The accumulation and growth of Pseudomonas aeruginosa on surfaces is modulated by surface mechanics via cyclic-di-GMP signaling.

Attachment of bacteria onto a surface, consequent signaling, and accumulation and growth of the surface-bound bacterial population are key initial steps in the formation of pathogenic biofilms. While recent reports have hinted that surface mechanics may affect the accumulation of bacteria on that surface, the processes that underlie bacterial perception of surface mechanics and modulation of accumulation in response to surface mechanics remain largely unknown. We use thin and thick hydrogels coated on glass to create composite materials with different mechanics (higher elasticity for thin composites; lower elasticity for thick composites) but with the same surface adhesivity and chemistry. The mechanical cue stemming from surface mechanics is elucidated using experiments with the opportunistic human pathogen Pseudomonas aeruginosa combined with finite-element modeling. Adhesion to thin composites results in greater changes in mechanical stress and strain in the bacterial envelope than does adhesion to thick composites with identical surface chemistry. Using quantitative microscopy, we find that adhesion to thin composites also results in higher cyclic-di-GMP levels, which in turn result in lower motility and less detachment, and thus greater accumulation of bacteria on the surface than does adhesion to thick composites. Mechanics-dependent c-di-GMP production is mediated by the cell-surface-exposed protein PilY1. The biofilm lag phase, which is longer for bacterial populations on thin composites than on thick composites, is also mediated by PilY1. This study shows clear evidence that bacteria actively regulate differential accumulation on surfaces of different stiffnesses via perceiving varied mechanical stress and strain upon surface engagement.

Bacterial mechanosensing of surface stiffness promotes signaling and growth leading to biofilm formation by Pseudomonas aeruginosa.

The attachment of bacteria onto a surface, consequent signaling, and the accumulation and growth of the surface-bound bacterial population are key initial steps in the formation of pathogenic biofilms. While recent reports have hinted that the stiffness of a surface may affect the accumulation of bacteria on that surface, the processes that underlie bacterial perception of and response to surface stiffness are unknown. Furthermore, whether, and how, the surface stiffness impacts biofilm development, after initial accumulation, is not known. We use thin and thick hydrogels to create stiff and soft composite materials, respectively, with the same surface chemistry. Using quantitative microscopy, we find that the accumulation, motility, and growth of the opportunistic human pathogen Pseudomonas aeruginosa respond to surface stiffness, and that these are linked through cyclic-di-GMP signaling that depends on surface stiffness. The mechanical cue stemming from surface stiffness is elucidated using finite-element modeling combined with experiments - adhesion to stiffer surfaces results in greater changes in mechanical stress and strain in the bacterial envelope than does adhesion to softer surfaces with identical surface chemistry. The cell-surface-exposed protein PilY1 acts as a mechanosensor, that upon surface engagement, results in higher cyclic-di-GMP levels, lower motility, and greater accumulation on stiffer surfaces. PilY1 impacts the biofilm lag phase, which is extended for bacteria attaching to stiffer surfaces. This study shows clear evidence that bacteria actively respond to different stiffness of surfaces where they adhere via perceiving varied mechanical stress and strain upon surface engagement.

Comparison of fentanyl iontophoretic transdermal system and routine care with morphine intravenous patient-controlled analgesia in the management of early postoperative mobilisation: results from a randomised study.

