Effects of Sigma-1 Receptor Ligands on Peripheral Nerve Regeneration

Peripheral nerve injuries lead to the loss of motor, sensory and autonomic functions in the territories supplied by the injured nerve. Currently, nerve injuries are managed by surgical repair procedures, and there are no effective drugs in the clinic for improving the capacity of axonal regeneration. Sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperon protein involved in many functions, including neuroprotection and neuroplasticity. A few previous studies using Sig-1R ligands reported results that suggest this receptor as a putative target to enhance regeneration. The aim of this study was to evaluate the possible effects of Sig-1R ligands on axonal regeneration in a sciatic nerve section and repair model in mice. To this end, mice were treated either with the Sig-1R agonist PRE-084 or the antagonist BD1063, and a Sig-1R knock-out (KO) mice group was also studied. The electrophysiological and histological data showed that treatment with Sig-1R ligands, or the lack of this protein, did not markedly modify the process of axonal regeneration and target reinnervation after sciatic nerve injury. Nevertheless, the nociceptive tests provided results indicating a role of Sig-1R in sensory perception after nerve injury, and immunohistochemical labeling indicated a regulatory role in inflammatory cell infiltration in the injured nerve

Effectiveness of a Surgery Admission Unit for patients undergoing major elective surgery in a tertiary university hospital

<p>Abstract</p> <p>Background</p> <p>The increasing demand on hospitalisation, either due to elective activity from the waiting lists or due to emergency admissions coming from the Emergency Department (ED), requires looking for strategies that lead to effective bed management. The aim of this study was to evaluate the effectiveness of a surgery admission unit for major elective surgery patients who were admitted for same-day surgery.</p> <p>Methods</p> <p>We included all patients admitted for elective surgery in a university tertiary hospital between the 1st of September and the 31st of December 2006, as well as those admitted during the same period of 2008, after the introduction of the Surgery Admission Unit. The main outcome parameters were global length of stay, pre-surgery length of stay, proportion of patients admitted the same day of the surgery and number of cancellations. Differences between the two periods were evaluated by the T-test and Chi-square test. Significance at P < 0.05 was assumed throughout.</p> <p>Results</p> <p>We included 6,053 patients, 3,003 during 2006 and 3,050 patients during 2008. Global length of stay was 6.2 days (IC 95%:6.4-6) in 2006 and 5.5 days (IC 95%:5.8-5.2) in 2008 (p < 0.005). Pre-surgery length of stay was reduced from 0.46 days (IC 95%:0.44-0.48) in 2006 to 0.29 days (IC 95%:0.27-0.31) in 2008 (p < 0.005). The proportion of patients admitted for same-day surgery was 67% (IC 95%:69%-65%) in 2006 and 76% (IC 95%:78%-74%) in 2008 (p < 0.005). The number of cancelled interventions due to insufficient preparation was 31 patients in 2006 and 7 patients in 2008.</p> <p>Conclusions</p> <p>The implementation of a Surgery Admission Unit for patients undergoing major elective surgery has proved to be an effective strategy for improving bed management. It has enabled an improvement in the proportion of patients admitted on the same day as surgery and a shorter length of stay.</p

Population pharmacokinetics of the two enantiomers of tramadol and O -demethyl tramadol after surgery in children

International audienceBACKGROUND : Few data are available on the stereoselective pharmacokinetics of tramadol in children. The aim of this study was to develop a population pharmacokinetic model for the (+)- and (-)-enantiomers of tramadol and its O-demethyl tramadol metabolite (M1) in children.METHODS : Twenty-five children (1-8 yr) were included in this study. Tramadol was administered after surgery by continuous infusion (loading dose, 2 mg kg(-1) i.v. over 10 min followed by continuous infusion of 8 mg kg(-1) over 24 h). If pain relief was inadequate, additional 1 mg kg(-1) i.v. bolus doses of tramadol were given over 10 min. A two-compartment structural model was used with NONMEM.RESULTS : For both enantiomers of tramadol, weight was the only patient characteristic parameter showing significant covariate effects on clearance (CL). CL increased by 5.7-6.1 litre h(-1) between 8-12 and 13-16 kg, and by 2.4-3.3 litre h(-1) between 13-16 and 17-33 kg. The rate constants associated with the metabolite elimination [0.144 h(-1), (+)-M1 and 0.18 h(-1), (-)-M1] were smaller than the elimination rate constants of the parent drugs [0.243 h(-1), (+)-tramadol and 0.241 h(-1), (-)-tramadol], suggesting that the metabolite disposition was rate-limited by its elimination. The presence of two subpopulations of patients was suspected on the basis of the observed bimodal distributions of the AUC(M1)/AUC(tramadol) ratios.CONCLUSIONS : The results of this study combine relationships between tramadol CL and patient covariates that may be useful for dose adjustment. Polymorphism is likely to contribute to the interpatient variability observed in the AUC M1/AUC tramadol ratios

Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors

Purpose Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should difer from other kind of tumors. Methods To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. Results Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated

Giochi da senatori

Megalencephalic leucoencephalopathy with subcortical cysts is a genetic brain disorder with onset in early childhood. Affected infants develop macrocephaly within the first year of life, after several years followed by slowly progressive, incapacitating cerebellar ataxia and spasticity. From early on, magnetic resonance imaging shows diffuse signal abnormality and swelling of the cerebral white matter, with evidence of highly increased white matter water content. In most patients, the disease is caused by mutations in the gene MLC1, which encodes a plasma membrane protein almost exclusively expressed in brain and at lower levels in leucocytes. Within the brain, MLC1 is mainly located in astrocyte-astrocyte junctions adjacent to the blood-brain and cereborspinal fluid-brain barriers. Thus far, the function of MLC1 has remained unknown. We tested the hypothesis that MLC1 mutations cause a defect in ion currents involved in water and ion homeostasis, resulting in cerebral white matter oedema. Using whole-cell patch clamp studies we demonstrated an association between MLC1 expression and anion channel activity in different cell types, most importantly astrocytes. The currents were absent in chloride-free medium and in cells with disease-causing MLC1 mutations. MLC1-dependent currents were greatly enhanced by hypotonic pretreatment causing cell swelling, while ion channel blockers, including Tamoxifen, abolished the currents. Down regulation of endogenous MLC1 expression in astrocytes by small interfering RNA greatly reduced the activity of this channel, which was rescued by overexpression of normal MLC1. The current-voltage relationship and the pharmacological profiles of the currents indicated that the channel activated by MLC1 expression is a volume-regulated anion channel. Such channels are involved in regulatory volume decrease. We showed that regulatory volume decrease was hampered in lymphoblasts from patients with megalencephalic leucoencephalopathy. A similar trend was observed in astrocytes with decreased MLC1 expression; this effect was rescued by overexpression of normal MLC1. In the present study, we show that absence or mutations of the MLC1 protein negatively impact both volume-regulated anion channel activity and regulatory volume decrease, indicating that megalencephalic leucoencephalopathy is caused by a disturbance of cell volume regulation mediated by chloride transport. © 2011 The Author

Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab : the BEYOND study (GEMCAD 17-01)

Altres ajuts: Fundació la Marató de TV3 (201330.10); Fundacion Olga Torres (Modalitat A. 2019/2020); Spanish Association Against Cancer (AECC, PROYE19040POST_001).Purpose: Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). Methods: In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). Results: Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. Conclusions: The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation