Prognostic significance of bone marrow 2-[18F]-fluoro-2-deoxy-d-glucose uptake in diffuse large B-cell lymphoma: relation to iliac crest biopsy results.

AIM: To investigate the prognostic significance of bone marrow (BM) 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) uptake in relation to posterior iliac crest BM biopsy (BMB) results in diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Pretreatment integrated positron-emission tomography(PET)/computed tomography (CT) images of 512 DLBCL patients who underwent BMB and received rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy were analysed retrospectively. BM uptake was assessed visually and by maximum standard uptake value (SUVmax). Associations with lymphoma-specific survival (LSS) were assessed using Kaplan-Meier and Cox regression analyses. RESULTS: FDG(+) BM was observed in 64 cases (41 focal, 12 heterogeneous, 11 diffuse). This finding distinguished iliac crest involvement (positive in 59 and negative in 453) with 89.6% accuracy (459/512) and 93.6% specificity (424/453). In BMB(+) patients, BM-to-liver SUVmax ratio >1.8 concurred perfectly with FDG(+) BM. During 52 months of follow-up, there were 156 lymphoma-related deaths. In the entire population, multivariate analysis revealed high International Prognostic Index (IPI; p<0.001), old age (p=0.003), bulky disease (p=0.011), BMB(+) (p=0.028), and FDG(+) BM (p=0.019) as independent predictors of worse LSS. In the BMB(+) subgroup, high National Comprehensive Cancer Network-revised IPI (NCCN-IPI; p=0.029) and FDG(+) BM (p=0.008) were significant independent predictors. Among BMB(+) patients with low to low-intermediate NCCN-IPI, FDG(+) BM was associated with significantly worse 2-year LSS (33.3% versus 100%; p=0.017). The same was true among those with high-intermediate NCCN-IPI (34.7% versus 76.9%.; p=0.026). CONCLUSION: Increased BM FDG in DLBCL is a predictor of worse LSS independent of BMB results and other prognostic variables including IPI/NCCN-IPI.

Derangement of PaCO2 requires physician attention in acute carbon monoxide poisoning.

The objective was to describe the prevalence of derangement of the partial pressure of arterial carbon dioxide (PaCO2) and to determine the association between PaCO2 and adverse cardiovascular events (ACVEs) in carbon monoxide (CO)-poisoned patients. Additionally, we evaluated whether the derangement of PaCO2 was simply secondary to metabolic changes. This retrospective study included 194 self-breathing patients after CO poisoning with an indication for hyperbaric oxygen therapy and available arterial blood gas analysis at presentation and 6 h later. The incidence rate of hypocapnia at presentation after acute CO poisoning was 67.5%, and the mean PaCO2 during the first 6 h was 33 (31-36.7) mmHg. The most common acid-base imbalance in 131 patients with hypocapnia was primary respiratory alkalosis. The incidence rate of ACVEs during hospitalization was 50.5%. A significant linear trend in the incidence of ACVEs was observed across the total range of PaCO2 variables. In multivariate regression analysis, mean PaCO2 was independently associated with ACVEs (odds ratio 0.051; 95% confidence interval 0.004-0.632). PaCO2 derangements were common after acute CO poisoning and were not explainable as a mere secondary response to metabolic changes. The mean PaCO2 during the first 6 h was associated with ACVEs. Given the high incidence of ACVEs and PaCO2 derangement and the observed association between the mean PaCO2 and ACVEs, this study suggests that (1) PaCO2 should be monitored in the acute stage to predict and/or prevent ACVEs and (2) further investigation is needed to validate this result and explore the early manipulation of PaCO2 as a treatment strategy.

The expression of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and HCN2 in the rat trigeminal ganglion, sensory root, and dental pulp.

Hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and 2 (HCN2) are abundantly expressed in primary sensory neurons and contribute to neuronal excitability and pathological pain. We studied the expression of HCN1 and HCN2 in the rat trigeminal ganglion (TG) neurons and axons in the dental pulp, and the changes in their expression following inflammation, using light- and electron-microscopic immunocytochemistry and quantitative analysis. HCN1 and HCN2 were expressed predominantly in large-sized, neurofilament 200-immunopositive (+) or parvalbumin+ soma in the TG whereas they were expressed mostly in unmyelinated and small myelinated axons in the sensory root. The expression was particularly strong along the plasma membrane in the soma. In the dental pulp, majority of HCN1+ and HCN2+ axons coexpressed calcitonin gene-related peptide. They were expressed mainly in the peripheral pulp and pulp horn where the axons branch extensively in the dental pulp. The expression of HCN1 and HCN2 in TG neurons increased significantly in rats with experimentally induced inflammation of the dental pulp. Our findings support the notion that HCN1 and HCN2 are expressed mainly by both the soma of mechanosensitive neurons in the TG and peripheral axons of nociceptive neurons in the sensory root, and may play a role in the mechanisms of inflammatory pain from the dental pulp.

