MR Imaging–Detected Carotid Plaque Hemorrhage Is Stable for 2 Years and a Marker for Stenosis Progression

BACKGROUND AND PURPOSE:MR imaging–detected carotid plaque hemorrhage is associated with an increased risk of recurrent ischemic cerebrovascular events and could be an indicator of disease progression; however, there are limited data regarding the dynamics of the MR imaging–detected carotid plaque hemorrhage signal. We assessed the temporal change of this signal and its impact on carotid disease progression.MATERIALS AND METHODS:Thirty-seven symptomatic patients with 54 carotid stenoses of >30% on sonography underwent serial MR imaging during 24 months. A signal-intensity ratio of >1.5 between the carotid plaque and adjacent muscle was defined as plaque hemorrhage, and a change in signal-intensity ratio of >0.31 between time points was considered significant. Sixteen patients underwent ≥2 carotid sonography scans to determine the peak systolic velocities and degree of stenosis with time.RESULTS:Of the 54 carotids, 28 had the presence of hyperintense signal on an MR imaging sequence (PH+) and 26 had the absence of hyperintense signal on an MR imaging sequence (PH−) at baseline. The signal-intensity ratio was stable in 33/54 carotid plaques, but 39% showed a change. Plaque hemorrhage classification did not change in 87% of carotid plaques, but 4 became PH+, and 3, PH−. As a group, PH+ carotids did not change significantly in signal-intensity ratio (P = .585), whereas PH− showed an increased signal-intensity ratio at 24.5 months (P = .02). In PH+ plaques, peak systolic velocities significantly increased by 22 ± 39.8 cm/s from baseline to last follow-up sonography (Z = 2.427, P = .013).CONCLUSIONS:During 2 years, MR imaging–detected carotid plaque hemorrhage status remained stable in most (87%) cases with 4 (7%) incident plaque hemorrhages. PH+ plaques were associated with increased flow velocity during the follow-up period.

Currently, the degree of ICA stenosis is the principal criterion on the basis of which the decision for carotid intervention is made. This is based on strong evidence from randomized controlled trials that carotid endarterectomy reduces stroke risk in patients with severe carotid artery stenosis.^1,2 However, those studies also showed that a significant proportion of patients with symptomatic carotid disease will not have a recurrence. Subsequently, much research is focused on the identification of high-risk subgroups,³ especially for those with moderate or asymptomatic carotid stenosis.Plaque hemorrhage (PH) is implicated in carotid plaque vulnerability⁴ and is detectable by MR imaging.^5,6 A recent longitudinal follow-up study and meta-analysis⁷ demonstrated that MR imaging–detected plaque hemorrhage (MR imaging-PH) strongly predicts recurrent ischemic events. The MR imaging-PH signal seems to be stable for 12 months,⁸ but stability of MR imaging-PH features beyond 12 months remains unclear. Knowledge of longer term stability of MR imaging-PH would be helpful if it is to be used to assist decision-making in interventions and to determine the need for follow-up imaging.Plaque volume progression on sonography recently has been shown to predict cerebrovascular events⁹; however, this measure was not used in the current study. Carotid stenosis progression has been suggested to be a better predictor of subsequent TIA/stroke than a single measurement.¹⁰ Although general carotid sonography surveillance may not be cost-effective,¹¹ this situation may well be different for a subgroup of patients with a higher risk for stenosis progression. It is conceivable that MR imaging-PH is also an indicator of disease progression¹² and, therefore, may be useful in this regard.The aim of this study was to determine MR imaging signal changes in the carotid artery plaque during 2 years and whether the presence of MR imaging-PH at baseline is associated with stenosis progression.     

