High-dose sequential chemotherapy (ICE) under circulating progenitor cells (CPC) protection in patients with small cell lung carcinoma (SCLC). Preliminary report on a multicentric study

Starting in February 1994, 20 patients (pt) with a median age of 50 years(range 41-63) from 7 European centers have been included. Completedata were obtained in 16 patients so far. CPC were mobilized with chemo(Epirubicine 75 mg/m2 /d, 01 + 02) followed by G-CSF 5 p.gfkg/d for14 days. HD chemo consisted in 3 sequential courses of ICE regimen(UOs. 10 g/m2 , Carbo. 1200 mg/m2 and Etop. 1200 mg/m2 ) underCPC protection and G-CSF 5 p.g/kg/d. Out of the 16 pt, 12 completedfull program (3 cycles). One pt died of septic shock before receivingany ICE course. One pt died during the first ICE of renal insufficiency.Two pt had only 2 courses because of toxicity. Among the 16 pt, responserate (RR) was: 7 CR, 6 PR, 1 PO; 3 pt are not evaluable dueto early withdrawal (overall RR: 13/16 = 81 %). Thirty-nine cycles ofHD chemo were given with a median hematological recovery of 9 days(range 7-12) until neutro. counts> 1.0 x 109 /1 and 9 days (range 717)until thrombo. > 20 x 109 /1. No cumulative, hematological toxicitywas seen. Accrual of patients is still ongoing and updated results will bepresented.

Intravenous streptomycin dosing regimen in a patient undergoing hemodialysis: Plasma level monitoring and pharmacokinetic simulation

Introduction: Streptomycin, as other aminoglycosides, exhibits concentration-dependent bacterial killing but has a narrow therapeutic window. It is primarily eliminated unchanged by the kidneys. Data and dosing information to achieve a safe regimen in patients with chronic renal failure undergoing hemodialysis (HD) are scarce. Although main adverse reactions are related to prolonged, elevated serum concentrations, literature recommendation is to administer streptomycin after each HD. Patients (or Materials) and Methods: We report the case of a patient with end-stage renal failure, undergoing HD, who was successfully treated with streptomycin for gentamicin-resistant Enterococcus faecalis bacteremia with prosthetic arteriovenous fistula infection. Streptomycin was administered intravenously 7.5 mg/kg, 3 hours before each dialysis (3 times a week) during 6 weeks in combination with amoxicillin. Streptomycin plasma levels were monitored with repeated blood sampling before, after, and between HD sessions. A 2-compartment model was used to reconstruct the concentration time profile over days on and off HD. Results: Streptomycin trough plasma-concentration was 2.8 mg/L. It peaked to 21.4 mg/L 30 minutes after intravenous administration, decreased to 18.2 mg/L immediately before HD, and dropped to 4.5 mg/L at the end of a 4-hour HD session. Plasma level increased again to 5.7 mg/L 2 hours after the end of HD and was 2.8 mg/L 48 hours later, before the next administration and HD. The pharmacokinetics of streptomycin was best described with a 2-compartment model. The computer simulation fitted fairly well to the observed concentrations during or between HD sessions. Redistribution between the 2 compartments after the end of HD reproduced the rebound of plasma concentrations after HD. No significant toxicity was observed during treatment. The outcome of the infection was favorable, and no sign of relapse was observed after a follow-up of 3 months. Conclusion: Streptomycin administration of 7.5 mg/kg 3 hours before HD sessions in a patient with end-stage renal failure resulted in an effective and safe dosing regimen. Monitoring plasma levels along with pharmacokinetic simulation document the suitability of this dosing scheme, which should replace current dosage recommendations for streptomycin in HD.

Implementation study of a clinical prediction score to rule out cardiogenic chest pain in community: Cluster randomized trial

1.1 Fundamentals Chest pain is a common complaint in primary care patients (1 to 3% of all consultations) (1) and its aetiology can be miscellaneous, from harmless to potentially life threatening conditions. In primary care practice, the most prevalent aetiologies are: chest wall syndrome (43%), coronary heart disease (12%) and anxiety (7%) (2). In up to 20% of cases, potentially serious conditions as cardiac, respiratory or neoplasic diseases underlie chest pain. In this context, a large number of laboratory tests are run (42%) and over 16% of patients are referred to a specialist or hospitalized (2).¦A cardiovascular origin to chest pain can threaten patient's life and investigations run to exclude a serious condition can be expensive and involve a large number of exams or referral to specialist -­‐ often without real clinical need. In emergency settings, up to 80% of chest pains in patients are due to cardiovascular events (3) and scoring methods have been developed to identify conditions such as coronary heart disease (HD) quickly and efficiently (4-­‐6). In primary care, a cardiovascular origin is present in only about 12% of patients with chest pain (2) and general practitioners (GPs) need to exclude as safely as possible a potential serious condition underlying chest pain. A simple clinical prediction rule (CPR) like those available in emergency settings may therefore help GPs and spare time and extra investigations in ruling out CHD in primary care patients. Such a tool may also help GPs reassure patients with more common origin to chest pain.

Intravitreal ranibizumab for age-related macular degeneration : optical coherence tomography guided retreatment intervals and their intra- and inter-individual variability

Purpose: To determine whether the need for retreatment after an initial phase of 3 monthly intravitreal injections of ranibizumab shows an intra-individual regular rhythm and to what degree it varies between different patients. Methods: Prospective study with 42 patients with exudative AMD, treatment naïve. Loading dose of 3 monthly doses of ranibizumab (0,5 mg), followed by a 12 months pro re nata (PRN) regimen according to early exudative signs on HD-OCT Cirrus, Zeiss. The follow-up visits were intensified (week 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, etc after each injection) in order to detect recurrences early, and injection followed within 3 days in cases of subretinal fluid, cysts, or central thickness increase of>50microns. Intervals were calculated between injections for the 12 month follow-up with PRN treatment. Variability was expressed as standard deviation (SD). Results: Visual acuity (VA) improved from a mean ETDRS score of 61.6 (SD 10.8) at baseline to 68.0 (SD 10.2) at month 3 and to 74.7(SD 9.0) at month 12. The 15 patients who have already completed the study showed maintenance of the VA improvement. Central foveal thickness improved from a mean value of 366 microns (baseline) to 253 microns (month 3), well maintained thereafter. Mean number of injections was 8.8 (SD 3.5,range 0-12) per 12 months of follow-up (after 3 doses), with mean individual treatment-recurrence (TR) intervals ranging from 28->365 days (mean 58). Intraindividual variability of TR intervals (SD) was 7.1 days as a mean value (range 1.7¡V22.6). It ranged within 20% of the mean intra-individual interval for 30 (91%) and within 15% for 21 patients (64%). The first interval was within 1 week of the mean intra-individual interval in 64% and within 2 weeks in 89% of patients. Conclusions: The majority of AMD patients showed a relatively stable rhythm for PRN injections of ranibizumab after initial loading phase, associated with excellent functional/anatomical results. The initial interval last loading dose-first recurrence may have a predictive value for further need of treatment, potentially facilitating follow-up and patient care.

Nouveaux desseins de plafons inventés et gravés / par J. le Potre

Ancien possesseur : Belbeuf, Louis Pierre François Godard Mis de

Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models.

Cannabinoid receptor 1 (CB(1) receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB(1) expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB(1) signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB(1) downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi-quantitative immunohistochemistry, we confirmed previous studies showing that CB(1) expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB(1) is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)-expressing interneurons while remaining unchanged in parvalbumin- and calretinin-expressing interneurons. CB(1) downregulation in striatal NPY/nNOS-expressing interneurons occurs in R6/2 mice, Hdh(Q150/Q150) mice and the caudate nucleus of patients with HD. In R6/2 mice, CB(1) downregulation in NPY/nNOS-expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro-survival signaling molecule cAMP response element-binding protein in NPY/nNOS-expressing interneurons. Loss of CB(1) signaling in NPY/nNOS-expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.

Macrophages promote epithelial repair through hepatocyte growth factor secretion.

Macrophages play a critical role in intestinal wound repair. However, the mechanisms of macrophage-assisted wound repair remain poorly understood. We aimed to characterize more clearly the repair activities of murine and human macrophages. Murine macrophages were differentiated from bone marrow cells and human macrophages from monocytes isolated from peripheral blood mononuclear cells of healthy donors (HD) or Crohn's disease (CD) patients or isolated from the intestinal mucosa of HD. In-vitro models were used to study the repair activities of macrophages. We found that murine and human macrophages were both able to promote epithelial repair in vitro. This function was mainly cell contact-independent and relied upon the production of soluble factors such as the hepatocyte growth factor (HGF). Indeed, HGF-silenced macrophages were less capable of promoting epithelial repair than control macrophages. Remarkably, macrophages from CD patients produced less HGF than their HD counterparts (HGF level: 84âeuro0/00±âeuro0/0027âeuro0/00pg/mg of protein and 45âeuro0/00±âeuro0/0034âeuro0/00pg/mg of protein, respectively, for HD and CD macrophages, Pâeuro0/00<âeuro0/000·009) and were deficient in promoting epithelial repair (repairing activity: 90·1âeuro0/00±âeuro0/004·6 and 75·8âeuro0/00±âeuro0/008·3, respectively, for HD and CD macrophages, Pâeuro0/00<âeuro0/000·0005). In conclusion, we provide evidence that macrophages act on wounded epithelial cells to promote epithelial repair through the secretion of HGF. The deficiency of CD macrophages to secrete HGF and to promote epithelial repair might contribute to the impaired intestinal mucosal healing in CD patients.

MACROPHAGES FROM CROHN'S DISEASE PATIENTS EXHIBIT DEFICIENT REPAIR FUNCTIONS

AbstractBackground: Mucosal healing is becoming a major goal in the treatment of Crohn's disease. It has been previously reported that myeloid cells induce mucosal healing in a mouse model of acute colitis. The aim in this study is to investigate the pro-repair function of myeloid cells in healthy donors (HD) and Crohn's disease patients (CD).Methods: Peripheral blood mononuclear cells (PBMC) from HD and CD patients were isolated from blood samples and tested either directly or after differentiation ex-vivo into macrophages (Μφ). Intestinal macrophages (IMACs) were isolated from the bowel mucosa of patients undergoing intestinal surgical resections. Through an in vitro wound healing assay the repairing ability of these various human myeloid cells and the mechanisms responsible of wound healing were evaluated.Results: PBMC and myeloid CD14+ cells from HD and CD were not able to repair at any tested cell concentration. Μφ from HD and ulcerative colitis (UC) patients were able to induce wound healing and this capacity was partially mediated by Hepatocyte Growth Factor (HGF). Remarkably, CD Μφ were unable to promote wound healing and produced lower levels of HGF as compared to Μφ from HD or UC patients. In particular, Μφ from CD in active phase (ACD) exhibited the weakest repair function, but this defect was rescued if rh- GM-CSF was added during the differentiation of PBMCs. Interestingly, IMACs from HD promoted wound healing and produced HGF.Conclusion: We demonstrated that CD Μφ, unlike HD or UC Μφ, were defective in promoting wound healing, in particular if coming from an ACD. This deficient pro-repair function was related to a lower production of HGF. IMACs from HD colonic mucosa induced wound healing, confirming the results obtained with Μφ. Our results are in keeping with the current theory of CD as an innate immunodeficiency. In this context, Μφ may be responsible for the mucosal repair defects observed in CD patients and for the subsequent chronic activation of the adaptive immune response.

Why Would the Deuteronomists Tell about the Sacrifice of Jephtah's Daughter?

It is commonly assumed that the story of Jephthah's vow refers to an 'old tradition' that was integrated into the Deuteronomistic History. But such a view is contrary to Dtr ideology which is absolutely hostile to any human sacrifice (2 Kgs 16.3; 17.17, 31; 21.6 etc.). A literary-critical approach to Judges 11 shows that vv. 30-31 [32] and 34-40 may be considered as post-Dtr. The author of Judg. 11.30-40 seems to know the story of the Aqedah, but he is not willing to make a happy ending. There is a tragic dimension in the story and quite an Hellenistic atmosphere (the best parallels to Judg. 11.30-40 may be fou Hellenistic nd in texts). So this text should be considered an insertion from the end of the Persian or beginning of the Hellenistic periods. The author tends to show that Jewish classics can be as tragic as Greek ones.

Transformations et influences dans «l'historiographie» juive de la fin du VIIe s. av. notre ère jusqu'à l'époque perse

The origins of biblical historiography may be dated to the end of the VIIth c. and linked to those of the deuteronomic school itself. In order to justify Josiah's politics, his scribes elaborated a collection of texts (Deut, Josh, Kings, a vita Mosis in Gen-Nb) which were widely inspired by Assyrian ideology. During the Babylonian exile, this literature underwent a transformation: the new created « Deuteronomistic History, (Deut-2 Kings) converted propaganda into theodicee. The Deuteronomists were still at work in the Persian period as can be seen in numerous texts in Deut-2 Kings, as well as in the edition of the prophetic corpus. From now on, dtr ideology was centered on three points: the restauration by law, the end of prophecy and the need to separate Israel from the « others » (cf. EsdNeh). But the Persian period was also the, time of compromise. The Pentateuch was made by putting together dtr and priestly ideologies, « autochtonous » and « exodic » views about the origins of Israel.

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.

