β-Adrenoreceptor Stimulation Mediates Reconsolidation of Social Reward-Related Memories

In recent years, the notion that consolidated memories become transiently unstable after retrieval and require reconsolidation to persist for later use has received strong experimental support. To date, the majority of studies on reconsolidation have focused on memories of negative emotions, while the dynamics of positive memories have been less well studied. Social play, the most characteristic social behavior displayed by young mammals, is important for social and cognitive development. It has strong rewarding properties, illustrated by the fact that it can induce conditioned place preference (CPP). In order to understand the dynamics of positive social memories, we evaluated the effect of propranolol, a β-adrenoreceptor antagonist known to influence a variety of memory processes, on acquisition, consolidation, retrieval and reconsolidation of social play-induced CPP in adolescent rats.Systemic treatment with propranolol, immediately before or after a CPP test (i.e. retrieval session), attenuated CPP 24 h later. Following extinction, CPP could be reinstated in saline--but not in propranolol-treated rats, indicating that propranolol treatment had persistently disrupted the CPP memory trace. Propranolol did not affect social play-induced CPP in the absence of memory retrieval or when administered 1 h or 6 h after retrieval. Furthermore, propranolol did not affect acquisition, consolidation or retrieval of social play-induced CPP.We conclude that β-adrenergic neurotransmission selectively mediates the reconsolidation, but not other processes involved in the storage and stability of social reward-related memories in adolescent rats. These data support the notion that consolidation and reconsolidation of social reward-related memories in adolescent rats rely on distinct neural mechanisms

Prediction of Drug-Target Interactions and Drug Repositioning via Network-Based Inference

Drug-target interaction (DTI) is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI), target-based similarity inference (TBSI) and network-based inference (NBI). Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning

Oxidative metabolism appears to be reduced in long-term hemodialysis patients

Background. As part of a study of whole-body protein metabolism in hemodialysis (HD) patients, we obtained values for whole-body bicarbonate production in control subjects and HD patients before and during dialysis by using stable isotopically labeled bicarbonate. Indirect calorimetry measurements have shown normal or increased energy expenditure in HD patients, which has been used to explain the malnutrition in many of these patients. However, this method becomes inaccurate when the dynamics of whole-body bicarbonate production change during measurement, as is the case with HD patients during dialysis. Methods: Whole-body bicarbonate production was measured in 6 control subjects, 9 patients on a nondialysis day (HD-), and 8 patients during an HD session (HD+) by means of a primed constant infusion of carbon 13 (C-13)-labeled sodium carbonate ((NaHCO3)-C-13). 13 C-Abundance of expired carbon dioxide was measured by means of isotope ratio mass spectrometry. Results Carbon dioxide production was 141 +/- 12, 123 +/- 11(star), and 148 +/- 19 mu mol/kg/min for the control, HD-, and HD+ groups, respectively (P-star <0.05 compared with the control and HD+ groups). Values for energy expenditure were derived and were 29.1 +/- 2.4, 24.9 +/- 2.1(star), and 32.6 +/- 2.0 kcal/kg/day, respectively (P-star <0.05 compared with the control and HD+ groups). Conclusion: Whole-body oxidation in HD patients is reduced compared with control subjects. During dialysis, bicarbonate turnover, as well as carbon dioxide expiration, increases because of the influx of bicarbonate from the dialyzer. (c) 2005 by the National Kidney Foundation, Inc

Membrane biocompatibility does not affect whole body protein metabolism during dialysis

Background: Protein-calorie malnutrition is present in 30-50% of dialysis patients. The lack of biocompatibility of the dialysis membrane, which results in low-grade inflammation, could be responsible for this malnutrition. We investigated whether protein-energy malnutrition could be partly due to incompatibility of the dialyzer during the dialysis session. Methods: Five patients were dialyzed during 2 periods of 3 weeks (cross-over) with either a single-use low-flux polysulfone or cellulose triacetate (biocompatible) or a single-use cuprophan (bio-incompatible) membrane. As a measure of whole body protein metabolism, a primed constant infusion of L-[1-C-13]-valine was used during a 4-hour dialysis session. Results: Cuprophan was a more powerful activator of the complement system than other membranes. Protein metabolism parameters during both study protocols were not different and resulted in the same protein balance during polysulfone/cellulose triacetate (-15 +/- 3) and cuprophan (-13 +/- 2 mu mol/kg/h) dialysis. Conclusion: In stable hemodialysis patients with no apparent complications, protein metabolism during dialysis is not affected by the compatibility of the dialysis membrane. Copyright (C) 2005 S. Karger AG, Basel

Comparison of amino acid oxidation and urea metabolism in haemodialysis patients during fasting and meal intake

Background. The PNA (protein equivalent of nitrogen appearance) is used to calculate protein intake from urea kinetics. One of the essential assumptions in the calculation of PNA is that urea accumulation in haemodialysis (HD) patients is equivalent to amino acid oxidation. However, urea is hydrolysed in the intestine and the resulting ammonia could be used metabolically. The magnitude and dependence on protein intake of this process are unknown in HD patients. Methods. Seven HD patients were studied twice, 1 week apart, on a similar protocol. After an overnight fast, patients fasted in the morning and received meals in the afternoon. On one day, amino acid oxidation was measured by infusion of L-[1-C-13]valine. Urea production, measured from the dilution of [C-13]urea, and urea accumulation, calculated from the increase in plasma urea concentration multiplied by the urea dilution volume, were measured during the other day. PNA was calculated using standard equations. Results. Amino acid oxidation and urea production were not significantly different during fasting. Urea accumulation during fasting was significantly lower than both amino acid oxidation and urea production. Urea accumulation during feeding remained significantly lower than amino acid oxidation. PNA was equal to the average of the urea accumulation values during fasting and feeding. Conclusion. We conclude that during fasting, urea accumulation is not associated with amino acid oxidation or urea production. During meal intake, amino acid oxidation, urea production and urea accumulation show acutely an almost identical increase. PNA represents the average of fasting and fed urea accumulation and is lower than average amino acid oxidation or urea production

Multiple myeloma related cells in patients undergoing autologous peripheral blood stem cell transplantation

A high incidence of oligoclonal serum M-components is observed in multiple myeloma (MM) patients treated with autologous Stem cell transplantation (ASCT). To determine whether these hi-components are produced by myeloma clonally related cells or caused by an aberrant B-cell regeneration we analysed by semi-nested ASO-RT-PCR and DNA sequencing the immunoglobulin (Ig) variable genes (VH) obtained from bone marrow samples obtained before and after transplantation and peripheral blood stern cell (PBSC) samples from seven patients. Myeloma clonally related cells are identifiable by the expression of variant Ig heavy chain isotypes and were detected in two patients at presentation. No myeloma clonally related cells were found in post-transplantation samples (n = 7) in spite of the appearance of new serum M-components, However, in two cases we amplified sequences from post-transplantation bone marrow cells that were able to bind to the B-cell clone-specific CDR3 oligonucleotides but showed no further similarity regarding the VDT rearrangement, These data indicate that serum oligoclonality posttransplantation is not caused by myeloma clonally related B cells but rather by the regenerating B-cell compartment