Efficacy of Yokukansan,a traditional Japanese herbal medicine,in patients with dizziness and irritability

ObjectiveIrritability is an emotional stress symptom that causes or exacerbates dizziness. Antidepressants may be helpful for some conditions that are accompanied by irritability; however, they do not completely inhibit irritability. Yokukansan (YKS), a traditional Japanese herbal medicine, has been used for neurosis, insomnia, and children's irritability and night crying. The study investigated the efficacy of YKS in nystagmus in patients with chronic dizziness and irritability.MethodsTwenty-two cases with chronic dizziness and irritability were reviewed retrospectively. The patients were divided into two groups: control patients (0–7 days of treatment) and YKS-treated patients (YKS cases; >7 days of treatment). Dizziness before and during (after, in the controls) YKS treatment was evaluated by scoring the nystagmus intensity on a 5-point scale. The average scores were calculated within a maximum of 6 months before and during or after treatment. The normalized scores were also calculated. The optimal treatment regimen was calculated via receiver operating characteristic (ROC) curve analysis.ResultsThere were six control cases (1 male, 5 females; mean age: 59.5 years). There were 16 YKS cases (3 males, 13 females; mean age: 61.8 years). While the group mean nystagmus intensity scores significantly decreased from 1.18 to 0.73 in the YKS cases, it did not change in the control cases. The group mean of the normalized nystagmus intensity scores during treatment was 0.73 in the YKS cases. The results of the ROC curve analysis indicated the optimal cut-off period of the YKS treatment was 10 days.ConclusionThe oral administration of YKS for more than 10 days was optimal. The treatments with YKS could be a good option for the treatments of vertigo.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

Mice lacking α1,3‐fucosyltransferase 9 exhibit modulation of in vivo immune responses against pathogens

Carbohydrate structures, including Lewis X (Le^x), which is not synthesized in mutant mice that lack α1,3‐fucosyltransferase 9 (Fut9^?/?), are involved in cell–cell recognition and inflammation. However, immunological alteration in Fut9^?/? mice has not been studied. Thus, the inflammatory response of Fut9^?/? mice was examined using the highly neurovirulent mouse hepatitis virus (MHV) JHMV srr7 strain. Pathological study revealed that inflammation induced in the brains of Fut9^?/? mice after infection was more extensive compared with that of wild‐type mice, although viral titers obtained from the brains of mutant mice were lower than those of wild‐type mice. Furthermore, the reduction in cell numbers in the spleens of wild‐type mice after infection was not observed in the infected Fut9^?/? mice. Although there were no clear differences in the levels of cytokines examined in the brains between Fut9^?/? and wild‐type mice except for interferon‐β (IFN‐β) expression, some of those in the spleens, including interferon‐γ (IFN‐γ), interleukin‐6 (IL‐6), and monocyte chemoattractant protein‐1 (MCP‐1), showed higher levels in Fut9^?/? than in wild‐type mice. Furthermore, Fut9^?/? mice were refractory to the in vivo inoculation of endotoxin (LPS) compared with wild‐type mice. These results indicate that Le^x structures are involved in host responses against viral or bacterial challenges.     

Shrinkage temperature and anti-calcification property of triglycidylamine-crosslinked autologous tissue

Since bioprosthetic valve dysfunction may arise due to histological calcification in the crosslinking process by glutaraldehyde (GA), non-GA crosslinking reagents have been investigated. We compared the efficacy of triglycidylamine (TGA), a newly synthesized epoxy compound, and GA as crosslinking reagents for the treatment of autologous tissues. We assessed the strength of crosslinked tissues using shrinkage temperature (Ts) measured by differential scanning calorimetry. We also conducted subdermal allografting of the crosslinked pericardium and thoracic aorta in rats, and verified the anti-calcification efficacy of TGA by histological evaluations with von Kossa stain, and immunological evaluations using tenascin-C (TN-C) or matrix metalloproteinase-9 (MMP-9). TGA treatment resulted in slower increases in Ts of the pericardium, and it required 9–12 h to reach Ts achieved by GA. In subdermal implantation of rat tissues, calcium content was lower in the TGA group than in the GA groups (p < 0.005). The expression site of TN-C and MMP-9 differed from the primary location of calcium deposition in the thoracic aorta treated with TGA suggesting a different underlying mechanism in calcification between GA and TGA crosslinking. In conclusion, TGA crosslinking in the allograft showed superior anti-calcification effect as compared to brief treatment by GA, although TGA crosslinking process was slow.     

