Associations between oral complications and days to death in palliative care patients.

PURPOSE: Adverse oral symptoms gradually appear in advanced cancer patients as the disease progresses. We retrospectively investigated the associations between the incidence of oral problems and the days to death (DTD) in patients receiving palliative care. METHODS: The dental assessment sheets and medical charts of 105 patients who had been admitted into the palliative care unit at our hospital were examined. Case data included evaluations of organic and functional oral conditions at the time of admission for all patients. The cohort was divided into two groups according to the DTD as the short group (<28 days from the time of dental assessment until death) and the long group (≥28 days). We compared the incidences of organic and functional oral problems between these groups. RESULTS: Dry mouth, tongue inflammation, and bleeding spots were significantly more frequent in the short group than in the long group (78 vs. 54% for dry mouth, 67 vs. 46% for tongue inflammation, 35 vs. 14% for bleeding spots, respectively; p < 0.05). Tongue coating and candidiasis were comparable between the two groups. Dysphagia was significantly more common in the short group (43%) than in the long group (20%) (p = 0.01), as was assistance with oral health care (76 vs. 50%) (p = 0.01). CONCLUSIONS: Our findings suggest that, during palliative care, oral complications appear more frequently when the DTD period is shorter. These symptoms may be useful indicators when deciding on the proper timing of intensive oral care intervention to decrease oral problems and pain in terminally ill patients.

Linagliptin provides effective, well-tolerated add-on therapy to pre-existing oral antidiabetic therapy over 1 year in Japanese patients with type 2 diabetes.

AIMS: To evaluate the long-term safety and efficacy of linagliptin as add-on therapy to one approved oral antidiabetic drug (OAD) in Japanese patients with type 2 diabetes mellitus and insufficient glycaemic control. METHODS: This 52-week, multicentre, open-label, parallel-group study evaluated once-daily linagliptin 5 mg as add-on therapy to one OAD [biguanide, glinide, glitazone, sulphonylurea (SU) or α-glucosidase inhibitors (A-GI)] in 618 patients. After a 2-week run-in, patients on SU or A-GI were randomized to either linagliptin (once daily, 5 mg) or metformin (twice or thrice daily, up to 2250 mg/day) as add-on therapy. Patients receiving the other OADs received linagliptin add-on therapy (non-randomized). RESULTS: Adverse events were mostly mild or moderate, and rates were similar across all groups. Hypoglycaemic events were rare, except in the SU group. Overall, 26 (5.8%) hypoglycaemic events were reported in patients receiving linagliptin (non-randomized). Hypoglycaemic events were similar for linagliptin and metformin added to A-GI (1/61 vs. 2/61, respectively) or SU (17/124 vs. 10/63, respectively). Significant reductions in glycated haemoglobin (HbA1c) levels (between -0.7 and -0.9%) occurred throughout the study period for the background therapy groups that received linagliptin (baseline HbA1c 7.9-8.1%). The decline in HbA1c levels was indistinguishable between linagliptin and metformin groups when administered as add-on therapy to A-GI or SU. CONCLUSIONS: Once-daily linagliptin showed safety and tolerability over 1 year and provided effective add-on therapy leading to significant HbA1c reductions, similar to metformin, over 52 weeks in Japanese patients.

Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease.

We have studied the recruitment and roles of distinct dendritic cell (DC) precursors from the circulation into Propionibacterium acnes-induced granulomas in mouse liver. During infection, F4/80(-)B220(-)CD11c(+) DC precursors appeared in the circulation, migrated into the perisinusoidal space, and matured within newly formed granulomas. Recruited DCs later migrated to the portal area to interact with T cells in what we term "portal tract-associated lymphoid tissue" (PALT). Macrophage inflammatory protein 1alpha attracted blood DC precursors to the sinusoidal granuloma, whereas secondary lymphoid organ chemokine (SLC) attracted mature DCs to the newly identified PALT. Anti-SLC antibody diminished PALT expansion while exacerbating granuloma formation. Therefore, circulating DC precursors can migrate into a solid organ like liver, and participate in the granulomatous reaction in response to specific chemokines.

Short communication: effect of grazing on the concentrations of total sialic acid and hexose in bovine milk.

Sialic acid, which is located at the terminal end of glycoconjugates, is believed to have important biological functions. Its concentration in bovine milk varies depending on lactation stage and season. However, it remains unclear whether dietary factors, especially fresh forage, affect the total sialic acid concentration in milk. The purpose of the present study was to investigate the effect of grazing on the concentrations of total sialic acid and hexose in bovine milk. Six healthy dairy cows were used in a crossover design (3 cows fed fresh forage and 3 cows fed grass silage) for 2 wk. Individual milk samples were collected at 2 consecutive milkings (morning and evening) at 0, 1, 3, 5, 8, 11, and 14 d of the experimental period, and 2 consecutive samples in each cow were combined on each sampling day in proportion of the morning and evening milk yields. No differences in body weight, milk yield, or milk composition were observed between the 2 groups during the experimental period. The hexose concentration in milk did not differ between these groups during the experimental period. Conversely, the total sialic acid concentration in the milk of each grazing cow significantly increased at 11 and 14 d of the experimental period compared with that at 0 d. In the grass silage group, the total sialic acid concentration at the end of the experimental period tended to be lower than that at 0 d, but the decrease was not significant. These results indicate that grazing management could have increased the concentration of sialoglycoconjugates in milk. This suggests that grazing may increase the biological function of milk because it is thought that sialic acid is significant in many ways.

The effect of butyric acid on adhesion molecule expression by human gingival epithelial cells.

BACKGROUND AND OBJECTIVE: Short-chain fatty acids, such as butyric acid, are detected in periodontal pockets and are thought to be involved in the initiation and progression of periodontal disease. In the present study, we examined the effects of butyric acid on adhesion molecule expression by human gingival epithelial cells. MATERIAL AND METHODS: The human gingival carcinoma cell line, Ca9-22, was cultured in media that contained different concentrations of butyric acid. RESULTS: Cell numbers were significantly decreased in a dose-dependent manner by butyric acid at concentrations of > or = 0.2 mM. The expression of intercellular adhesion molecule-1 mRNA was significantly increased 6 h after stimulation. By contrast, the expression levels of integrins alpha 6 and beta 4 were decreased. Similar results were obtained by flow cytometry. CONCLUSION: The results of the present study indicate that butyric acid alters the expression of adhesion molecules by Ca9-22 cells. The elucidation of the mechanism of action of butyric acid on the periodontium may help to clarify several aspects of the onset and progression of periodontal disease.

Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease.

We examined the molecular pathogenesis of graft-versus-host disease-associated (GVHD-associated) liver injury in mice, focusing on the role of chemokines. At the second week after cell transfer in the parent-into-F1 model of GVHD, CD8(+) T cells -- especially donor-derived CD8(+) T cells -- infiltrated the liver, causing both portal hepatitis and nonsuppurative destructive cholangitis (NSDC). These migrating cells expressed CCR5. Moreover, macrophage inflammatory protein-1alpha (MIP-1alpha), one of the ligands for CCR5, was selectively expressed on intralobular bile duct epithelial cells, endothelial cells, and infiltrating macrophages and lymphocytes. Administration of anti-CCR5 antibody dramatically reduced the infiltration of CCR5(+)CD8(+) T lymphocytes into the liver, and consequently protected against liver damage in GVHD. The levels of Fas ligand (FasL) mRNA expression in the liver were also decreased by anti-CCR5 antibody treatment. Anti-MIP-1alpha antibody treatment also reduced liver injury. These results suggest that MIP-1alpha-induced migration of CCR5-expressing CD8(+) T cells into the portal areas of the liver plays a significant role in causing liver injury in GVHD; thus, CCR5 and its ligand may be the novel target molecules of therapeutic intervention of hepatic GVHD.

Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions.

We have examined the expression of chemokines and their receptors in the atopic dermatitis-like (AD-like) lesions of NC/Nga mice. Such lesions develop when the mice are kept in conventional conditions, but not when they are kept isolated from specific pathogens. The thymus- and activation-regulated chemokine TARC is unexpectedly highly expressed in the basal epidermis of 14-week-old mice with lesions, whereas it is not expressed in the skin without lesions. Production of TARC by keratinocytes was confirmed by culturing murine keratinocytic cell line cells (PAM212) with TNF-alpha, IFN-gamma, or IL-1beta. Expression of another Th2 chemokine, macrophage-derived chemokine (MDC), was observed in the skin from mice kept in both conventional and pathogen-free conditions, but expression of MDC was increased severalfold in the skin with lesions. The cellular origin of MDC was identified to be dermal dendritic cells. Infiltration of the skin by IL-4-producing T cells and mast cells, and the increase of CCR4 mRNA in the skin, coincided with the development of AD lesions. These observations indicate that TARC and MDC actively participate in the pathogenesis of AD-like lesions in NC/Nga mice and that these Th2 chemokines could be novel targets for intervention therapy of AD in humans.

Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice.

Thymus and activation-regulated chemokine (TARC) is a recently identified lymphocyte-directed CC chemokine which specifically chemoattracts T helper type 2 CD4(+) T cells in human. To establish the pathophysiological roles of TARC in vivo, we investigated whether a monoclonal antibody (mAb) against TARC could inhibit the induction of hepatic lesions in murine model using Propionibacterium acnes and lipopolysaccharide (LPS). P. acnes-induced intrahepatic granuloma formation in the priming phase is essential to the subsequent liver injury elicited by a low dose of LPS. The priming phase appears to be dominated by Th1 type immune responses determined by the profile of chemokine and chemokine receptor expression. TARC was selectively produced by granuloma-forming cells, and CC chemokine receptor 4 (CCR4)-expressing CD4(+) T cells migrated into the liver after LPS administration. In vivo injection of anti-TARC mAb just before LPS administration protected the mice from acute lethal liver damage, which was accompanied by a significant reduction of both CCR4 mRNA expression and IL-4 production by liver-infiltrating CD4(+) T cells. Moreover, both TNF-alpha and Fas ligand expressions in the liver were decreased by anti-TARC treatment. These results suggest that recruitment of IL-4-producing CCR4(+) CD4(+) T cells by granuloma-derived TARC into the liver parenchyma may be a key cause of massive liver injury after systemic LPS administration.

What are the consequences of being left-clawed in a predominantly right-clawed fiddler crab?

Male fiddler crabs (genus Uca) have an enlarged major claw that is used during fights. In most species, 50% of males have a major claw on the left and 50% on the right. In Uca vocans vomeris, however, less than 1.4% of males are left-clawed. Fights between opponents with claws on the same or opposite side result in different physical alignment of claws, which affects fighting tactics. Left-clawed males mainly fight opposite-clawed opponents, so we predicted that they would be better fighters due to their relatively greater experience in fighting opposite-clawed opponents. We found, however, that (i) a left-clawed male retains a burrow for a significantly shorter period than a size-matched right-clawed male, (ii) when experimentally displaced from their burrow, there is no difference in the tactics used by left- and right-clawed males to obtain a new burrow; however, right-clawed males are significantly more likely to initiate fights with resident males, and (iii) right-clawed residents engage in significantly more fights than left-clawed residents. It appears that left-clawed males are actually less likely to fight, and when they do fight they are less likely to win, than right-clawed males. The low-level persistence of left-clawed males is therefore unlikely to involve a frequency-dependent advantage associated with fighting experience.

Selenium addition to colostrum increases immunoglobulin G absorption by newborn calves.

The objective of this study was to show a new function of Se in IgG absorption from colostrum by newborn calves. The same amount and quality of colostrum with or without Se addition was fed to paired calves (n = 60) 4 times at <2, 12, 24, and 36 h after birth, respectively. Four-time feeding of colostrum containing 1.0 ppm Se significantly increased IgG amount in the blood plasma of calves 24 h after birth; however, its effect was small (about 20% increase). Although the addition of 3.0 ppm Se once at the first colostrum feeding was more effective on IgG absorption, its significant effect was a 42% increase on average. The increased IgG concentration of blood plasma continued for about 2 wk. It is known that the absorption of colostrum IgG is mediated by intestinal pinocytosis, which continues for only 24 h after birth. The addition of Se to colostrum might directly activate this physiological pinocytosis of intestinal epithelial cells because of the rapidity of the reaction. This effect is not nutritional but rather pharmacological. Supplemented Se also resulted in its increased concentration in blood plasma. Selenium is an essential mineral for animals; however, newborn calves are always deficient in Se at birth. Application of this method in calves would also provide an immediate supply of Se and might contribute to the development of the immune system of calves. This study showed that Se supplementation to colostrum increased IgG amount and Se concentration in blood plasma in newborn calves.

