Insights into new mechanisms and models of cancer stem cell multidrug resistance.

The acquisition of genetic alterations, clonal evolution, and the tumor microenvironment promote cancer progression, metastasis and therapy resistance. These events correspond to the establishment of the great phenotypic heterogeneity and plasticity of cancer cells that contribute to tumor progression and resistant disease. Targeting resistant cancers is a major challenge in oncology; however, the underlying processes are not yet fully understood. Even though current treatments can reduce tumor size and increase life expectancy, relapse and multidrug resistance (MDR) ultimately remain the second cause of death in developed countries. Recent evidence points toward stem-like phenotypes in cancer cells, promoted by cancer stem cells (CSCs), as the main culprit of cancer relapse, resistance (radiotherapy, hormone therapy, and/or chemotherapy) and metastasis. Many mechanisms have been proposed for CSC resistance, such as drug efflux through ABC transporters, overactivation of the DNA damage response (DDR), apoptosis evasion, prosurvival pathways activation, cell cycle promotion and/or cell metabolic alterations. Nonetheless, targeted therapy toward these specific CSC mechanisms is only partially effective to prevent or abolish resistance, suggesting underlying additional causes for CSC resilience. This article aims to provide an integrated picture of the MDR mechanisms that operate in CSCs' behavior and to propose a novel model of tumor evolution during chemotherapy. Targeting the pathways mentioned here might hold promise and reveal new strategies for future clinical therapeutic approaches.

Present-day uplift of the western Alps.

Collisional mountain belts grow as a consequence of continental plate convergence and eventually disappear under the combined effects of gravitational collapse and erosion. Using a decade of GPS data, we show that the western Alps are currently characterized by zero horizontal velocity boundary conditions, offering the opportunity to investigate orogen evolution at the time of cessation of plate convergence. We find no significant horizontal motion within the belt, but GPS and levelling measurements independently show a regional pattern of uplift reaching ~2.5 mm/yr in the northwestern Alps. Unless a low viscosity crustal root under the northwestern Alps locally enhances the vertical response to surface unloading, the summed effects of isostatic responses to erosion and glaciation explain at most 60% of the observed uplift rates. Rock-uplift rates corrected from transient glacial isostatic adjustment contributions likely exceed erosion rates in the northwestern Alps. In the absence of active convergence, the observed surface uplift must result from deep-seated processes.

Asymmetry of Bispectral Index (BIS) in severe brain-injured patients treated by barbiturates with unilateral or diffuse brain injury.

OBJECTIVE: Bispectral index (BIS) may be used in traumatic brain-injured patients (TBI) with intractable intracranial hypertension to adjust barbiturate infusion but it is obtained through a unilateral frontal electrode. The objective of this study was to evaluate differences in BIS between hemispheres in two groups: unilateral frontal (UFI) and diffuse (DI) injured. PATIENTS AND METHODS: Prospective monocenter observational study in 24 TBI treated with barbiturates: 13 UFI and 11 DI. Simultaneous BIS and EEG was recorded for 1h. Goal of monitoring was a left BIS between 5 and 15. Biases in BIS were considered as clinically relevant if greater than 5. Differences in biases were interpreted from both statistical (Mann-Whitney test) and clinical points of view. RESULTS: Mean BIS in the two hemispheres remained in the same monitoring range. There were statistic and clinical differences in some values in the two groups of patients (15% of bias greater than I5I in UFI group and 10% in DI group). BIS monitoring allowed the adequate number of bursts/minutes to be predicted in 18 patients and did not detect an overdosage in 2. CONCLUSIONS: While asymmetric BIS values in TBI patients occur whatever the kind of injury, they were not found to be clinically relevant in most of these heavily sedated patients. Asymmetrical BIS monitoring might be sufficient to monitor barbiturate infusion in TBI provided that the concordance between BIS and EEG is regularly checked.

Alternative splicing of Bim and Erk-mediated Bim(EL) phosphorylation are dispensable for hematopoietic homeostasis in vivo.

