Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial.

BACKGROUND: Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Characterizing tissue stiffness at the tip of a rigid needle using an opto-mechanical force sensor.

We present a novel device that allows the user to measure the Young Modulus of a material at the opening of a 5 mm diameter needle. The device relies on a miniaturized cantilever spring mounted at the end of the needle and interrogated via Fabry-Pérot optical fiber interferometry. The probe is repetitively brought in and out of contact with the sample at the end of the needle by means of a steel cable that is controlled via a piezoelectric actuator located at the proximal end. We demonstrate the ability of our device to detect and quantify layers of varying stiffness during needle insertion in a gelatin phantom and to successfully locate tissue boundaries in bovine liver tissue embedded in gelatin.

Opto-mechanical probe for combining atomic force microscopy and optical near-field surface analysis.

We have developed a new easy-to-use probe that can be used to combine atomic force microscopy (AFM) and scanning near-field optical microscopy (SNOM). We show that, using this device, the evanescent field, obtained by total internal reflection conditions in a prism, can be visualized by approaching the surface with the scanning tip. Furthermore, we were able to obtain simultaneous AFM and SNOM images of a standard test grating in air and in liquid. The lateral resolution in AFM and SNOM mode was estimated to be 45 and 160 nm, respectively. This new probe overcomes a number of limitations that commercial probes have, while yielding the same resolution.

Suction-Based Optical Coherence Elastography for the Biomechanical Characterization of Pathological Skin Conditions: A Pilot Study.

Accurate characterization of mechanical properties is crucial in the evaluation of therapeutic effects for problematic skin conditions. A pilot study was carried out using a novel optical coherence elastography (OCE) device, combining mechanical characterization through suction-based deformation and imaging through optical coherence tomography. Using AI-assisted image segmentation and a power-law model, we were able to describe the mechanical behavior, comparing with measurements from the most commonly used commercial instrument (Cutometer) and subjective analyses of stiffness using the Patient and Observer Scar Assessment Scale. Twenty subjects were included with either keloids or hypertrophic scars. Measurements were fast and produced no discomfort. Mechanical and structural (epidermal thickness and rugosity) descriptors in pathologic skin conditions differed significantly from those in control tissue. We showed for the first time, the clinical feasibility of this novel suction-based OCE device in evaluating mechanical and structural properties in pathological skin conditions such as scars.

Fibre-top atomic force microscope probe with optical near-field detection capabilities.

We present a fibre-top probe fabricated by carving a tipped cantilever on an optical fibre, with the tip machined in correspondence of the fibre core. When approached to an optical prism illuminated under total internal reflection conditions, the tip of the cantilever detects the optical tunnelling signal, while the light coupled from the opposite end of the fibre measures the deflection of the cantilever. Our results suggest that fibre-top technology can be used for the development of a new generation of hybrid probes that can combine atomic force microscopy with scanning near field optical microscopy.

Tuning the mass of chameleon fields in Casimir force experiments.

We have calculated the chameleon pressure between two parallel plates in the presence of an intervening medium that affects the mass of the chameleon field. As intuitively expected, the gas in the gap weakens the chameleon interaction mechanism with a screening effect that increases with the plate separation and with the density of the intervening medium. This phenomenon might open up new directions in the search of chameleon particles with future long-range Casimir force experiments.

Effect of total body temperature on toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).

One hundred eighty-two rats were divided into groups to test the effect of three different total body temperature levels on the toxic effect of three different dose levels of 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) and to assess the effect of delayed total body temperature elevation on BCNU breakdown products. Results were tabulated on the basis of life survival figures. At depressed total body temperatures (28 degrees C), normally expected toxicity was avoided. Elevated body temperatures, on the other hand, enhanced the toxic effect of BCNU. Delayed total body temperature elevation (3 and 6 days after BCNU administration) created similar toxicity. This finding was not observed when total body temperature elevation was delayed 10 days. The results point toward an interesting interaction between BCNU and heat (immediate and delayed) on the basis of an elevated metabolic rate of tissue, a synergistic effect of two therapeutic modalities, interference with normal reparative processes by the combination, or an enhancement of retained serum protein-bound breakdown products of BCNU.

Brain-tumor cell kinetics correlated with survival.

In a review of 38 glioblastoma patients for whom fresh tissue kinetic data were available before any therapy was instituted, no correlation between the labeling index and survival time could be statistically determined. This relationship seems entirely consistent with the published theoretical determinants of tumor behavior: that is, altered ability for growth arrest and differentiation, constantly evolving mutant sublines, genetic instability, and an ever-changing metabolic and vascular environment.

