The effects of dexmedetomidine on left ventricular function during hypoxia and reoxygenation in isolated rat hearts

Hypoxia resulting from apnea in patients with sleep apnea is an important factor in heart disease. We designed the present study to determine whether dexmedetomidine (DEX) has a direct protective effect against hypoxia-reoxygenation-induced left ventricular dysfunction without systemic hemodynamic and humoral effects. Isolated rat hearts were exposed to 60-min hypoxia followed by 30-min reoxygenation with 0, 10, or 100 nM DEX prehypoxia administration (n = 7 each group). In a second experiment (n = 7), 100 nM DEX was administered posthypoxia. In a third experiment (n = 7 each group), an alpha 2 antagonist, yohimbine was given with and without 100 nM DEX prehypoxia administration. DEX prehypoxia, but not posthypoxia, administration significantly improved the recovery of left ventricular developed pressure after reoxygenation (0, 10, 100 nM DEX prehypoxia or 100 nM DEX posthypoxia values were 53 +/- 6, 64 +/- 9, 78 +/- 13, or 62 +/- 12 mm Hg [mean +/- sd]) and reversed by yohimbine, 58 +/- 8 mm Hg, respectively. We conclude that DEX exerts the direct protective effect on the left ventricular dysfunction caused by hypoxia-reoxygenation through mainly alpha 2-adrenergic stimulation before and during the hypoxic period.     

Alendronate inhibits bone resorption at the bone-screw interface

In the current study, we investigated whether the systemic administration of alendronate, a third-generation bisphosphonate, suppressed the loosening of screws at the bone-screw interface. We systemically administered alendronate to rats fitted with external fixators. External fixators with two half pins were applied to the right femurs of rats, and alendronate was administrated once a week during a 5-week postoperative period. Radiographic, histologic, and immunohistochemical findings subsequently were analyzed. Treatment with alendronate reduced the width of the fibrous loosening membrane and the number of osteoclasts at the bone-screw interface. These findings indicate that systemic treatment with alendronate exerts an inhibitory effect on local bone resorption at the bone-screw interface.     

Clinical and pathologic characteristics of dilated cardiomyopathy in hemodialysis patients

BACKGROUND: Some dialysis patients have impaired left ventricular (LV) function without coronary artery disease. The pathologic changes and prognoses of these patients have not been well described. METHODS: We performed LV endomyocardial biopsies on 40 hemodialysis patients with dilated cardiomyopathy (DCM; an ejection fraction <50% and a left ventricular end-diastolic volume index >90 mL/m(2) without coronary artery disease), and on 50 nondialysis patients with idiopathic DCM as the control group. Following LV biopsies, the patients were followed-up for a mean of 3.1 +/- 2.3 years. RESULTS: The pathologic characteristics of the dialysis group were severe myocyte hypertrophy (the mean myocyte diameter across the nucleus: 37.6 +/- 10.5 mum vs. 25.6 +/- 7.7 mum, P= 0.001), myocyte disarray (30%), and extensive fibrosis (the mean percent area of left ventricular fibrosis: 22.3 +/- 18.4% vs. 21.3 +/- 14.6%, P= NS). These pathologic characteristics resembled the dilated phase of hypertrophic cardiomyopathy. In the dialysis group, a high percent area of LV fibrosis was the only significant predictor of cardiac death by multivariate analysis (P= 0.02). The 3-year cumulative event-free survival rate for cardiac death in dialysis patients with severe fibrosis (more than 30%) was 42%, while that for patients without severe fibrosis was 82% (P= 0.03). CONCLUSION: The pathologic characteristics of the heart in dialysis patients with DCM are interstitial fibrosis and severe myocyte hypertrophy with occasional disarray. The extent of LV fibrosis is a strong predictor of cardiac death. Careful follow-up and treatment are necessary for dialysis patients with a high percent area of LV fibrosis.     

Hepatic CCR7lowCD62LlowCD45RClow allograft dendritic cells migrate to the splenic red pulp in immunologically unresponsive rats

