Is the effect of inguinal field block with 0.5 % bupivacaine on postoperative pain after hernia repair enhanced by addition of ketorolac or S(+) ketamine ?

Résumé Malgré l'apparition de nouvelles techniques chirurgicales dites « sans tension », l'antalgie post-opératoire après cure de hernie inguinale reste un défi pour les anesthésiologistes. Récemment on a suggéré que l'addition de ketamine ou d'un anti-inflammatoire non-stéroïdien (AINS) à un anesthésique local pourrait améliorer et prolonger l'analgésie postopératoire. Le but de cette étude, à laquelle ont participé 36 patients ASA I-II, était d'évaluer si la coadministration de S(+) ketamine ou de ketorolac renforcerait les effets analgésiques de la bupivacaïne après cure ambulatoire de hernie inguinale sous anesthésie générale. L'analgésie a consisté en une infiltration de la plaie associé à un bloc inguinal avec soit 30 ml de bupivacaïne 0,5 % (n=12), soit 27 ml de bupivacaïne 0,5 % + 3 ml de S(+) ketamine (75 mg) (n=12), soit 28 ml de bupivacaïne 0,5 % + 2 ml de ketorolac (60 mg) (n=12). La prise orale d'antalgique en phase postopératoire était standardisée. L'intensité des douleurs a été évaluée au moyen d'une échelle visuelle analogique (EVA), d'un score verbal d'estimation et par algométrie de pression respectivement 2, 4, 6, 24 et 48 heures après l'intervention. Les trois groupes de patients ont présenté le score de douleur évalué par EVA le plus élevé à 24 heures, score significativement différent de ceux mesurés à 6 et 48 heures (P <0.05). A part une sensation de douleurs significativement moindre (score verbal d'estimation) dans le groupe ketorolac à 24 et 48 heures et seulement à 48 heures dans le groupe ketamine, il n'y avait aucune autre différence entre les groupes pour la durée de l'étude (48 heures) en ce qui concerne les scores de douleur, les seuils de douleur à la pression ou la prise postopératoire d'antalgiques « de secours ». En conclusion, l'addition de S(+) ketamine ou de ketorolac, n'améliore que marginalement l'effet analgésique de la bupivacaïne. Ceci peut-être mis en relation avec la technique de cure de hernie « sans tension » induisant un bas niveau de douleur postopératoire. Abstract Objective: The aim of the study was to assess whether coadministration of S(±) ketamine or ketorolac would enhance or prolong local analgesic effect of bupivacaine after inguinal hernia repair. Design: Prospective double-blind randomized study evaluating pain intensity after surgery under general anesthesia. Setting: Outpatient facilities of the University Hospital of Lausanne. Patient: Thirty-six ASA I-II outpatients scheduled for elective day-case inguinal herniorraphy. Intervention: Analgesia strategy consisted of a wound infiltration and an inguinal field block either with 30 mL bupivacairie (0.5%) or with the same volume of a mixture of 27 mL bupivacaine (0.5%) + 3 mL S(+) ketamine (75 mg) or a 28 mL bupivacaine (0.5%) + 2 ML ketorolac (60 mg). Postoperative analgesic regimen was standardized. Outcome Measures: Pain intensity was assessed with a Visual Analog Seale, a verbal rating score, and by pressure algometry 2, 4, 6, 24, and 48 hours after surgery. Results: The 3 groups of patients experienced the highest Visual Analog Scale pain score at 24 hours, which was different from those at 6 and 48 hours (P < 0.05). Apart from a significantly lower pain sensation (verbal rating score) in the ketorolac group at 24 and 48 hours and only at 48 hours with ketamine, there were no other differences in pain scores, pain pressure thresholds, or rescue analgesic consumption between groups throughout the 48-hour study period. Conclusion: The addition of S (+)-ketamine or ketorolac only minimally improves the analgesic effect of bupivacaine. This may be related to the tension-free hernia repair technique associated with low postoperative pain.

Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease.

BACKGROUND: In patients with outer retinal degeneration, a differential pupil response to long wavelength (red) versus short wavelength (blue) light stimulation has been previously observed. The goal of this study was to quantify differences in the pupillary re-dilation following exposure to red versus blue light in patients with outer retinal disease and compare them with patients with optic neuropathy and with healthy subjects. DESIGN: Prospective comparative cohort study. PARTICIPANTS: Twenty-three patients with outer retinal disease, 13 patients with optic neuropathy and 14 normal subjects. METHODS: Subjects were tested using continuous red and blue light stimulation at three intensities (1, 10 and 100 cd/m2) for 13 s per intensity. Pupillary re-dilation dynamics following the brightest intensity was analysed and compared between the three groups. MAIN OUTCOME MEASURES: The parameters of pupil re-dilation used in this study were: time to recover 90% of baseline size; mean pupil size at early and late phases of re-dilation; and differential re-dilation time for blue versus red light. RESULTS: Patients with outer retinal disease showed a pupil that tended to stay smaller after light termination and thus had a longer time to recovery. The differential re-dilation time was significantly greater in patients with outer retinal disease (median = 28.0 s, P < 0.0001) compared with controls and patients with optic neuropathy. CONCLUSIONS: A differential response of pupil re-dilation following red versus blue light stimulation is present in patients with outer retinal disease but is not found in normal eyes or among patients with visual loss from optic neuropathy.

Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fields.

Over the last decade, there has been a significant increase in the number of high-magnetic-field MRI magnets. However, the exact effect of a high magnetic field strength (B0 ) on diffusion-weighted MR signals is not yet fully understood. The goal of this study was to investigate the influence of different high magnetic field strengths (9.4 T and 14.1 T) and diffusion times (9, 11, 13, 15, 17 and 24 ms) on the diffusion-weighted signal in rat brain white matter. At a short diffusion time (9 ms), fractional anisotropy values were found to be lower at 14.1 T than at 9.4 T, but this difference disappeared at longer diffusion times. A simple two-pool model was used to explain these findings. The model describes the white matter as a first hindered compartment (often associated with the extra-axonal space), characterized by a faster orthogonal diffusion and a lower fractional anisotropy, and a second restricted compartment (often associated with the intra-axonal space), characterized by a slower orthogonal diffusion (i.e. orthogonal to the axon direction) and a higher fractional anisotropy. Apparent T2 relaxation time measurements of the hindered and restricted pools were performed. The shortening of the pseudo-T2 value from the restricted compartment with B0 is likely to be more pronounced than the apparent T2 changes in the hindered compartment. This study suggests that the observed differences in diffusion tensor imaging parameters between the two magnetic field strengths at short diffusion time may be related to differences in the apparent T2 values between the pools. Copyright © 2013 John Wiley & Sons, Ltd.

Multiplex ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification in human plasma of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, anidulafungin, and caspofungin.

Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 μl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 μg/ml; those of echinocandin quantification, 0.06 to 0.1 μg/ml), accurate (intra- and interassay biases of -9.9 to +5% and -4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 μg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC-MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research.

Endothelial Cell-Derived Nitric Oxide Enhances Aerobic Glycolysis in Astrocytes via HIF-1α-Mediated Target Gene Activation.

Astrocytes exhibit a prominent glycolytic activity, but whether such a metabolic profile is influenced by intercellular communication is unknown. Treatment of primary cultures of mouse cortical astrocytes with the nitric oxide (NO) donor DetaNONOate induced a time-dependent enhancement in the expression of genes encoding various glycolytic enzymes as well as transporters for glucose and lactate. Such an effect was shown to be dependent on the hypoxia-inducible factor HIF-1α, which is stabilized and translocated to the nucleus to exert its transcriptional regulation. NO action was dependent on both the PI3K/Akt/mTOR and MEK signaling pathways and required the activation of COX, but was independent of the soluble guanylate cyclase pathway. Furthermore, as a consequence of NO treatment, an enhanced lactate production and release by astrocytes was evidenced, which was prevented by downregulating HIF-1α. Several brain cell types represent possible sources of NO. It was found that endothelial cells, which express the endothelial NO synthase (eNOS) isoform, constitutively produced the largest amount of NO in culture. When astrocytes were cocultured with primary cultures of brain vascular endothelial cells, stabilization of HIF-1α and an enhancement in glucose transporter-1, hexokinase-2, and monocarboxylate transporter-4 expression as well as increased lactate production was found in astrocytes. This effect was inhibited by the NOS inhibitor l-NAME and was not seen when astrocytes were cocultured with primary cultures of cortical neurons. Our findings suggest that endothelial cell-derived NO participates to the maintenance of a high glycolytic activity in astrocytes mediated by astrocytic HIF-1α activation.