Ferrule-top nanoindenter: an optomechanical fiber sensor for nanoindentation.

Ferrule-top probes are self-aligned all-optical devices obtained by fabricating a cantilever on the top of a ferruled optical fiber. This approach has been proven to provide a new platform for the realization of small footprint atomic force microscopes (AFMs) that adapt well to utilization outside specialized laboratories [D. Chavan et al., Rev. Sci. Instrum. 81, 123702 (2010); ibid. 82, 046107 (2011)]. In this paper we now show that ferrule-top cantilevers can be also used to develop nanoindenters. Our instrument combines the sensitivity of commercial AFM-based indentation with the ease-of-use of more macroscopic instrumented indenters available today on the market. Furthermore, the all-optical design allows smooth operations also in liquids, where other devices are much more limited and often provide data that are difficult to interpret. This study may pave the way to the implementation of a new generation user-friendly nanoindenters for the measurement of the stiffness of samples in material sciences and medical research.

Note: ferrule-top atomic force microscope. II. Imaging in tapping mode and at low temperature.

In a recent paper [D.Chavan et al., Rev. Sci. Instrum. 81, 123702 (2010)] we have demonstrated that ferrule-top cantilevers, obtained by carving the end of a ferruled fiber, can be used for contact mode atomic force microscopy in ambient conditions. Here we show that those probes can provide tapping mode images at both room and cryogenic temperatures (12 K).

Ferrule-top atomic force microscope.

Ferrule-top cantilevers are a new generation of all-optical miniaturized devices for utilization in liquids, harsh environments, and small volumes [G. Gruca et al., Meas. Sci. Technol. 21, 094033 (2010)]. They are obtained by carving the end of a ferruled fiber in the form of a mechanical beam. Light coupled from the opposite side of the fiber allows detection of cantilever deflections. In this paper, we demonstrate that ferrule-top cantilevers can be used to develop ultra compact AFMs for contact mode imaging in air and in liquids with sensitivity comparable to that of commercial AFMs. The probes do not require any alignment procedure and are easy to handle, favoring applications also outside research laboratories.

Halving the Casimir force with conductive oxides.

The possibility to modify the strength of the Casimir effect by tailoring the dielectric functions of the interacting surfaces is regarded as a unique opportunity in the development of micro- and nanoelectromechanical systems. In air, however, one expects that, unless noble metals are used, the electrostatic force arising from trapped charges overcomes the Casimir attraction, leaving no room for exploitation of Casimir force engineering at ambient conditions. Here we show that, in the presence of a conductive oxide, the Casimir force can be the dominant interaction even in air, and that the use of conductive oxides allows one to reduce the Casimir force up to a factor of 2 when compared to noble metals.

Modulation of mild bleeding disorder during remissions and exacerbations of Graves' disease.

A patient with Graves' disease had a symptomatic thrombocytopathy during periods of remission. When euthyroid, she noticed bruising, petechiae, and epistaxis. Hemostatic abnormalities included prolongation of the bleeding time by aspirin, reduced platelet retention (a second-phase defect), and abnormal thrombin-induced aggregation and serotonin release. When hyperthyroid, bleeding symptoms resolved, and platelet function returned to normal. These observations suggest that mild bleeding disorders may be influenced either directly or indirectly by thyroid hormone levels.

Biphasic glucocorticoid regulation of pulmonary SP-A: characterization of inhibitory process.

Pulmonary surfactant, which is necessary for normal lung function, is under both developmental and hormonal regulation. Glucocorticoids induce all components of surfactant and have a unique biphasic effect on surfactant protein A (SP-A), either stimulating or inhibiting accumulation in cultured fetal lung depending on dose and time of exposure. In this study we further characterized glucocorticoid inhibition of SP-A in cultured explants of human fetal lung. Decreased content of SP-A mRNA was the dominant response to dexamethasone added either early or later during culture. Inhibition occurred at < or = 1 nM dexamethasone on prolonged exposure, was blocked by RU 486, and was observed with other glucocorticoids but not sex steroids. When cortisol was removed from the culture medium, inhibition was rapidly reversed. The immediate inhibitory effect of 100 nM dexamethasone on SP-A mRNA content was completely blocked in the presence of cycloheximide. SP-A gene transcription, measured by nuclear elongation assay, was decreased by 60% after 4- to 8-h exposure to 100 nM dexamethasone. Stability of SP-A mRNA, determined both by addition of actinomycin D and by label-chase experiments, was transiently decreased immediately after adding dexamethasone (t1/2 approximately 3 h). In tissue treated with dexamethasone for > or = 8 h the stability of SP-A mRNA in control and treated explants was not different (t1/2 approximately 8 h). Our findings indicate that inhibition of SP-A is the dominant response to glucocorticoid. This effect is receptor mediated and apparently involves induction of a labile protein(s) that decreases gene transcription and transiently reduces mRNA stability.

Experimental evaluation of nonspecific immunostimulation and chemotherapy in the intracranial tumor-bearing Fisher rat.

One hundred sixty rats bearing intracranial tumors were divided into groups of 10 to evaluate C-I interval +, effect of chemotherapy alone (BCNU), chemotherapy and C. parvum, and C. parvum alone in the rat tumor model. All therapy was administered intraperitoneally: BCNU -5.2 mg/kg (40% of LD10) on the 9th and 16th post tumor implant day, and C. parvum-1.4 mg regardless of the body weight and the 6th or 23rd day and 6th and 23rd post tumor implant day. An additional group received BCNU on the 9th and 16th day and C. parvum every 3rd day beginning with the 11th post implant day. It is concluded that C. parvum given before BCNU yields the greatest increase in survival in this animal system. Two or more injections were detrimental and injections after BCNU were of less value. C. parvum alone was minimally effective. If nonspecific immunostimulation is contemplated in this animal tumor system, it would appear to be best given before chemotherapy. This may relate to the brain as a "privileged immune site", or a peculiarity of the blood brain barrier in an intracranial lesion as it related to combined therapy.

Effect of preterm birth on pulmonary function at school age: a prospective controlled study.

OBJECTIVE: To assess long-term pulmonary outcome of a regional cohort of children born at < 32 weeks' gestation compared with a matched term control group. STUDY DESIGN: All 125 surviving children born at 24 to 31 weeks' gestation during a 1-year period and a sociodemographically matched term control group were evaluated at age 7 years. RESULTS: Preterm children with previous bronchopulmonary dysplasia (BPD) were twice as likely to require rehospitalization during the first 2 years of life than were preterm children without BPD (53% vs 26%, P < .01). At 7 years of age the BPD group had more airway obstruction than did both preterm children without BPD and the term control group (significantly reduced mean forced vital capacity, forced expiratory volume in 1 second, and forced expiratory flow, 25% to 75% vital capacity, all, P < .001). Lung function among preterm children without previous BPD was similar to that of the term control group. Bronchodilator responsiveness was observed twice as often in preterm children with previous BPD (20 of 43, 47%) compared with preterm children without BPD (13 of 53, 25%) or the term control group (23 of 108, 21%, P < .001). These differences remained significant after adjustment was done for birth weight and gestational age. CONCLUSION: Preterm children without BPD demonstrate pulmonary function at school age similar to that of children in a healthy term control group, whereas preterm children with previous BPD demonstrate abnormal pulmonary function.

Differential glucocorticoid regulation of the pulmonary hydrophobic surfactant proteins SP-B and SP-C.

Glucocorticoids increase expression of the genes for the pulmonary surfactant-associated proteins SP-B and SP-C in fetal lung both in vivo and in vitro. To examine the mechanism of these effects, we studied induction of SP-B and SP-C mRNAs in human fetal lung cultured as explants. Both mRNA levels rose rapidly in response to 100 nM dexamethasone (Dex), with a faster response for SP-B: maximal levels of induction were achieved in < or = 12 h for SP-B (3.5-fold versus control) versus approximately 24 h for SP-C mRNA (35-fold versus control). Cycloheximide (2.5 micrograms/ml) did not affect glucocorticoid induction of SP-B mRNA but markedly decreased induction of SP-C mRNA. In control cultures, cycloheximide did not significantly reduce levels of either transcript. In nuclear run-on assays, Dex increased the rate of gene transcription for both SP-B (2.8 +/- 0.3-fold versus control, n = 4) and SP-C (10- to 30-fold). Using actinomycin D to assess mRNA stability, the t1/2 of SP-B mRNA was increased from 7.5 +/- 0.4 h to 18.8 +/- 2.9 h by Dex treatment (P < 0.05), whereas the t1/2 of SP-C mRNA was not affected (9.3 +/- 1.7 h versus 8.1 +/- 1.2 h; NS). A similar increase in SP-B mRNA t1/2 with Dex (from 6 h to 19 h) was observed in label-chase studies with [3H]uridine. We conclude that glucocorticoids regulate the hydrophobic surfactant proteins of alveolar type II cells by different mechanisms: induction of SP-B is a primary response and includes an increase in both transcription rate and mRNA stability, whereas induction of SP-C is a secondary process, requiring ongoing protein synthesis, involving increased transcription rate without a change in mRNA stability.