers in isolated fascicles of human sural nerve. Application of retigabine (3-10 microM) produced an increase in membrane threshold. This effect was pronounced in depolarized axons and small in hyperpolarized axons. This finding indicates that retigabine produces a membrane hyperpolarization which is limited by the K(+) equilibrium potential. The retigabine-induced reduction in excitability was accompanied by modifications of the post-spike recovery cycle. Most notable is the development of a late subexcitability at 250-400 ms following a short burst of action potentials. All effects of retigabine were blocked in the presence of XE991 (10 microM). The data show that Kv7 channels are present on axons of unmyelinated, including nociceptive, peripheral human nerve fibers. It is likely that activation of these channels by retigabine may reduce the ectopic generation of action potentials in neuropathic pain.

[Therapy of chronic ischemic pain in peripheral arterial disease. A survey among physicians]. / Therapie chronischer Ischämieschmerzen bei peripherer arterieller Verschlusskrankheit. Eine Arztebefragung.

BACKGROUND: The intention of this study was to determine the status quo of commonly used pain therapies amongst treating physicians of different specialties and to examine their view on the problem of chronic ischemic pain. METHODS: A total of 281 physicians treating patients with chronic ischemic pain were surveyed. The surveyed physicians were mainly specialists in the fields of surgery, pain therapy, and internal medicine. RESULTS: Mainly a pharmacological therapy (metamizol/paracetamol, weak and strong opioids) was used in the treatment of chronic ischemic pain. We found differences between the specialties, for instance pain specialists used antidepressants and anticonvulsants more often than others. Therapeutic options were also evaluated differently by surgeons, pain therapists, and internal specialists: 57% of the surgeons considered the available symptomatic treatment options as sufficient whereas only 21% of the pain specialists agreed with that opinion. CONCLUSION: The differences among the specialties and the fact that the majority of physicians characterized the available symptomatic treatment options as insufficient point towards a need to review the treatment of ischemic pain in an interdisciplinary approach.

Characterization of neuronal nicotinic acetylcholine receptors in the membrane of unmyelinated human C-fiber axons by in vitro studies.

Application of acetylcholine to peripheral nerve terminals in the skin is a widely used test in studies of human small-fiber functions. However, a detailed pharmacological profile and the subunit composition of nicotinic acetylcholine receptors in human C-fiber axons are not known. In the present study, we recorded acetylcholine-induced changes of the excitability and of the intracellular Ca2+ concentration in C-fiber axons of isolated human nerve segments. In addition, using immunohistochemistry, an antibody of a subtype of nicotinic acetylcholine receptor was tested. Acetylcholine and agonists reduced the current necessary for the generation of action potentials in C fibers by > 5-Iodo-A-85380 > 1,1-dimethyl-4-phenylpiperazinium iodide > nicotine > cytisine > acetylcholine; choline had no effect. The epibatidine-induced increase in axonal excitability was blocked by mecamylamine and, less efficiently, by methyllycacontine and dihydro-beta-erythroidine. Many C-fiber axons were labeled by an antibody that recognizes the alpha5 subunit of nicotinic acetylcholine receptors. In summary, electrophysiological and immunohistochemical data indicate the functional expression of nicotinic acetylcholine receptors composed of alpha3, alpha5, and beta4 but not of alpha4/beta2 or of alpha7 subunits in the axonal membrane of unmyelinated human C fibers. In addition, the observations suggest that the axonal membrane of C fibers in isolated segments of human sural nerve can be used as a model for presumed cholinergic chemosensitivity of axonal terminals.

Selectivity and Related Measures for nth-Order Data.

Analytical figures of merit are often used as criteria to decide whether or not a given instrumental method is suitable for attacking an analytical problem. To date, figures of merit primarily exist for analytical instruments producing data indexed by one variable, i.e., first-order instruments and first-order data. Almost none exist for instruments that generate data indexed by two variables, i.e., second-order instruments and data, and none exist for instruments supplying data indexed by three or more variables, i.e., nth-order instruments and data. This paper develops practical mathematical tools that can be used to create several figures of merit for nth-order instrumentation, namely, selectivity, net analyte signal, and sensitivity. In particular, the paper fully develops a local selectivity measure for second-order instrumentation and tests its performance using simulated second-order data and real second-order data obtained by gas chromatography with Fourier transform infrared detection and liquid chromatography with photodiode array detection. Also included in the paper is a brief discussion on practical uses of nth-order figures of merit.

Recent changes in atmospheric carbon monoxide.

Measurements of carbon monoxide (CO) in air samples collected from 27 locations between 71 degrees N and 41 degrees S show that atmospheric levels of this gas have decreased worldwide over the past 2 to 5 years. During this period, CO decreased at nearly a constant rate in the high northern latitudes. In contrast, in the tropics an abrupt decrease occurred beginning at the end of 1991. In the Northern Hemisphere, CO decreased at a spatially and temporally averaged rate of 7.3 (+/-0.9) parts per billion per year (6.1 percent per year) from June 1990 to June 1993, whereas in the Southern Hemisphere, CO decreased 4.2 (+/-0.5) parts per billion per year (7.0 percent per year). This recent change is opposite a long-term trend of a 1 to 2 percent per year increase inferred from measurements made in the Northern Hemisphere during the past 30 years.