Differentiation of Wharton's jelly mesenchymal stem cells into neurons in alginate scaffold

Alginate scaffold has been considered as an appropriate biomaterial for promoting the differentiation of embryonic stem cells toward neuronal cell lineage. We hypothesized that alginate scaffold is suitable for culturing Wharton's jelly mesenchymal stem cells(WJMSCs) and can promote the differentiation of WJMSCs into neuron-like cells. In this study, we cultured WJMSCs in a three-dimensional scaffold fabricated by 0.25% alginate and 50 m M Ca Cl2 in the presence of neurogenic medium containing 10 μM retinoic acid and 20 ng/m L basic fibroblast growth factor. These cells were also cultured in conventional two-dimensional culture condition in the presence of neurogenic medium as controls. After 10 days, immunofluorescence staining was performed for detecting β-tubulin(marker for WJMSCs-differentiated neuron) and CD271(motor neuron marker). β-Tubulin and CD271 expression levels were significantly greater in the WJMSCs cultured in the three-dimensional alginate scaffold than in the conventional two-dimensional culture condition. These findings suggest that three-dimensional alginate scaffold cell culture system can induce neuronal differentiation of WJMSCs effectively.     

12 hours after cerebral ischemia is the optimal time for bone marrow mesenchymal stem cell transplantation

Cell therapy using stem cell transplantation against cerebral ischemia has been reported. However, it remains controversial regarding the optimal time for cell transplantation and the transplantation route. Rat models of cerebral ischemia were established by occlusion of the middle cerebral artery. At 1, 12 hours, 1, 3, 5 and 7 days after cerebral ischemia, bone marrow mesenchymal stem cells were injected via the tail vein. At 28 days after cerebral ischemia, rat neurological function was evaluated using a 6-point grading scale and the pathological change of ischemic cerebral tissue was observed by hematoxylin-eosin staining. Under the fluorescence microscope, the migration of bone marrow mesenchymal stem cells was examined by PKH labeling. Caspase-3 activity was measured using spectrophotometry. The optimal neurological function recovery, lowest degree of ischemic cerebral damage, greatest number of bone marrow mesenchymal stem cells migrating to peri-ischemic area, and lowest caspase-3 activity in the ischemic cerebral tissue were observed in rats that underwent bone marrow mesenchymal stem cell transplantation at 12 hours after cerebral ischemia. These findings suggest that 12 hours after cerebral ischemia is the optimal time for tail vein injection of bone marrow mesenchymal stem cell transplantation against cerebral ischemia, and the strongest neuroprotective effect of this cell therapy appears at this time.     

Hb Dhonburi (Neapolis) [beta126(H4)Val-->Gly] identified in a family from northern Iran

Thalassemias are the most common hereditary diseases in Iran, resulting from synthesis defects in one or more hemoglobin (Hb) subunits. The majority of patients suffer from beta-thalassemia (thal), but cases with microcytic hypochromic anemia and normal electrophoretic patterns are suspected to have alpha- or silent beta-thal. A family from the northern part of Iran, an area highly prevalent for thalassemias, was referred to us for prenatal diagnosis. The hematological data of the father indicated a pattern of beta-thal minor. Reverse hybridization analysis for the most common beta-globin mutations identified IVS-II-1 (G-->A) in the heterozygous state. The maternal laboratory data indicated a case more compatible with alpha-thal. Iron deficient anemia was ruled out, and common alpha-thal point mutations and deletions were investigated. As no mutation was detected, chain synthesis was performed and showed an alpha/beta chain ratio of 2.1, that was in the range of beta-thal minor. DNA sequencing of the entire beta-globin gene identified a heterozygous GTG-->GGG (Val-->Gly) mutation at codon 126, also known as Hb Dhonburi (Neapolis). Prenatal diagnosis of the fetal DNA showed the absence of the IVS-II-1 and codon 126 anomalies. This result demonstrates the importance of screening of individuals with mild microcytic hypochromic anemia for both alpha- and silent beta-thal mutations.     

Optimal β-blocker for prevention of atrial fibrillation after on-pump coronary artery bypass graft surgery: Carvedilol versus metoprolol

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia after coronary artery bypass graft (CABG) surgery. It has been shown that prophylactic oral beta-blocker administration reduces the incidence of post-CABG AF. However, the optimal beta-blocker has not been identified. OBJECTIVE: This study sought to determine whether oral carvedilol (with its unique anti-inflammatory and antioxidant properties) is more effective than oral metoprolol for prevention of AF after CABG surgery. METHODS: Between April 2006 and December 2006, 120 patients (63 men, mean age 61 +/- 9.4 years) who were scheduled to undergo their first on-pump CABG were enrolled in this study. The patients were randomized in a prospective 1:1 manner to receive either oral carvedilol (n = 60) or oral metoprolol (n = 60). The end point of the study was the occurrence of the new-onset AF during the first 5 days after CABG. RESULTS: AF occurred in 29 of 120 patients (24.0%). The incidence of postoperative AF was 15.0% (9 of 60) in the carvedilol group and 33% (20 of 60) in the metoprolol group (P = .022). The carvedilol group was treated with mean daily dose of 46 +/- 9 mg and metoprolol group with mean daily dose of 93 +/- 11 mg. There were no differences between the study groups regarding any known preoperative, perioperative, or postoperative characteristics (all values were P >.05). No significant adverse effect was observed in either group. CONCLUSION: This prospective study suggested that oral carvedilol is more effective than oral metoprolol in the prevention of AF after on-pump CABG. It is well tolerated when started before and continued after the surgery. However, further prospective studies are needed to clarify this issue.     

Adult-onset deletion of Pten increases islet mass and beta cell proliferation in mice

Aims/hypothesis

Adult beta cells have a diminished ability to proliferate. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that antagonises the function of the mitogenic phosphatidylinositol 3-kinase (PI3K) pathway. The objective of this study was to understand the role of PTEN and PI3K signalling in the maintenance of beta cells postnatally.

Methods

We developed a Pten ^lox/lox; Rosa26 ^lacZ; RIP-CreER ⁺ model that permitted us to induce Pten deletion by treatment with tamoxifen in mature animals. We evaluated islet mass and function as well as beta cell proliferation in 3- and 12-month-old mice treated with tamoxifen (Pten deleted) vs mice treated with vehicle (Pten control).

Results

Deletion of Pten in juvenile (3-month-old) beta cells significantly induced their proliferation and increased islet mass. The expansion of islet mass occurred concomitantly with the enhanced ability of the Pten-deleted mice to maintain euglycaemia in response to streptozotocin treatment. In older mice (>12 months of age), deletion of Pten similarly increased islet mass and beta cell proliferation. This novel finding suggests that PTEN-regulated mechanisms may override the age-onset diminished ability of beta cells to respond to mitogenic stimulation. We also found that proteins regulating G1/S cell-cycle transition, such as cyclin D1, cyclin D2, p27 and p16, were altered when PTEN was lost, suggesting that they may play a role in PTEN/PI3K-regulated beta cell proliferation in adult tissue.

Conclusions/interpretation

The signals regulated by the PTEN/PI3K pathway are important for postnatal maintenance of beta cells and regulation of their proliferation in adult tissues.     

Chemical induction of hepatic apoptosis in rodents

The urge of identifying new pharmacological interventions to prevent or attenuate liver injury is of critical importance and needs an expanded experimental toolbox. Hepatocyte injury and cellular death is a prominent feature behind the pathology of liver diseases. Several research activities focused on identifying chemicals and hepatotoxicants that induce cell death by apoptosis, in addition to presenting its corresponding signaling pathway. Although such efforts provided further understanding of the mechanisms of cell death, it has also raised confusion concerning identifying the involvement of several modes of cell death including apoptosis, necrosis and fibrosis. The current review highlights the ability of several chemicals and potential hepatotoxicants to induce liver damage in rodents by means of apoptosis while the probable involvement of other modes of cell death is also exposed. Thus, several chemical substances including hepatotoxins, mycotoxins, hyperglycemia inducers, metallic nanoparticles and immunosuppressant drugs are reviewed to explore the hepatic cytotoxic spectrum they could exert on hepatocytes of rodents. In addition, the current review address the mechanism by which hepatotoxicity is initiated in hepatocytes in different rodents aiding the researcher in choosing the right animal model for a better research outcome.