Decreased expression of hippocampal cholinergic neurostimulating peptide precursor protein mRNA in the hippocampus in Alzheimer disease

Hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the phenotype development of the septo-hippocampal system. HCNP precursor protein (HCNP-pp) is known to interact with other molecules including phosphatidylethanolamine and Raf-1 kinase, and is also known as phosphatidylethanolamine-binding protein and raf kinase-inhibitory protein. To assess whether HCNP-pp is involved in the pathogenesis of Alzheimer disease (AD), the expression levels of its mRNA in the hippocampus of autopsy brains from patients with dementia (including AD and ischemic vascular dementia) were compared with those of non-demented control subjects. The in situ hybridization analysis revealed that the expression of HCNP-pp mRNA in patients with clinically late-onset AD was decreased in the hippocampal CA1 field, but not in the CA3 field or the dentate gyrus. The early-onset AD patients showed a wide range of expression levels in the hippocampal sub-regions. Northern blot analysis of HCNP-pp mRNA in brain tissue supported these observations. Since HCNP is known to stimulate the enzymatic activity of choline acetyltransferase in neurons, its low expression in the CAI field of AD patients may explain the downregulation of cholinergic neurons seen in these patients and may thus contribute to the pathogenic processes underlying AD.     

Doxorubicin encapsulation and diffusional release from stable, polymeric, hydrogel nanoparticles.

We have recently described the preparation of stable, polymeric nanoparticles, composed of poly(ethylene glycol) and poloxamer 407 (Pluronic F127), prepared via inverse emulsion photopolymerization. In the present study we report on the performance of this novel colloidal system as a controlled delivery system for small hydrophobic drugs. Successful encapsulation of doxorubicin occurred through hydrophobic interactions, taking advantage of particle nanoarchitecture. Loadings of up to 8.7wt.% were achieved with a reproducible, fast, solvent evaporation procedure. In vitro drug release, monitored by fluorescence spectrometry and HPLC, revealed a minor burst (approximately 10% at 37 degrees C) and sustained, diffusional release for over 1 week; furthermore, drug encapsulation significantly delayed doxorubicin degradation kinetics.     

Lack of Ku80 alteration in multiple myeloma.

Chromosomal rearrangement involving the immunoglobulin gene locus, as a result of marked chromosomal instability, is the hallmark of human multiple myeloma (MM) cells. Since Ku80 plays a key role in the non-homologous end-joining (NHEJ) system, we investigated whether Ku80 alteration contributes to this genetic instability by examining its status in 16 MM cell lines. Our study demonstrated a lack of Ku80 alterations at the protein, mRNA and gene level in 15 out of the 16 cell lines. Only the U266 cell line carried a missense mutation of Ser335Leu in one allele of the cDNA. Six marrow samples derived from myeloma patients also did not show any aberrant Ku80 protein, in terms of size. Accordingly, Ku80 alteration is unlikely to be involved in MM, in disagreement with a previous study reporting frequent presence of a 69-kD Ku80 variant (Ku86v) with reduced DNA binding activity in MM cells.     

Hemodynamic changes during off-pump coronary artery bypass anastomosis in patients with coexisting mitral regurgitation: improvement with milrinone

We hypothesized that mitral regurgitation (MR) would be exacerbated, cardiac index (CI) decreased, and mean pulmonary artery pressure (MPAP) increased in patients with coexisting MR during off-pump coronary artery bypass (OPCAB) anastomosis, and that milrinone could ameliorate increases in MR that occur during OPCAB anastomosis. Subjects comprised 140 patients scheduled for elective OPCAB divided into three groups: patients without MR (MR(-) group; n = 57), patients with MR (MR(+) group; n = 41), and patients with MR who received milrinone (M+MR(+) group; n = 42). Patients with grade 1+ or 2+ MR were included, whereas those with grade 3+ or 4+ MR were excluded. Hemodynamic variables were measured after the induction of anesthesia and during anastomosis. IV infusion of milrinone (0.5 microg . kg(-1) . min(-1)) started immediately after the induction of anesthesia in the M+MR(+) group. CI was significantly decreased (P < 0.0001), and MPAP and MR were significantly increased (P < 0.001) during left coronary anastomosis in the MR(+) group compared with the MR(-) group. CI was significantly higher (P < 0.001), and neither MPAP nor MR were increased (P < 0.05) during left coronary artery anastomosis in the M+MR(+) group compared to the MR(+) group. In patients with MR, anastomosis of the left coronary artery branches was associated with decreased CI and increased regurgitation and MPAP. In such patients, treatment with milrinone helps to stabilize hemodynamics during anastomosis.     

Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction.     

Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-germinal center phenotype"

Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centromere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n = 1 for gene amplification, and n = 1 for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein overexpression were classified into at least two heterogeneous molecular groups, based on the results of the FISH analysis.     

Acute onset and worsening of diabetes concurrent with administration of statins

We report a patient in whom the administration of HMG CoA reductase inhibitors (statins) might have triggered the onset and worsening of diabetes. The patient was a 48-year-old Japanese man who underwent annual medical examination but had never been told of hyperglycemia. Four months after the commencement of atorvastatin (10 mg/day) treatment, a diagnosis of diabetes mellitus was made from his typical symptoms of hyperglycemia, postprandial plasma glucose level of 29.8 mmol/l and HbA1c of 11.5%. After 2 months of insulin therapy and 3 months after the cessation of atorvastatin, almost complete resolution of diabetes was observed. During the subsequent 3 months, diet therapy alone was sufficient to control blood glucose level. Then, we prescribed pravastatin (20 mg/day). During the subsequent 3 months, HbA1c was gradually increased. However, after discontinuation of pravastatin, HbA1c was gradually decreased. In the general population, statin does not seem to have critical adverse effects on glucose tolerance, but it may uncommonly modify the natural course of the development of diabetes in certain patients.