Review of clinical studies on the nocebo effect.

Objective: To review clinical studies on the nocebo effect. PubMed was searched for relevant clinical studies as well as studies on the relationship between the nocebo effect and genes. Data sources: A total of 35 clinical studies on the nocebo effect and one study on its relationship with genes were selected for review. All were conducted outside Japan. Results and conclusion: An increasing number of clinical studies on the nocebo effect are being published. The 36 studies selected for review were grouped into the following five categories: (1) studies of how differences in participant characteristics such as personality affect susceptibility to the nocebo effect, (2) studies of how differences in provision of information about side effects affect susceptibility to the nocebo effect, (3) studies of how nocebo conditioning affects susceptibility to the nocebo effect, (4) studies of nocebo response mechanisms, and (5) studies of the nocebo effect and genetic polymorphisms. The first four categories comprised 5, 19, 8, and 3 studies, respectively, and the fifth comprised 1 study. Most of the studies investigated how differences in the provision of information affect susceptibility to the nocebo effect. Few studies investigated individual differences in the nocebo effect (differences between responders and non-responders) or mechanisms of the nocebo effect.

Relationship between medication adherence and glycemic control in Japanese patients with type 2 diabetes.

A cross-sectional survey of 358 patients was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). Univariate and multivariate regression analyses of glycosylated hemoglobin (HbA1c) were performed in addition to assessing demographic and disease characteristics and MMAS-8. In conclusion, medication adherence as measured by the MMAS-8 score independently contributes to altering the HbA1c level in the range of 1.12 %. The number of medications prescribed and insulin use are also related to HbA1c.

Case report: Electron microscopic evaluation of bone from a patient treated with cinacalcet hydrochloride, maxacalcitol, and alfacalcidol for hyperparathyroid bone disease with secondary hyperparathyroidism.

Evaluation of bone is of great importance in chronic kidney disease patients, as these patients are at an increased risk for fractures. We treated a hemodialysis patient suffering from hyperparathyroid bone disease with cinacalcet hydrochloride and concurrent administration of maxacalcitol and alfacalcidol for a year. Hyperparathyroid bone disease is characterized by cortical thinning, increased cortical porosity, reduced trabecular bone volume, and increased hypomineralized matrix volume, and there is little information to date about the effects of treatment with cinacalcet hydrochloride on the bone fragility in patients with hyperparathyroid bone disease. In the present study, histological and backscattered electron microscopic evaluation of this combination treatment revealed an excellent improvement of both bone volume and bone morphology. This treatment improved cortical thinning, cortical porosity, and trabecular thinning. Furthermore, the treatment also reduced hypomineralized matrix volume, indicative of improved mineralization by osteocytes. We speculate that the intermittent maxacalcitol administration may have effectively stimulated the vitamin D receptors expressed on osteocytes and osteoblasts, resulting in increased mineralization. Our approach for evaluating the bone in patients with chronic kidney disease by backscattered electron microscopy is novel.

Quasi-solid electrolyte: a thixotropic gel of imogolite and an ionic liquid.

We report a quasi-solid electrolyte comprising a transparent thixotropic gel swelled by an ionic liquid that is formed by a framework of single-walled aluminosilicate cylindrical inorganic "imogolite" nanotubes. The quasi-solid electrolyte shows moldability, thermal stability, and high ionic conductivity, and has potential applications in free-moldable conductive and anti-icing coatings, or electrolytes for batteries.

Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies.

BACKGROUND: The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318-1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials. METHODS: Patients in both studies were randomized (2:1) to tapentadol ER (25-250 mg) or placebo for 12 weeks (≤6-week titration plus maintenance periods). RESULTS: For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were -0.1 (-1.04, 0.80) in the OA/LBP study and -0.1 (-1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated. CONCLUSIONS: Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis.

