Spectral analysis of the electroencephalogram in neonatal rats chronically treated with the NMDA antagonist MK-801.

In order to study the involvement of NMDA-receptor activation in brain development, rat pups were chronically treated with the non-competitive NMDA antagonist MK-801 during the neonatal period. We recorded the cortical EEG at various vigilance states throughout the treatment period. Spectral analysis of the EEG showed reduced power in the delta (delta) frequency range (1.5-4 Hz) during quiet sleep and less power in the theta (theta) range (4-7 Hz) during REM-sleep in MK-801 animals than in controls. No significant differences were found for the total time spent in each of the different vigilance states. We conclude that chronic MK-801 treatment probably causes a developmental retardation in state-related brain activities.     

Evidence that dopamine in the nucleus accumbens is involved in the ability of rats to switch to cue-directed behaviours.

Recently we have reported that injections of d-amphetamine into the nucleus accumbens enhanced the number of switches to cue-directed behaviours without an effect on the number of switches to non-cue-directed behaviours in a swimming test. In the present study we investigated to what extent this effect is mediated via the dopaminergic system in the nucleus accumbens. For that purpose drugs selective for D1- and D2-receptors were studied in this swimming test. It was found that the selective D2-agonist LY 171 555 (50 ng/0.5 microliters) enhanced the number of different cue-directed behaviours. The selective D2-antagonist raclopride (50 ng/0.5 microliters) decreased it. Furthermore an ineffective dose of raclopride attenuated the effect of LY 171 555. Both the selective D1-antagonist SCH 23390 (400 ng/0.5 microliters) and the selective D1-agonist SKF 38393 (50-400 ng/0.5 microliters) decreased the number of different cue-directed behaviours. The effect induced by SCH 23390 could not be blocked by SKF 38393. Similarly the effect induced by SKF could not be attenuated by SCH 23390. These data point to a role for dopamine D2-receptors in the ability to switch to cue-directed behaviours. The present findings do not yet allow the conclusion that D1-receptors are involved.     

Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg

To cover intermediate sensitive Candida glabrata in ICU patients,fluconazole plasma peak levels at least in the range of 16–32µg/ml appear necessary for treatment. Previous studiesdid not reach these fluconazole levels under continuous veno-venoushaemofiltration (CVVHF) with dosages of 200–600 mg fluconzoledaily. In the present study, nine patients simultaneously requiringCVVHF for treatment of acute oligoanuric renal failure and antimycotictherapy of Candida septicemia received fluconazole 800 mg/day.Fluconazole plasma levels were determined to evaluate whetherthis dosage is adequate to reach the advised fluconazole levels.Patients were dialysed on two consecutive days with an ultrafiltrationrate (UF) of 1000 ml/h or 2000 ml/h, respectively, in a randomizedorder. The predilution was 800 ml/h and 1800 ml/h, respectively.The treatment was tolerated without adverse effects. All patientsreached plasma fluconazole concentrations between 16 and 32µg/ml, remaining in this range for a minimum of 1 up to24 h with a mean of 9.6 h and a UF rate of 2000 ml/h, and 15.7h with a UF rate of 1000 ml/h. So far, there are no in vivodata on the fluconazole plasma concentrations required for effectivetreatment. However, our data demonstrate, that at least thefluconazole concentrations desirable on the basis of in vitrosusceptibility testing can be reached in critically ill patientson CVVHF in an ICU setting. However, in these patients, 800mg fluconazole/day are necessary to achieve fungicidal drugconcentrations.     

Intracardiac transplantation of a mixed population of bone marrow cells improves both regional systolic contractility and diastolic relaxation.

BACKGROUND: Pre-clinical and clinical studies suggest that transplantation of bone marrow-derived stem cells can improve global cardiac function. However, no quantitative assessment of regional systolic contraction and correlation with phenotype has been made. Therefore, we used our model of cryoinfarcted rabbit myocardium for intracardiac transplantation of a mixed population of bone marrow-derived cells and assessed both regional function and myogenic conversion of the cells. METHODS: Nineteen New Zealand white rabbits underwent cryoinjury of the left ventricle. Autologous bone marrow (BM) cells were expanded in vitro. After 2 weeks, either 1 x 10(8) mixed BM-derived progenitor cells (BM group, n = 11) or vehicle (control group, n = 8) were injected into the cryoinjured region. Regional systolic function was measured using micromanometry and sonomicrometry before and 4 weeks after cell injection; cell phenotype was evaluated histologically. RESULTS: All animals in the BM group significantly improved both systolic shortening (0.11 +/- 0.7 vs -0.05 +/- 0.05 mm in the control group, p < 0.05) and regional stroke work when compared with control (9.6 +/- 2.4 vs -1.2 +/- 1.2 mm . mm Hg, p < 0.003). In addition, the BM group had improved global diastolic function, as measured by minimum dP/dt and end-diastolic pressure. On histologic assessment, BM cells differentiated toward a myogenic phenotype. CONCLUSIONS: Transplanting a mixed population of marrow-derived cells that can adopt a myogenic phenotype improves regional contractility and diastolic relaxation after myocardial infarction.     

MRP8 and MRP14, S-100-like proteins associated with myeloid differentiation, are translocated to plasma membrane and intermediate filaments in a calcium-dependent manner

MRP8 and MRP14 are two Ca(2+)-binding proteins of the S-100 family expressed by myelomonocytic cells. Both proteins assemble to noncovalently associated complexes in a Ca(2+)-dependent manner. Members of the S-100 family are known to play a role in cytoskeletal- membrane interactions; therefore, we investigated the subcellular distribution of MRP8/MRP14 and their complexes in human monocytes. Using differential centrifugation and subsequent Western blot or enzyme- linked immunosorbent assay analysis, we found that MRP8/MRP14 were almost completely translocated from the cytoplasma to membrane and cytoskeletal structures in a Ca(2+)-dependent manner. Using a cross- linking technique, complexed forms of MRP8/MRP14 were found to be associated with the plasma membrane. Analysis of MRP-transfected L132 cells showed that the MRP8 as well as the MRP14 component of the MRP8/MRP14 complex may independently bind to membrane and cytoskeletal structures. Furthermore, immunogold electron microscopy showed a colocalization of MRP8/MRP14 and the intermediate filament type III protein vimentin in A23187-treated monocytes. Our data indicate that, in analogy to other S-100-like proteins, MRP8 and MRP14 play a role in Ca(2+)-dependent cytoskeletal-membrane interactions. Restriction of MRP8/MRP14 expression to distinct stages of myelomonocytic differentiation suggests that these proteins are involved in highly specific pathways of intracellular signaling in phagocytes.     

Sequential 99mTc-hydrazinonicotinamide-annexin V imaging for predicting response to chemotherapy.

This study was undertaken to evaluate changes in relative (99m)Tc-hydrazinonicotinamide (HYNIC)-annexin V tumor uptake over time in patients undergoing chemotherapeutic treatment at baseline and at 5-7 h and 40-44 h after treatment initiation. Imaging results are related to clinical outcomes, as assessed with response evaluation criteria in solid tumors (RECIST). METHODS: We prospectively included 20 patients (11 men and 9 women; mean age, 59.8 y; range, 22-75 y) scheduled for chemotherapy (n = 19) or bisphosphonate treatment (n = 1). Curable disease was present in 5 patients. The other patients had metastatic disease and were treated in a palliative setting. Three of the 20 enrolled patients were excluded from analysis: 1 patient ultimately refused the proposed chemotherapy treatment; because of difficulties with the labeling procedure, 1 patient did not receive a pretreatment scan; and 1 patient presented with an allergic reaction (rash and nausea) to the (99m)Tc-HYNIC-annexin V formulation. The remaining 17 patients underwent 3 scintigraphic scans with (99m)Tc-HYNIC-annexin V: before treatment and 5-7 h and 40-44 h after treatment initiation. The tumor response was evaluated with RECIST and related to observed changes in the ratios of tumor activity to background activity for the largest known lesion; values exceeding 25% the baseline value on either the 5- to 7-h scan or the 40- to 44-h scan were considered significant. RESULTS: With the proposed sequential imaging protocol and a 25% change threshold, responders to treatment could be separated from nonresponders with a 94% accuracy (16/17 patients). CONCLUSION: Sequential (99m)Tc-HYNIC-annexin V imaging may allow for assessment of the response to chemotherapy within 3 d after treatment initiation.     

Hyperphosphataemia and related mortality.

Sir, With great interest we read the editorial review of Jean etal. [1] on the relationship between hyperphosphataemia and mortalityin end-stage renal disease patients. The authors summarize resultsfrom the large USRDS and DOPPS studies in which associationsof hyperphosphataemia and increased mortality risks were