Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy

Background

Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated.

Methods

Sixty-four MM patients (50 ± 15 years, 44 % male) and 25 matched controls (52 ± 14 years, 36 % male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: a) CPEO/KSS (N = 33); b) MELAS/–like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17).

Results

Among the 64 MM patients, 34 (53 %) had at least one abnormal CMR finding: 18 (28 %) demonstrated an impaired left ventricular ejection-fraction (LV-EF <60 %), 14 (22 %) had unexplained LV hypertrophy and 21 (33 %) were LGE-positive. Compared to controls, MM patients showed significantly higher maximal wall thickness (10 ± 3 vs. 8 ± 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 ± 0.27 vs. 0.67 ± 0.11, p < 0.0001) with frequent presence of non-ischemic LGE (30 % vs. 0 %, p = 0.001). CPEO/KSS showed a predominantly intramural pattern of LGE mostly confined to the basal LV inferolateral wall (8/10; 80 %) in addition to a tendency toward concentric remodelling. MELAS/-like patients showed the highest frequency of cardiac disease (in 10/11 (91 %)), a mostly concentric LV hypertrophy (6/9; 67 %) with or without LV systolic dysfunction and a predominantly focal, patchy LGE equally distributed among LV segments (8/11; 73 %). Patients with MERRF and non-specific MM had no particular findings. Pathological CMR findings indicating cardiac involvement were detected significantly more often than pathological ECG results or elevated cardiac serum biomarkers (34 (53 %) vs. 18 (28 %) vs. 21 (33 %); p = 0.008).

Conclusion

Cardiac involvement is a frequent finding in MM patients – and particularly present in KSS/CPEO as well as MELAS/-like patients. Despite a high variability in clinical presentation, CPEO/KSS patients typically show an intramural pattern of LGE in the basal inferolateral wall whereas MELAS patients are characterized by overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE.

Electronic supplementary material

The online version of this article (doi:10.1186/s12968-015-0145-x) contains supplementary material, which is available to authorized users.     

A Quantitative and Dynamic Model for Plant Stem Cell Regulation

Plants maintain pools of totipotent stem cells throughout their entire life. These stem cells are embedded within specialized tissues called meristems, which form the growing points of the organism. The shoot apical meristem of the reference plant Arabidopsis thaliana is subdivided into several distinct domains, which execute diverse biological functions, such as tissue organization, cell-proliferation and differentiation. The number of cells required for growth and organ formation changes over the course of a plants life, while the structure of the meristem remains remarkably constant. Thus, regulatory systems must be in place, which allow for an adaptation of cell proliferation within the shoot apical meristem, while maintaining the organization at the tissue level. To advance our understanding of this dynamic tissue behavior, we measured domain sizes as well as cell division rates of the shoot apical meristem under various environmental conditions, which cause adaptations in meristem size. Based on our results we developed a mathematical model to explain the observed changes by a cell pool size dependent regulation of cell proliferation and differentiation, which is able to correctly predict CLV3 and WUS over-expression phenotypes. While the model shows stem cell homeostasis under constant growth conditions, it predicts a variation in stem cell number under changing conditions. Consistent with our experimental data this behavior is correlated with variations in cell proliferation. Therefore, we investigate different signaling mechanisms, which could stabilize stem cell number despite variations in cell proliferation. Our results shed light onto the dynamic constraints of stem cell pool maintenance in the shoot apical meristem of Arabidopsis in different environmental conditions and developmental states.     

Management of chronic hepatitis B: status and challenges beyond treatment guidelines

Several national and international guidelines have been published in the last years focusing on the problem of how to best treat patients with chronic hepatitis B virus (HBV) infection. Therapy with interferon or nucleos(t)ide analogues has been shown to be most effective in suppressing HBV deoxyribonucleic acid (DNA) levels and preventing fibrosis progression herby also reducing the risk of hepatocellular carcinoma (HCC). However even suppression of viral replication below the limit of detection does not prevent HCC development although fibrosis can be stopped. Thus, improvement of therapeutic strategies and the establishment of more sensitive markers that may help to decide when therapy should be initiated and stopped remain important goals in hepatitis research. The present review discusses several major issues in this respect such as strategies to identify the optimal time point for treatment indication and end of therapy. It also concentrates on questions and queries that have to do with the interpretation of viral parameters like HBsAg quantification, HBV genotypes, and HBeAg, or the characterization of risk patients prone to develop fatal sequel of the HBV infection.     