Augmentation of vaccenate production and suppression of vaccenate biohydrogenation in cultures of mixed ruminal microbes.

To increase ruminal outflow of trans-vaccenic acid (t-VA), a new strain of Butyrivibrio fibrisolvens (MDT-10) was isolated that has a great ability to hydrogenate linoleic acid (LA) to t-VA. When strain MDT-10 was added to the batch cultures of mixed ruminal microbes (1% of the total number of viable ruminal bacteria), LA conversion to t-VA increased greatly; after 3 h, t-VA levels were > 4-fold higher than the control. By 10 h, all of the t-VA was hydrogenated to stearic acid. However, when a new strain of Bifidobacterium adolescentis (HF-11), which has a high capacity for incorporation of t-VA, was added in conjunction with MDT-10 (1% of the total number of ruminal bacteria), t-VA levels after 10 h were 6 times higher than with MDT-10 alone. These results suggest that t-VA produced by MDT-10 was incorporated into HF-11 cells, resulting in protection of t-VA from t-VA-hydrogenating microbes. Similar results were obtained in a continuous culture of mixed ruminal microbes in which addition of HF-11 simultaneously with MDT-10 increased the amount of t-VA in the effluent 2.5-fold. Both MDT-10 and HF-11 appeared to grow readily in the presence of mixed ruminal microbes. Sixty-two percent of t-VA incorporated by HF-11 was present in the free form, whereas 19, 15, and 3%, respectively, were incorporated into monoacylglycerol, glycerophospholipid, and diacylglycerol fractions. Because these lipids can be digested in the small intestine, it is likely that most t-VA in HF-11 cells is absorbed. Thus, introduction of MDT-10 and HF-11 simultaneously to the rumen might increase the amount of t-VA absorbed and might consequently increase the conversion of t-VA to conjugated linoleic acid in tissue.

Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells.

TRAIL has gained much attention for its specific induction of apoptosis in cancer cells but not in normal cells. This phenomenon has been explained thus: that cancer cells dominantly express death receptors while normal cells express decoy receptors. However, recent reports have shown that some cancer cell lines are resistant to TRAIL-induced apoptosis despite the absence of decoy receptors and the presence of death receptors. This suggested the existance of an inhibitory factor. We herein showed that NF-kappaB is a key molecule underlying the TRAIL-resistant mechanism in renal cell carcinoma (RCC) cell lines. We observed that NF-kappaB is constitutively activated in resistant cell lines. Forced expression of antisense cDNA of IkappaBalpha, a specific inhibitor of NF-kappaB, in TRAIL-sensitive cell lines with a low NF-kappaB activity result in constitutive activation of NF-kappaB and resistance to TRAIL-induced apoptosis. Adenoviral expression of a stable form of IkappaBalpha in the TRAIL-resistant cell lines induced apoptosis. These data suggest that RCC can be classified into two subsets: TRAIL-sensitive RCC with a low NF-kappaB activity and TRAIL-resistant RCC with constitutively activated NF-kappaB. In the former group TRAIL can be a treatment option, while in the latter group a molecular approach targeting NF-kappaB appears to be a promising therapy.

Serum interleukin 6 as a prognostic factor in patients with prostate cancer.