Peripheral G protein-coupled inwardly rectifying potassium channels are involved in δ-opioid receptor-mediated anti-hyperalgesia in rat masseter muscle.

BACKGROUND: Although the efficacy of peripherally administered opioid has been demonstrated in preclinical and clinical studies, the underlying mechanisms of its anti-hyperalgesic effects are poorly understood. G protein-coupled inwardly rectifying potassium (GIRK) channels are linked to opioid receptors in the brain. However, the role of peripheral GIRK channels in analgesia induced by peripherally administered opioid, especially in trigeminal system, is not clear. METHODS: Expression of GIRK subunits in rat trigeminal ganglia (TG) was examined with reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. Chemical profiles of GIRK-expressing neurons in TG were further characterized. Behavioural and Fos experiments were performed to examine the functional involvement of GIRK channels in δ-opioid receptor (DOR)-mediated anti-hyperalgesia under an acute myositis condition. RESULTS: TG expressed mRNA and proteins for GIRK1 and GIRK2 subunits. Majority of GIRK1- and GIRK2-expressing neurons were non-peptidergic afferents. Inhibition of peripheral GIRK using Tertiapin-Q (TPQ) attenuated antinociceptive effects of peripherally administered DOR agonist, [D-Pen(2), D-Pen(6) ]-enkephalin (DPDPE), on mechanical hypersensitivity in masseter muscle. Furthermore, TPQ attenuated the suppressive effects of peripheral DPDPE on neuronal activation in the subnucleus caudalis of the trigeminal nucleus (Vc) following masseteric injection of capsaicin. CONCLUSIONS: Our data indicate that peripheral DOR agonist-induced suppression of mechanical hypersensitivity in the masseter muscle involves the activity of peripheral GIRK channels. These results could provide a rationale for developing a novel therapeutic approach using peripheral GIRK channel openers to mimic or supplement the effects of peripheral opioid agonist.

A case of ricin poisoning following ingestion of Korean castor bean.

Ricin is a member of a group of protein toxins whose cytosolic target is the 28S rRNA of the 60S ribosomal subunit. It was recently introduced as a weapon of terrorism in some countries. There is little evidence about the mechanism, diagnosis and treatment of ricin poisoning. The case history is reported of a patient with ricin poisoning who presented with nausea and vomiting following ingestion of Korean castor bean.

Cellular responses and proteomic analysis of Escherichia coli exposed to green tea polyphenols.

The purpose of this study was to characterize the cellular response and proteomic analysis of Escherichia coli exposed to tea polyphenols (TPP) extracted from Korean green tea (Camellia sinensis L). TPP showed a dose-dependent bactericidal effect on E. coli. Analysis of cell-membrane fatty acids of E. coli cultures treated with TPP identified unique changes in saturated and unsaturated fatty acids, whereas scanning electron microscopic analysis demonstrated the presence of perforations and irregular rod forms with wrinkled surfaces in cells treated with TPP. Two-dimensional polyacrylamide gel electrophoresis of soluble protein fractions from E. coli cultures exposed to TPP showed 17 protein spots increased or decreased by TPP. Nine upregulated proteins were identified (including GroEL and proteins involved in cellular defense, such as GyrA, RpoS, SodC, and EmrK), whereas the expression of eight proteins was downregulated by exposure to TPP (including proteins involved in carbon and energy metabolism, such as Eno, SdhA, and UgpQ, as well as those involved in amino-acid biosynthesis, such as GltK and TyrB). These results provide clues for understanding the mechanism of TPP-induced stress and cytotoxicity on E. coli.

Fermented mushroom milk-supplemented dietary fibre prevents the onset of obesity and hypertriglyceridaemia in Otsuka Long-Evans Tokushima fatty rats.

AIM: Fermented milk product containing edible mushroom water extracts (mushroom yogurt; MY) has been reported to have glycaemic control and triglyceride-lowering effects in streptozotocin (STZ)-induced diabetic rats and Zucker diabetic fatty (ZDF) rats. Here, we investigated how MY-supplemented dietary fibre (10 and 20%, v/w) influences the onset of obesity and hypertriglyceridaemia in Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS: The OLETF rats were fed a powdered chow diet supplemented with MY at the levels of 10 (v/w) and 20% for 6 weeks from 10 weeks of age, but the OLETF control rats were not supplemented. Their weight, fat distribution and lipid profile have been determined. RESULTS: The body weights in MY-fed rats were reduced compared with the control rats. The perirenal fat was decreased in both MY groups, but the visceral and epididymal fats reduced only in the MY 20% group. The concentrations of serum triglyceride and non-esterified fatty acid in MY-fed rats were decreased in a dose-dependent manner. However, the levels of other serum lipid profiles [total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol] were comparable among all rats. CONCLUSION: Anti-obesity and triglyceride lowering by MY-supplemented dietary fibre in OLETF rats might have resulted from the synergistic effect of components in the fermented mushroom-milk product.

