The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus.

PURPOSE: When treating peripheral ectatic disease-like pellucid marginal degeneration (PMD), corneal cross-linking with UV-A and riboflavin (CXL) must be applied eccentrically to the periphery of the lower cornea, partly irradiating the corneal limbus. Here, we investigated the effect of standard and double-standard fluence corneal cross-linking with riboflavin and UV-A (CXL) on cornea and corneal limbus in the rabbit eye in vivo. METHODS: Epithelium-off CXL was performed in male New Zealand White rabbits with two irradiation diameters (7 mm central cornea, 13 mm cornea and limbus), using standard fluence (5.4 J/cm(2)) and double-standard fluence (10.8 J/cm(2)) settings. Controls were subjected to epithelial removal and riboflavin instillation, but were not irradiated with UV-A. Following CXL, animals were examined daily until complete closure of the epithelium, and at 7, 14, 21, and 28 days. Animals were killed and a corneoscleral button was excised and processed for light microscopy and immunohistochemistry. RESULTS: For both irradiation diameters and fluences tested, no signs of endothelial damage or limbal vessel thrombosis were observed, and time to re-epithelialization was similar to untreated controls. Histological and immunohistochemical analysis revealed no differences in the p63 putative stem cell marker expression pattern. CONCLUSIONS: Even when using fluence twice as high as the one used in current clinical CXL settings, circumferential UV-A irradiation of the corneal limbus does not alter the regenerative capacity of the limbal epithelial cells, and the expression pattern of the putative stem cell marker p63 remains unchanged. This suggests that eccentric CXL may be performed safely in PMD.

Sédation par propofol administrée par un non-anesthésiste pour l'endoscopie digestive [Administration of propofol by non-anesthesiologists for digestive endoscopy].

Propofol is progressively replacing benzodiazepines for sedation during endoscopy, even when the sedation is administered by non-anesthesiologists. Propofol ensures a more rapid induction of sedation and recovery and, in certain conditions, higher patient satisfaction and improved quality of endoscopic examination. Specific training is required to use this drug. Patients at risk of complications should be identified before the endoscopy to optimize patient management with an anesthesiologist. After sedation, psychomotor recovery is faster with propofol compared to traditional sedation agents but tasks requiring particular attention (eg, driving) should be avoided. It is important to advise patients of these restrictions in advance.

Alveolar overdistension as a cause of lung injury: differences among three animal species.

This study analyses characteristics of lung injuries produced by alveolar overdistension in three animal species. Mechanical ventilation at normal tidal volume (10 mL/Kg) and high tidal volume (50 mL/Kg) was applied for 30 min in each species. Data were gathered on wet/dry weight ratio, histological score, and area of alveolar collapse. Five out of six rabbits with high tidal volume developed tension pneumothorax, and the rabbit results were therefore not included in the histological analysis. Lungs from the pigs and rats showed minimal histological lesions. Pigs ventilated with high tidal volume had significantly greater oedema, higher neutrophil infiltration, and higher percentage area of alveolar collapse than rats ventilated with high tidal volume. We conclude that rabbits are not an appropriate species for in vivo studies of alveolar overdistension due to their fragility. Although some histological lesions are observed in pigs and rats, the lesions do not appear to be relevant.

Protocolo para el seguimiento del tratamiento farmacológico individualizado en pacientes con sedación paliativa

Publicado en la página web de la Consejería de Salud y Bienestar Social / Profesionales / Nuestro Compromiso por la Calidad / Estrategia de cuidados de Andalucía / Estrategia de cuidados de Andalucía

Monitoring of sedation during neuroaxial blockade.