Effect of a smoking ban on respiratory health in nonsmoking hospitality workers: a prospective cohort study

OBJECTIVE: The aim of this study was to examine the effect of a smoking ban on lung function, fractional exhaled nitric oxide, and respiratory symptoms in nonsmoking hospitality workers. METHODS: Secondhand smoke exposure at the workplace, spirometry, and fractional exhaled nitric oxide were measured in 92 nonsmoking hospitality workers before as well as twice after a smoking ban. RESULTS: At baseline, secondhand smoke-exposed hospitality workers had lung function values significantly below the population average. After the smoking ban, the covariate-adjusted odds ratio for cough was 0.59 (95% confidence interval, 0.36 to 0.93) and for chronic bronchitis 0.75 (95% confidence interval, 0.55 to 1.02) compared with the preban period. CONCLUSIONS: The below-average lung function before the smoking ban indicates chronic damages from long-term exposure. Respiratory symptoms such as cough decreased within 12 months after the ban.

Probability of achieving optimal molecular response to imatinib in chronic myeloid leukemia (CML) patients: Pharmacokinetic/Pharmacodynamic (PK/PD) relationships observed under field-conditions

Objectives: Imatinib has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations (Cmin) correlate with response rates in CML patients. This analysis aimed to evaluate the impact of imatinib exposure on optimal molecular response rates in a large European cohort of patients followed by centralized TDM.¦Methods: Sequential PK/PD analysis was performed in NONMEM 7 on 2230 plasma (PK) samples obtained along with molecular response (PD) data from 1299 CML patients. Model-based individual Bayesian estimates of exposure, parameterized as to initial dose adjusted and log-normalized Cmin (log-Cmin) or clearance (CL), were investigated as potential predictors of optimal molecular response, while accounting for time under treatment (stratified at 3 years), gender, CML phase, age, potentially interacting comedication, and TDM frequency. PK/PD analysis used mixed-effect logistic regression (iterative two-stage method) to account for intra-patient correlation.¦Results: In univariate analyses, CL, log-Cmin, time under treatment, TDM frequency, gender (all p<0.01) and CML phase (p=0.02) were significant predictors of the outcome. In multivariate analyses, all but log-Cmin remained significant (p<0.05). Our model estimates a 54.1% probability of optimal molecular response in a female patient with a median CL of 14.4 L/h, increasing by 4.7% with a 35% decrease in CL (percentile 10 of CL distribution), and decreasing by 6% with a 45% increased CL (percentile 90), respectively. Male patients were less likely than female to be in optimal response (odds ratio: 0.62, p<0.001), with an estimated probability of 42.3%.¦Conclusions: Beyond CML phase and time on treatment, expectedly correlated to the outcome, an effect of initial imatinib exposure on the probability of achieving optimal molecular response was confirmed in field-conditions by this multivariate analysis. Interestingly, male patients had a higher risk of suboptimal response, which might not exclusively derive from their 18.5% higher CL, but also from reported lower adherence to the treatment. A prospective longitudinal study would be desirable to confirm the clinical importance of identified covariates and to exclude biases possibly affecting this observational survey.

Recurrent idiopathic neuroretinitis: natural history and effect of treatment.

BACKGROUND: Previous reports have emphasized the self-limited nature of idiopathic neuroretinitis. There is less information about a subgroup of patients who suffer recurrent episodes with worse visual outcome. We sought to better characterize the clinical features of recurrent idiopathic neuroretinitis including the effects of immunosuppressive treatment. METHODS: Retrospective chart review of neuroretinitis patients from a single institution from 1983 to 2008. Inclusion criteria included two or more episodes of acute visual loss with disc oedema and macular exudates in a star pattern. Cases due to a specific infectious or inflammatory aetiology were excluded. RESULTS: Forty-one patients were included with an average follow up of 67 months. Median age at the time of the first episode was 28 years (range 10-54 years). Attacks were bilateral sequential in 34 patients (83%). We documented a total of 147 episodes in 75 eyes with an average of 3.6 attacks per patient. The average interval between attacks was 3 years. Visual field loss had a nerve fibre bundle pattern in most cases. Only 36% of eyes retained 6/12 or better visual acuity and greater than two-thirds of their visual field. Long-term immunosuppressive treatment in 13 patients decreased the attack rate by 72%. CONCLUSIONS: Recurrent idiopathic neuroretinitis typically affects young adults, with no gender preference. Recovery is limited and visual loss is cumulative with repeated attacks, often resulting in severe permanent visual loss. Immunosuppressive treatment appears to lessen the attack frequency.

Endothelial nitric oxide synthase gene transfer restores endothelium-dependent relaxations and attenuates lesion formation in carotid arteries in apolipoprotein E-deficient mice.