Effect of hesperetin, a citrus flavonoid, on the liver triacylglycerol content and phosphatidate phosphohydrolase activity in orotic acid-fed rats.

The effect of dietary hesperetin on the hepatic lipid content and the enzyme activities involved in triacylglycerol (TG) synthesis in rats fed diets with or without 1% orotic acid (OA) was studied. Hepatic TG content was raised by approximately 5-fold after administration of OA for 10 days. The OA-feeding significantly increased the activity of hepatic microsomal phosphatidate phosphohydrolase (PAP), which is the rate-limiting enzyme for TG synthesis. Hepatic glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme activities were also increased. An addition of 1% hesperetin to the OA-supplemented diet resulted in the decrease of the hepatic TG content by 44% and of microsomal PAP activity. Dietary hesperetin alone neither affected liver TG content nor PAP activity significantly. OA-feeding caused an increased liver cholesterol level, whereas simultaneous addition of hesperetin and OA reduced its content to the control level. A slight reduction of hepatic cholesterol by hesperetin was also observed in the OA-free dietary group. The present study demonstrated that dietary hesperetin can reduce the hepatic TG accumulation induced by OA, and this was associated with the reduced activity of TG synthetic enzyme, PAP.

The effect of electrical stimulation on the trunk control in young children with spastic diplegic cerebral palsy.

This study was designed to determine the effectiveness of electrical stimulation over the trunk in improving sitting balance in young children with spastic diplegic cerebral palsy who displayed poor trunk control. The subjects ranged in age from 8 to 16 months and were randomly assigned to two groups. Both group had physical therapy for 6 weeks. Electrical stimulation (ES) group had additional electrical stimulation over the abdomen and posterior back muscles. Radiographic studies were carried out on the whole spine while they were sitting before and after treatment. Kyphotic angle, Cobb's angle and lumbo-sacral angle were measured. Additionally, sitting score-Gross Motor Function Measure (GMFM) was also evaluated. There was no difference of these values at initial evaluation between the two groups. Following 6 weeks of intensive therapy, the changes of kyphotic angle and sitting score-GMFM were significantly higher in ES group statistically when compared with those of the control group. The Cobb's angle following treatment was improved in ES group, but not statistically compared with that of control group. This study suggests that electrical stimulation over the trunk become a beneficial therapeutic technique in improving the sitting posture and trunk control in young children with spastic diplegic cerebral palsy.

Changes in external ear resonance after ventilation tube (Grommet) insertion in children with otitis media with effusion.

OBJECTIVE: As otitis media with effusion is common in children, the effects of a ventilation tube should be taken into account in the prescription of hearing aids for children. In ears with a ventilation tube, the external auditory canal communicates directly with the middle ear space, and so the impedance of the middle ear may change. Consequently, this will affect external-ear resonance. The aim of this study is to observe the effects of the tympanic membrane perforations caused by the ventilation tube on external-ear resonance. We selected 30 ears with otitis media with effusion to measure external-ear resonance before and after ventilation tube insertion. We compared the external-ear resonance of a control group with that of the otitis media with the effusion group and two types of ventilation-tube groups, respectively. In the subjects who have otitis media with effusion, the average gain of the peak resonance was larger than that in the control group. After ventilation-tube insertion, the amplitude of the gain decreased to the same level as the control group, but a characteristic negative gain appeared around 1000 Hz in about half of all cases. This negative gain was observed more frequently in the ventilation tube with a larger diameter. The raised peak resonance gain in the otitis media with effusion group decreased to a level roughly the same as that of the control group after ventilation-tube insertion. Provision of an additional gain in the low frequencies around 1000 Hz should be considered for patients with a ventilation tube when prescribing hearing aids.

Effect of bioflavonoids extracted from the bark of Pinus maritima on proinflammatory cytokine interleukin-1 production in lipopolysaccharide-stimulated RAW 264.7.

