Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside

Genetic defects of the dystrophin-glycoprotein complex (DGC) cause hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have previously described a mechanism involved in enterovirus-induced dilated cardiomyopathy: The enteroviral protease 2A directly cleaves dystrophin in the hinge 3 region, leading to functional dystrophin impairment. During infection of mice with coxsackievirus B3, the DGC in the heart is disrupted and the sarcolemmal integrity is lost in virus-infected cardiomyocytes. Additionally, dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy in vivo, suggesting a pathogenetic role of the dystrophin cleavage in enterovirus-induced cardiomyopathy. Here, we extend these experimental findings to a patient with dilated cardiomyopathy due to a coxsackievirus B2 myocarditis. Endomyocardial biopsy specimens showed an inflammatory infiltrate and myocytolysis. Immunostaining for the enteroviral capsid antigen VP1 revealed virus-infected cardiomyocytes. Focal areas of cardiomyocytes displayed a loss of the sarcolemmal staining pattern for dystrophin and -sarcoglycan identical to previous findings in virus-infected mouse hearts. In vitro, coxsackievirus B2 protease 2A cleaved human dystrophin. These findings demonstrate that in human coxsackievirus B myocarditis a focal disruption of the DGC can principally occur and may contribute to the pathogenesis of human enterovirus-induced dilated cardiomyopathy.     

Evaluation of Routine Coronary Angiography Before Pulmonary Thromboendarterectomy

1. Download : Download high-res image (253KB)
2. Download : Download full-size image

     

Female Gender and Diabetes Mellitus Increase the Risk of Recurrence after Laparoscopic Incisional Hernia Repair

Background

Laparoscopic hernia repair is used widely for the repair of incisional hernias. Few case studies have focussed on purely ‘incisional’ hernias. This multicentre series represents a collaborative effort and employed statistical analyses to provide insight into the factors predisposing to recurrence of incisional hernia after laparoscopic repair. A specific hypothesis (ie, laterality of hernias as well as proximity to the xyphoid process and pubic symphysis predisposes to recurrence) was also tested.

Methods

This was a retrospective study of all laparoscopic incisional hernias undertaken in six centres from 1 January 2004 to 31 December 2010. It comprised a comprehensive review of case notes and a follow-up using a structured telephone questionnaire. Patient demographics, previous medical/surgical history, surgical procedure, postoperative recovery, and perceived effect on quality of life were recorded. Repairs undertaken for primary ventral hernias were excluded. A logistic regression analysis was then fitted with recurrence as the primary outcome.

Results

A total of 186 cases (91 females) were identified. Median follow-up was 42 months. Telephone interviews were answered by 115/186 (62%) of subjects. Logistic regression analyses suggested that only female sex (odds ratio (OR) 3.53; 95% confidence interval (CI) 1.39–8.97) and diabetes mellitus (3.54; 1–12.56) significantly increased the risk of recurrence. Position of the defect had no statistical effect.

Conclusions

These data suggest an increased risk of recurrence after laparoscopic incisional hernia repair in females and subjects with diabetes mellitus. These data will help inform surgeons and patients when considering laparoscopic management of incisional hernias. We recommend a centrally hosted, prospectively maintained national/international database to carry out additional research.     

Geographic variation of epilepsy for older Americans: How close to the geographic variation of stroke?

Purpose: Given the strong association of stroke and epilepsy in older persons, and the existence of a Stroke Belt in the United States, we hypothesized that geographic variation in epilepsy prevalence would follow geographic patterns similar to stroke. Methods: We used a 2005 5% random sample of Medicare beneficiaries 65 and older in 48 U.S. contiguous states. Epilepsy was identified from claims for physician visits, hospitalizations, and outpatient procedures. Prevalence was obtained by state and county. Logistic regressions determined the independent association of the likelihood of epilepsy (prevalent or new case) and residence in Stroke Belt states, controlling for residence in highest epilepsy prevalence states, demographics (race, age, gender), comorbid conditions, cerebrovascular disease, dementia, and county characteristics. Key Findings: Of 1,212,015 beneficiaries, 11.9 per 1,000 had prevalent and 2.9 new cases of epilepsy. Nine of 11 Stroke Belt states were among the 20 states with the highest epilepsy prevalence. Counties in the 10 highest epilepsy prevalence states were more likely to be large urban counties with a higher number of neurologists or neurosurgeons per capita. The higher likelihood of prevalent epilepsy cases associated with Stroke Belt residence was explained by beneficiaries’ race; that associated with residence in high epilepsy prevalence states was not. The likelihood of new epilepsy cases was negatively associated with Stroke Belt residence when controlling for covariates. Significance: The geographic variation in epilepsy prevalence is not explained by variations in known risk factors. Further research should investigate why eastern U.S. states have higher frequency of epilepsy.     

Ictal Single-Photon Emission Computed Tomography Imaging in Extra Temporal Lobe Epilepsy Using Statistical Parametric Mapping

PURPOSE: To examine the application of statistical parametric mapping (SPM) to analyze ictal single-photon emission computed tomography (SPECT) scans in surgical candidates with extratemporal lobe epilepsy. METHODS: The authors selected patients who underwent successful ictal SPECT acquisition in the process of surgical treatment of intractable partial epilepsy. Thirteen patients were identified who met inclusion criteria for confident seizure localization from either intracranial electroencephalogram recordings or epilepsy surgery outcome. In these cases, ictal scans were registered to an in-house-developed normal SPECT atlas composed of 14 spatially normalized brains of normal subjects. SPM96 was used to test on a voxel-by-voxel basis for statistically significant increases in blood flow associated with each patient's ictal scan. The results were then mapped back onto the patient's magnetic resonance image (MRI) for final interpretation. Statistical parametric mapping (SPM) analysis of ictal SPECT scans was compared to both conventional visual interpretation and the analysis of subtraction ictal SPECT co-registered to MRI (SISCOM). RESULTS: Ten of 13 patient scans showed localizing focal ictal increases in regional cerebral blood flow, all of which were concordant with ultimate epilepsy localization. Of the 3 cases not localized with SPM, 1 was localized by conventional visual interpretation and another, not localized by visual interpretation, was correctly localized with SISCOM. Two cases not localized by SISCOM were localized by both visual and SPM analysis. CONCLUSIONS: This work provides supportive evidence for proof of principle that SPM can be used to provide objective, accurate analysis of ictal SPECT scans in patients with extratemporal lobe epilepsy.     

Bilateral hippocampal atrophy: consequences to verbal memory following temporal lobectomy

BACKGROUND: Bilateral hippocampal damage is a risk factor for memory decline after anterior temporal lobectomy (ATL). OBJECTIVE: To investigate verbal memory outcome in patients with temporal lobe epilepsy (TLE) with either unilateral or bilateral hippocampal atrophy as measured by MRI. METHODS: The authors selected 60 patients with TLE who had undergone ATL (left = 31, right = 29). They determined normalized MRI hippocampal volumes by cursor tracing 1.5-mm slices from three-dimensional MRI acquisition. Hippocampal volumes were defined as atrophic if the volumes were below 2 SD for control subjects. Bilateral hippocampal atrophy was present in 10 patients with left TLE and 11 patients with right TLE. The authors assessed acquisition, retrieval, and recognition components of verbal memory both before and after ATL. RESULTS: Groups did not differ across age, education, intelligence, age at seizure onset, or seizure duration. Seizure-free rates after ATL were 70% or higher for all groups. Before surgery, patients with left TLE displayed worse verbal acquisition performance compared with patients with right TLE. Patients with left TLE with bilateral hippocampal volume loss displayed the lowest performance across all three memory components. After surgery, both groups of patients with left TLE exhibited worse verbal memory outcome compared with patients with right TLE. Bilateral hippocampal atrophy did not worsen outcome in the patients with right TLE. A higher proportion of patients with left TLE with bilateral hippocampal atrophy experienced memory decline compared with the other TLE groups. CONCLUSION: Bilateral hippocampal atrophy in the presence of left TLE is associated with worse verbal memory before and after ATL compared with patients with unilateral hippocampal volume loss or right TLE with bilateral hippocampal volume loss.     

Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population‐based cohort study

Aim The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population‐based cohort of very preterm infants. Method As part of EPIPAGE, a population‐based prospective cohort study, perinatal data and outcome at 5 years of age were recorded for 1812 infants born before 33 weeks of gestation in nine regions of France in 1997. Results The study group comprised 942 males (52%) and 870 females with a mean gestational age of 30 weeks (SD 2wks; range 24–32wks) and a mean birthweight of 1367g (SD 393g; range 450–2645g). CP was diagnosed at 5 years of age in 159 infants (prevalence 9%; 95% confidence interval [CI] 7–10%), 97 males and 62 females, with a mean gestational age of 29 weeks (SD 2wks; range 24–32wks) and a mean birthweight of 1305g (SD 386g; range 500–2480g). Among this group, 67% walked without aid, 14% walked with aid, and 19% were unable to walk. Spastic, ataxic, and dyskinetic CP accounted for 89%, 7%, and 4% of cases respectively. The prevalence of CP was 61% among infants with cystic periventricular leukomalacia, 50% in infants with intraparenchymal haemorrhage, 8% in infants with grade I intraventricular haemorrhage, and 4% in infants without a detectable cerebral lesion. After controlling for cerebral lesions and obstetric and neonatal factors, only male sex (odds ratio [OR] 1.52; 95% CI 1.03–2.25) and preterm premature rupture of membranes or preterm labour (OR 1.72; 95% CI 0.95–3.14) were predictors of the development of CP in very preterm infants. Interpretation Cerebral lesions were the most important predictor of CP in very preterm infants. In addition, infant sex and preterm premature rupture of membranes or preterm labour were also independent predictors of CP.     

Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis

Apoptosis, or programmed cell death, is a general mechanism for removal of unwanted cells from the immune system. It is characterized by chromatin condensation, a reduction in cell volume, and endonuclease cleavage of DNA into oligonucleosomal length fragments. Apoptosis is also accompanied by a loss of membrane phospholipid asymmetry, resulting in the exposure of phosphatidylserine at the surface of the cell. Expression of phosphatidylserine at the cell surface plays an important role in the recognition and removal of apoptotic cells by macrophages. Here we describe a new method for the detection of apoptotic cells by flow cytometry, using the binding of fluorescein isothiocyanate-labeled annexin V to phosphatidylserine. When Burkitt lymphoma cell lines and freshly isolated germinal center B cells are cultured under apoptosis inducing conditions, all cells showing chromatin condensation strongly stain with annexin V, whereas normal cells are annexin V negative. Moreover, DNA fragmentation is only found in the annexin V-positive cells. The nonvital dye ethidium bromide was found to stain a subpopulation of the annexin V-positive apoptotic cells, increasing with time. Our results indicate that the phase in apoptosis that is characterized by chromatin condensation coincides with phosphatidylserine exposure. Importantly, it precedes membrane damage that might lead to release from the cells of enzymes that are harmful to the surrounding tissues. Annexin V may prove important in further unravelling the regulation of apoptosis.