Nitric oxide (NO) and monocyte chemoattractant protein-1 (MCP-1) exert partly opposing effects in vascular biology. NO plays pleiotropic vasoprotective roles including vasodilation and inhibition of platelet aggregation, smooth muscle cell proliferation, and endothelial monocyte adhesion, the last effect being mediated by MCP-1 downregulation. Early stages of arteriosclerosis are associated with reduced NO bioactivity and enhanced MCP-1 expression. We have evaluated adenovirus-mediated gene transfer of human endothelial NO synthase (eNOS) and of a N-terminal deletion (8ND) mutant of the MCP-1 gene that acts as a MCP-1 inhibitor in arteriosclerosis-prone, apolipoprotein E-deficient (ApoE(-/-)) mice. Endothelium-dependent relaxations were impaired in carotid arteries instilled with a noncoding adenoviral vector but were restored by eNOS gene transfer (p < 0.01). A perivascular collar was placed around the common carotid artery to accelerate lesion formation. eNOS gene transfer reduced lesion surface areas, intima/media ratios, and macrophage contents in the media at 5-week follow-up (p < 0.05). In contrast, 8ND-MCP-1 gene transfer did not prevent lesion formation. In conclusion, eNOS gene transfer restores endothelium-dependent vasodilation and inhibits lesion formation in ApoE(-/-) mouse carotids. Further studies are needed to assess whether vasoprotection is maintained at later disease stages and to evaluate the long-term efficacy of eNOS gene therapy for primary arteriosclerosis.

Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis.

PURPOSE: To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU). METHODS: EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization. The pharmacokinetics of tresperimus was evaluated in the ocular tissues and plasma. The in vitro effect of tresperimus was evaluated on macrophages. EAU was graded clinically and histologically. Blood ocular barrier permeability was evaluated by protein concentration in ocular fluids. Immune response to S-Ag was examined by delayed type hypersensitivity, the expression of inflammatory cytokines in lymph nodes, ocular fluids and serum by multiplex ELISA, and in ocular cells by RT-PCR. RESULTS: In vitro, tresperimus significantly reduced the production of inflammatory cytokines by lipopolysaccharide-stimulated macrophages. In vivo, in the treatment protocol, efficient tresperimus levels were measured in the eye but not in the plasma up to 8 days after the last injection. Tresperimus efficiently reduced inflammation, retinal damage, and blood ocular barrier permeability breakdown. It inhibited nitric oxide synthase-2 and nuclear factor κBp65 expression in ocular macrophages. IL-2 and IL-17 were decreased in ocular media, while IL-18 was increased. By contrast, IL-2 and IL-17 levels were not modified in inguinal lymph nodes draining the immunization site. Moreover, cytokine levels in serum and delayed type hypersensitivity to S-Ag were not different in control and treated rats. In the prevention/treatment protocol, ocular immunosuppressive effects were also observed. CONCLUSIONS: Locally administered tresperimus appears to be a potential immunosuppressive agent in the management of intraocular inflammation.

The borehole-fluid effect in electrical resistivity imaging

Fluid that fills boreholes in crosswell electrical resistivity investigations provides the necessary electrical contact between the electrodes and the rock formation but it is also the source of image artifacts in standard inversions that do not account for the effects of the boreholes. The image distortions can be severe for large resistivity contrasts between the rock formation and borehole fluid and for large borehole diameters. We have carried out 3D finite-element modeling using an unstructured-grid approach to quantify the magnitude of borehole effects for different resistivity contrasts, borehole diameters, and electrode configurations. Relatively common resistivity contrasts of 100:1 and borehole diameters of 10 and 20 cm yielded, for a bipole length of 5 m, apparent resistivity underestimates of approximately 12% and 32% when using AB-MN configurations and apparent resistivity overestimates of approximately 24% and 95% when using AM-BN configurations. Effects are generally more severe at shorter bipole spacings. We report the results obtained by either including or ignoring the boreholes in inversions of 3D field data from a test site in Switzerland, where approximately 10,000 crosswell resistivity-tomography measurements were made across six acquisition planes among four boreholes. Inversions of raw data that ignored the boreholes filled with low-resistivity fluid paradoxically produced high-resistivity artifacts around the boreholes. Including correction factors based on the modeling results fora ID model with and without the boreholes did not markedly improve the images. The only satisfactory approach was to use a 3D inversion code that explicitly incorporated the boreholes in the actual inversion. This new approach yielded an electrical resistivity image that was devoid of artifacts around the boreholes and that correlated well with coincident crosswell radar images.

Breath acetone to monitor life style interventions in field conditions: An exploratory study.