The pro-apoptotic BH3-only protein Bim has a major role in hematopoietic homeostasis, particularly in the lymphocyte compartment, where it strongly affects immune function. The three major Bim isoforms (Bim(EL), Bim(L) and Bim(S)) are generated by alternative splicing. Bim(EL), the most abundant isoform, contains a unique sequence that has been reported to be the target of phosphorylation by several MAP kinases. In particular, Erk1/2 has been shown to interact with Bim(EL) through the DEF2 domain of Bim(EL) and specifically phosphorylate this isoform, thereby targeting it for ubiquitination and proteasomal degradation. To examine the physiological importance of this mechanism of regulation and of the alternative splicing of Bim, we have generated several Bim knock-in mouse strains and analyzed their hematopoietic system. Although mutation in the DEF2 domain reduces Bim(EL) degradation in some circumstances, this mutation did not significantly increase Bim's pro-apoptotic activity in vivo nor impact on the homeostasis of the hematopoietic system. We also show that Bim(EL) and Bim(L) are interchangeable, and that Bim(S) is dispensable for the function of Bim. Hence, we conclude that physiological regulation of Bim relies on mechanisms independent of its alternative splicing or the Erk-dependent phosphorylation of Bim(EL).

[Neonatal seizures management]. / Prise en charge des crises du nouveau-né

For several decades, experimental studies have sought to explain the biological causes of newborn seizures and to assess the anatomical and functional consequences. Laboratory studies have shown that prolonged or repeated seizures disturb central nervous system development and may predispose to later epilepsy or cognitive deficits. Although these findings have not been clinically demonstrated in humans, several observations suggest that neonatal seizures have a deleterious effect on the immature brain and generate long-term sequelae. No therapeutic trial, however, has directly demonstrated the benefits of treatment, underlining the need for controlled studies that integrate the advances in electroencephalographic monitoring and pharmacology of anticonvulsant drugs.

Continuous non-invasive arterial pressure measurement: evaluation of CNAP device during vascular surgery.

OBJECTIVE: Standard non-invasive blood pressure (BP) monitoring is an intermittent, discontinuous procedure. Beat-to-beat BP monitoring requires invasive measurement via an arterial catheter and may be associated with serious complications. The Infinity CNAP SmartPod (Dräger Medical AG & Co. KG, Lübeck, Germany) has recently been proposed for non-invasive continuous beat-to-beat BP measurements. The present study was designed to compare BP obtained with the CNAP and with an invasive method in the operating room. STUDY DESIGN: Prospective study. PATIENTS AND METHODS: Twenty-five patients undergoing major vascular surgery were included. Systolic, mean and diastolic BP were monitored invasively (SAP, MAP and DAP respectively) and not invasively using the CNAP (CNAP-S, CNAP-M and CNAP-D respectively). Measurements were performed intraoperatively every minute during 1 hour. RESULTS: One thousand and five hundred pairs of simultaneous CNAP and invasive BP measurements were obtained and 148 were eliminated. The range of BP measurements was 63-205 mmHg for SAP and 57-187 mmHg for CNAP-S, 38-143 mmHg for MAP and 43-142 mmHg for CNAP-M, 29-126 mmHg for DAP and 33-121 mmHg for CNAP-D. Bias and 95% limit of agreement between CNAP and invasive BP measurements were respectively 7.2 and -17.7 to 32.2 mmHg for SAP, -1.8 and -22.0 to 18.3 mmHg for MAP, and -7.5 and -27.3 to 12.4 mmHg for DAP. The percentage of CNAP measurements with a bias <10% with the arterial line was 69%, 86% and 91% for systolic, diastolic and mean pressures, respectively. CONCLUSION: Despite low accuracy for SAP and DAP measurements, CNAP system seems more accurate for MAP measurement in patients undergoing vascular surgery.

[Skin hydration and hyaluronic acid]. / Acide hyaluronique et hydratation cutanée.

Skin hydration mechanism is complex. Hyaluronic acid is a widely distributed glycosaminoglycan and one of the chief component of the extracellular matrix. It has a high water retaining ability and has recently been shown to be present in the epidermis. HA plays a central role in hydration and elasticity of skin.

Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability.

A single heat shock factor (HSF), mediating the heat shock response, exists from yeast to Drosophila, whereas several related HSFs have been found in mammals. This raises the question of the specific or redundant functions of the different members of the HSF family and in particular of HSF1 and HSF2, which are both ubiquitously expressed. Using immortalized mouse embryonic fibroblasts (iMEFs) derived from wild-type, Hsf1(-/-), Hsf2(-/-) or double-mutant mice, we observed the distinctive behaviors of these mutants with respect to proteasome inhibition. This proteotoxic stress reduces to the same extent the viability of Hsf1(-/-)- and Hsf2(-/-)-deficient cells, but through different underlying mechanisms. Contrary to Hsf2(-/-) cells, Hsf1(-/-) cells are unable to induce pro-survival heat shock protein expression. Conversely, proteasome activity is lower in Hsf2(-/-) cells and the expression of some proteasome subunits, such as Psmb5 and gankyrin, is decreased. As gankyrin is an oncoprotein involved in p53 degradation, we analyzed the status of p53 in HSF-deficient iMEFs and observed that it was strongly stabilized in Hsf2(-/-) cells. This study points a new role for HSF2 in the regulation of protein degradation and suggests that pan-HSF inhibitors could be valuable tools to reduce chemoresistance to proteasome inhibition observed in cancer therapy.

The 'relics of Joan of Arc': a forensic multidisciplinary analysis.

Archaeological remains can provide concrete cases, making it possible to develop, refine or validate medico-legal techniques. In the case of the so-called 'Joan of Arc's relics' (a group of bone and archaeological remains known as the 'Bottle of Chinon'), 14 specialists analysed the samples such as a cadaver X of carbonised aspect: forensic anthropologist, medical examiners, pathologists, geneticists, radiologist, biochemists, palynologists, zoologist and archaeologist. Materials, methods and results of this study are presented here. This study aims to offer an exploitable methodology for the modern medico-legal cases of small quantities of human bones of carbonised aspect.

Melkersson-Rosenthal syndrome and acquired C1 inhibitor deficiency.

BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare disease whose full-blown form is characterized by orofacial swelling, facial palsy and lingua plicata. OBJECTIVE: To investigate the complement system as well as its role in patients with MRS. METHODS: Seven patients presenting at this hospital between November 2002 and May 2003 and meeting the diagnostic criteria according to Hornstein were evaluated retrospectively. The investigations included clinical signs, an analysis of the complement system including levels of CH50, C3, C4, C1 inhibitor (INH) functions and C1-INH antigen detection. RESULTS: Two female patients showed isolated low levels of functional C1-INH as determined by duplicate tests. Both patients took estrogen-progestin contraceptives. CONCLUSION: Since deficiency in plasma protease C1-INH is known to lead to recurrent angioedema, we hypothesize that low levels of functional C1-INH may have contributed to the orofacial swelling in the 2 patients.

[Controlled hypernatremia]. / Hypernatrémie contrôlée.

Hypernatremia exerts its main effect on the brain through the osmotic gradient it creates on either side of the blood brain barrier, which is impermeable to sodium. This generates a transfer of water from the intracellular to the vascular sector leading to temporary cell shrinkage. Osmoregulation permits cerebral cells to accumulate osmoactive molecules in order to restore their initial volume. It has been demonstrated in animals with brain injury that intracellular dehydration occurs essentially in the nonlesioned hemisphere. In most experimental studies, the reduction in cerebral volume obtained by hypertonic saline (HS) perfusion is accompanied by an intracranial pressure decrease, even under hemorrhagic shock conditions. Initially, clinical studies successfully used HS, as an alternative to mannitol, in the treatment of acute and refractory intracranial hypertension. Then continuous infusion of HS, with the objective of inducing hypernatremia, had produced encouraging effects on intracranial pressure control. However, these results were limited to non-randomized studies, without control groups and mainly in pediatric patients. Nevertheless, the use of HS on intracranial hypertension, refractory to conventional treatments, could be reasonable under strict monitoring of natremia as well as its adverse effects.