Application of K-feldspar-jadeite-quartz barometry to eclogite facies metagranites and metapelites in the Sesia Lanzo Zone (Western Alps, Italy)

The eclogite facies assemblage K-feldspar-jadeite-quartz in metagranites and metapelites from the Sesia-Lanzo Zone (Western Alps, Italy) records the equilibration pressure by dilution of the reaction jadeite + quartz = albite. The metapelites show partial transformation from a pre-Alpine assemblage of garnet (Alm(63)Prp(26)Grs(10))-K-feldspar-plagioclase-biotite +/- sillimanite to the Eo-Alpine high-pressure assemblage garnet (Alm(50)Prp(14)Grs(35))-jadeite (Jd(80-97)Di(0-4)Hd(0-8)Acm(0-7))=zoisite-phengite. Plagioclase is replaced by jadeite-zoisite-kyanite-K-feldspar-quartz and biotite is replaced by garnet-phengite or omphacite-kyanite-phengite. Equilibrium was attained only in local domains in the metapelites and therefore the K-feldspar-jadeite-quartz (KJQ) barometer was applied only to the plagioclase pseudomorphs and K-feldspar domains. The albite content of K-feldspar ranges from 4 to 11 mol% in less equilibrated assemblages from Val Savenca and from 4 to 7 mol% in the partially equilibrated samples from Monte Mucrone and the equilibrated samples from Montestrutto and Tavagnasco. Thermodynamic calculations on the stability of the assemblage K-feldspar-jadeite-quartz using available mixing data for K-feldspar and pyroxene indicate pressures of 15-21 kbar (+/- 1.6-1.9 kbar) at 550 +/- 50 degrees C. This barometer yields direct pressure estimates in high-pressure rocks where pressures are seldom otherwise fixed, although it is sensitive to analytical precision and the choice of thermodynamic mixing model for K-feldspar. Moreover, the KJQ barometer is independent of the ratio P-H2O/P-T. The inferred limiting a(H2O) for the assemblage jadeite-kyanite in the metapelites from Val Savenca is low and varies from 0.2 to 0.6.

VLA multifrequency observations of RSCVn binaries

We present multiepoch Very Large Array (VLA) observations at 1.4 GHz, 4.9 GHz, 8.5 GHz and 14.9 GHz for a sample of eight RS CVn binary systems. Circular polarization measurements of these systems are also reported. Most of the fluxes observed are consistent with incoherent emission from mildly relativistic electrons. Several systems show an increase of the degree of circular polarization with increasing frequency in the optically thin regime, in conflict with predictions by gyrosynchrotron models. We observed a reversal in the sense of circular polarization with increasing frequency in three non-eclipsing systems: EI Eri, DM Uma and HD 8358. We find clear evidence for coherent plasma emission at 1.4 GHz in the quiescent spectrum of HD 8358 during the helicity reversal. The degrees of polarization of the other two systems could also be accounted for by a coherent emission process. The observations of ER Vul revealed two U-shaped flux spectra at the highest frequencies. The U-shape of the spectra may be accounted for by an optically thin gyrosynchrotron source for the low frequency part whereas the high frequency part is dominated by a thermal emission component.

Parâmetros cinéticos e morfológicos da absorção de nutrientes em cultivares de milho com variabilidade genética contrastante

Genótipos de milho com variabilidade genética contrastante apresentam potenciais produtivos diferentes. Isso pode ser causado, pelo menos em parte, por diferenças morfológicas no sistema radicular e nos parâmetros cinéticos de absorção de nutrientes. Este trabalho objetivou quantificar esses parâmetros em três cultivares de milho. Foram comparados um híbrido simples (HS), um híbrido duplo (HD) e uma variedade de polinização aberta (VPA). Determinaram-se os parâmetros de absorção (influxo máximo, Imax, constante de Michalies-Menten, Km, e concentração na solução onde a absorção cessa, Cmin) para N, P, K, Ca e Mg, além de atributos morfológicos radiculares, em experimentos efetuados em câmara de crescimento, com solução nutritiva. A morfologia das raízes variou pouco entre os genótipos, provavelmente por causa do cultivo das plantas em meio líquido. As diferenças entre genótipos quanto aos parâmetros cinéticos de absorção dependeram do nutriente. O Imax diferiu entre os cultivares para P; o Km, para N e P, e o Cmin, para N e K. A VPA, por apresentar maior variabilidade genética, deveria apresentar menores valores para Km e Cmin do que os híbridos. Contudo, isso só aconteceu para P em relação ao Km. O HS, por apresentar maior potencial produtivo, deveria expressar os maiores valores para Imax, mas isso não ocorreu com nenhum dos macronutrientes avaliados. Portanto, a absorção de nutrientes não parece ser um fator determinante nas diferenças de rendimento de grãos entre genótipos de milho com bases genéticas contrastantes.