Donor dendritic cells (DC) migrate into the recipient spleen after hepatic transplantation. Immunological unresponsiveness to rat hepatic allografts can be induced by prior donor-specific blood transfusion (DST). We investigated homing receptor phenotype and splenic distribution of donor DC after allografting and DST. Immunostaining revealed OX62+ cells in the splenic red pulp of animals receiving pre-transplant DST but only in the white pulp of untreated animals. Most OX62 cells were positive for OX76. There were two subsets of DC in the spleen, CD45RChighOX62+ and CD45RClowOX62+ cells. RT-PCR revealed that CD45RClowOX62+ cells expressed interleukin (IL)-10, while CD45RChighOX62+ cells expressed IL-2 and low levels of IL-10 mRNA. CD45RChighOX62+ cells strongly expressed CCR5 and CCR7, compared with weak expression in CD45RClowOX62+ cells. The Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC/MIP3beta) was expressed mainly within the splenic white pulp. Mucosal vascular addressin-cell adhesion molecule-1 (MAdCAM-1) was expressed in the marginal zone and white pulp, but expression of splenic MAdCAM-1 was down-regulated in DST-treated animals. L-selectin (CD62L), the ligand for MAdCAM-1, was strongly expressed on CD45RChighOX62+ cells but not on CD45RClowOX62+ cells. In conclusion, differential splenic migration of CCR5lowCCR7lowCD62Llow CD45RClow DC expressing Th2-type cytokines is associated with immunological unresponsiveness to rat hepatic allografts.     

Visceral pleural invasion is an invasive and aggressive indicator of non-small cell lung cancer

OBJECTIVE: Although visceral pleural invasion by non-small cell lung cancer is considered a poor-prognostic factor, further information is lacking, especially in relation to other clinicopathologic prognostic factors. We assessed the relationship between visceral pleural invasion and other clinicopathologic characteristics and evaluated its significance as a prognostic factor. METHODS: We reviewed 1074 patients with surgically resected T1/2 non-small cell lung cancer for their clinicopathologic characteristics and prognoses. The patients were divided into 2 groups according to visceral pleural invasion status (visceral pleural invasion group and non-visceral pleural invasion group). Both groups were compared with regard to age, sex, histology, tumor size, tumor differentiation, lymph node involvement, lymphatic invasion, vascular invasion, scar grade, nuclear atypia, mitotic index, serum carcinoembryonic antigen level, and survival. Univariate and multivariate analyses were conducted. RESULTS: Visceral pleural invasion was identified in 288 (26.8%) of the resected specimens. Survival was 76.0% at 5 years and 53.2% at 10 years in the non-visceral pleural invasion group and was 49.8% at 5 years and 37.0% at 10 years in the visceral pleural invasion group. The difference between groups was highly significant ( P < .0001). Visceral pleural invasion was also significantly associated with a higher frequency of lymph node involvement. However, regardless of N status (N0 or N1/2), there was a significant difference in survival when the visceral pleura was invaded. Visceral pleural invasion was observed significantly more frequently in tumors with factors indicative of tumor aggressiveness/invasiveness: moderate/poor differentiation, lymphatic invasion, vascular invasion, high scar grade, high nuclear atypia grade, high mitotic index, and high serum carcinoembryonic antigen level. By multivariate analysis, visceral pleural invasion proved to be a significant independent predictor of poor prognosis in non-small-cell lung cancer patients with or without lymph node involvement. CONCLUSIONS: Visceral pleural invasion is a significant poor-prognostic factor, regardless of N status. Our analyses indicated that visceral pleural invasion is an independent indicator of non-small cell lung cancer invasiveness and aggressiveness.     

Surgical procedures for decompression of excessive shear stress in small-for-size living donor liver transplantation--new hepatic vein reconstruction

We have reported that acute elevation of portal pressure, reflecting wall shear stress of sinusoidal endothelial cells, triggers liver regeneration after partial hepatectomy and that excessive portal hypertension induces liver failure. For prevention of excessive shear stress in small-for-size living donor liver transplantation (LDLT), we developed a new hepatic vein reconstruction to expand the anastomotic site. Fourteen adult patients, who underwent LDLT, were divided into two groups: previous end-to-end hepatic vein reconstruction in nine patients (group P) and the new method in five patients (group N). The outside middle and left hepatic veins of the graft were incised and enlarged to 40 mm. The vena cava was cut 40 mm longitudinally. The graft was positioned a quarter turn counterclockwise with the hepatic vein of the graft anastomosed end-to-side to the vena cava longitudinally. Postoperative portal pressures and serum total bilirubin levels of these two groups showed portal pressure in group N to rapidly decrease below 25 cm H2O following LDLT. No cases showed posttransplanted hyperbilirubinemia above 10 mg/dL in group N; however, all cases were small-for-size grafts. Moreover, serum total bilirubin levels in group N were significantly lower than those in group P. This procedure is simple despite not using a venous patch. If the hepatic vein is narrow or obstructed, such as in Budd-Chiari syndrome, the procedure is applicable. Even in small-for-size grafts, excessive tension did not occurred at the portal vein or hepatic artery anastomoses. Moreover, it is possible to avoid outflow block and posttransplanted hyperbilirubinemia.     

