Trajectory of Serum Albumin Prior to Death in Patients Receiving Hemodialysis.

OBJECTIVE: Although some clinical expert guidelines recommend regular monitoring of serum albumin levels in patients undergoing maintenance hemodialysis, little is known about the serum albumin trajectory patterns over time, and it is unclear how the trajectory change before death. METHODS: We performed this retrospective study using data from 421 patients receiving hemodialysis in a dialysis facility. We divided patients into died and survived groups according to whether they died during the observation period. To compare the albumin trajectories during the observation period between the died and survived groups, linear mixed-effect models and a backward timescale from the year of death or study end were used. RESULTS: During the observation period (median, 5.1 years; maximum, 8.4 years), 115 patients receiving dialysis died. The serum albumin level showed steeper decline 3 years before death in the died group than in the survived group. The difference in albumin between the died and survived groups became apparent 3 years before death (difference, 0.08 g/dL; 95% confidence interval, 0.00-0.15 g/dL; P = .04), and the difference widened over time (difference at 1 year before death, 0.24 g/dL; 95% confidence interval, 0.14-0.33 g/dL; P < .001). Furthermore, in an analysis of albumin trajectories according to cause of death, the albumin level showed a downward trend regardless of the cause of death. CONCLUSION: The serum albumin trajectory differed between patients undergoing hemodialysis who died and who survived, supporting the importance of monitoring the albumin trajectory in clinical practice.

Clinical features and predictors of patients with critical limb ischemia who responded to autologous mononuclear cell transplantation for therapeutic angiogenesis.

The clinical features of patients with critical limb ischemia (CLI) who responded to angiogenesis using autologous peripheral blood mononuclear cell transplantation (PB-MNC) have not yet been fully characterized, and there are no useful predictors to judge the curative effect in the early period after PB-MNC. This study sought to clarify the clinical features and predictors in patients with CLI who were successfully treated using PB-MNC. 30 consecutive patients [arteriosclerosis obliterans: 24 patients, thromboangiitis obliterans: 6 patients] who were diagnosed with major amputation despite maximal medical therapy were enrolled in this study. The study endpoint was major amputation within 3 months after PB-MNC. The collected data were evaluated for correlation between patients with and without major amputation within 3 months after PB-MNC. Six patients underwent major amputation and 1 patient underwent minor amputation. In the patients with major amputation, transcutaneous oxygen tension before PB-MNC and transplanted CD34-positive cells were lower than those of patients without major amputation. In the patients with amputation, interleukin-6 (IL-6) continued to increase after the first PB-MNC, and basic fibroblast growth factor (bFGF) decreased within 3 days after the first PB-MNC. PB-MNC was useful for the patients who were managed for inflammation and who had revascularization of the upper-popliteal arteries and two of the infra-popliteal arteries by endovascular and/or surgical revascularization. Variation in IL-6 and bFGF in the early period after PB-MNC could be useful predictors for the requirement of amputation within 3 months after PB-MNC.

Is there a relation between triglyceride concentrations in very low density lipoprotein and the index of insulin resistance in nondiabetic subjects?

BACKGROUND: Serum very low density lipoprotein (VLDL) levels increase during the early stages of insulin resistance; therefore, determination of VLDL levels would be useful for evaluating the progression of metabolic syndrome and diabetes mellitus. The aim of this study was to clarify the clinical utility of triglyceride in VLDL (VLDL-TG) level, determined using a homogeneous assay kit (Shino-test Corporation, Tokyo, Japan), as an index of insulin resistance. METHODS: We enrolled 74 subjects in this study (diabetic subjects, n = 42; nondiabetic subjects, n = 32). The levels of VLDL-TG, remnant-like lipoprotein particle cholesterol, preheparin lipoprotein lipase mass, and other biochemical markers were determined. RESULTS: VLDL-TG levels were significantly higher in the diabetic group (1.04 ± 0.84 mmol/l vs. 0.64 ± 0.42 mmol/l, P < 0.01) than in the nondiabetic group. In the nondiabetic group, VLDL-TG was significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), the index for insulin resistance (r = 0.513, P = 0.003). VLDL-TG levels, but not TG levels, were higher in the highest quartile (HOMA-IR) of the nondiabetic group. CONCLUSION: VLDL-TG level was a useful early marker for insulin resistance, especially in nondiabetic subjects. The homogeneous VLDL-TG assay is a simple, low-cost method for determining insulin resistance.