[Digoxin-Josamycin: a dangerous drug interaction in children]. / Digoxine-Josamycine: une interaction dangereuse chez l'enfant.

Digitalis intoxication is usually accidental in children. We report the case of a young infant with congenital heart disease in whom the coadministration of digoxin and josamycin led to a 50% increase in the digoxin concentration, generating sinoatrial block and cardiac failure. Clinical and electrocardiographic symptoms very quickly resolved following immunotherapy with antidigitalis Fab fragments. Digoxin concentrations must be carefully monitored in patients concomitantly receiving macrolides to ensure that the digoxin dose can be readjusted if necessary.

[Protocol for advanced prehospital emergency care of severe head injury]. / Description d'un protocole de prise en charge préhospitalière du traumatisé crânien grave.

OBJECTIVES: To analyze the frequency of systemic factors leading to secondary brain insults in victims of serious head trauma in a prehospital setting and to evaluate a protocol for the advanced prehospital emergency care by mobile intensive care unit (i.e., the French Samu-Smur system). STUDY DESIGN: Prospective study, over a period of 24 months. PATIENTS AND METHODS: This prospective study involved 60 victims of severe head injuries (with the exception of polytrauma patients). Tracheal intubation was performed on each patient under direct laryngoscopy and after induction of anaesthesia (fentanyl-etomidate-rocuronium). Controlled ventilation and vascular loading (objectives: SpO(2) >or= 97%, PETCO(2) between 30 and 35 mmHg, SAP >or= 90 mmHg) were administered. RESULTS: Hypoxaemia was found to be the most frequent cause of secondary insults (57% of patients with SpO(2) < 97%). In the case involving an accident that occurred 17 km from the hospital (with extremes of 6-65 km), the speed of medical intervention was note-worthy: tracheal intubation was performed 50 min after the accident, and the patient was admitted into a trauma centre 101 min after impact (median). However, faster intervention could be obtained if the transmission of the alert was improved. The conditions under which the tracheal intubation was performed were found to be satisfactory (difficult intubation 1.6%) without deteriorating the haemodynamic status. This is probably related to the use of muscle relaxants and the choice of etomidate as the first line hypnotic in the prehospital emergency care.

Bradykinin-induced neuropeptide Y release by human pheochromocytoma tissue.

Neuropeptide Y (NPY) and noradrenaline (NA) are frequently co-localized and co-released in the sympathetic nervous system. Since bradykinin (BK) is known to stimulate neurotransmitter release as NA in adrenal glands, we therefore hypothesized that BK might also be involved in the release of NPY. The effect of BK(1-9) on immunoreactive NPY (Ir-NPY) release was investigated in superfused human pheochromocytoma tissue. BK(1-9) (10(-7)-10(-5) M) was shown to induce a rapid Ir-NPY release in a concentration-dependent manner. This effect of BK(1-9) (10(-6) M) was mimicked by the B2 agonist [Phe(8)(CH(2)NH)Arg(9)]-bradykinin (10(-5) M) and blocked by the selective B2-receptor antagonist HOE140 (10(-5) M). Increasing Ir-NPY release was probably not mediated by nitric oxide (NO) since the outflow of Ir-NPY was not influenced by the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M). In presence of bapta-AM (10(-5) M), a chelator of cytosolic calcium, W7 (10(-5) M), a calmodulin inhibitor, TMB-8 (10(-5) M), a blocker of intracellular calcium mobilization and ryanodine (10(-5) M), a selective inhibitor of the Ca(2+)-induced release mechanism, the NPY release by BK(1-9) was significantly inhibited by 126%, 98%, 91%, and 94%, respectively. These results indicate that BK increased the release of NPY by the tumor acting through the interaction with the BK-B2 receptor and request intracellular calcium mobilization independently of a NO mechanism.

Epidemiology of severe brain injuries: a prospective population-based study.

BACKGROUND: The aim of this prospective study was to estimate annual incidences of hospitalization for severe traumatic brain injury (TBI) (maximum Abbreviated Injury Score in the head region [HAIS] 4 or 5) in a defined population of 2.8 million. METHODS: Severe TBI patients were included in the emergency departments in the 19 hospitals of the region. A prospective data form was completed with initial neurologic state, computed tomographic scan lesions, associated injuries, length of unconsciousness, and length of stay in acute care centers. Outcome at the time the patient left acute hospitalization was retrospectively assessed from medical notes. RESULTS: During the 1-year period (1996), 497 residents fulfilled the inclusion criteria, leading to an annual incidence rate of 17.3 per 100,000 population; 58.1% were HAIS5. Mortality rate was 5.2 per 100,000. Men accounted for 71.4% of cases. Median age was 44 years, with a quarter of patients more than 70 years old. Traffic accidents were the most frequent causes (48.3%), but falls accounted for 41.8% of all patients. Age and severity were different according to the major categories of external causes. In HAIS5 patients, 86.5% were considered as comatose (coma lasting more than 24 hours or leading to immediate death) but only 60.9% had an initial Glasgow Coma Scale score < 9. In the HAIS4 group, 7.2% had an initial Glasgow Coma Scale score < 9. Fatality rates were 30.0% in the whole study group, 7.7% in HAIS4, 12.8% in HAIS5 without coma, and 51.2% in HAIS5 with coma. CONCLUSION: This study shows a decrease in severe TBI incidence when results are compared with another study conducted 10 years earlier in the same region. This is because of a decrease in traffic accidents. However, this results in an increase in the proportion of falls in elderly patients and an increase in the median age in our patients. This increased age influences the mortality rate.

Role of nitric oxide on atrial natriuretic peptide release induced by angiotensin II in superfused rat atrial tissue.

The present study investigated the role of nitric oxide (NO) on atrial natriuretic peptide (ANP) release stimulated by angiotensin II (Ang II) (10(-7) M) in superfused sliced rat atrial tissue. The use of N(G)-nitro-L-arginine methyl ester (L-NAME) at 10(-4) M, an inhibitor of nitric oxide synthase did not modify basal ANP release. In presence of Ang II (10(-7) M), we observed that L-NAME enhanced ANP secretion induced by Ang II. Furthermore, cGMP levels increased significantly in the presence of Ang II and was attenuated by L-NAME. On the other hand, the perfusion of 8 bromo-cGMP (10(-5) M) with Ang II reduced the effect of this octapeptide on ANP secretion. Secondly, we evaluated the effect of authentic NO on ANP release and observed that perfusion of NO reduced significantly the effect of Ang II on ANP release. We propose that the effect of Ang II on ANP secretion was modulated by NO likely via cGMP pathway.

Temperature response of leaf photosynthetic capacity in seedlings from seven temperate tree species.