The present study was undertaken to evaluate the prognostic significance of the serum levels of interleukin 6 (IL-6) in patients with prostate cancer. Serum IL-6 levels were measured in 74 patients with prostate cancer. The tumor was stage B in 23 patients, stage C in 14 patients, and stage D in 37 patients. Prognostic significance of tumor histology, performance status (PS), bone metastasis, serum prostate-specific antigen (PSA) level, serum alkaline phosphatase (ALP) level, serum lactate dehydrogenase level, serum IL-6 levels, and hemoglobin on disease-specific survival was assessed using univariate and multivariate Cox's proportional hazards model analyses. Serum IL-6 was significantly correlated with the clinical stage of prostate cancer. Univariate analysis of all patients demonstrated that an extent of disease (EOD) on bone scanning > or = 1, IL-6 > or = 7 pg/ml, PS > or = 1, PSA > 100 ng/ml, and ALP > 620 IU/liter were associated with a significantly lower survival rate than their respective counterparts. In multivariate analysis, however, the only two significant prognostic factors were EOD and IL-6. In 51 patients with stage C and stage D prostate cancer, univariate analysis showed that EOD > or = 1, IL-6 > or = 7 pg/ml, PS > or = 1, PSA > 100 ng/ml, LDH > 200 IU/liter, and ALP > 620 IU/liter were significantly related to survival, whereas multivariate analysis again demonstrated that EOD > or = 1 and IL-6 > or = 7 pg/ml were significant prognostic factors. These results indicate that the serum IL-6 level is a significant prognostic factor for prostate cancer as well as EOD.

Association between tumor necrosis factor in serum and cachexia in patients with prostate cancer.

The present study was undertaken to evaluate the relationship between serum tumor necrosis factor (TNF) and cachexia in patients with prostate cancer. TNF levels were determined in 110 serum samples from prostate cancer patients by an enzyme immunoassay. Serum TNF activity was positive in 76% of the patients with relapsed disease, whereas only 11% of the untreated patients and 0% of the patients in remission as a result of endocrine therapy were positive. The serum total protein and albumin levels, hemoglobin levels, and body mass index of the patients with elevated serum TNF levels were significantly lower (P < 0.05) than the corresponding values in patients with undetectable serum TNF levels. The serum TNF levels of patients with serum albumin levels of <3.5 g/dl, serum total protein levels of <7.0 g/dl, hemoglobin levels of <11.0 g/dl, and a body mass index of <21 kg/m2 were significantly higher (P < 0.05) than the values in their respective counterparts. There was a significant correlation between the detectability of serum TNF and performance status (P < 0.05). Patients with elevated serum TNF levels had a significantly higher mortality rate (P < 0.05) than those with undetectable serum TNF levels. These findings suggest that TNF may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer.

Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-3 peptide.

Recent investigations have demonstrated the efficacy of autologous dendritic cells (DCs) pulsed with tumor antigens to generate tumor-specific CTLs against cancer cells. Melanoma antigens (MAGE) are a family of tumor-specific antigens shown to be expressed in various tumors, including bladder cancers and melanoma, but not in normal tissues except for the testis. Because invasive bladder cancers are frequently reported to express MAGE, we explored the possibility of establishing a new immunotherapeutic modality against advanced bladder cancer using autologous DCs pulsed with one of the MAGE-3 epitope peptides (IMPKAGLLI), which is synthesized to bind specifically to HLA-A24. A MAGE-3-expressing bladder cancer cell line, FY, was newly established from a lymph node metastasis of bladder cancer in a HLA-A24+ patient. The FY cell-specific CTL response was significantly higher when CTL was induced by autologous DCs pulsed with IMPKAGLLI than by FY cells alone or by nonpulsed DCs in vitro. A total of four HLA-A24+ patients with advanced MAGE-3+ bladder cancers were treated with s.c. injections of autologous DCs pulsed with IMPKAGLLI every 2 weeks for a minimum of 6 and a maximum of 18 times. Three of four patients showed significant reductions in the size of lymph node metastases and/or liver metastasis. No significant untoward side effects were noted in these patients. This study indicated that, at sometime in the future, tumor-specific DC-based cancer immunotherapy may be useful as an additional treatment modality against advanced bladder cancer.

Contribution of mannose receptor to signal transduction in Fc gamma receptor-mediated phagocytosis of mouse peritoneal macrophages induced by liposomes.