Therapeutic strategy using extracorporeal life support, including appropriate indication, management, limitation and timing of switch to ventricular assist device in patients with acute myocardial infarction.

The appropriate indication for, management of and limitations to extracorporeal life support (ECLS) and the timing of a switch to a ventricular assist device (VAD) remain controversial issues in patients with acute myocardial infarction (AMI) complicated with cardiogenic shock or cardiopulmonary arrest. To evaluate and discuss these issues, we studied patients with AMI treated with ECLS and compared deceased and discharged patients. Thirty-eight patients with AMI who needed ECLS [35 men (92.1 %), aged 59.9 ± 13.5 years] were enrolled in this study. Of these 38 patients, 34 subsequently underwent percutaneous coronary intervention (PCI), and four subsequently received coronary artery bypass grafting (CABG). Fourteen patients (36.8 %) were discharged from the hospital. The outcome was not favorable for those patients with deteriorating low output syndrome (LOS) and the development of leg ischemia, hemolysis and multiple organ failure during ECLS. Levels of creatine kinase, creatine kinase-MB (CK-MB), lactate dehydrogenase, serum creatinine (Cr) and amylase after the patient had been put on ECLS and fluctuation of the cardiac index, blood pressure, arterial blood gas analysis and CK-MB and Cr levels during ECLS were indicators to switch from the ECLS to VAD. In the case of patients with no complication associated with ECLS, 4.6-5.6 days after initiation of ECLS was assumed to be the threshold to decide whether to switch from ECLS to VAD. Patients with AMI who suddenly developed refractory pulseless ventricular tachycardia or ventricular fibrillation without deteriorating LOS and who underwent successful PCI or CABG, and who prevented the complications associated with ECLS, showed a high probability of recovering with ECLS.

Two-week interval optical coherence tomography: imaging evidence on neointimal coverage completion after implantation of the Endeavor zotarolimus-eluting stent.

OBJECTIVE: To obtain imaging evidence by 2-week optical coherence tomography (OCT) on the completion of neointimal coverage (NIC; the percentage of stent strut coverage and thickness of the formed neointima) completion after implantation of the Endeavor zotarolimus-eluting stent (E-ZES). BACKGROUND: Despite the fact that NIC is a cardinal process in the pathomechanism of late stent thrombosis, little imaging information is available on morphological changes thereof on a short-time interval basis. METHODS: 27 Japanese patients with stable angina pectoris and de novo native coronary artery lesions were enrolled, and 27 lesions (30 implantations) were examined. OCT was performed at weeks 2, 4, 6, 8, and 10 after E-ZES implantation. NIC was examined using cross-sectional OCT images obtained at the 1.0-mm intervals. RESULTS: In total, 621 cross-sectional OCT images, which depicted 7,747 stent struts, were analyzed. The mean percentages of stent strut coverage at weeks 2, 4, 6, 8, and 10 after E-ZES implantation were 12.3, 70.4, 67.9, 86.0, and 99.2%, respectively; a marked increase was found between weeks 2 and 4. The mean thicknesses of the formed neointima were 40.2, 52.1, 48.1, 86.5, and 146.2 µm at respective weeks, with the high-signal and thick neointima (146 µm) at week 10. An intracoronary thrombus was detected in only one stent at week 4. CONCLUSIONS: The full circumferential coverage of the vessel wall by the high-signal neointima was found at as early as week 10 after E-ZES implantation, imparting a surrogate index for vascular healing by NIC.

Physical function and physical activity in hemodialysis patients with peripheral artery disease.

INTRODUCTION: Peripheral artery disease (PAD) is commonly observed in patients undergoing hemodialysis. PAD impairs the vasculature and leads to pathophysiologic changes in the skeletal muscles, causing physical function impairment and physical inactivity in general. However, it is unclear whether PAD adversely affects physical function and physical activity in patients on hemodialysis. METHODS: We performed a cross-sectional study with a retrospective review of the data to determine whether PAD is associated with impaired physical function and physical activity in patients undergoing hemodialysis. The study population comprised 310 patients and 88 healthy subjects. PAD was diagnosed based on an ankle-brachial index of <1.00 in patients on hemodialysis. Measurements of physical function included maximum walking speed, muscle strength in the lower extremities, and balance while standing. FINDINGS: Of the 310 patients, 84 (27.1%) had PAD. When patients undergoing hemodialysis were divided into those without PAD and those with PAD, both groups had poorer physical function and physical activity than the healthy control subjects. After adjustments for potential confounders, it was found that patients on hemodialysis with PAD had slower walking speed, poorer standing balance, and less physical activity than those without PAD. However, there was no significant difference in lower extremity muscle strength between the two groups. DISCUSSION: PAD diagnosed based on an ankle-brachial index of <1.00 was independently associated with impaired physical function and reduced physical activity in patients undergoing hemodialysis.