Seedlings of seven temperate tree species (Acer pseudoplatanus L., Betula pendula Roth, Fagus sylvatica L., Fraxinus excelsior L., Juglans regia L., Quercus petraea Matt. Liebl. and Quercus robur L.) were grown in a nursery under neutral filters transmitting 45% of incident global irradiance. During the second or third year of growth, leaf photosynthetic capacity (i.e., maximal carboxylation rate, Vcmax, maximal photosynthetic electron transport rate, Jmax, and dark respiration, Rd) was estimated for five leaves from each species at five or six leaf temperatures (10, 18, 25, 32, 36 and 40 degrees C). Values of Vcmax and Jmax were obtained by fitting the equations of the Farquhar model on response curves of net CO2 assimilation (A) to sub-stomatal CO2 mole fraction (ci), at high irradiance. Primary parameters describing the kinetic properties of Rubisco (specificity factor, affinity for CO2 and for O2, and their temperature responses) were taken from published data obtained with spinach and tobacco, and were used for all species. The temperature responses of Vcmax and Jmax, which were fitted to a thermodynamic model, differed. Mean values of Vcmax and Jmax at a reference temperature of 25 degrees C were 77.3 and 139 micromol m(-2) s(-1), respectively. The activation energy was higher for Vcmax than for Jmax (mean values of 73.1 versus 57.9 kJ mol(-1)) resulting in a decrease in Jmax/Vcmax ratio with increasing temperature. The mean optimal temperature was higher for Vcmax than for Jmax (38.9 versus 35.9 degrees C). In addition, differences in these temperature responses were observed among species. Temperature optima ranged between 35.9 and above 45 degrees C for Vcmax and between 31.7 and 43.3 degrees C for Jmax, but because of data scatter and the limited range of temperatures tested (10 to 40 degrees C), there were few statistically significant differences among species. The optimal temperature for Jmax was highest in Q. robur, Q. petraea and J. regia, and lowest in A. pseudoplatanus and F. excelsior. Measurements of chlorophyll a fluorescence revealed that the critical temperature at which basal fluorescence begins to increase was close to 47 degrees C, with no difference among species. These results should improve the parameterization of photosynthesis models, and be of particular interest when adapted to heterogeneous forests comprising mixtures of species with diverse ecological requirements.

Complicaciones de la cirugía laparoscópica / Complications in laparoscopic surgery

Introducción. La gran difusión de la cirugía laparoscópica y la adaptación de los cirujanos a la misma ha supuesto la aparición de nuevas complicaciones que deben ser perfectamente conocidas para poder evitar en lo posible las causas que las desencadenan. Objetivos. En el presente trabajo se pretende analizar las complicaciones que pueden darse en la cirugía laparoscópica, tanto las inherentes a la técnica laparoscópica en sí como a las propias de cada una de las técnicas que son aplicadas para el tratamiento de las distintas afecciones. Material y métodos. Se realiza una revisión de la bibliografía a la vez que se revisa la experiencia del Servicio de Cirugía del Hospital Dr. Peset desde la puesta en marcha de esta nueva forma de abordar los problemas quirúrgicos. Resultados. Se analizan los resultados obtenidos con las distintas técnicas empleadas en cirugía biliar, gastroesofágica, cólica, etc., haciendo hincapié en la manera de evitar las complicaciones propias de esta forma de aplicar la técnica quirúrgica. Conclusiones. La cirugía laparoscópica se encuentra en pleno desarrollo aunque aún son limitadas las indicaciones en las que se acepta de forma universal su utilización. Es necesario que las tasas de morbilidad sean iguales o inferiores a las de cirugía convencional para que los pacientes se beneficien de las ventajas que comporta esta cirugía menos agresiva (AU)

[Type 2 Diabetes and Short Form 36-items Health Survey]. / Evaluation de la qualité de vie de diabétiques de type 2 par l'échelle internationale SF 36.

OBJECTIVES: This study explores the quality of life in patients with type 2 diabetes with the French Short Form 36-items Health Survey which involves eight health concepts: physical functioning, body pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, general mental health, social functioning, energy and general health perceptions. MATERIAL AND METHODS: The French SF 36 was proposed to 282 diabetic patients, 70 years of age and under, randomly selected from the database of Social Security healthcare office in Lyon (total: 4 644 patients). 160 healthy controls, matched for age and sex, were enrolled. 12 questionaires were not analysed because of linguistic difficulties. RESULTS: The data show that quality of life is altered into T2D compared with the control population in all 8 dimensions of SF-36 items Health Survey. CONCLUSIONS: Quality of life is an interesting element to take into account for practitioners during management of diabetic patients, that could prove useful in order to obtain a better compliance of the patients.