INTRODUCTION: Fentanyl iontophoretic transdermal system (ITS) (IONSYS®, The Medicines Company, Parsippany, NJ, USA) and morphine intravenous (IV) patient-controlled analgesia (PCA) have demonstrated equivalent pain control in several published studies. The primary objective of the current study was to compare fentanyl ITS with morphine IV PCA with regard to the patient's ability to mobilise with acute postoperative pain. METHODS: In this multicentre, open-label, randomised, active-controlled, prospective phase IV study, postoperative patients initially received IV morphine and were titrated to pain score ⩽ 4out of 10 on a Numeric Rating Scale (NRS) and then received fentanyl ITS (up to 240 µg (6 doses)/hour; up to a maximum of 3.2 mg (80 doses)/24 hours) or morphine IV PCA (doses up to 20 mg morphine/2 hours, up to 240 mg/24 hours). The primary efficacy measure was ability to mobilise, assessed using patient responses to three validated questions regarding mobility on a 6-point Likert scale (0 = no difficulty to mobilise to 5 = a very great deal of difficulty to mobilise). The study was originally planned to include ~200 patients. However, following the early suspension and termination of the study, a total of 108 patients were randomised to study treatment. RESULTS: One hundred and eight patients were recruited prior to undergoing surgical procedures (orthopaedic surgical procedures (72%) or underwent major abdominal procedures (28%)). Postoperatively, 58 were randomised to receive fentanyl ITS, and 50 to morphine IV PCA. Fentanyl ITS patients had a greater ability to mobilise at the time of stopping study drug, with an adjusted mean ability to mobilise score (95% confidence interval (CI)) of 0.14 (-0.19, 0.47) for fentanyl ITS patients and 2.37 (1.98, 2.76) for morphine IV PCA patients (p < 0.001). CONCLUSION: Patients treated with fentanyl ITS reported that they were better able to mobilise than patients treated with morphine IV PCA, at all time-points following surgery out to 24 hours.

Is tapentadol different from classical opioids? A review of the evidence.

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids.

The Association Between Chronic Pain and Cardiac Disease: A Cross-sectional Population Study.

OBJECTIVES: Chronic pain may increase the risk of cardiac disease, but the extent to which confounding variables account for this association has yet to be satisfactorily established. This study aims to examine the possibility of an independent association between these 2 variables. METHODS: We applied logistic regression analysis to data from 8596 adults surveyed in a population study of the health of the population of England. The association between cardiac disease (angina and/or myocardial infarction) and chronic pain (pain lasting >3 months) was explored, taking account of 10 potentially confounding variables including the regular use of nonsteroidal anti-inflammatory drugs. RESULTS: Participants reporting chronic pain (n=3023) were more likely to experience cardiac disease than those without pain: odds ratio (OR), 1.55; 95% confidence interval (CI), 1.15-2.07. Subsets of participants fulfilling various criteria for high-intensity chronic pain demonstrated stronger associations with cardiac disease suggesting a "dose-response" element to the relationship: chronic widespread pain (OR, 3.3; 95% CI, 1.42-7.68); higher-disability chronic pain (OR, 2.35; 95% CI, 1.71-3.23); and higher average chronic pain score (OR, 1.95; 95% CI, 1.40-2.71). Adjustment for regular prescription of nonsteroidal anti-inflammatory drugs did not reduce the association of chronic pain with cardiac disease. DISCUSSION: Patients reporting chronic pain, in particular those most severely affected, may be at significantly increased risk of cardiac disease. Future studies should focus on determining whether reducing the impact of chronic pain can improve cardiac health.