The tyrosine kinase WEE1 controls the timing of entry into mitosis in eukaryotes and its genetic deletion leads to pre-implantation lethality in mice. Here, we show that besides the premature mitotic entry phenotype, Wee1 mutant murine cells fail to complete mitosis properly and exhibit several additional defects that contribute to the deregulation of mitosis, allowing mutant cells to progress through mitosis at the expense of genomic integrity. WEE1 interacts with the anaphase promoting complex, functioning as a negative regulator, and the deletion of Wee1 results in hyper-activation of this complex. Mammary specific knockout mice overcome the DNA damage response pathway triggered by the mis-coordination of the cell cycle in mammary epithelial cells and heterozygote mice spontaneously develop mammary tumors. Thus, WEE1 functions as a haploinsufficient tumor suppressor that coordinates distinct cell division events to allow correct segregation of genetic information into daughter cells and maintain genome integrity.

Relationship between glomerular filtration rate and plasma N-terminal pro B-type natriuretic peptide concentrations in dogs with chronic kidney disease.

Plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations increase in dogs with azotemia. However, the correlation between glomerular filtration rate (GFR) and NT-proBNP concentrations in dogs has not been evaluated. The objective of this study was to evaluate the correlation between GFR and plasma NT-proBNP concentrations in dogs with chronic kidney disease (CKD). In this retrospective cross-sectional study, plasma creatinine (Cre) and NT-proBNP concentrations, plasma iohexol clearance (PCio) values and blood pressure were measured in dogs with CKD. Dogs were classified according to PCio values into D group (dogs with decreased PCio values), and N group (dogs with normal PCio values). Dogs were further categorized on the basis of their systolic blood pressure and PCio values into NT-D group (normotensive dogs with decreased PCio values), NT-N group (normotensive dogs with normal PCio values), HT-D group (hypertensive dogs with decreased PCio values) and HT-N group (hypertensive dogs with normal PCio values). Significant correlations were observed between plasma NT-proBNP and Cre concentrations (r=0.360, P<0.05) and PCio values (r=-0.470, P<0.01). Plasma NT-proBNP concentrations were significantly higher in the D group than in the N group (P<0.001). Plasma NT-proBNP concentrations were significantly higher in the HT-D group than in the other three groups (P ≤ 0.007). No differences in plasma NT-proBNP concentrations were observed between the NT-D and HT-N groups (P=0.28). Plasma NT-proBNP concentrations were significantly lower in the NT-N group than in the other three groups (P ≤ 0.043). Our findings suggest that decreased GFR might be associated with increased plasma NT-proBNP concentrations in dogs, similar to that in humans. In addition, the complication of hypertension in CKD might be associated with further increases in plasma NT-proBNP concentrations. In conclusion, the effects of GFR and blood pressure on the plasma NT-proBNP concentration were small, but it could be necessary to consider the effects when this marker is used to evaluate canine cardiac disease.

Various patterns of traumatic triangular fibrocartilage complex tear.

We demonstrate various patterns of traumatic triangular fibrocartilage complex (TFCC) tears including some atypical that cannot be categorized under Palmer's classification. TFCC traumatic tears in 173 wrists were examined arthroscopically or macroscopically and divided into disk tears (subdivided into four types: slit tear, flap tear, horizontal tear and tear within the distal radioulnar joint) and peripheral tears (subdivided into six types: ulnocarpal ligament tear, dorsal tear, radial tear, ulnar styloid tear, foveal tear and distal radioulnar ligament tear). Combinations of these types were found in 32 wrists. Wrist arthroscopy revealed various traumatic TFCC tears that do not come under Palmer's classification; therefore establishment of a new classification for traumatic TFCC tears seems to be warranted.

Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest, and mitotic catastrophe.

Epidemiological studies revealed that amount of consumption of soy was inversely related to incidence of breast cancer. Genistein, the predominant isoflavone in soy, has been reported to reduce the incidence of breast cancer in animal models. To investigate whether genistein has a therapeutic effect on BRCA1-associated breast cancer, we treated Brca1 mutant mammary tumor cells with genistein. We showed that genistein treatment depleted the G1 population of cells, which was accompanied by an accumulation of cells at G2. Some genistein-treated cells entered mitosis; however, they exhibited chromosome abnormalities and maintained tetraploidy owing to abortive mitotic exit. A fraction of G2 cells underwent endoreduplication and became polyploid, which was accompanied by increased cell death through activating DNA damage response. Furthermore, our data indicated that Brca1 mutant cells were more sensitive to genistein than some other types of cancer cells, highlighting a good therapeutic potential of genistein for BRCA1-associated breast cancer.

Pathogenic mechanisms for parathyroid hyperplasia.

Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and parathyroid hormone-suppressive properties of calcitriol therapy.

Changes in coagulative and fibrinolytic activities in patients with intracranial hemorrhage.

OBJECTIVE: To investigate whether any changes occur in the coagulative/fibrinolytic cascade in patients with subarachnoid hemorrhage (SAH) or hypertensive intracerebral hemorrhage (HICH). DESIGN AND METHODS: Subjects included 143 patients with intracranial hemorrhage (SAH, n = 50; HICH, n = 82; ROSC-SAH [return of spontaneous circulation after cardiopulmonary arrest due to SAH], n = 11). Coagulative and fibrinolytic factors were measured in blood samples taken on admission. RESULTS: The prothrombin fragment 1+2 level was significantly higher (p < 0.005) in SAH patients than in HICH patients. The fibrinolytic factors (plasmin alpha 2-plasmin inhibitor complex, D-dimer, or fibrinogen degradation products) in SAH and ROSC-SAH were both significantly higher than those in HICH, but the significance of difference was stronger in the case of ROSC-SAH (p < 0.05). DISCUSSION: Both coagulative and fibrinolytic activities were altered after the onset of SAH. These results demonstrate that the coagulative/fibrinolytic cascade might be activated via different mechanisms in different types of stroke. It remains unclear, however, whether a significant alteration of the fibrinolytic cascade in patients with ROSC-SAH might be a nonspecific phenomenon attributable to the reperfusion after collapse.

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation.

Aurora-A/STK15/BTAK, which encodes a centrosome-associated kinase, is amplified and overexpressed in multiple types of human tumors, including breast cancer. However, the causal relationship between overexpression of Aurora-A and tumorigenesis has not been fully established due to contradictory data obtained from different experimental systems. To investigate this, we generated a mouse strain that carries an MMTV-Aurora-A transgene. We showed that all the MMTV-Aurora-A mice displayed enhanced branch morphogenesis in the mammary gland and about 40% developed mammary tumors at 20 months of age. The tumor incidence was significantly increased in a p53(+/-) mutation background with about 70% MMTV-Aurora-A;p53(+/-) animals developed tumors at 18 months of age. Of note, overexpression of Aurora-A led to genetic instability, characterized by centrosome amplification, chromosome tetraploidization and premature sister chromatid segregation, at stages prior to tumor formation. Most notably, the severe chromosomal abnormality did not cause cell death owing to the activation of AKT pathway, including elevated levels of phosphorylated AKT and mammalian target of rapamycin, and nuclear accumulation of cyclin D1, which enabled continuous proliferation of the tetraploid cells. These data establish Aurora-A as an oncogene that causes malignant transformation through inducing genetic instability and activating oncogenic pathways such as AKT and its downstream signaling.

Cervical intervertebral disc injury during simulated frontal impact.