OBJECTIVE: To assess whether breath acetone concentration can be used to monitor the effects of a prolonged physical activity on whole body lipolysis and hepatic ketogenesis in field conditions. METHODS: Twenty-three non-diabetic, 11 type 1 diabetic, and 17 type 2 diabetic subjects provided breath and blood samples for this study. Samples were collected during the International Four Days Marches, in the Netherlands. For each participant, breath acetone concentration was measured using proton transfer reaction ion trap mass spectrometry, before and after a 30-50 km walk on four consecutive days. Blood non-esterified free fatty acid (NEFA), beta-hydroxybutyrate (BOHB), and glucose concentrations were measured after walking. RESULTS: Breath acetone concentration was significantly higher after than before walking, and was positively correlated with blood NEFA and BOHB concentrations. The effect of walking on breath acetone concentration was repeatedly observed on all four consecutive days. Breath acetone concentrations were higher in type 1 diabetic subjects and lower in type 2 diabetic subjects than in control subjects. CONCLUSIONS: Breath acetone can be used to monitor hepatic ketogenesis during walking under field conditions. It may, therefore, provide real-time information on fat burning, which may be of use for monitoring the lifestyle interventions.

Role of glutathione in macrophage activation: effect of cellular glutathione depletion on nitrite production and leishmanicidal activity.

We have examined the effects of two agents depleting the intracellular pool of glutathione (GSH) on macrophage activation induced by IFN-gamma + LPS, as measured by nitrite production and leishmanicidal activity. Diethylmaleate (DEM), which depletes intracellular GSH by conjugation via a reaction catalyzed by the GSH-S-transferase, strongly inhibited nitrite secretion and leishmanicidal activity when added before or at the time of addition of IFN-gamma + LPS; this inhibition was progressively lost when addition of DEM was delayed up to 10 hr. A close correlation was observed between levels of intracellular soluble GSH during activation and nitrite secretion. Inhibition was partially reversed by the addition of glutathione ethyl ester (GSH-Et). Buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, also inhibited macrophage activation, although to a lesser extent than DEM despite a more pronounced soluble GSH depletion. This inhibition was completely reversed by the addition of GSH-Et. DEM and BSO did not alter cell viability or PMA-triggered O2- production by activated macrophages, suggesting that the inhibitory effects observed on nitrite secretion and leishmanicidal activity were not related to a general impairment of macrophage function. DEM and BSO treatment reduced iNOS specific activity and iNOS protein in cytosolic extracts. DEM also decreased iNOS mRNA expression while BSO had no effect. Although commonly used as a GSH-depleting agent, DEM may have additional effects because it can also act as a sulhydryl reagent; BSO, on the other hand, which depletes GSH by enzymatic inhibition, has no effect on protein-bound GSH. Our results suggest that both soluble and protein-bound GSH may be important for the induction of NO synthase in IFN-gamma + LPS-activated macrophages.

MP2RAGE, a self bias-field corrected sequence for improved segmentation and T-1-mapping at high field

The large spatial inhomogeneity in transmit B, field (B-1(+)) observable in human MR images at hi h static magnetic fields (B-0) severely impairs image quality. To overcome this effect in brain T-1-weighted images the, MPRAGE sequence was modified to generate two different images at different inversion times MP2RAGE By combining the two images in a novel fashion, it was possible to create T-1-weigthed images where the result image was free of proton density contrast, T-2* contrast, reception bias field, and, to first order transmit field inhomogeneity. MP2RAGE sequence parameters were optimized using Bloch equations to maximize contrast-to-noise ratio per unit of time between brain tissues and minimize the effect of B-1(+) variations through space. Images of high anatomical quality and excellent brain tissue differentiation suitable for applications such as segmentation and voxel-based morphometry were obtained at 3 and 7 T. From such T-1-weighted images, acquired within 12 min, high-resolution 3D T-1 maps were routinely calculated at 7 T with sub-millimeter voxel resolution (0.65-0.85 mm isotropic). T-1 maps were validated in phantom experiments. In humans, the T, values obtained at 7 T were 1.15 +/- 0.06 s for white matter (WM) and 1.92 +/- 0.16 s for grey matter (GM), in good agreement with literature values obtained at lower spatial resolution. At 3 T, where whole-brain acquisitions with 1 mm isotropic voxels were acquired in 8 min the T-1 values obtained (0.81 +/- 0.03 S for WM and 1.35 +/- 0.05 for GM) were once again found to be in very good agreement with values in the literature. (C) 2009 Elsevier Inc. All rights reserved.