Assessing the relationship between chronic pain and cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic pain is a potentially disabling condition affecting one in three people through impaired physical function and quality of life. While the psychosocial impact of chronic pain is already well established, little is known about the potential biological consequences. Chronic pain may be associated with an increased prevalence of cardiovascular disease, an effect that has been demonstrated across a spectrum of chronic pain conditions including low back pain, pelvic pain, neuropathic pain and fibromyalgia. The aim of this study was to review and summarize the evidence for a link between chronic pain and cardiovascular disease. We sought to clarify the nature of the relationship by examining the basis for a dose-response gradient (whereby increasing pain severity would result in greater cardiovascular disease), and by evaluating the extent to which potentially confounding variables may contribute to this association. METHODS: Major electronic databases MEDLINE, EMBASE, Psychinfo, Cochrane, ProQuest and Web of Science were searched for articles reporting strengths of association between chronic pain (pain in one or more body regions, present for three months or longer) and cardiovascular outcomes (cardiovascular mortality, cardiac disease, and cerebrovascular disease). Meta-analysis was used to pool data analysing the association between chronic pain and the three principal cardiovascular outcomes. The impact of pain severity, and the role of potentially confounding variables were explored narratively. RESULTS: The searches generated 11,141 studies, of which 25 matched our inclusion criteria and were included in the review. Meta-analysis (of unadjusted study outcomes) demonstrated statistically significant associations between chronic pain and mortality from cardiovascular diseases: pooled odds ratio 1.20, (95% confidence intervals 1.05-1.36); chronic pain and cardiac disease: pooled odds ratio 1.73 (95% confidence intervals 1.42-2.04); and chronic pain and cerebrovascular disease: pooled odds ratio 1.81 (95% confidence intervals 1.51-2.10). The systematic review also found evidence supporting a dose-response relationship, with greater pain intensity and distribution producing a stronger association with cardiovascular outcomes. All of the included studies were based on observational data with considerable variation in chronic pain taxonomy, methodology and study populations. The studies took an inconsistent and incomplete approach in their adjustment for potentially confounding variables, making it impossible to pool data after adjustments for confounding variables, so it cannot be concluded that these associations are causal. CONCLUSIONS: Our review supports a possible dose-response type of association between chronic pain and cardiovascular disease, supported by a range of observational studies originating from different countries. Such research has so far failed to satisfactorily rule out that the association is due to confounding variables. What is now needed are further population based longitudinal studies that are designed to allow more robust exploration of a cause and effect relationship. IMPLICATIONS: Given the high prevalence of chronic pain in developed and developing countries our results highlight a significant, but underpublicized, public health concern. Greater acknowledgement of the potentially harmful biological consequences of chronic pain may help to support regional, national and global initiatives aimed at reducing the burden of chronic pain.

A Quantile Regression Approach to Estimating the Distribution of Anesthetic Procedure Time during Induction.

Although procedure time analyses are important for operating room management, it is not easy to extract useful information from clinical procedure time data. A novel approach was proposed to analyze procedure time during anesthetic induction. A two-step regression analysis was performed to explore influential factors of anesthetic induction time (AIT). Linear regression with stepwise model selection was used to select significant correlates of AIT and then quantile regression was employed to illustrate the dynamic relationships between AIT and selected variables at distinct quantiles. A total of 1,060 patients were analyzed. The first and second-year residents (R1-R2) required longer AIT than the third and fourth-year residents and attending anesthesiologists (p = 0.006). Factors prolonging AIT included American Society of Anesthesiologist physical status ≧ III, arterial, central venous and epidural catheterization, and use of bronchoscopy. Presence of surgeon before induction would decrease AIT (p < 0.001). Types of surgery also had significant influence on AIT. Quantile regression satisfactorily estimated extra time needed to complete induction for each influential factor at distinct quantiles. Our analysis on AIT demonstrated the benefit of quantile regression analysis to provide more comprehensive view of the relationships between procedure time and related factors. This novel two-step regression approach has potential applications to procedure time analysis in operating room management.

Nano/micro fluorhydroxyapatite crystal pastes in the treatment of dentin hypersensitivity: an in vitro study.

OBJECTIVES: Dentin hypersensitivity (DH) is a prevalent problem. This study aimed to formulate a paste using fluorhydroxyapatite (FA) crystals dispersed in different carriers to treat DH. The ability to occlude patent dentinal tubules and to release ions was investigated. MATERIALS AND METHODS: Twenty percent FA/sodium alginate, 40% FA/poly(hydroxyethyl methacylate(HEMA)), and 40% FA/poly(DMA-co-MEA) were applied to etched dentin samples and examined with scanning electron microscopy (SEM) to determine the degree of tubule occlusion. Fluoride electrode was used to measure F release and spectroscopy to evaluate Ca and PO4 release. The cytotoxicity of the synthesized poly(DMA-co-MEA) gel was tested. Kruskall-Wallis test was used to test the differences in ion release between the groups. RESULTS: FA/poly(DMA-co-MEA) paste obstructed up to 80% of the dentinal tubules, while the coverage was up to 70% for FA/poly(HEMA) and less than 50% for FA/sodium alginate. Fluoride and Ca release was the highest for FA/P(HEMA), 7.2 ± 0.7 and 139.8 ± 32.5 ppm, respectively. The highest concentration of PO4 was 46.2 ± 16.4 ppm for FA/Sodium alginate. No statistical significance was found. CONCLUSIONS: FA/Poly(DMA-co-MEA) and FA/poly(HEMA) pastes may offer immediate short-term relief of DH because of their ability to occlude the tubules and adhere to wet dentin surfaces. The release of the F, Ca, and PO4 ions may offer long-term relief by forming a mineral barrier both within the dentinal tubules and on the dentin surface. CLINICAL SIGNIFICANCE: The tested materials may offer a long-term treatment for DH.

The common link between functional somatic syndromes may be central sensitisation.

OBJECTIVES: Functional somatic syndromes are common and disabling conditions that all include chronic pain, and which may be related to central nervous system sensitisation. Here, we address the concept of central sensitisation as a physiological basis for the functional somatic syndromes. METHODS: A narrative review of the current literature on central sensitisation and physiological studies in the functional somatic syndromes. RESULTS: Central sensitisation may be a common neurophysiological process that is able to explain non-painful as well as painful symptoms in these disorders. Furthermore, central sensitisation may represent an endophenotypic vulnerability to the development of these syndromes that potentially explains why they cluster together. CONCLUSIONS: Further research is needed to verify these findings, including prospective studies and the standardisation of combined methods of investigation in the study of central sensitisation in functional somatic syndromes. In turn, this may lead to new explanatory mechanisms and treatments being evaluated. Our conclusions add to the debate over the nomenclature of these syndromes but importantly also provide an explanation for our patients.

Effect of respiratory-induced intensity variations on finger SpO2 measurements in volunteers.

Photoplethysmographic (PPG) signals were recorded from the fingers of 16 healthy volunteers with periods of timed and forced respiration. The aim of this pilot study was to compare estimations of arterial oxygen saturation (SpO2) recorded using a dedicated pulse oximetry system while subjects were breathing regularly with and without a mouthpiece containing a flow resistor. The experiments were designed to mimic the effects of mechanical ventilation in anesthetized patients. The effect of estimated airway pressures of ± 15 cmH2O caused observable modulation in the recorded red and PPG signals. SpO2 values were calculated from the pre-recorded PPG signals. Mean SpO2 values were 95.4% with the flow resistor compared with 97.3% with no artificial resistance, with statistical significance demonstrated using a Student's t-test (P = 0.006).

Physical and chemical characterization of the surface layers formed on dentin following treatment with an experimental anhydrous stannous fluoride dentifrice.

PURPOSE: To characterize, in vitro, the mode of action of stannous fluoride containing formulations in occluding dentin tubules, by means of high resolution microscopy techniques. METHODS: Focused ion beam scanning electron microscopy (FIB SEM) was used to site-specifically prepare cross sections for SEM and TEM imaging and analysis of dentin samples treated with either a stannous fluoride dispersion in glycerol or an experimental stannous fluoride dentifrice. RESULTS: An experimental stannous fluoride dentifrice formed a protective layer over the dentin surface and occluded dentin tubules. Additional supporting data derived from a stannous fluoride dispersion in glycerol suggest that stannous fluoride is a key component of this occluding system. Multiple SEM images obtained from sequential FIB cross-sections were reconstructed into 3-dimensional tomograms that showed a formed layer and tubule occlusion. Sections thinned by FIB techniques were observed by transmission electron microscopy (TEM) and related methods and showed that the coating, which was up to 3 microm-thick, consisted of a tin containing precipitate. Chemical analysis by energy dispersive x-ray spectroscopy (EDS) mapping that used scanning TEM (STEM) methods showed interdiffusion of tin up to 200 nm into the dentin structure.

Perfusion assessment in rat spinal cord tissue using photoplethysmography and laser Doppler flux measurements.

Animal models are widely used to investigate the pathological mechanisms of spinal cord injury (SCI), most commonly in rats. It is well known that compromised blood flow caused by mechanical disruption of the vasculature can produce irreversible damage and cell death in hypoperfused tissue regions and spinal cord tissue is particularly susceptible to such damage. A fiberoptic photoplethysmography (PPG) probe and instrumentation system were used to investigate the practical considerations of making measurements from rat spinal cord and to assess its suitability for use in SCI models. Experiments to assess the regional perfusion of exposed spinal cord in anesthetized adult rats using both PPG and laser Doppler flowmetry (LDF) were performed. It was found that signals could be obtained reliably from all subjects, although considerable intersite and intersubject variability was seen in the PPG signal amplitude compared to LDF. We present results from 30 measurements in five subjects, the two methods are compared, and practical application to SCI animal models is discussed.

Self-assembly of LiMo3Se3 nanowire networks from nanoscale building-blocks in solution.

LiMo(3)Se(3) is a highly anisotropic solid comprised of a regular pattern of quasi-1-D wire-like structures. Solutions of LiMo(3)Se(3) deposited on substrates and TEM grids reveal the presence of two-dimensional network morphologies. High resolution STEM imaging reveals that the junctions within these networks are not formed by discrete overlying LiMo(3)Se(3) fibers or wires. Rather the junctions are continuous in that the wires are seamlessly interwoven from one bundle to the next. We investigated network formation by dynamic light scattering and AFM and demonstrate that the networks are not pre-existent in solution but rather form via self-assembly of nanoscale building blocks that is driven by solvent evaporation.

Patterning of crystalline organic materials by electro-hydrodynamic lithography.

The control of semi-crystalline polymers in thin films and in micrometer-sized patterns is attractive for (opto-)electronic applications. Electro-hydrodynamic lithography (EHL) enables the structure formation of organic crystalline materials on the micrometer length scale while at the same time exerting control over crystal orientation. This gives rise to well-defined micro-patterned arrays of uniaxially aligned polymer crystals. This study explores the interplay of EHL structure formation with crystal alignment and studies the mechanisms that give rise to crystal orientation in EHL-generated structures.

Modulation of finger photoplethysmographic traces during forced respiration: venous blood in motion?

Photoplethysmographic (PPG) signals were recorded from the fingers of 10 healthy volunteers during forced respiratory inspiration. The aim of this pilot study was to assess the effect of negative airway pressure on the blood volumes within the tissue bed of the finger, and the resultant modulation of PPG signals. The acquired signals were analysed and oxygen saturations estimated from the frequency spectra in the cardiac and respiratory frequency ranges. Assuming that respiratory modulation affects blood volumes in veins to a greater extent than in arteries, the local venous oxygen saturation was estimated. Estimated venous oxygen saturation was found to be 3.1% (±4.2%) lower than the estimated arterial saturation.

Photoplethysmographic measurements from the esophagus using a new fiber-optic reflectance sensor.

A prototype fiber-optic reflectance-mode pulse oximetry sensor and measurement system is developed for the purposes of estimating arterial oxygen saturation in the esophagus. A dedicated probe containing miniature right-angled glass prisms coupled to light sources and a photodetector by means of optical fibers is designed and used to record photoplethysmographic (PPG) signals from the esophageal epithelium in anesthetized patients. The probe is inserted simply by an anesthesiologist in all cases, and signals are recorded successfully in all but one of 20 subjects, demonstrating that esophageal PPG signals can be reliably obtained. The mean value of the oxygen saturation recorded from the esophagus for all subjects is 94.0 ± 4.0%. These results demonstrate that SpO(2) may be estimated in the esophagus using a fiber-optic probe.

An in vivo investigation of photoplethysmographic signals and preliminary pulse oximetry estimation from the bowel using a new fiberoptic sensor.