The influence of drug-exposure conditions on the development of resistance to methotrexate or ZD1694 in cultured human leukaemia cells

The influence of drug-exposure conditions on the development of resistance to methotrexate (MTX) or ZD1694 was studied by treating MOLT-3 human lymphoblastic-leukaemia cells in a continuous or a pulsatile (high-dose, short-term) drug-exposure schedule. Continuous exposure of the cells to MTX with stepwise escalation of the drug concentrations resulted in a MTX-resistant sub-line (MOLT-3/MTX_10,000) with impaired reduced-folate carrier (RFC) and increased dihydrofolate-reductase (DHFR) activity. Conversely, a MTX-resistant clone (MOLT-3/MTX·P-9) with unaltered RFC and DHFR activity, but with decreased cellular accumulation of antifolates, was selected by high-dose short-term treatment of the cells with MTX. MTX resistance in the latter cells was pronounced after short-term rather than continuous-exposure incubation with MTX, suggesting defective polyglutamation of the drug. On the other hand, 2 ZD1694-resistant sub-lines which were established by continuous (MOLT-3/ZD1694·C) or by pulsatile drug-exposure schedule (MOLT-3/ZD1694·P-9) demonstrated extremely low accumulation and poor retention of [³H]ZD1694, with no change of initial drug uptake and little or no increase of thymidylate-synthase (TS) activity, irrespective of drug-exposure conditions for their establishment. HPLC analysis displayed a virtual absence of ZD1694 polyglutamates in both ZD1694-resistant sub-lines and low accumulation in MOLT-3/MTX·P-9 as compared with the parent line. However, folylpolyglutamate-synthetase (FPGS) mRNA was only moderately decreased in the 2 ZD1694-resistant sub-lines and to an even lesser extent in MOLT-3/MTX·P-9. In addition, γ-glutamyl-hydrolase (GGH) activity was not increased, but was slightly down-regulated in the polyglutamation-defective sublines. These results indicate that the mechanism(s) of the resistance developed may depend not only on drug-exposure conditions while raising resistance but also on the biochemical properties of the drug. © 1996 Wiley-Liss, Inc.     

Differential induction of helper and killer T cells from isolated CD4+CD8+ thymocytes in suspension culture

Thymocytes of T cell receptor transgenic mice with nonselecting and RAG-2^−/− backgrounds were developmentally arrested at the CD4⁺CD8⁺ stage before positive selection. These thymocytes underwent lineage commitment upon transient stimulation with a combination of ionomycin, a calcium ionophore, and phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, in suspension culture. The effective drug doses were limited within narrow ranges and much lower than those which induce proliferation of mature T cells. The doses corresponded to those which inhibit glucocorticoid-induced apoptosis in these thymocytes. CD4 lineage commitment required longer duration, higher intensity of the stimulation, or both, than CD8 lineage commitment. Functional helper T cells (Th1 and Th2) were induced from the CD4 lineage-committed cells upon secondary stimulation with a combination of ionomycin and PMA followed by lymphokine treatment. Cytotoxic T cells were induced from the CD8 lineage-committed cells upon incubation with concanavalin A and irradiated splenic dendritic cells, but not with the combination of ionomycin and PMA. These results indicate that positive selection is mimicked by the pharmacological stimulation in the absence of other cell types, but that final maturation of CD8 T cells may require a different signal.     

Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance

Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCbeta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCbeta1 and -beta2, but not PKCalpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCbeta1 and -beta2, but not PKCalpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCbeta2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance.