Impaired renal secretion of substrates for the multidrug resistance protein 2 in mutant transport-deficient (TR-) rats

Previous studies with mutant transport-deficient rats (TR(-)), in which the multidrug resistance protein 2 (Mrp2) is lacking, have emphasized the importance of this transport protein in the biliary excretion of a wide variety of glutathione conjugates, glucuronides, and other organic anions. Mrp2 is also present in the luminal membrane of proximal tubule cells of the kidney, but little information is available on its role in the renal excretion of xenobiotics. The authors compared renal transport of the fluorescent Mrp2 substrates calcein, fluo-3, and lucifer yellow (LY) between perfused kidneys isolated from Wistar Hannover (WH) and TR(-) rats. Isolated rat kidneys were perfused with 100 nM of the nonfluorescent calcein-AM or 500 nM fluo3-AM, which enter the tubular cells by diffusion and are hydrolyzed intracellularly into the fluorescent anion. The urinary excretion rates of calcein and fluo-3 were 3 to 4 times lower in perfused kidneys from TR(-) rats compared with WH rats. In contrast, the renal excretion of LY (10 micro M, free anion) was somewhat delayed but appeared unimpaired in TR(-) rats. Membrane vesicles from Sf9 cells expressing human MRP2 or human MRP4 indicated that MRP2 exhibits a preferential affinity for calcein and fluo-3, whereas LY is a better substrate for MRP4. We conclude that the renal clearance of the Mrp2 substrates calcein and fluo-3 is significantly reduced in TR(-) rat; for LY, the absence of the transporter may be compensated for by (an)other organic anion transporter(s).     

Survival and postoperative complication in daily practice after neoadjuvant therapy in resectable stage IIIA-N2 non-small cell lung cancer

Regarding persisting controversies about neoadjuvant treatment (NT), we studied the impact of neoadjuvant therapy in daily practice. Patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) resected after NT were eligible. Data on preoperative treatments, surgical procedure, postoperative complications and survival were collected. Overall, 71 (60 men, median age of 60 years) patients met inclusion criteria. All patients received a two-drug platinum-based regimen (median of 2.5 cycles [2-4 cycles]) and 15 (21%) had an associated radiotherapy (20-40 Gy). Nine complete and 27 partial responses were achieved. Surgical procedure principally was a lobectomy (44%), a left (15.5%) or a right (27%) pneumonectomy. Operative mortality was 4.2% while 21 patients (29%) experienced postoperative complications. Median survival was 17 months (95% CI, 13-21 months) with 3- and 5-year survival rates of 24 and 13%, respectively. Five-year survival was worse if postoperative complication occurred (18 versus 0%, p=0.09). Multivariate analysis showed male gender (RR=0.37, 95% CI, 0.16-0.81, p=0.013) and postoperative positive lymph node (RR=2.7, 95% CI, 1.4-5.2, p=0.002) to influence survival. In conclusion, achievement of a clinical and pathological response after NT for stage IIIA-N2 NSCLC patients enables a better survival. More efficient but also less toxic regimens of chemotherapy should be developed regarding its impact on long-term survival.     

Extra-anatomic aortic bypass for complex (re-) coarctation and hypoplastic aortic arch in adolescents and adults

Various surgical approaches have been proposed for complex (re-) coarctation and aortic arch hypoplasia (AAH). We report seven patients (mean age 19.6+/-9.5 years) with complex coarctation or re-coarctation and AAH successfully treated by extra-anatomic ascending-to-descending aortic bypass (ADB) via sternotomy between 1995 and 2002 without mortality and no relevant complication early postoperatively and during a follow-up of 24+/-29 (0.2-84) months. ADB may therefore be considered in selected patients with (re-) coarctation with AAH, with the need for concomitant ascending aortic or cardiac surgery and in patients with aortic arch stenosis and increased risk of complications under DHCA.     

Pulmonary cystic hydatid disease in Ireland

Background Hydatid disease is rare in Ireland and its incidence and prevalence are unknown. Most cases are diagnosed by a combination of clinical findings, morphological features on imaging and by serological testing. Aims We describe an Irish case of pulmonary hydatid disease detected at bronchoscopy by bronchoalveolar lavage, and discuss the diagnosis and treatment of the disorder.     

The same TCR (N)Dbeta(N)Jbeta junctional region is associated with several different vbeta13 subtypes in a multiple sclerosis patient at the onset of the disease

In multiple sclerosis (MS), the T-cell receptors (TCRS) of autoreactive T lymphocytes recognize various myelin components or derivatives including peptides of the myelin basic protein (MBP). Using the exhaustive immunoscope approach we showed that the T-cell repertoires of MS patients differ from those of healthy controls, with expansion of Vβ13 cell clones in cerebrospinal fluid (CSF) and in peripheral blood lymphocytes (PBLs). Sequencing of the β13⁺ chains of T cells recovered from the CSF revealed high interindividual diversity, and no particular Vβ13⁺ rearrangements were shown to be myelin-autoreactive. Within the overall Vβ13 repertoire in the CSF of patient MS3 at the onset of the disease, most of the overrepresented (N)Dβ(N)Jβ junctional regions were found to be associated with two or three different Vβ13 segments. These rearrangements were most common in the PBLs of patient MS3. No such associations were detected in the Vβ5 multigene family that was used as a control. Thus, Vβ13 T cells infiltrating the CSF from patient MS3 may have been selected on the basis of both the Vβ13 segments and the (N)Dβ(N)Jβ junctional CDR3 sequence.     

Effects of intra-accumbens focal administrations of glutamate antagonists on object recognition memory in mice

Generally recognition memory is distinguished into spatial and object memories that have been suggested to relay at a cortical level on different neural substrates. Recent studies point to a possible involvement of the nucleus accumbens (Nac) in spatial memory, demonstrating that blockade of glutamate antagonists within this structure impairs acquisition and consolidation of spatial information, while not many data are available on the potential role of this structure in object recognition. Thus in this study we wanted to investigate the effects of intra-accumbens focal administrations of NMDA antagonist, AP-5 (0.05, 0.1, 0.15 or 0.2 microg per side), and AMPA antagonist, DNQX (0.0005 or 0.001 microg per side), in object recognition memory. The spontaneous preference displayed by mice for novel objects was taken as an index for measuring object recognition. Pre-training focal administrations of both antagonists impaired the ability of mice to selectively explore the novel object in test session. However, the AMPA antagonist induced also a decrease in exploration and locomotion. In order to assess whether glutamate receptors located within the Nac were also involved in subsequent steps of object information processing, we performed additional experiments injecting AP-5 and DNQX immediately after training and testing the animals 24-h later. In this case, AP-5 but not the AMPA antagonist impaired exploration of the novel object. These results demonstrate that the Nac is involved in object recognition, and confirm that the different glutamate receptors mediate different component of information processing within the accumbens.     

High-dose azithromycin versus high-dose amoxicillin-clavulanate for treatment of children with recurrent or persistent acute otitis media

Infants and young children, especially those in day care, are at risk for recurrent or persistent acute otitis media (AOM). There are no data on oral alternatives to high-dose amoxicillin-clavulanate for treating AOM in these high-risk patients. In this double-blind, double-dummy multicenter clinical trial, we compared a novel, high-dose azithromycin regimen with high-dose amoxicillin-clavulanate for treatment of children with recurrent or persistent AOM. Three hundred four children were randomized; 300 received either high-dose azithromycin (20 mg/kg of body weight once a day for 3 days) or high-dose amoxicillin-clavulanate (90 mg/kg divided twice a day for 10 days). Tympanocentesis was performed at baseline; clinical response was assessed at day 12 to 16 and day 28 to 32. Two-thirds of patients were aged < or =2 years. A history of recurrent, persistent, or recurrent plus persistent AOM was noted in 67, 18, and 14% of patients, respectively. Pathogens were isolated from 163 of 296 intent-to-treat patients (55%). At day 12 to 16, clinical success rates for azithromycin and amoxicillin-clavulanate were comparable for all patients (86 versus 84%, respectively) and for children aged < or =2 years (85 versus 79%, respectively). At day 28 to 32, clinical success rates for azithromycin were superior to those for amoxicillin-clavulanate for all patients (72 versus 61%, respectively; P = 0.047) and for those aged < or =2 years (68 versus 51%, respectively; P = 0.017). Per-pathogen clinical efficacy against Streptococcus pneumoniae and Haemophilus influenzae was comparable between the two regimens. The rates of treatment-related adverse events for azithromycin and amoxicillin-clavulanate were 32 and 42%, respectively (P = 0.095). Corresponding compliance rates were 99 and 93%, respectively (P = 0.018). These data demonstrate the efficacy and safety of high-dose azithromycin for treating recurrent or persistent AOM.