Propofol increases the rate of albumin-unbound free midazolam in serum albumin solution

Propofol and midazolam have a synergistic anesthetic action. One of the reasons for this is thought to be the inhibitory effect of propofol on midazolam metabolism. However, because both drugs bind strongly to serum protein, their interaction may not only involve the effects of propofol on midazolam metabolism, but may also involve propofol’s effects on serum protein-binding. Against this background, we investigated the characteristics of midazolam binding to serum albumin, and evaluated the effects of both propofol and ketamine on this binding. Midazolam was added to a serum albumin solution with propofol or ketamine, and, after incubation for 1 h, albumin-free solution was separated from the sample and the midazolam concentration was measured using a high-performance liquid chromatography system. The albumin-unbound rate of midazolam was evaluated and compared with the rate in the control solution (only midazolam). Propofol significantly raised the rate of albumin-unbound free midazolam, while ketamine had no effect on the binding of midazolam to serum albumin. These findings suggest that the increase in albumin-unbound free midazolam brought about by propofol is involved in the synergistic effect of these two agents.     

Role of renin–angiotensin aldosterone system on short-term blood pressure variability in hypertensive patients

The relationship between the renin–angiotensin aldosterone system and short-term blood pressure variability has not been well elucidated. Here, we investigated whether blood pressure variability determined by ambulatory blood pressure monitoring differed among patients with primary aldosteronism (PA), renovascular hypertension (RVHT), and essential hypertension (EHT). We examined 25 patients with PA, 28 patients with RVHT, and 18 patients with EHT. Ambulatory blood pressure monitoring was conducted in all patients. Short-term blood pressure variability was evaluated by calculating the standard deviation (SD), coefficient of variation (CV), and average real variability (ARV) of 24-h, daytime, and nighttime blood pressure values. Day–night differences in blood pressure were also determined. The mean 24-h systolic blood pressure (SBP) and the mean diastolic blood pressure (DBP) in the PA and RVHT groups were found to be comparable to those in the EHT group. The SD, the CV, nor the ARV of the 24-h, daytime, and nighttime blood pressures showed any significant differences among the three groups. The day–night differences in blood pressure were comparable among the three groups. The short-term blood pressure variabilities evaluated by ambulatory blood pressure monitoring were comparable among the patients with EHT, RVHT, and PA. The results suggest that the renin–angiotensin aldosterone system may contribute little to short-term blood pressure variability in individuals with hypertension.     

Layilin, a talin-binding hyaluronan receptor, is expressed in human articular chondrocytes and synoviocytes and is down-regulated by interleukin-1β

Objective

Layilin (LAYN), a 55-kDa transmembrane protein with homology to C-type lectins, has been identified as a receptor of hyaluronan (HA). Interestingly, LAYN does not share any sequence homology with CD44, a primary HA receptor. The primary aim of our study was to examine the expression and potential function of LAYN in human articular chondrocytes and synoviocytes.

Methods

Samples were obtained from patients undergoing joint arthroplasty. Cells were grown in vitro, then stimulated with interleukin (IL)-1β or tumor necrosis factor alpha (TNFα) for 24 h and the expression of LAYN was analyzed. To assess the function of LAYN, we transfected chondrocytes with siRNA against LAYN, treated them with HA and IL-1β, and then analyzed the production of matrix metalloproteinase (MMP)-1 and MMP-13 in the treated chrondrocytes.

Results

The results showed that LAYN was constitutively expressed in human articular chondrocytes and synoviocytes and that IL-1β significantly suppressed the expression of LAYN in these cells. HA repressed IL-1β-induced MMP-1 and MMP-13 production in chondrocytes, but this was significantly abrogated in chondrocytes transfected with siRNA against LAYN.

Conclusions

Our results show that human chondrocytes express LAYN, a novel HA receptor, and that LAYN may contribute to the regulation of HA functions in the arthritic condition. Further investigation of the HA receptor may lead to the development of novel therapeutics to regulate HA signaling in inflammatory arthritis.     

Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study

Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006–2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (P<0.01), donor type (P<0.01) aand disease indications (P<0.01) differed significantly between countries and regions. Transplant rates were associated with Gross National Income/capita (P<0.01) but showed a wide variation of explanatory content by donor type, disease indication and World Health Organization region. Hematopoietic stem cell transplantation activity is increasing worldwide. The preferential increase in high income countries, the widening gap between low and high income countries and the significant regional differences suggest that different strategies are required in individual countries to foster hematopoietic stem cell transplantation as an efficient and cost-effective treatment modality.     

