Stem cell therapy enhances electrical viability in myocardial infarction

Clinical studies suggest increased arrhythmia risk associated with cell therapy for myocardial infarction (MI); however, the underlying mechanisms are poorly understood. We hypothesize that the degree of electrical viability in the infarct and border zone associated with skeletal myoblast (SKMB) or mesenchymal stem cell (MSC) therapy will determine arrhythmia vulnerability in the whole heart. Within 24 h of LAD ligation in rats, 2 million intramyocardially injected SKMB (n=6), intravenously infused MSC (n=7), or saline (n=7) was administered. One month after MI, cardiac function was determined and novel optical mapping techniques were used to assess electrical viability and arrhythmia inducibility. Shortening fraction was greater in rats receiving SKMB (17.8%+/-5.3%, p=0.05) or MSC (17.6%+/-3.0%, p<0.01) compared to MI alone (10.1%+/-2.2%). Arrhythmia inducibility score was significantly greater in SKMB (2.8+/-0.2) compared to MI (1.4+/-0.5, p=0.05). Inducibility score for MSC (0.6+/-0.4) was significantly lower than SKMB (p=0.01) and tended to be lower than MI. Optical mapping revealed that MSC therapy preserved electrical viability and impulse propagation in the border zone, but SKMB did not. In addition, injected SKMBs were localized to discrete cell clusters where connexin expression was absent. In contrast, infused MSCs engrafted in a more homogeneous pattern and expressed connexin proteins. Even though both MSC and SKMB therapy improved cardiac function following MI in rat, SKMB therapy significantly increased arrhythmia inducibility while MSC therapy tended to lower inducibility. In addition, only MSC therapy was associated with enhanced electrical viability, diffuse engraftment, and connexin expression, which may explain the differences in arrhythmia inducibility.     

Cardiac effects of MDMA on the metabolic profile determined with 1H-magnetic resonance spectroscopy in the rat

Despite the potential for deleterious (even fatal) effects on cardiac physiology, 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) abuse abounds driven mainly by its euphoric effects. Acute exposure to MDMA has profound cardiovascular effects on blood pressure and heart rate in humans and animals. To determine the effects of MDMA on cardiac metabolites in rats, MDMA (0, 5, or 10 mg/kg) was injected every 2 h for a total of four injections; animals were sacrificed 2 h after the last injection (8 h drug exposure), and their hearts removed and tissue samples from left ventricular wall dissected. High resolution magic angle spinning proton magnetic resonance spectroscopy ((1)H-MRS) at 11.7 T, a specialized version of MRS aptly suited for analysis of semi-solid materials such as intact tissue samples, was used to measure the cardiac metabolomic profile, including alanine, lactate, succinate, creatine, and carnitine, in heart tissue from rats treated with MDMA. MDMA effects on MR-visible choline, glutamate, glutamine, and taurine were also determined. Body temperature was measured following each MDMA administration and serotonin and norepinephrine (NE) levels were measured by high pressure liquid chromatography (HPLC) in heart tissue from treated animals. MDMA significantly and dose-dependently increased body temperature, a hallmark of amphetamines. Serotonin, but not NE, levels were significantly and dose-dependently decreased by MDMA in the heart wall. MDMA significantly altered the MR-visible profile with an increase in carnitine and no change in other key compounds involved in cardiomyocyte energy metabolomics. Finally, choline levels were significantly decreased by MDMA in heart. The results are consistent with the notion that MDMA has significant effects on cardiovascular serotonergic tone and disrupts the metabolic homeostasis of energy regulation in cardiac tissue, potentially increasing utilization of fatty acid metabolism. The contributions of serotonergic signaling on MDMA-induced changes in cardiac metabolism remain to be determined.     

Rectal prolapse secondary to antibiotic-associated colitis in a dog

Many animals with rectal prolapse have an antecedent history of dyschezia and tenesmus associated with colonic inflammatory disease. However, it seems that there are no reports of rectal prolapse concurrent with antibiotic-associated colitis in the veterinary literature. A 3-month-old male cross-bred dog presented with a history of recurrent episodes of rectal prolapse following the administration of oral cephalexin. The rectal prolapse was corrected surgically. Based on the dog's recent history of antibiotic use, the sudden onset of bloody diarrhoea, tenesmus and subsequent rectal prolapse, antibiotic-associated diarrhoea was considered as the primary cause of rectal prolapse in this case. Clostridium perfringens were isolated from a bacteriological stool culture. The dog was treated with amoxicillin for three consecutive weeks. There were no detectable signs of diarrhoea or a recurrence of rectal prolapse during the 2-month follow-up period.     

Neurophysiologic assessment of brain maturation after an 8-week trial of skin-to-skin contact on preterm infants

ObjectiveSkin-to-skin contact (SSC) promotes physiological stability and interaction between parents and infants. Analyses of EEG-sleep studies can compare functional brain maturation between SSC and non-SSC cohorts.MethodsSixteen EEG-sleep studies were performed on eight preterm infants who received 8 weeks of SSC, and compared with two non-SSC cohorts at term (N = 126), a preterm group corrected to term age and a full-term group. Seven linear and two complexity measures were compared (Mann–Whitney U test comparisons p < .05).ResultsFewer REMs, more quiet sleep, increased respiratory regularity, longer cycles, and less spectral beta were noted for SSC preterm infants compared with both control cohorts. Fewer REMs, greater arousals and more quiet sleep were noted for SSC infants compared with the non-SSC preterms at term. Three right hemispheric regions had greater complexity in the SSC group. Discriminant analysis showed that the SSC cohort was closer to the non-SSC full-term cohort.ConclusionsSkin-to-skin contact accelerates brain maturation in healthy preterm infants compared with two groups without SSC.SignificanceCombined use of linear and complexity analysis strategies offer complementary information regarding altered neuronal functions after developmental care interventions. Such analyses may be helpful to assess other neuroprotection strategies.     

Managing Philadelphia chromosome-positive acute lymphoblastic leukemia: role of tyrosine kinase inhibitors

Before the introduction of tyrosine kinase inhibitors, the prognosis for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was poor. The treatment of choice, stem cell transplantation, is a potentially curative option, but it is available only for a minority of patients and is associated with significant risk of morbidity and mortality. Although imatinib is largely effective, a substantial proportion of patients become resistant or intolerant to it. The activity of imatinib may be enhanced by coadministration with chemotherapy; such treatment is effective in many patients. Dasatinib is established as a second-line treatment in patients with resistance to or intolerance of imatinib. Recent data suggest that dasatinib, either alone or in combination with chemotherapy, has utility as first-line therapy. Dasatinib is more potent than imatinib, is less susceptible to drug-resistance mechanisms, and has been shown to penetrate the blood-brain barrier, making it potentially effective for treating central nervous system disease. Patients who relapse during treatment with dasatinib frequently carry the T315I mutation of BCR-ABL. Future regimens combining dasatinib with an agent able to inhibit this mutation may further improve outcome.     

New treatments and strategies in acute myeloid leukemia

Despite considerable progress in the treatment of acute myeloid leukemia in the past several decades, the prognosis of the majority of patients with this disease remains guarded. Advances in supportive care and better characterization of disease subsets through cytogenetics and molecular analysis have led to significant success in treating specific subsets of patients, such as those with acute promyelocytic leukemia and core binding factor leukemias, particularly among the younger patients who are able to better tolerate the effects of cytotoxic chemotherapy. However, overall, only about 40% of younger patients and <10% of older patients with this disease are alive at 5 years. Current research is focusing on the identification of new cellular targets amenable to specific inhibitors, designing the best strategies for combining these novel agents with traditional chemotherapy regimens, and determining prognostic indicators that may allow us to better stratify therapy.     

**504 Detection of Cytogenetic Abnormalities Associated with Outcome Differences in Acute Myeloid Leukemia Using Array-Based Comparative Genomic Hybridization (aCGH) Analysis

The aCGH analysis of 48 patients treated uniformly with Idarubicin and Cytarabine identified loss of a 155 kilobase region on 5q33.3 associated with achievement of CR (p<0.05) and loss of 17p11.2-q11.1 associated with poor overall survival (Kaplan-Meier analysis, p=0.0096).

Full Abstract: Background

Recent availability of high-resolution analysis by aCGH technology has facilitated rapid detection of cytogenetic abnormalities previously undetected by the conventional G-banded karyotyping. We determined whether specific cytogenetic abnormalities, as detected by the aCGH analysis, are associated with differences in clinical outcomes in a uniformly treated group of AML.

Methods

A total of 111 patients with newly diagnosed AML (Median age: 55 years; range, 22 to 73 years) were enrolled in the study. All patients were treated with Idarubicin 12 mg/m2 IV daily × 3 days and Cytarabine 1.5 g/m2 by continuous IV infusion daily × 4 days (3 days in patients older than 60). The diagnostic bone marrow samples from 48 of these patients were analyzed by aCGH using a 44K CGH array with a spatial resolution of 50-75 kb (Agilent Inc, Santa Clara, CA). Correlation of aCGH-detected

Results

The comparison of aCGH findings between the patients achieving CR and the resistant patients showed significant association of loss of a 155 kilobase region on 5q33.3 with achievement of CR (p<0.05). Additionally, the loss of 17p11.2-q11.1 spanning 3194 kilobases was associated with poor overall survival (Kaplan-Meier analysis, p=0.0096). This deleted region involved 342 genes and 12 microRNAs. Conventional karyotyping detected loss of 17p in 10/48 (21%) patients, whereas the aCGH analysis

Conclusion

The aCGH analysis indicates that the loss of 5q33.3 is associated with achievement of complete remission and the loss of 17p11.2-q11.1 is associated with poor overall survival in AML patients treated with Idarubicin and Cytarabine.

     

High prevalence of chronic kidney disease in Iran: a large population-based study

Background  

Chronic kidney disease (CKD) is a global public health threat, associated with an alarming increase in morbidity and mortality. The importance is the worldwide increase in its incidence and prevalence.     

The Impact of Dose and Solubility of Additives on the Release from HPMC Matrix Tablets—Identifying Critical Conditions

Purpose  The dissolution of HPMC matrix tablets containing different amounts of highly soluble (mannitol) or poorly soluble (dicalcium phosphate, DCP) was studied to deduce the parameters critical to release robustness. Methods  The release of HPMC and additives was studied using a modified USP II method at two paddle stirring rates, 50 and 125 rpm, at HPMC content varying from 15% to 100%. Results  At HPMC contents between 30% and 35% a critical point was identified and found crucial to the release from the HPMC/mannitol tablets. Below this point the matrix rapidly disintegrated in a non robust manner. At higher HPMC contents the mannitol release became increasingly diffusion controlled with maintained matrix integrity. The release robustness was lower for HPMC/DCP than HPMC/mannitol tablets at high HPMC contents, however, lacking critical points. The critical point was interpreted as the percolation threshold for HPMC and differences explained in terms of water transport into the matrix. Conclusion  The release robustness was lower for formulations with additives of low solubility having an erosion controlled release than for additives with higher solubility and a diffusion controlled release. However, for additives creating a steep osmotic pressure gradient, an HPMC content above the percolation threshold becomes vital for maintaining the release robustness.