Phosphoglucomutase activity as a novel biomarker in patients with acute myocardial infarction.

BACKGROUND: Phosphoglucomutase (PGM), a key enzyme in cellular glucose utilization and energy homeostasis, has been reported to show a relationship with oxidative stress. However, the clinical importance of PGM activity has not been investigated in patients with ischemic heart disease (IHD). The aim of the present pilot study was to clarify whether PGM activity has potential as a cardiovascular risk predictor in patients with IHD. METHODS AND RESULTS: The levels of serum PGM activity in 237 patients with IHD (63 patients with acute myocardial infarction (AMI) and 174 patients with stable effort angina pectoris (EAP)) were evaluated. PGM activity was compared with levels of various myocardial, thrombosis, and inflammatory biomarkers on admission. PGM activity in the AMI group was significantly increased relative to that in the EAP group on admission (AMI, 55.5 µmol·min(-1)·L(-1) (U/L); EAP, 14.4 U/L (P<0.001)), and was observed to increase in parallel with well-established myocardial markers (P<0.001). Moreover, PGM activity and the lipid, thrombosis, and inflammatory biomarkers in the AMI group were higher than those in the EAP group. CONCLUSIONS: PGM activity increased with levels of myocardial, thrombosis, and inflammatory biomarkers in patients with AMI, and might be useful in diagnostic applications during the acute phase in patients with AMI.

The T wave inversion score is useful for evaluating the time-course of acute pulmonary embolism.

BACKGROUND: The 12-lead electrocardiogram (ECG) has relatively poor specificity for identifying acute pulmonary embolism (APE). The aim of this study was to investigate ECG abnormalities according to 2 different criteria and their usefulness for assessing changes in APE. METHODS AND RESULTS: Fifty-two APE patients underwent ECG examinations in the acute and chronic phases. ECG abnormalities were assessed according to Stein's criteria (QRS complex abnormalities and T wave inversion in any lead except aV(L), III, aV(R), or V1) and Kosuge's criteria (T wave inversion in any lead except aV(R) or aV(L)). Many patients had electrocardiographic abnormalities in the acute phase, but no specific abnormalities were found. According to Kosuge's criteria, the frequency of T wave inversion was higher than that of abnormal QRS complexes and T wave inversion according to Stein's criteria (P < 0.01). In 20 cases with preclinical ECG records, the time-course of changes in the T wave inversion score (total numbers of T wave inversions per patient) was examined. The peak T wave inversion score was noted at 3 days after onset (P < 0.01). CONCLUSIONS: These results suggest that the T wave inversion score, calculated according to Kosuge's criteria, is useful for predicting the time-course of APE.

Prognosis of hemodialysis patients with progressive aortic stenosis: a prospective cohort study.

BACKGROUND: Whether progressive mild to moderate aortic stenosis in hemodialysis patients influences their prognosis has not been elucidated. This prospective cohort study explored whether progressive aortic stenosis predicted the rate of cardiac events and mortality in those patients. METHODS: A total of 283 consecutive hemodialysis patients (no aortic stenosis, 248; progressive aortic stenosis, 35) underwent echocardiography for assessment of aortic stenosis, with a median follow-up period of 4.1 years. Study endpoints were cardiac events, all-cause mortality, and cardiac death. Kaplan-Meier analysis and multivariate Cox proportional hazard analysis were performed to estimate cardiac events, all-cause mortality, and cardiac death. RESULTS: Cumulative cardiac event rate, all-cause mortality rate, and the rate of cardiac death at 3-year follow-up were 44.9%, 40.5%, and 26.4% in patients with progressive aortic stenosis and 22.1%, 19.0%, and 7.5% in those without aortic stenosis, respectively. Kaplan-Meier analysis demonstrated the cumulative rates of cardiac events and all-cause mortality. And cardiac death was significantly higher in patients with progressive aortic stenosis than in those without aortic stenosis. Multivariate Cox proportional hazard analysis revealed that progressive aortic stenosis was predictive of cardiac events (adjusted hazard ratio 2.47; 95% confidence interval 1.38-4.39) and cardiac death (adjusted hazard ratio 4.21; 95% confidence interval 2.10-8.46). Age, physical activity, C-reactive protein, and serum albumin levels-but not progressive aortic stenosis-predicted all-cause mortality. CONCLUSIONS: The rates of cardiac events and cardiac death were higher in hemodialysis patients with progressive aortic stenosis than in those without aortic stenosis. Furthermore, progressive aortic stenosis predicted cardiac events and cardiac death. Compared with those without aortic stenosis, patients with progressive aortic stenosis had higher all-cause mortality, which was related to their comorbidities.Trial registration This study was retrospectively registered with University Hospital Medical Information Network Clinical Trials Registry (registration number, UMIN 000024023) at September 12th, 2016.

Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown. METHODS: To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37). RESULTS: Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes. CONCLUSION: Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

Effect of erythropoietin on angiogenesis with the increased adhesion of platelets to the microvessels in the hind-limb ischemia model in mice.

Erythropoietin (EPO) has been shown to enhance angiogenesis, but its precise mechanisms of enhancement during ischemia are not fully elucidated. We examined the effect of EPO on blood flow recovery from acute hind-limb ischemia induced by ligation of the femoral artery in male C57Bl/6 mice. The density of microvessels with platelet adhesion in ischemic tissues was assessed by intravital microscopy. Treatment with EPO (100 and 1000 IU/kg, i.p.) restored blood flow in a dose-dependent manner and increased plasma levels of soluble-P-selectin, vascular endothelial growth factor (VEGF), and stromal cell-derived factor (SDF-1). Flow cytometric analysis revealed increased P-selectin expression on platelets in EPO-treated mice compared to PBS-treated mice. Intravital microscopic studies showed that EPO increased density of microvessels with platelet adhesion selectively in the ischemic tissues. Neutralizing antibody against P-selectin reduced the density of microvessels with platelet adhesion enhanced with EPO and impaired blood flow recovery with reductions in VEGF and SDF-1 levels. These results suggest that EPO administration enhances recovery from hind-limb ischemia, and platelet adhesion to the microvessels is a key event to enhance the angiogenesis in the ischemic tissues.

Patient selection and therapeutic strategy for emergency percutaneous cardiopulmonary system in cardiopulmonary arrest patients.

BACKGROUND: To clarify the appropriate application and therapeutic strategy for the percutaneous cardiopulmonary system (PCPS) in patients in cardiopulmonary arrest (CPA), the effects of the duration of cardiopulmonary resuscitation (CPR), diagnosis of underlying diseases, subsequent intervention and complications were retrospectively investigated for the correlation between discharge or death of patients. The patients were treated under an identical therapeutic PCPS protocol. METHODS AND RESULTS: The 69 CPA patients [55 males (78.6%), 14 females; age, 55.0 +/-15.3 years; age range 15-79 years, 50 in-hospital CPA (I-CPA) and 19 out-of-hospital CPA (O-CPA) patients] were treated with emergency PCPS. The mean duration of CPR was 43.6 +/-37.4 min. Of 18 discharged patients (26.1%), 14 had I-CPA and 4 had O-CPA. Significant factors in the discharge of patients were confirmed diagnosis, subsequent treatment and prevention of complications associated with PCPS. CONCLUSIONS: Appropriate patient selection for PCPS in cases of O-CPA is likely to give a similar survival rate as for I-CPA. Patient selection and reversibility of the underlying disease and clinical state after starting PCPS affect the prognosis. Aggressive diagnosis and therapy for the underlying disease and prevention of complications associated with PCPS are essential factors in successful discharge of patients. Patients with an unknown etiology are not expected to fully recover, despite PCPS.

Effect of hypothermia therapy after outpatient cardiac arrest due to ventricular fibrillation.

BACKGROUND: Several investigators have emphasized the positive effect of hypothermia therapy on patients who have suffered from cardiac arrest. Salvaging patients from circulatory collapse is a pivotal task, but it is unclear whether additional hypothermia can practically contribute to an improvement in the neurological outcome. METHODS AND RESULTS: Since December 2005, our hospital has been using hypothermia therapy. Forty-six comatose patients after recovery of spontaneous circulation were consecutively enrolled in the present study. Twenty-five of the enrolled patients received hypothermia therapy and 21 did not because they were treated prior to 2005. The time from collapse to spontaneous circulation (P=0.09), the rates of performance of bystander CPR (P=0.370) and presence of a witnessed collapse (P=0.067) were not significantly different between the recovery group (n=28) and the non-recovery group (n=18). The additional hypothermia therapy was an independent predictor of neurological recovery (P=0.005, OR 6.5, 95%CI 1.74-24.27). The recovery rate was significantly higher in patients who received hypothermia therapy (80%) compared to those who did not (38%). CONCLUSIONS: Hypothermia therapy is very useful for treating patients who have had an out-of-hospital cardiac arrest; it should be induced rapidly and smoothly.

Effects of ezetimibe add-on therapy for high-risk patients with dyslipidemia.

BACKGROUND: Ezetimibe (Zetia) is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, an inhibitor of cholesterol synthesis, is the first-choice drug to reduce low-density lipoprotein-cholesterol (LDL-C) for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-C levels. Because a high dose of statins cause concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-C in high-risk patients with hypercholesterolemia treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-C safely with both monotherapy and combination therapy with statins. RESULTS: To investigate the effect of ezetimibe as "add-on" therapy to statin on hypercholesterolemia, we examined biomarkers and vascular endothelial function in 14 patients with hypercholesterolemia before and after the 22-week ezetimibe add-on therapy. Ezetimibe add-on therapy reduced LDL-C by 24% compared with baseline (p < 0.005), with 13 patients (93%) reaching their LDL cholesterol goals. Of the Ezetimibe add-on therapy significantly improved not only LDL-C, high-density lipoprotein-cholesterol (HDL-C), and apolipoprotein (apo)B levels, but also reduced levels of triglyceride (TG), the ratio of LDL/HDL-C, the ratio of apoB/apoA-I, and a biomarker for oxidative stress (d-ROMs). Furthermore, ezetimibe add-on therapy improved vascular endothelial function in high-risk patients with hypercholesterolemia. CONCLUSION: In conclusion, ezetimibe as add-on therapy to statin might be a therapeutic good option for high-risk patients with atherosclerosis.

Heat-shock protein 72 promotes platelet aggregation induced by various platelet activators in rats.

Increase of thrombus in the coronary arteries is positively correlated with the level of heat-shock protein 72 (HSP72) in the blood of patients with acute myocardial infarction (AMI). Platelet aggregation participates in thrombus formation on ruptured plaque in AMI. In this study, we aimed to clarify the role of HSP72 in thrombus formation by evaluating the effects of HSP72 on platelet aggregation. Platelet aggregation activities were measured in platelet-rich plasma obtained from male Sprague-Dawley rats with or without the platelet activators, such as adenosine diphosphate (ADP), collagen, thrombin receptor-activating peptide-6 (TRAP-6), ristocetin, and arachidonic acid. Changes in aggregation were estimated by the co-addition of recombinant HSP72 and anti-HSP72 antibodies. Our results showed that addition of HSP72 increased platelet aggregation in the presence of low concentrations of ADP, collagen, TRAP-6, ristocetin, and arachidonic acid. Increased platelet aggregation stimulated by ADP and HSP72 was reduced by the co-addition of anti-HSP72 antibodies. Thus, these findings suggested that HSP72 was released extracellularly in response to stress, promoting thrombus formation and AMI. Additionally, treatment with anti-HSP72 antibodies may control platelet aggregation induced by extracellular HSP72.

Serum levels of interleukin-10 on admission as a prognostic predictor of human fulminant myocarditis.

OBJECTIVES: We assessed the significance of serum cytokine levels in patients with fulminant myocarditis. BACKGROUND: Although many investigations have demonstrated the crucial role of cytokines in the development of myocarditis, it remains uncertain whether serum levels of cytokines enable one to predict the prognosis of human myocarditis, especially concerning cardiogenic shock (CS) requiring a mechanical cardiopulmonary support system (MCSS). METHODS: We studied 22 consecutive patients with fulminant myocarditis and compared them with 15 patients with acute myocardial infarction (AMI) requiring MCSS. The patients with myocarditis were classified into three groups: eight patients with CS requiring MCSS on admission (group 1); six patients who unexpectedly lapsed into CS requiring MCSS more than two days after catecholamine had been initiated (group 2); and eight patients without MCSS (group 3). Furthermore, 14 patients with myocarditis requiring MCSS were divided into a fatal group (n = 5) and a survival group (n = 9). Biochemical markers, including serum cytokine levels and hemodynamic variables on admission, were analyzed. RESULTS: Serum levels of interleukin (IL)-10 and tumor necrosis factor-alpha, but not other cytokines, were significantly higher in myocarditis than in AMI. Only serum levels of IL-10 were significantly higher in group 1 and 2 than in group 3 (49.1 +/- 37.5/20.7 +/- 17.6 pg/ml vs. 2.4 +/- 1.1 pg/ml; p = 0.0008/0.0012). Serum IL-10 levels were also significantly higher in the fatal group than in the survival group with myocarditis (74.0 +/- 27.0 pg/ml vs. 16.4 +/- 8.8 pg/ml; p = 0.003). CONCLUSIONS: Serum IL-10 levels on admission enabled one to predict subsequent CS requiring MCSS and mortality of fulminant myocarditis patients.

Clinical Characteristics of Patients on Hemodialysis With Peripheral Arterial Disease.

Patients on hemodialysis (HD; n = 210) were examined for peripheral arterial disease (PAD) using ankle-brachial index (ABI) and toe-brachial index (TBI). The prevalence of PAD was 38.1%. Among patients with PAD, 87.5% were newly diagnosed with PAD, 42.5% were diagnosed with TBI <0.6 despite ABI ≥ 0.9, and 68.7% had no lower limb symptoms. In patients with PAD, the prevalence rate of cerebrovascular disease was 36.3%, coronary artery disease was 42.5%, spinal stenosis was 33.2%, and vertebral fracture 15.0% and was significantly higher than those of the non-PAD patients. Low high-density lipoprotein cholesterol was the most important biomarker among patients with PAD. PAD has been underdiagnosed and untreated in patients on HD because most patients do not have symptoms that could be due to diabetic neuropathy or have insufficient daily activity to experience exertional leg symptoms. Screening for PAD using the ABI and TBI increased diagnostic efficiency in patients on HD and may lead to effective early treatments, including pharmacotherapy, revascularization therapy, and exercise rehabilitation to avoid the worst possible scenario such as lower limb amputation, cardiovascular event, and death.

The role of neural crest and epicardium-derived cells in conduction system formation.

During cardiac development the heart tube loops and is septated into a four-chambered structure. The initial peristaltic contraction of the primitive myocardium is replaced by a system of working myocardium and a myocardial-derived central and peripheral conduction system. The genes guiding this differentiation process are still under investigation and it has yet to be decided whether we are dealing with a recruitment or a specification model. We have shown that the complicated looping process of the heart tube brings together the essential parts of the sinoatrial and primary ring myocardium, that are the embryonic precursors of the definitive conduction system. From our studies it is evident that during development there are sinoatrial tracts that run between the sinoatrial and the atrioventricular node as well as tracts surrounding the pulmonary veins and the coronary sinus. Furthermore, we show that both in the chicken and mouse embryo neural crest cells reach the confinement of the central conduction system through the inflow and outflow tract. For the Purkinje system there is a close approximation with the epicardium-derived cells. We postulate that both extracardiac-derived cell types have an influence on the differentiation of the definitive conduction system.

Changing intracellular compartmentalization of beta-galactosidase in the ROSA26 reporter mouse during embryonic development: a light- and electron-microscopic study.

The beta-geo (LacZ) reporter gene encodes for beta-galactosidase (beta-gal) in all cells of the ROSA26 mouse during embryonic development. As such, beta-gal activity constitutes an excellent marker for in situ labeling of expressing cells. However, the intracellular distribution of beta-gal differs between cells, and changes during embryonic development. Therefore, we studied LacZ-encoded beta-gal using light and electron microscopy in the heart, lung, liver, and small intestine on days 13 and 16 of gestation, and the kidney on day 16 of gestation in ROSA26 mice. The Bluo-gal method was carried out under standardized conditions, including fixation, washing, and incubation procedures. Intracellular beta-gal staining is encountered in a combination of membranous compartments, including the nuclear envelope, the endoplasmic reticulum, and the plasma membrane. Its exact localization depends on the cell type and is regulated during development. Therefore, one must take the compartmental transition of intracellular beta-gal staining into consideration when interpreting results obtained from experiments using ROSA26 mice.