Monitoring of Epstein-Barr virus-infected cells by flow cytometer permits early diagnosis and evaluation of disease progression in EBV-associated hemophagocytic lymphohistiocytosis

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is characterized by clonal expansion of EBV-infected CD8(+)T-cells. We have recently demonstrated that detection of a clonally expanded population of EBV-infected CD8(+)T-cells with CD5 down-regulation was a useful tool to distinguish EBV-HLH from EBV-related disorders such as severe infectious mononucleosis. A 5-year-old girl who presented with fever, pancytopenia and liver dysfunction was diagnosed by this method in addition to conventional diagnostic tests. Further, EBV-infected cells were identified as CD5(-)HLA-DR(+) TCR V β3(+) CD8(+)T cells, an increase or decrease of which over time reflected the disease severity in this patient. Treatment of patients with EBV-HLH varies from steroid alone to intensive chemotherapy or hematopoietic stem cell transplantation. Easy monitoring of EBV-infected cells by using flow cytometry over time may provide useful information to choose an appropriate treatment for each individual patient with EBV-HLH.     

High-dose 131I-mIBG as consolidation therapy in pediatric patients with relapsed neuroblastoma and ganglioneuroblastoma: the Japanese experience

Annals of Nuclear Medicine - Children with relapsed neuroblastoma have a poor prognosis despite modern multimodality therapy. Novel and more effective therapeutic strategies are required for...     

Coronary artery bypass grafting in patients with depressed left ventricular function: Operative results and long-term follow-up

Nine consecutive patients with coronary artery disease who had a left ventricular ejection fraction (LVEF) of less than 0.4 and underwent coronary artery bypass grafting (CABG) at our institution were studied. All patients had angina pectoris and six of the nine patients (67%) had a history of congestive heart failure. The mean EF was 0.37±0.03 and the mean LV end-diastolic pressure was 10.1±4.9 mm Hg. An average of 1.56±0.50 grafts per patient were placed and there was no operative death. The graft patency rate was 92.9% and the mean EF rose significantly from 0.37 to 0.53 after surgery (P<0.05). There was one late death, the 4-year actuarial survival rate being 88.9%. Of the eight long-term survivors, six (75%) were totally asymptomatic and only two had mild angina on exertion. This study confirmed that CABG for patients with depressed LV dysfunction can be performed safely with an acceptably low operative mortality, a significant improvement of LV function, and excellent long-term results.     

Physiologically based pharmacokinetic study on a cyclosporin derivative,SDZ IMM 125

The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio=8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membranelimited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (K _P) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady statein vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances;in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration andAUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.     

Adenovirus-mediated expression of brain-derived neurotrophic factor protects spiral ganglion neurons from ototoxic damage

Hair cell loss, the most common cause of deafness, is often associated with auditory nerve degeneration. Our goal was to determine the influence of combined ciliary-derived neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) gene therapy on the survival of spiral ganglion neurons (SGNs) after elimination of inner hair cells in the mature guinea pig ear. Seven days after bilateral deafening, a 5-microl suspension of CNTF and/or BDNF adenovirus vectors was injected into the left scala tympani through the round window. Animals were sacrificed 28 days after deafening, and their inner ears were prepared for SGN counts. The SGN counts revealed that BDNF alone and the combined CNTF and BDNF treatment significantly enhanced SGN survival. CNTF did not significantly enhance the protective effect of BDNF. These data present possible strategies for enhancing SGN survival in cochlear implant procedures.     

Effects of ML-236B (Compactin) on Sterol Synthesis and Low Density Lipoprotein Receptor Activities in Fibroblasts of Patients with Homozygous Familial Hypercholesterolemia

We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of ¹²⁵I-LDL were 0.5±0.3 ng/mg protein (mean±SEM), 14±8 and 8±6 ng/mg protein per 6 h (four normal cells; 44±3, 386±32, and 1,335±214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of ¹²⁵I-LDL were 6±2, 29±8, and 90±32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed ~46% of the normal activities of receptor.     

Effect of Ejnell's laterofixation of the vocal fold for bilateral fixation at the median position

We reviewed the effect of Ejnell's laterofixation of the vocal fold for bilateral fixation at the median position. Subjects were 10 patients undergoing bilateral vocal fold fixation at the median position from October 1998 to September 2005. We evaluated outcome using indices of FEV1.0/PEFR (ml/L/min) and PEFR (%), which reflect the severity of upper airway obstruction and whether tracheostoma could be closed if tracheostomy preceded Ejnell's procedure. Mean FEV1.0/PEFR and PEFR in 5 patients undergoing breathing capacity examination before and after surgery improved from 13.21 to 9.85 and 30.9 to 51.9. respectively. Six of the 8 undergoing tracheostomy prior to Ejnell's procedure tolerated decannulation. Another 2 whose tracheostoma could not be closed had complications, one having COPD and the other poorly controllable diabetes mellitus, with swollen false vocal fold and arytenoids and granulation. Our results suggest that Ejnell's laterofixation of the vocal fold is effective in treating bilateral vocal fold fixation at the median position. A patient's complications should, however, be taken into consideration before proceeding to Ejnell's laterofixation.