Comparison of the vector systems for gene transduction into rat dendritic cells and peritoneal exudate cells

Specialized antigen-presenting cells (APC), known as dendritic cells (DC), play a pivotal role in initiating primary immune responses. It has been reported that several vector systems, including adenoviral vectors, retroviral vectors, Hemagglutinating Virus of Japan (HVJ)-related vectors, and electroporation, are able to transduce genes into mouse and human DC. This has not been achieved for rat DC. To our knowledge, there is no direct evidence to support the view that the currently used vector systems are able to transduce genes into mature DC. Because most, if not all, gene transfer studies investigating DC or DC-related cell populations are carried out using heterogeneous groups of cells, it is therefore very important to determine to what extent gene transduction occurs in rat DC, and also selected mature DC (CD161a+ fully mature DC). In this study, we provide evidence that none of 4 vector systems are able to transfer genes into fully mature rat DC, which are derived from bone marrow cells (BMC), driven by Flt3/Flk2 ligand and interleukin (IL)-6, and purified by CD161a. Nevertheless, the most efficient gene transduction was observed in the developing DC progenitor cells during the long-term culture of rat BMC, and its gene expression was successfully achieved after 2 weeks of culture only with a human immunodeficiency virus (HIV)-based lentiviral vector system. The most critical time point for lentiviral gene transduction was around the 7th day from the beginning of culture with lentiviral vectors. Rat peritoneal exudate cells (PEC) and another cell line (K562) were easily transducted by adenoviral vectors and lentiviral vectors.     

Effects of immunosuppressive agents on magnesium metabolism early after allogeneic hematopoietic stem cell transplantation

BACKGROUND: The calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus, cause hypomagnesemia by suppressing reabsorption of magnesium (Mg) from renal tubules. To assess whether the effect on Mg metabolism after allogeneic hematopoietic stem cell transplantation (HSCT) differs among calcineurin inhibitors, we prospectively evaluated the Mg metabolism in recipients of allogeneic HSCT who received CSA or tacrolimus METHODS: Patients who underwent allogeneic HSCT were enrolled. CSA and tacrolimus were given by continuous infusion starting from day -1. Serum Mg and the total amount of urinary Mg excretion were measured once before starting of CSA or tacrolimus, and once weekly after HSCT for 4 weeks. Mg was supplemented with magnesium l-aspartate by continuous infusion to maintain the serum Mg level >1.4 mEq/L. RESULTS: Thirty-six patients were evaluated (12 in the CSA group, 24 in the tacrolimus group). The serum Mg level began to decrease in both groups at the first week after HSCT, and the mean serum Mg levels were significantly lower in the tacrolimus group than in the CSA group from the first to the third week. The total amount of urinary Mg excretion and Mg supplementation began to increase in both groups at the second week after HSCT, and the amounts in the tacrolimus group were significantly higher than those in the CSA group. CONCLUSIONS: Although both calcineurin inhibitors increased urinary Mg excretion and caused hypomagnesemia shortly after HSCT, the effect was more significant with tacrolimus than with CSA. This observation may explain the higher incidence of renal impairment and encephalopathy in patients receiving tacrolimus.     

Allograft glomerulitis: histologic characteristics to detect chronic humoral rejection

The aim of this study was to clarify the histopathologic significance of allograft glomerulitis in chronic allograft nephropathy (CAN). Review of our renal allograft biopsy files revealed 140 specimens with CAN among 115 selected patients. They were classified into two groups: one had CAN with glomerulitis (group G), and the other was free of this finding (group NG). We evaluated the clinicopathologic parameters as follows: levels of serum creatinine and proteinuria in the biopsy; presence of circulating anti-donor antibodies; allograft failure rate; history of biopsy-proven acute cellular rejection (ACR) and acute humoral rejection (AHR); complications of ACR and chronic rejection (CR); and results of immunofluorescence studies for C4d and HLA-DR. The glomerulitis group showed a significantly greater incidence of CR complications, the presence of circulating anti-donor antibodies, and C4d deposition in peritubular and glomerular capillaries. This group also showed higher levels of serum creatinine and proteinuria, higher graft loss rate, and increased AHR incidence, although the differences were not significant. There was also no statistical significance in the HLA-DR expression on tubular epithelial cells. The present results strongly suggest that humoral factors may play an important role in the progression of glomerulitis in CAN. Therefore, we suspect that glomerulitis in CAN is one of the main histologic markers for CR. The presence of glomerulitis may represent humoral factor-dependent inflammation. It should be considered an important diagnostic criterion for CR in addition to double-contour formation and elastica disruptions with or without subendothelial inflammation (Banff '97).