Currently, bioflavonoids have been known to have strong antioxidant capacities, and a variety of efforts have been made to identify the utilities of bioflavonoids in treating various diseases based on their antioxidant capacities. The effects of bioflavonoids extracted from the bark of Pinus maritima Pycnogenol (PYC) on free radical formation, activation of redox sensitive transcription factors, as well as interleukin-1 beta (IL-1 beta) production were investigated in murine macrophage cell lines. PYC exerted strong scavenging activities against reactive oxygen species generated either by H(2)O(2) or PMA in RAW 264.7 and IC-21 cells, respectively. In situ ELISA, immunoblot analysis, and competitive RT-PCR demonstrated that PYC pretreatment of LPS-stimulated RAW 264.7 cells dose-dependently reduced both the production of IL-1 beta and its mRNA levels. Furthermore, in the same cells, PYC blocked the activation of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1), two major transcription factors centrally involved in IL-1 beta gene expression. When RAW 264.7 cells were stimulated with LPS, the inhibitor protein I kappa B largely disappeared from cytosolic fractions. However, pretreatment of the cells with PYC abolished the LPS-induced I kappa B degradation. These results suggest that PYC can inhibit the expression of the proinflammatory cytokine IL-1 by regulating redox-sensitive transcription factors. This study may support the possibility that bioflavonoids including PYC can be used as antiinflammatory and immunosuppressive drugs based on their radical scavenging activities.

Phospholipase Cgamma1 inhibitory principles from the sarcotestas of Ginkgo biloba.

Ten phenolic compounds were isolated from the CHCl3 extract of Ginkgo biloba sarcotestas (Ginkgoaceae) as a new class of phosphatidylinositol-specific phospholipase Cgamma1 (PI-PLCgamma1) inhibitors. The substances without the long chain were ineffective. On the other hand, the activities of these compounds were dramatically decreased by acetylation of aromatic hydroxyl groups of cardanol, phenolic acid, and bilobol and by methylation of the aromatic carboxyl group of phenolic acid. The unsaturated long chain as well as the aromatic hydroxyl and carboxyl groups might play a key role for the PI-PLCgamma1 inhibitory activity. These compounds also inhibited the growth of a number of human cancer cell lines, but were less cytotoxic against a human normal colon cell line.

The role of thiols in protecting against simultaneous toxicity of menadione to platelet plasma and intracellular membranes.

Our previous study suggested that menadione (MEN) is cytotoxic to platelets of rats due to oxidative stress. To elucidate the mechanism of this toxicity, MEN-induced depletion of total cellular thiols or depletion of gutathione was studied in intact rat platelets. Treatment with MEN resulted in dose and time dependent damage to plasma (assessed by lactate dehydrogenase leakage) and intracellular (assessed by serotonin release) membranes. These events were well correlated with total cellular thiol depletion by MEN treatment, however MEN-induced glutathione depletion occurred rapidly and before plasma and intracellular membrane damage. Unlike hepatocytes, oxidized glutathione was not formed, suggesting that protein arylation, rather than oxidative stress, might be the ultimate mechanism for MEN cytotoxicity in platelets. Platelets were pretreated with dithiothreitol to supplement the total cellular thiol pool or with 1-chloro-2,4-dinitrobenzene to deplete glutathione, a soluble thiol. Dithiothreitol pretreatment to platelets protected against MEN-induced toxicity to both plasma membranes (prevented lactate dehydrogenase leakage and changes in platelet turbidity) and intracellular membranes (prevented serotonin release), although 1-chloro-2,4-dinitrobenzene pretreatment potentiated these toxicities. These results indicate that the total cellular pool of thiols plays a vital role in maintaining plasma and intracellular membrane integrity.

Dietary casein and soybean protein affect the concentrations of serum cholesterol, triglyceride and free amino acids in rats.

This work was undertaken to investigate the concentrations of free amino acids in blood after food was withheld from growing, male Wistar rats fed cholesterol-free, low fat (1 g corn oil/100 g) diets with casein or soybean protein for 2 wk. A diet containing 22.5 or 23.5 g/100 g of soybean protein was hypocholesterolemic compared with a diet containing 20.0 g casein/100 g diet. A comparison of serum amino acids in soybean protein-fed vs. casein-fed rats showed that, whereas concentrations of many amino acids were lower in the soybean protein-fed rats compared with the casein-fed groups, glycine was the only amino acid having a higher concentration. Further, alanine was significantly lower in the soybean protein-fed rats compared with the casein-fed rats, and the protein-induced differences in glycine and alanine concentrations of unfed rats were reproducible. When diets containing 15.0% casein or 30.0% soybean protein, a casein diet supplemented with glycine and a soybean protein diet supplemented with methionine were compared, the changes in serum glycine and alanine correlated with the changes in serum cholesterol. Concentrations of several amino acids, particularly valine, leucine and tyrosine, also changed when serum cholesterol concentrations varied, but these effects could not be explained by our experiments. The results suggest that a change in serum concentration of glycine and alanine of unfed rats may be related to the change in serum cholesterol concentration.