A case of desmoplastic malignant mesothelioma with elevated serum CYFRA 21-1]

A 70-year-old woman was admitted to our hospital for medical evaluation of a right side pleural effusion, which was pointed out at another hospital. Chest CT revealed a right pleural effusion with diffuse and irregular pleural thickening. Percutaneous pleural biopsy showed hypocellular collagenous tissue without malignant cells. Though she received antituberculosis therapy, the pleural thickening progressed and the serum CYFRA 21-1 level was elevated. Chest pain and dyspnea appeared, and she was readmitted. However, pneumonia was present as a complication, and she died. At autopsy, the right pleura was thickened and invasion of the lung and the chest wall was observed. Microscopic findings showed increased amounts of hyalinized collagen fibers forming a storiform pattern. At the tumor foci, atypical cells with distinct nucleoli were observed. Desmoplastic malignant mesothelioma, which is rarely reported in Japan, was diagnosed.     

Indications for partial left ventriculectomy in pediatric dilated cardiomyopathy.

The purpose of this study was to define the role and indications of partial left ventriculectomy (PLV) in children with end-stage dilated cardiomyopathy (DCM). Clinical data were collected by retrospective chart review of children with DCM who were treated from 1997 to 2000. Four patients underwent PLV (PLV group) and 5 patients were managed without PLV (non-PLV group). In the PLV group, 2 patients are well 18 and 35 months postoperatively. One infant survived 6 months and then successfully underwent heart transplantation, and the other child died of hemoptysis 2 weeks postoperatively. Factors affecting outcome were preoperative status, in particular whether surgery was performed urgently or electively. In the non-PLV group, 4 patients were well controlled by medical treatment and 1 infant underwent mitral valve replacement for severe mitral regurgitation. The cardiothoracic ratio ranged from 72% to 76% in the PLV group and from 45% to 60% in the non-PLV group. The percentage of the expected left ventricular diastolic dimension ranged from 184% to 218% in the PLV group and from 109% to 163% in the non-PLV group. Ejection fractions in the PLV group were from 10% to 22% and from 36% to 56% in the non-PLV group. The serum brain natriuretic peptide concentration was above 1,200 pg/ml in the PLV group and below 168 pg/ml in the non-PLV group. In conclusion, PLV is indicated for selected children with end-stage DCM, and is most appropriate when medical therapy is not effective and heart transplantation is unavailable.     

Dual response to Fas ligation in human endothelial cells: apoptosis and induction of chemokines,interleukin-8 and monocyte chemoattractant protein-1

BACKGROUND: To maintain the integrity of tissues, endothelial cells play critical roles. Fas ligand (FasL) is well known to deliver a death signal through its receptor, Fas. The Fas/FasL system may concomitantly induce expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) besides triggering apoptosis in endothelial cells. We also investigated whether an inhibitor of caspase-8 (Z-IETD-FMK) does modulate IL-8 and MCP-1 secretion. METHODS AND RESULTS: After treatment with interferon-gamma (IFN-gamma), human recombinant FasL (hr FasL) or Fas agonistic antibody (CH-11) was added to cultured human endothelial cells. IFN-gamma up-regulated Fas mRNA levels. Fas ligation promoted apoptosis assessed by fluorescent-activated cell sorter (FACS) analysis in a dose-dependent manner and induced prominent DNA fragmentation. Simultaneously, IL-8 and MCP-1 were secreted from the endothelial cells in response to hr FasL or CH-11 in a dose-dependent manner (P < 0.01). Fas-neutralizing agent (Fas-Fc) suppressed the Fas-mediated secretions of IL-8 and MCP-1 (P < 0.01) both as well as the Fas-mediated apoptosis. On the other hand, whereas Z-IETD-FMK suppressed apoptosis, the inhibitor enhanced the Fas-mediated secretions of both IL-8 and MCP-1 beyond the value of the Fas stimulation alone (P < 0.01), suggesting an enhanced signalling for the chemokine expression. CONCLUSION: In human endothelial cells, the Fas/FasL system induces both IL-8 and MCP-1 secretions probably via a caspase-8 independent pathway. The Fas/FasL system may amplify the inflammatory cascade in the vascular injury and atherogenesis by recruiting leukocytes at the region of apoptotic endothelial damage.     

Hemodialysis Product and Hip Fracture in Hemodialysis Patients: A Nationwide Cohort Study in Japan

Some have raised concerns that longer and more frequent hemodialysis (HD) would be associated with bone fractures due to excess phosphate removal. We examined the effects of hemodialysis product (HDP) on hip fracture incidence among Japanese HD patients using registry data of the Japanese Society for Dialysis Therapy. During a 1‐year study period, 1411 hip fractures occurred among 135 984 patients. After adjusting for demographic and clinical factors, patients with a high HDP did not show a significant risk of hip fracture. Interestingly, patients with polycystic kidney disease had a lower risk of hip fracture. Our findings did not support the hypothesis that patients undergoing longer and more frequent HD would face a higher risk of hip fracture than those undergoing shorter and less frequent HD. Polycystic kidney disease was identified as a new significant factor for hip fracture; relative to glomerulonephritis, this condition was associated with a lower risk of hip fracture.