Abstract Study objective: The arousal state changes during spinal anesthesia. It is not clear if BIS and others devices could monitor the induced neuroaxial blockade sedation. Our objective was evaluate BIS and entropy values when spinal anesthesia is done. Design: We developed a prospective study. Patients: 40 patients were included in this study, ASA I-III, over 60 years old, undergoing spinal anesthesia, without premedication scheduled for orthopedics procedures. Intervention: Spinal anesthesia was performed with the unseated volunteer in the lateral decubitus position with a 25-gauge Whitacre needle at L2-L3 space, andanesthesia was done with 12 mg of 0.5% hyperbaric bupivacaine. Patients were positioned supine for 5 min after spinal anesthesia. Measurements: Observer’s Assessment of Alertness/Sedation OAA/S, response (RE) and state entropy (SE) and BIS, and standard hemodynamic measures. Main results: Statistical analysis were performed by Wilcoxon test or ANOVA, p<0.05 was considered statistically significant.RE and BIS showed a better correlation with the OAA/S scale values (Pk 0.81 and 0.82) than SE (Pk 0.69). The OAA/S, RE and SE showed significative differences from basal values after 30 min of neuroaxial anesthesia (ANOVA p<0.05). BIS showed differences after 40 min (ANOVA p<0.05). There were no differences between BIS and RE values along the study (ANOVA p>0.05). Conclusions: The spinal anesthesia decreased the cortical activity and these were founded by OAA/S scale and depth anesthetics monitors. OAA/S was a more sensitive value of this induced sedation. BIS and RE showed a better correlation with OAA/S scale than SE.

Irinotecan loaded in eluting beads: preclinical assessment in a rabbit VX2 liver tumor model.

PURPOSE: The purpose of this study was to study the pharmacokinetics of irinotecan injected intravenously, intra-arterially, or loaded onto a delivery platform. MATERIAL AND METHODS: Fifty-four New Zealand White rabbits with VX2 liver tumor, divided in 3 groups of 17 rabbits, each received irinotecan either by intravenous (IV) route, intra-arterial hepatic (IA) route, or loaded on drug-eluting beads (DEBIRI). Animals were killed at 1, 6, and 24 h. Irinotecan and SN-38 concentrations were measured at different time points in serum, tumor, and normal liver. RESULTS: Twelve milligrams of irinotecan were injected IV and IA, whereas 6-16.5 mg were injected loaded onto DEBIRI. Normalized serum irinotecan reached a peak of 333 ng/ml (range 198.8-502.5) for IV, 327.1 ng/ml (range 277.1-495.6) for IA, and 189.7 ng/ml (range 111.1-261.9) for DEBIRI (P < 0.001) delivery. The area-under-the-curve value from 10 to 60 min of serum irinotecan concentration was significantly lower for DEBIRI (P = 0.0009). Tumor irinotecan levels for IV, IA, and DEBIRI (in ng/200 mg of tissue followed by ranges in parentheses) were, respectively, 23.6 (0.3-24.9), 36.5 (7.7-1914.1), and 20.2 (2.9-319) at 1 h; 4.2 (1-27.9), 99.3 (46.6-159.5), and 42.1 (11.3-189) at 6 h; and 2.7 (2.5-6.9), 18.3 (1.5-369.1), and 174.4 (3.4-5147.3) at 24 h (P = 0.02). At 24 h, tumor necrosis was 25% (10-30), 60% (40-91.25), and 95% (76.25-95) for IV, IA, and DEBIRI, respectively (P = 0.03). CONCLUSION: Compared with IV or IA, DEBIRI induces lower early serum levels of irinotecan, a high and prolonged intratumoral level of irinotecan, and a greater rate of tumor necrosis at 24 h. Further evaluation of the clinical benefit of DEBIRI is warranted.

Evaluation of the antitumoral effect sunitinib eluting beads in VX2 liver tumour in a rabbit model.

Background: We demonstrated that DC Bead (Biocompatibles UK, Ltd) could be loaded with sunitinib and injected intra-arterially in the rabbit without unexpected toxicity. The purpose of this study is to evaluate the antitumoral effect of sunitinib eluting beads in the VX2 tumor model of liver cancer. Methods: VX2 tumors were implanted in the left liver lobe of New-Zealand white rabbits. Animals were assigned to 3 groups: Group 1 (n=6) received 1.5mg of sunitinib loaded in 0.05ml of 100-300um DC Bead, group 2 (n=5) received 0.05ml of 100-300um DC Bead, group 3 (n=5) received 0.05ml NaCl 0.9% in the left hepatic artery. One animal in each group was sacrificed at 24 hours and the others were followed for survival until day 15. Liver enzymes were measured daily. In group 1, plasmatic sunitinib concentration were measured daily by LC MS/MS tandem mass spectroscopy. At day 15 all living animals were sacrificed. After sacrifice, the livers were harvested for determination of the VEGF receptor tyrosine kinase activity by western blot and histopathological examination. Results: In group 1, no animals died during follow-up. In group 2, 2 animals died during follow-up on day x. In control group 3, 3 animals died during follow up on day x. In group 1 plasmatic sunitinib levels remained under therapeutic concentration throughout the experiment. Very high concentrations of sunitinib were measured in the liver tissue 24 and 15 days after embolization. Inhibition of the phosphorylation of the RTK was demonstrated at 24h and 15 days in groups 1. Sunitinib eluting beads seemed to penetrate in the tumor more effectively and there was more necrosis around the beads than their bland counterparts. Conclusions: Administration of sunitinib eluting beads in VX2 carrying rabbits resulted invery high drug concentrations at the site of embolization with minimal systemic passage. Despite the very high tissular sunitinib concentration we did not observe any additional toxicity with loaded beads. Sunitinib eluting beads inhibit the activation of RTK's triggered by ischemia and seem to prolong survival of the treated animals. Therefore we consider that local treatment with sunitinib may provide a promising approach for the treatment of liver cancer.

Détermination spécifique d'individus vivants des deux espèces jumelles Sorex araneus et S. coronatus, par deux techniques biochimiques (Insectivora, Soricidae)

As the morphological determination of living individuals of the two sibling species S. araneus and S. coronatus is not possible, we have tested two biochemical methods to determine these shrews in ecological studies. After producing specific antibodies by rabbits, we performed an immunological test on 25 individuals. With this first method, a correct determination was achieved in 76% of the cases only. The second method proved very successful: a polyacrylamide gel electrophoresis showed a systematic difference for albumin (73 individuals analyzed). According to our experience, the necessary blood sampling (10-20 μl) seems harmless for the shrews

Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study.

BACKGROUND: Prehospital oligoanalgesia is prevalent among trauma victims, even when the emergency medical services team includes a physician. We investigated if not only patients' characteristics but physicians' practice variations contributed to prehospital oligoanalgesia. METHODS: Patient records of conscious adult trauma victims transported by our air rescue helicopter service over 10 yr were reviewed retrospectively. Oligoanalgesia was defined as a numeric rating scale (NRS) >3 at hospital admission. Multilevel logistic regression analysis was used to predict oligoanalgesia, accounting first for patient case-mix, and then physician-level clustering. The intraclass correlation was expressed as the median odds ratio (MOR). RESULTS: A total of 1202 patients and 77 physicians were included in the study. NRS at the scene was 6.9 (1.9). The prevalence of oligoanalgesia was 43%. Physicians had a median of 5.7 yr (inter-quartile range: 4.2-7.5) of post-graduate training and 27% were female. In our multilevel analysis, significant predictors of oligoanalgesia were: no analgesia [odds ratio (OR) 8.8], National Advisory Committee for Aeronautics V on site (OR 4.4), NRS on site (OR 1.5 per additional NRS unit >4), female physician (OR 2.0), and years of post-graduate experience [>4.0 to ≤5.0 (OR 1.3), >3.0 to ≤4.0 (OR 1.6), >2.0 to ≤3.0 (OR 2.6), and ≤2.0 yr (OR 16.7)]. The MOR was 2.6, and was statistically significant. CONCLUSIONS: Physicians' practice variations contributed to oligoanalgesia, a factor often overlooked in analyses of prehospital pain management. Further exploration of the sources of these variations may provide innovative targets for quality improvement programmes to achieve consistent pain relief for trauma victims.

Delay for admission of unstable hospitalized patients to intensive care unit: a need for a medical emergency team?

INTRODUCTION. Patients admitted in Intensive Care Unit (ICU) from general wards are more severe and have a higher mortality than those admitted from emergency department as reported [1]. The majority of them develop signs of instability (e.g. tachypnea, tachycardia, hypotension, decreased oxygen saturation and change in conscious state) several hours before ICU admission. Considering this fact and that in-hospital cardiac arrests and unexpected deaths are usually preceded by warning signs, immediate on site intervention by specialists may be effective. This gave an impulse to medical emergency team (MET) implementation, which has been shown to decrease cardiac arrest, morbidity and mortality in several hospitals. OBJECTIVES AND METHODS. In order to verify if the same was true in our hospital and to determine if there was a need for MET, we prospectively collected all non elective ICU admissions of already hospitalized patients (general wards) and of patients remaining more than 3 h in emergency department (considered hospitalized). Instability criteria leading to MET call correspond to those described in the literature. The delay between the development of one criterion and ICU admission was registered. RESULTS. During an observation period of 12 months, 321 patients with our MET criteria were admitted to ICU. 88 patients came from the emergency department, 115 from the surgical and 113 from the medical ward. 65% were male. The median age was 65 years (range 17-89). The delay fromMETcriteria development to ICU admission was higher than 8 h in 155 patients, with a median delay of 32 h and a range of 8.4 h to 10 days. For the remaining 166 patients, an early MET criterion was present up to 8 h (median delay 3 h) before ICU admission. These results are quite concordant with the data reported in the literature (ref 1-8). 122 patients presented signs of sepsis or septic shock, 70 patients a respiratory failure, 58 patients a cardiac emergency. Cardiac arrest represent 5% of our collective of patients. CONCLUSIONS.Similar to others observations, the majority of hospitalized patients admitted on emergency basis in our ICU have warning signs lasting for several hours. More than half of them were unstable for more than 8 h. This shows there is plenty of time for early acute management by dedicated and specialized team such as MET. However, further studies are required to determine if MET implementation can reduce in-hospital cardiac arrests and influence the morbidity, the length of stay and the mortality.

Role of bradykinin in the neonatal renal effects of angiotensin converting enzyme inhibition.

The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme (ACE): production of angiotensin II and degradation of bradykinin. The deleterious effect of converting enzyme inhibitors (CEI) on neonatal renal function have been ascribed to the elevated activity of the renin-angiotensin system. In order to clarify the role of bradykinin in the CEI-induced renal dysfunction of the newborn, the effect of perindoprilat was investigated in anesthetized newborn rabbits with intact or inhibited bradykinin B2 receptors. Inulin and PAH clearances were used as indices of GFR and renal plasma flow, respectively. Perindoprilat (20 microg/kg i.v.) caused marked systemic and renal vasodilation, reflected by a fall in blood pressure and renal vascular resistance. GFR decreased, while urine flow rate did not change. Prior inhibition of the B2 receptors by Hoe 140 (300 microg/kg s.c.) did not prevent any of the hemodynamic changes caused by perindoprilat, indicating that bradykinin accumulation does not contribute to the CEI-induced neonatal renal effects. A control group receiving only Hoe 140 revealed that BK maintains postglomerular vasodilation via B2 receptors in basal conditions. Thus, the absence of functional B2 receptors in the newborn was not responsible for the failure of Hoe 140 to prevent the perindoprilat-induced changes. Species- and/or age-related differences in the kinin-metabolism could explain these results, suggesting that in the newborn rabbit other kininases than ACE are mainly responsible for the degradation of bradykinin.