BACKGROUND: The continuous monitoring of splanchnic organ oxygen saturation could make the early detection of inadequate tissue oxygenation feasible, reducing the risk of hypoperfusion, severe ischemia, multiple organ failure, and, ultimately, death. Current methods for assessing splanchnic perfusion have not been widely accepted for use in the clinical care environment. In an attempt to overcome the limitations of the current techniques, a new fiberoptic photoplethysmographic (PPG)/pulse oximetry sensor was developed as a means of assessing splanchnic organ perfusion during surgery in humans. METHODS: A new fiberoptic splanchnic pulse oximeter and an optically identical fiberoptic finger pulse oximeter have been developed. Simultaneous PPG signals and preliminary estimates of arterial oxygen saturation from the bowel (small and large) and finger were obtained in 17 patients (3 men and 14 women) undergoing open laparotomy. RESULTS: Good quality PPG signals were obtained from the small and large bowel and from the finger in all patients (lower 95% confidence limit for the proportion was 0.64). Comparisons of blood oxygen saturation values acquired when using the splanchnic and the finger fiberoptic sensors and a commercial finger pulse oximeter indicated that there was no statistically significant difference between them (all P>0.454). A Bland and Altman plot of the difference between blood oxygen saturation values from the bowel fiberoptic pulse oximeter and the fiberoptic finger pulse oximeter against their mean showed that the limits of agreement between the 2 pulse oximeters were -3.8% and 4.2% for small bowel measurements, and -3.4% and 4.3% for large bowel measurements. The 95% prediction interval for the difference between the 2 devices was between -4.2% and 4.7%. CONCLUSION: This study demonstrated that good quality PPG signals can be obtained from the bowel using a new fiberoptic sensor. Further evaluation is required to determine whether fiberoptic pulse oximetry of the bowel may provide a suitable method for monitoring splanchnic perfusion.

Measurement of splanchnic photoplethysmographic signals using a new reflectance fiber optic sensor.

Splanchnic organs are particularly vulnerable to hypoperfusion. Currently, there is no technique that allows for the continuous estimation of splanchnic blood oxygen saturation (SpO(2)). As a preliminary to developing a suitable splanchnic SpO(2) sensor, a new reflectance fiber optic photoplethysmographic (PPG) sensor and processing system are developed. An experimental procedure to examine the effect of fiber source detector separation distance on acquired PPG signals is carried out before finalizing the sensor design. PPG signals are acquired from four volunteers for separation distances of 1 to 8 mm. The separation range of 3 to 6 mm provides the best quality PPG signals with large amplitudes and the highest signal-to-noise ratios (SNRs). Preliminary calculation of SpO(2) shows that distances of 3 and 4 mm provide the most realistic values. Therefore, it is suggested that the separation distance in the design of a fiber optic reflectance pulse oximeter be in the range of 3 to 4 mm. Preliminary PPG signals from various splanchnic organs and the periphery are obtained from six anaesthetized patients. The normalized amplitudes of the splanchnic PPGs are, on average, approximately the same as those obtained simultaneously from the periphery. These observations suggest that fiber optic pulse oximetry may be a valid monitoring technique for splanchnic organs.

Investigation of photoplethysmographic changes using a static compression model of spinal cord injury.

Little is known about cell death in spinal cord tissue following compression injury, despite compression being a key component of spinal injuries. Currently models are used to mimic compression injury in animals and the effects of the compression evaluated by observing the extent and duration of recovery of normal motor function in the days and weeks following the injury. A fiber-optic photoplethysmography system was used to investigate whether pulsation of the small arteries in the spinal cord occurred before, during and after compressive loads were applied to the tissue. It was found that the signal amplitudes were reduced and this reduction persisted for at least five minutes after the compression ceased. It is hoped that results from this preliminary study may improve knowledge of the mechanism of spinal cord injury.

Evaluation of a fiber-optic esophageal pulse oximeter.

A dual-wavelength fiber-optic pulse oximetry system was developed for the purposes of estimating oxygen saturation from the esophagus. A probe containing miniature right-angled glass prisms was used to record photoplethysmographic (PPG) signals from the esophageal wall. Signals were recorded successfully in 19 of 20 patients, demonstrating that PPG signals could be reliably obtained from an internal vascularized tissue site such as the esophageal epithelium. The value of the mean oxygen saturation recorded from the esophagus was 94.0 +/- 4.0%. These results demonstrate that SpO(2) may be estimated in the esophagus using a fiber-optic probe and this may be the first report of such measurements.