Cervical disc injury due to frontal impact has been observed in both clinical and biomechanical investigations; however, there is a lack of data that elucidate the mechanisms of disc injury during these collisions. The goals of the current study were to determine the peak dynamic disc annular tissue strain and disc shear strain during simulated frontal impact of the whole human cervical spine model with muscle force replication at 4 g, 6 g, 8 g and 10 g horizontal accelerations of the T1 vertebra. These data were compared with those obtained during physiological loading, and with previously reported rear impact data. Peak disc shear strain and peak annular tissue strain during frontal impact exceeded (p<0.05) corresponding physiological limits at the C2-C3 intervertebral level, beginning at 4 g and 6 g, respectively. These subsequently spread throughout the entire cervical spine at 10 g, with the exception of C4-C5. The C5-C6 intervertebral level was at high risk for injury during both frontal and rear impacts, while during frontal impact, in addition to C5-C6, subfailure injuries were likely at superior intervertebral levels, including C2-C3. The disc injuries occurred at lower impact accelerations during rear impact as compared with frontal impact. The subfailure injuries of the cervical intervertebral disc that occur during frontal impact may lead to the chronic symptoms reported by patients, such as head and neck pain.

Clinical success of Neoral absorption profile.

We investigated the clinical benefits of cyclosporine microemulsion preconcentrate (CyA-MEPC; Neoral) in 16 de novo renal transplant recipients. The dose of CyA-MEPC was managed from AUC(0-4h), with serial target values of AUC(0-4h) at 5000-->4000-->3000-->2000 ng. hr/mL. The frequency of acute rejection episodes was 25%. The decreased renal function reached a low value of 12.5%, and creatinine was stable. Therefore, setting the target AUC(0-4h) value in the early phase at 5000 ng.hr/mL is an effective strategy to prevent acute rejection episodes. The single dose of Neoral given immediately after the renal transplant was 6 mg/kg (making a daily dose of 12 mg/kg). Thereafter, the dose-normalized AUC(0-4h) was set at a constant value to 4 weeks posttransplant. At week 4, the single dose was decreased to 4 mg/kg twice daily (a daily dose of 8 mg/kg). From these studies a daily dose of 12 mg/kg is suggested to be the appropriate amount for the first dose immediately after transplant. The renal biopsy performed at 6 months posttransplant showed neither cyclosporine-induced renal impairments, nor findings of chronic rejection, suggesting that 2000 ng.hr/mL is an appropriate target AUC(0-4h) value in the maintenance phase. These results suggest that it is possible to set the target value of C2 monitoring in the maintenance phase to a value slightly lower than that proposed from other studies.

DeltaFosB, but not FosB, induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line.

The fates of Rat1a cells expressing FosB and DeltaFosB as fusion proteins (ER-FosB, ER-DeltaFosB) with the ligand binding domain of human estrogen receptor were examined. The binding of estrogen to the fusion proteins resulted in their nuclear translocation and triggered cell proliferation, and thereafter delayed cell death was observed only in cells expressing ER-DeltaFosB. The proliferation of Rat1a cells, but not cell death triggered by ER-DeltaFosB, was completely abolished by butyrolactone I, an inhibitor of cycline-dependent kinases, and was partly suppressed by antisense oligonucleotides against galectin-1, whose expression is induced after estrogen administration. The cell death was accompanied by the activation of caspase-3 and -9, the fragmentation of the nuclear genome and cytochrome c release from the mitochondria, and was suppressed by zDEVD-fmk and zLEHD-fmk but not zIETD-fmk. The cell death was not suppressed by exogenous His-PTD-Bcl-x(L) at all, suggesting involvement of a Bcl-x(L)-resistant pathway for cytochrome c release.

Correlation of Lorenz scatterplots with frequency-domain heart rate variability.

Heart rate (HR) variability is important with respect to disease prognosis and the effects of drugs. Lorenz scatterplots provide a simple way to evaluate HR variability visually. The relation of Lorenz scatterplots to frequency-domain HR variability was examined in 75 Holter recordings and in simulated HR trends. The length of Lorenz scatterplots was double-exponentially correlated with total frequency and very-low frequency powers, with correlation coefficients (r) of 0.88. The width of Lorenz scatterplots was highly correlated with the high frequency power (r=0.98). The sum of the width and length of Lorenz scatterplots was highly correlated with the total frequency power (r=0.92). Identical results were obtained when simulated HR trends were used. In conclusion, Lorenz scatterplots provide a simple way to estimate the frequency-domain HR variability.