Influence of deep sternal wound infection on long-term survival after cardiac surgery.

BACKGROUND: This study aimed to investigate the influence of deep sternal wound infection on long-term survival following cardiac surgery. MATERIAL AND METHODS: In our institutional database we retrospectively evaluated medical records of 4732 adult patients who received open-heart surgery from January 1995 through December 2005. The predictive factors for DSWI were determined using logistic regression analysis. Then, each patient with deep sternal wound infection (DSWI) was matched with 2 controls without DSWI, according to the risk factors identified previously. After checking balance resulting from matching, short-term mortality was compared between groups using a paired test, and long-term survival was compared using Kaplan-Meier analysis and a Cox proportional hazard model. RESULTS: Overall, 4732 records were analyzed. The mean age of the investigated population was 69.3±12.8 years. DSWI occurred in 74 (1.56%) patients. Significant independent predictive factors for deep sternal infections were active smoking (OR 2.19, CI95 1.35-3.53, p=0.001), obesity (OR 1.96, CI95 1.20-3.21, p=0.007), and insulin-dependent diabetes mellitus (OR 2.09, CI95 1.05-10.06, p=0.016). Mean follow-up in the matched set was 125 months, IQR 99-162. After matching, in-hospital mortality was higher in the DSWI group (8.1% vs. 2.7% p=0.03), but DSWI was not an independent predictor of long-term survival (adjusted HR 1.5, CI95 0.7-3.2, p=0.33). CONCLUSIONS: The results presented in this report clearly show that post-sternotomy deep wound infection does not influence long-term survival in an adult general cardio-surgical patient population.

Impaired left ventricular function as a predictive factor for mid-term survival in octogenarians after primary coronary artery bypass surgery.

BACKGROUND: The impact of preoperative impaired left ventricular ejection fraction (EF) in octogenarians following coronary bypass surgery on short-term survival was evaluated in this study. METHODS: A total of 147 octogenarians (mean age 82.1 ± 1.9 years) with coronary artery diseases underwent elective coronary artery bypass graft between January 2000 and December 2009. Patients were stratified into: Group I (n = 59) with EF >50%, Group II (n = 59) with 50% > EF >30% and in Group III (n = 29) with 30% > EF. RESULTS: There was no difference among the three groups regarding incidence of COPD, renal failure, congestive heart failure, diabetes, and preoperative cerebrovascular events. Postoperative atrial fibrillation was the sole independent predictive factor for in-hospital mortality (odds ratio (OR), 18.1); this was 8.5% in Group I, 15.3% in Group II and 10.3% in Group III. Independent predictive factors for mortality during follow up were: decrease of EF during follow-up for more that 5% (OR, 5.2), usage of left internal mammary artery as free graft (OR, 18.1), and EF in follow-up lower than 40% (OR, 4.8). CONCLUSIONS: The results herein suggest acceptable in-hospital as well short-term mortality in octogenarians with impaired EF following coronary artery bypass grafting (CABG) and are comparable to recent literature where the mortality of younger patients was up to 15% and short-term mortality up to 40%, respectively. Accordingly, we can also state that in an octogenarian cohort with impaired EF, CABG is a viable treatment with acceptable mortality.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma.

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.

Long-term cerebral plasticity-related gene expression : a study of the respective role of CBP and CRTC1 in CREB transcriptional activation