The contribution of mannose receptors on the cell surface of mouse peritoneal macrophages to the process of liposome-induced phagocytosis of immunoglobulin G-opsonized sheep red blood cells (SRBCs) through Fc gamma receptor has been investigated. Fc gamma receptor-mediated phagocytosis of opsonized SRBCs was activated by modified alpha 2-macroglobulin, which was produced in the incubation mixture of alpha 2-macroglobulin and liposome-treated splenic B cells. The phagocytosis was specifically inhibited by the addition of D-mannose, and the inhibition was dependent on the D-mannose concentration. The binding of modified alpha 2-macroglobulin to macrophages was also reduced by the addition of D-mannose. The activation effect of modified alpha 2-macroglobulin was not inhibited when in the presence of alpha 2-macroglobulin-trypsin and -methylamine complexes. In the presence of cycloheximide, activated phagocytosis was reduced to the control level. By Scatchard plot analysis of IgG binding studies, the number of Fc gamma receptors of a macrophage had been increased to 4.6-fold that of a control macrophage by treatment with modified alpha 2-macroglobulin. These findings suggest that macrophage mannose receptors are involved in activating the process of Fc gamma receptor-mediated phagocytosis of opsonized SRBCs induced by modified alpha 2-macroglobulin. Lectins may participate in a signal transduction in macrophage activation by liposomes.

IL-12 plays a pivotal role in LFA-1-mediated T cell adhesiveness by up-regulation of CCR5 expression.

The chemokine receptor CCR5 has been implicated in the recruitment of T cells to inflammatory sites. However, the regulation of CCR5 induction on T cells and its contribution to T cell adhesiveness are poorly understood. Using a Th1 clone, 2D6, that can be maintained with interleukin (IL)-12 or IL-2 alone (designated 2D6(IL-12) or 2D6(IL-2), respectively), we investigated how CCR5 is induced on T cells and whether CCR5 is responsible for up-regulating the function of adhesion molecules. 2D6(IL-12) grew, forming cell aggregates, in culture containing IL-12. This was due to lymphocyte function-associated antigen (LFA)-1-intercellular adhesion molecule (ICAM)-1 interaction, because 2D6(IL-12) expressed both LFA-1 and ICAM-1 and cell aggregation was inhibited by anti-ICAM-1 monoclonal antibody. Despite comparable levels of LFA-1 and ICAM-1 expression, 2D6(IL-2) cells did not aggregate in culture with IL-2. It is important that there was a critical difference in CCR5 expression between 2D6(IL-12) and 2D6(IL-2); the former expressed high levels of CCR5, and the latter expressed only marginal levels. Both types of cells expressed detectable albeit low levels of RANTES (regulated on activation, normal T expressed and secreted) mRNA. Unlike IL-12 or IL-2, IL-18 induced high levels of RANTES mRNA expression without modulating CCR5 expression. Therefore, combined stimulation with IL-12 and IL-18 strikingly up-regulated 2D6 cell aggregation. Notably, LFA-1-mediated aggregation of 2D6(IL-12) cells was suppressed by anti-CCR5 antibody. These results indicate that IL-12 plays a critical role in CCR5 expression on Th1 cells and consequently contributes to CCR5-mediated activation of LFA-1 molecules.

Regimen of tacrolimus-based immunosuppression with basiliximab, mycophenolate mofetil, and low-dose steroid reduces acute rejection in kidney transplants.

BACKGROUND: Acute rejection is a major problem in kidney transplantation. To reduce its likelihood, we investigated the efficacy and safety of an immunosuppressive regimen including tacrolimus, basiliximab, mycophenolate mofetil, and low-dose steroids. METHODS: Fifty-seven patients, including 14 pediatric patients, were enrolled in this study. The mean age at the time of transplantation was 33.5 years, and the mean observation period was 8.2 months. The mean trough concentrations of FK at 1, 6, and 12 months posttransplant were 10.2, 6.6, and 6.0 ng/mL, respectively. RESULTS: All recipients survived without graft loss. The cumulative incidence of acute rejection in adults was 2.3% and 8.4% at 6 and 12 months posttransplant, respectively. Of the adverse events, 11 recipients (19.3%) were positive for CMV antigenemia or had CMV infections. Four recipients (7.0%) exhibited mild hyperglycemia. CONCLUSIONS: Our immunosuppressive regimen demonstrated favorable results, reducing the incidence of acute rejection without causing severe adverse events, especially in adults.