Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.     

Cholestasis induces apoptosis in mice cardiac cells: the possible role of nitric oxide and oxidative stress

Background/Aims: Acute cholestasis is associated with cardiovascular complications. The purpose of the present study was to investigate the effect of cholestasis on heart apoptosis and the involvement of nitric oxide (NO) and oxidative stress in the possible altered apoptosis of cholestatic hearts. Methods: Cholestasis was induced by bile duct–ligation, and sham‐operated mice served as controls. Three days after the surgery, heart tissues were evaluated for apoptosis and the level of malondialdehyde (MDA), and the activities of catalase (CAT), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) have been studied in cardiac tissues. The role of treatment with l ‐NAME, a non‐selective inhibitor of NO synthase, or with d ‐NAME, an inactive isomer of l ‐NAME, on cholestatic and sham cardiac apoptosis, level of MDA and CAT, SOD and GSHPx activities was also investigated. The content of NO in cardiac tissue was also determined. Results: Cholestatic hearts showed structural abnormalities and increased apoptosis compared with sham hearts. Treatment with l ‐NAME, but not d ‐NAME, improved both structural abnormalities and enhanced apoptosis of cholestatic hearts. Cholestatic hearts also had an increased level of MDA and decreased activities of CAT and GSHPx, which were not modified by d ‐NAME treatment. By l ‐NAME treatment, the level of MDA decreased and activities of CAT, GSHPx and SOD increased in BDL mice. The content of NO was higher in cholestatic cardiac tissue, which was decreased by l ‐NAME treatment. Conclusion: In conclusion, apoptosis in cholestatic heart might have occurred because of NO overproduction, which could induce oxidative stress in the heart of cholestatic mice.     

Risk factors for rectal colonization with vancomycin-resistant enterococci in Shiraz, Iran.

OBJECTIVES: In order to determine the risk factors for rectal colonization with vancomycin-resistant enterococci (VRE) at the Shiraz Namazi Hospital, we performed a nested case-control study. METHODS: From December 2003 to July 2004 rectal swabs were taken from 700 randomly selected hospitalized patients every 5 days. RESULTS: A total of 99 of the 700 patients (14%) were colonized with VRE (cases) and 59 patients were colonized with vancomycin-sensitive strains (VSE), serving as controls. In the univariate analysis, history of antibiotic use (p=0.04), underlying disease (p=0.013), hemodialysis (p=0.03), use of third generation cephalosporins (p=0.04), use of vancomycin (p=0.04), and duration of vancomycin therapy longer than 7 days (p=0.02) were significantly associated with VRE colonization. In a multivariate analysis, underlying disease and the duration of vancomycin use longer than 7 days were independently associated with VRE colonization. CONCLUSION: Our study, the first on VRE carriage in Iran, demonstrates that VRE prevalence is high in Shiraz and confirms earlier observations in other countries. The identified risk factor 'use of vancomycin longer than 7 days' may be avoidable, indicating a feasible intervention strategy in the control of VRE.     

Determination of sensitivity and specificity of a novel gene dosage assay for prenatal screening of trisomy 21 syndrome

ObjectiveTo compare the gene dosage results achieved by a novel multiplex quantitative assay with cytogenetic and quantitative fluorescent polymerase chain reaction (QF-PCR) analysis for prenatal screening of trisomy 21 syndrome on corresponding fetal samples.Design and methodsFetal samples (n = 134) were collected from pregnant women considered high risk for having trisomy 21 affected fetus. Cytogenetic analysis and QF-PCR were performed. Then, the relative gene dosage of DSCAM and DYRK1A2 genes was determined on corresponding samples using comparative delta cycle of threshold (ΔC_T) method.ResultsThe mean gene dosage ratio was 1.55 ± 0.11 (95% CI:1.51–1.58) in trisomy 21 cases and 1.01 ± 0.12 (95% CI:0.98–1.03) in normal samples (p value < 0.001). The results were in agreement to the results of cytogenetic and QF-PCR analysis with the overall specificity of 0.96 (95% CI:0.91–0.98) and the sensitivity of 0.80 (95% CI:0.49–0.94).ConclusionsThis gene dosage assay is appropriate for the screening of high risk pregnant women and is readily amenable to automation.     

Does lowering pulmonary arterial pressure eliminate severe functional tricuspid regurgitation? Insights from pulmonary thromboendarterectomy

OBJECTIVES: Because pulmonary thromboendarterectomy (PTE) can result in an immediate reduction in pulmonary artery (PA) pressure, we sought to evaluate the effect of PTE on severe tricuspid regurgitation (TR) without tricuspid annuloplasty. BACKGROUND: Few data exist regarding the frequency and magnitude of functional TR improvement after reduction in PA pressure. METHODS: We identified 27 patients with severe TR, defined by a regurgitant index (RI) >33%, who underwent PTE. The RI, tricuspid annular diameter (TAD), apical displacement of leaflet coaptation, and estimated PA systolic pressure were determined on pre- and post-PTE echocardiograms. Patients were stratified based on resolution (RI < or =33%) or persistence (RI >33%) of severe TR. RESULTS: Comparing pre- and post-PTE echocardiography results, severe TR resolved in 19 of 27 (70%) patients. This group had a more effective PA systolic pressure reduction after PTE (49 +/- 20 mm Hg vs. 32 +/- 16 mm Hg by echocardiography, p = 0.075, and 37 +/- 16 mm Hg vs. 16 +/- 13 mm Hg by catheter measurement, p = 0.004). No difference was observed in TAD, apical displacement of the tricuspid valve, or other features compared with the group with persistent severe TR. There was a trend toward longer hospital stays in the group with persistent severe TR (19 +/- 15 days vs. 14 +/- 9 days; p = 0.55). CONCLUSIONS: After significant PA pressure reduction by PTE, severe functional TR with a dilated annulus may improve without annuloplasty despite dilated tricuspid annulus diameters.     

Hyperbaric oxygen therapy for severe acute pancreatitis

Despite improvements in the supportive management of severe acute pancreatitis over the last decade, the morbidity and mortality rate remains high. The main feature of this condition is pancreatic necrosis leading to sepsis, with both localized and systemic inflammatory response syndromes. Early pathophysiological changes of the pancreas include alterations in microcirculation, ischemia reperfusion injury, and leukocyte and cytokine activation. The efficacy of hyperbaric oxygen (HBO) therapy in improving these pathophysiological disturbances is documented for various conditions. However, its effect in the treatment of severe acute pancreatitis is undetermined. This report documents the case of a 56-year-old woman presenting with severe acute pancreatitis treated by HBO therapy. The severity of disease was based on an Acute Physiology and Chronic Health Evaluation (APACHE II) illness grading score of 11 and a Baltazar based computed tomography severity index (CTSI) score of 9. Administration of 100% oxygen was commenced within 72 h of presentation at a pressure of 2.5 atmospheres for 90 min and given twice daily for a total of 5 days. Therapy was well tolerated with improvements in APACHE II and CTSI grading scores. HBO therapy for severe acute pancreatitis appeared to be safe and may have a role in improving treatment outcomes. Further study is required.     

Robust conversion of marrow cells to skeletal muscle with formation of marrow-derived muscle cell colonies: a multifactorial process

OBJECTIVE: Murine marrow cells are capable of repopulating skeletal muscle fibers. A point of concern has been the "robustness" of such conversions. We have investigated the impact of type of cell delivery, muscle injury, nature of delivered cell, and stem cell mobilizations on marrow-to-muscle conversion. METHODS: We transplanted green fluorescence protein (GFP)-transgenic marrow into irradiated C57BL/6 mice and then injured anterior tibialis muscle by cardiotoxin. One month after injury, sections were analyzed by standard and deconvolutional microscopy for expression of muscle and hematopoietic markers. RESULTS: Irradiation was essential to conversion, although whether by injury or induction of chimerism is not clear. Cardiotoxin- and, to a lesser extent, PBS-injected muscles showed significant number of GFP(+) muscle fibers, while uninjected muscles showed only rare GFP(+) cells. Marrow conversion to muscle was increased by two cycles of G-CSF mobilization and to a lesser extent by G-CSF and steel or GM-CSF. Transplantation of female GFP to male C57BL/6 and GFP to ROSA26 mice showed fusion of donor cells to recipient muscle. High numbers of donor-derived muscle colonies and up to 12% GFP(+) muscle cells were seen after mobilization or direct injection. These levels of donor muscle chimerism approach levels that could be clinically significant in developing strategies for the treatment of muscular dystrophies. CONCLUSION: In summary, the conversion of marrow to skeletal muscle cells is based on cell fusion and is critically dependent on injury. This conversion is also numerically significant and increases with mobilization.     

Fc gamma receptor IIa polymorphism in patients with brucellosis

Recent evidence suggests that certain Fc gamma receptor alleles are genetic risk factors for infectious diseases. In this study, we evaluated Fc gamma RIIa polymorphism in patients with brucellosis. In a case-control study, the frequency of two alleles and three genotypes for Fc gamma RIIa were measured by PCR in 150 patients with brucellosis and 125 healthy controls. The H131 and R131 alleles were found in 133 (44.3%) and 167 patients (47.6%), respectively. The frequencies for the three genotypes (a/a, a/r, r/r) were 10 (6.7%), 113 (75.3%) and 27 (18%), respectively. There was no significant difference in the distribution of Fc gamma RIIa genotypes and the two allelic forms between the patients and controls. Our study indicates that Fc gamma RIIa polymorphism is not decisive for the acquisition of brucellosis.     

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.     

Late (> 48 hr) myocardial infarction after PTCA: clinical and angiographic characteristics of infarction related or not to the angioplasty site.

Since late myocardial infarctions after percutaneous coronary interventions have not been well characterized, we intended to evaluate the characteristics of myocardial infarctions occurring > 48 hr after balloon angioplasty of native coronary arteries or saphenous vein grafts. The Montreal Heart Institute database (1985-1996) was interrogated for all patients readmitted with a diagnosis of MI more than 48 hr after successful percutaneous transluminal coronary angioplasty (PTCA). We compared the clinical, procedural, and angiographic variables between MIs related or not to the index PTCA site. One hundred and ninety-three patients presented with late myocardial infarction (MI) following balloon angioplasty. The median time elapsed between PTCA and MI was 55 days compared to 968 days when MI was unrelated to the PTCA site. MIs related to the PTCA site were more likely non-Q-wave (76% vs. 35%, P = 0.0001) with less marked CK-MB rise. Angiography showed less complex lesions (63% vs. 90%, P = 0.001) and better thrombolysis in myocardial infarction (TIMI) grade flow (TIMI II to III, 66% vs. 56%, P = 0.01) when the culprit lesion was at the PTCA site. Independent predictors of MI at the PTCA site were vein graft dilation, female sex, and residual stenosis post-PTCA. Myocardial infarctions occurring late after PTCA have a distinct time course and present specific characteristics according to their relationship or not to the previously dilated site.