1.1 AbstractThe treatment of memory disorders and cognitive deficits in various forms of mental retardation may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. Different forms of memory have distinct molecular requirements.Short-term memory (STM) is thought to be mediated by covalent modifications of existing synaptic molecules, such as phosphorylation or dephosphorylation of enzymes, receptors or ion channels. In contrast, long-term memoiy (LTM) is thought to be mediated by growth of new synapses and restructuring of existing synapses. There is extensive evidence that changes in gene expression and de novo protein synthesis are key processes for LTM formation. In this context, the transcription factor CREB (cAMP-response element-binding protein) was shown to be crucial. Activation of CREB requires phosphorylation of a serine residue (Ser-133), and the subsequent recruitment of a coactivator called CREB-binding protein (CBP). Moreover, we have recently shown that another coactivator called CREB Regulated Transcription Coactivator 1 (CRTC1) functions as a calcium- and cAMP-sensitive coincidence detector in neurons, and is involved in hippocampal long-term synaptic plasticity. Given the importance of cAMP and calcium signaling for plasticity-related gene expression in neurons and in astrocytes, we sought to determine the respective involvement of the CREB coactivators CBP and CRTC1 in CREB-mediated transcription.We developed various strategies to selectively interfere with these CREB coactivators in mouse primary neurons and in astrocytes in vitro. However, despite several pieces of evidence implicating CBP and/or CRTC1 in the regulation of neuronal plasticity genes, we could not clearly determine the respective requirement of these coactivators for the activation of these genes. Nevertheless, we showed that calcineurin activity, which is important for CRTC1 nuclear translocation, is necessary for the expression of some CREB-regulated plasticity genes. We associated this phenomena to physiopathological conditions observed in Down's syndrome. In addition, we demonstrated that in astrocytes, noradrenaline stimulates CREB-target gene expression through β-adrenergic receptor activation, intracellular cAMP pathway activation, and CRTC-induced CREB transactivation.Defining the respective role of CREB and its coactivators CBP and CRTC1 in neuronal and astrocytic cultures in vitro sets the stage for future in vivo studies and for the possible development of new therapeutic strategies to improve the treatment of memoiy and cognitive disorders.1.2 RésuméUne meilleure connaissance des mécanismes moléculaires et cellulaires responsables de la formation de la mémoire pourrait grandement améliorer le traitement des troubles de la mémoire ainsi que des déficits cognitifs observés dans différentes formes de pathologies psychiatriques telles que le retard mental. Les différentes formes de mémoire dépendent de processus moléculaires différents.La mémoire à court terme (STM) semble prendre forme suite à des modifications covalentes de molécules synaptiques préexistantes, telles que la phosphorylation ou la déphosphorylation d'enzymes, de récepteurs ou de canaux ioniques. En revanche, la mémoire à long terme (LTM) semble être due à la génération de nouvelles synapses et à la restructuration des synapses existantes. De nombreuses études ont permis de démontrer que les changements dans l'expression des gènes et la synthèse de protéine de novo sont des processus clés pour la formation de la LTM. Dans ce contexte, le facteur de transcription CREB (cAMP-response element-binding protein) s'est avéré être un élément crucial. L'activation de CREB nécessite la phosphorylation d'un résidu sérine (Ser-133), et le recrutement d'un coactivateur nommé CBP (CREB binding protein). En outre, nous avons récemment démontré qu'un autre coactivateur de CREB nommé CRTC1 (CREB Regulated Transcription Coactivator 1) agit comme un détecteur de coïncidence de l'AMP cyclique (AMPc) et du calcium dans les neurones et qu'il est impliqué dans la formation de la plasticité synaptique à long terme dans l'hippocampe. Etant donné l'importance des voies de l'AMPc et du calcium dans l'expression des gènes impliqués dans la plasticité cérébrale, nous voulions déterminer le rôle respectif des coactivateurs de CREB, CBP et CRTC1.Nous avons développé diverses stratégies pour interférer de façon sélective avec les coactivateurs de CREB dans les neurones et dans les astrocytes chez la souris in vitro. Nos résultats indiquent que CBP et CRTC1 sont tous deux impliqués dans la transcription dépendante de CREB induite par l'AMPc et le calcium dans les neurones. Cependant, malgré plusieurs évidences impliquant CBP et/ou CRTC1 dans l'expression de gènes de plasticité neuronale, nous n'avons pas pu déterminer clairement leur nécessité respective pour l'activation de ces gènes. Toutefois, nous avons montré que l'activité de la calcineurine, dont dépend la translocation nucléaire de CRTC1, est nécessaire à l'expression de certains de ces gènes. Nous avons pu associer ce phénomène à une condition physiopathologique observée dans le syndrome de Down. Nous avons également montré que dans les astrocytes, la noradrénaline stimule l'expression de gènes cibles de CREB par une activation des récepteurs β- adrénergiques, l'activation de la voie de l'AMPc et la transactivation de CREB par les CRTCs.Définir le rôle respectif de CREB et de ses coactivateurs CBP et CRTC1 dans les neurones et dans les astrocytes in vitro permettra d'acquérir les connaissances nécessaires à de futures études in vivo et, à plus long terme d'éventuellement développer des stratégies thérapeutiques pour améliorer les traitements des troubles cognitifs.

Long-term treatment of eosinophilic esophagitis esophagitis with budesonide

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS: In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS: During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS: This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.

Spaced training facilitates long-term retention of place navigation in adult but not in adolescent rats

Young and adult Long Evans rats were tested in the water maze according to two different procedures: half of the subjects were given one session of four trials a day for 6 days, whereas the other subjects had the same amount of training massed in 1 day. For both conditions, a 14-day retention interval was then introduced to test long-term memory. This was followed by a four-trial reversal session. All groups showed a significant learning curve, but escape latencies were shorter for the adult than for the young rats, without differential effect of the training procedure. A first probe trial (PT1) confirmed similar accurate short-term retention in all the groups. But unimpaired long-term memory was only seen in the adult rats trained with the spaced procedure. The young rats trained over 1 day also showed some retention of the platform location after 14 days, but not the other two groups. Reversal acquisition of the new platform location was rapid in the four groups. These results indicate that although accurate short-term spatial memory in the water maze is seen after a 1-day massed training in both age groups, unimpaired long-term retention is only observed in adult rats trained with 24-h inter-session intervals.

Astrocyte-neuron lactate transport is required for long-term memory formation.

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.

Deficit in memory consolidation (abnormal forgetting rate) in childhood temporal lobe epilepsy. Pre and postoperative long-term observation.

Deficits in memory consolidation have been reported in adult patients with epilepsy but, not to our knowledge, in children. We report the long-term follow-up (9 y. o. to 18 y. o.) of a boy who suffered from temporal lobe epilepsy and underwent a left temporal lobectomy with amygdalo-hippocampal resection at the age of 10. He showed an abnormal forgetting rate when trying to encode new information and a significant deficit for retrieving remote episodic memories (when compared with his twin brother), both consistent with a consolidation disorder. His memory condition slightly improved after cessation of the epilepsy, nevertheless did not normalize. No standard memory assessment could pinpoint his memory problem, hence an adapted methodology was needed. We discuss the nature of the memory deficit, its possible causes and its clinical implications.

Effect of short-duration lipid supplementation on fat oxidation during exercise and cycling performance.

The effect of intramyocellular lipids (IMCLs) on endurance performance with high skeletal muscle glycogen availability remains unclear. Previous work has shown that a lipid-supplemented high-carbohydrate (CHO) diet increases IMCLs while permitting normal glycogen loading. The aim of this study was to assess the effect of fat supplementation on fat oxidation (Fox) and endurance performance. Twenty-two trained male cyclists performed 2 simulated time trials (TT) in a randomized crossover design. Subjects cycled at ∼53% maximal voluntary external power for 2 h and then followed 1 of 2 diets for 2.5 days: a high-CHO low-fat (HC) diet, consisting of CHO 7.4 g·kg(-1)·day(-1) and fat 0.5 g·kg(-1)·day(-1); or a high-CHO fat-supplemented (HCF) diet, which was a replication of the HC diet with ∼240 g surplus fat (30% saturation) distributed over the last 4 meals of the diet period. On trial morning, fasting blood was sampled and Fox was measured during an incremental exercise; a ∼1-h TT followed. Breath volatile compounds (VOCs) were measured at 3 time points. Mental fatigue, measured as reaction time, was evaluated during the TT. Plasma free fatty acid concentration was 50% lower after the HCF diet (p < 0.0001), and breath acetone was reduced (p < 0.05) "at rest". Fox peaked (∼0.35 g·kg(-1)) at ∼42% peak oxygen consumption, and was not influenced by diet. Performance was not significantly different between the HCF and HC diets (3369 ± 46 s vs 3398 ± 48 s; p = 0.39), nor were reaction times to the attention task and VOCs (p = NS for both). In conclusion, the short-term intake of a lipid supplement in combination with a glycogen-loading diet designed to boost intramyocellular lipids while avoiding fat adaptation did not alter substrate oxidation during exercise or 1-hour cycling performance.