What Was I Thinking? Eye-Tracking Experiments Underscore the Bias that Architecture Exerts on Nuclear Grading in Prostate Cancer.

We previously reported that nuclear grade assignment of prostate carcinomas is subject to a cognitive bias induced by the tumor architecture. Here, we asked whether this bias is mediated by the non-conscious selection of nuclei that "match the expectation" induced by the inadvertent glance at the tumor architecture. 20 pathologists were asked to grade nuclei in high power fields of 20 prostate carcinomas displayed on a computer screen. Unknown to the pathologists, each carcinoma was shown twice, once before a background of a low grade, tubule-rich carcinoma and once before the background of a high grade, solid carcinoma. Eye tracking allowed to identify which nuclei the pathologists fixated during the 8 second projection period. For all 20 pathologists, nuclear grade assignment was significantly biased by tumor architecture. Pathologists tended to fixate on bigger, darker, and more irregular nuclei when those were projected before kigh grade, solid carcinomas than before low grade, tubule-rich carcinomas (and vice versa). However, the morphometric differences of the selected nuclei accounted for only 11% of the architecture-induced bias, suggesting that it can only to a small part be explained by the unconscious fixation on nuclei that "match the expectation". In conclusion, selection of « matching nuclei » represents an unconscious effort to vindicate the gravitation of nuclear grades towards the tumor architecture.

Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia.

BACKGROUND: Postanoxic status epilepticus (PSE) is considered a predictor of fatal outcome and therefore not intensively treated; however, some patients have had favorable outcomes. The aim of this study was to identify favorable predictors for awakening beyond vegetative state in PSE. METHODS: We studied six subjects treated with hypothermia improving beyond vegetative state after cerebral anoxia, despite PSE. They were among a cohort of patients treated for anoxic encephalopathy with therapeutic hypothermia in our institution between October 1999 and May 2006 (retrospectively, 3/107 patients) and June 2006 and May 2008 (prospectively, 3/74 patients). PSE was defined by clinical and EEG criteria. Outcome was assessed according to the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: All improving patients had preserved brainstem reflexes, cortical somatosensory evoked potentials, and reactive EEG background during PSE. Half of them had myoclonic PSE, while three had nonconvulsive PSE. In the prospective arm, 3/28 patients with PSE showed this clinical-electrophysiologic profile; all awoke. Treatments consisted of benzodiazepines, various antiepileptic drugs, and propofol. One subject died of pneumonia in a minimally conscious state, one patient returned to baseline (CPC1), three had moderate impairment (CPC2), and one remained dependent (CPC3). Patients with nonconvulsive PSE showed a better prognosis than subjects with myoclonic PSE (p = 0.042). CONCLUSION: Patients with postanoxic status epilepticus and preserved brainstem reactions, somatosensory evoked potentials, and EEG reactivity may have a favorable outcome if their condition is treated as status epilepticus.

Expression of neuroectodermal antigens common to melanomas, gliomas, and neuroblastomas. I. Identification by monoclonal anti-melanoma and anti-glioma antibodies.

The reactivity spectrum of five different monoclonal anti-melanoma antibodies cross-reacting with gliomas and neuroblastomas and one monoclonal anti-glioma antibody cross-reacting with melanomas and neuroblastomas was investigated. Comparison of the binding activity of these monoclonal antibodies for 11 melanoma, seven glioma, and three neuroblastoma cell lines showed that each of these clones had a different pattern of cross-reactivity. The results indicated that the antigenic determinants detected by these antibodies were not associated with the same antigen and thus suggested the existence of at least six different antigens common to melanomas, gliomas, and neuroblastomas. Since all these tumors are known to derive from cells originating embryologically from the neural crest, it can be assumed that the antigens recognized by our monoclonal antibodies are neuroectodermal differentiation antigens. However, absorption with fetal brain homogenates abolished only the binding of monoclonal anti-glioma antibody, but did not modify the binding of monoclonal anti-melanoma antibodies.