Loss of CD103~+ intestinal dendritic cells during colonic inflammation

AIM:To investigate possible differences in dendritic cells(DC)within intestinal tissue of mice before and after induction of colitis. METHODS:Mucosal DC derived from intestinal tissue,as well as from mesenteric lymph nodes and spleen,were analyzed by fluorescence activated cell sorting(FACS) analysis.Supernatants of these cells were analyzed for secretion of different pro-and anti-inflammatory cytokines. Immunohistochemistry and immunofluorescence were performed on cryosections of mucosal tissue derived fro...     

Usefulness of Intraprocedural Pulmonary Venous Flow for Predicting Recurrent Mitral Regurgitation and Clinical Outcomes After Percutaneous Mitral Valve Repair With the MitraClip

Objectives

The aim of this study was to determine the prognostic value of pulmonary venous (PV) flow during MitraClip implantation.

Feasibility of real-time magnetic resonance-guided stent-graft placement in a swine model of descending aortic dissection.

AIMS: To evaluate the pre-clinical feasibility of real-time magnetic resonance imaging (rtMRI) to guide stent-graft placement for experimental aortic dissection (AD) and to alleviate disadvantages of ionising radiation and nephrotoxic contrast media. Endovascular stent-graft placement for thoracic aortic disease is usually performed under X-ray guidance. The feasibility of rtMRI-guided stent-graft placement is currently not known. METHODS AND RESULTS: By using a catheter-based technique, dissections of the descending thoracic aorta were successfully created in eight domestic pigs. Subsequent implantation of commercially available, nitinol-based stent-grafts was performed entirely under rtMRI guidance. By pre-interventional MRI, the mean minimal true-lumen diameter was 0.9 (0.825-0.975) cm. rtMRI permitted not only the successful and safe device navigation within the true lumen from the iliac arteries to the thoracic aorta, but also the precise positioning and deployment of the stent-graft and safe withdrawal of the delivery catheter in seven of eight pigs. This was achieved without any other complications. After the stent-graft placement, MRI demonstrated complete obliteration of the false lumen, which was confirmed at autopsy. All stent-grafts were well expanded resulting in an increase in the size of the true-lumen diameter to 2.05 (1.925-2.1) cm (P=0.066 vs. baseline). CONCLUSION: In experimental AD, rtMRI-guided endovascular stent-graft placement is feasible and safe and has the potential for mitigating radiation and contrast-related side effects. Additionally, it allows not only pre-interventional diagnosis and detailed anatomic diagnosis, but also permits immediate post-interventional, anatomical, and functional delineation of procedure success that may serve as a baseline for future comparison during follow-up.     

Acute and long-term alteration of chemokine mRNA expression after anti-viral and anti-inflammatory treatment in herpes simplex virus encephalitis

Mortality and morbidity rates remain high among patients with herpes simplex virus encephalitis (HSVE). Chemokine-mediated recruitment and activation of leukocytes to focal areas of viral CNS infection are crucial steps in antiviral response and clearance. However, the inflammatory reaction and cellular antiviral response may enhance collateral damage to neurons and account for chronic progressive brain damage. We identified a specific mRNA expression of the interferon-gamma-inducible chemokines (CXCL9, CXCL10 and CXCL11), and RANTES (CCL5) in the acute course and long-term of experimental HSVE. This pattern was substantially altered by anti-viral and anti-inflammatory treatment. Our findings indicate a pivotal role of these chemokines in the immunopathogenesis of HSVE.     

A sertoli cell-specific knockout of connexin43 prevents initiation of spermatogenesis

The predominant testicular gap junctional protein connexin43 (cx43) is located between neighboring Sertoli cells (SCs) and between SCs and germ cells. It is assumed to be involved in testicular development, cell differentiation, initiation, and maintenance of spermatogenesis with alterations of its expression being correlated with various testicular disorders. Because total disruption of the cx43 gene leads to perinatal death, we generated a conditional cx43 knockout (KO) mouse using the Cre/loxP recombination system, which lacks the cx43 gene solely in SCs (SCCx43KO), to evaluate the SC-specific functions of cx43 on spermatogenesis in vivo. Adult SCCx43KO(-/-) mice showed normal testis descent and development of the urogenital tract, but testis size and weight were drastically lower compared with heterozygous and wild-type littermates. Histological analysis and quantitation of mRNA expression of germ cell-specific marker genes revealed a significant reduction in the number of spermatogonia but increased SC numbers/tubule with only a few tubules left showing normal spermatogenesis. Thus, SC-specific deletion of cx43 mostly resulted in an arrest of spermatogenesis at the level of spermatogonia or SC-only syndrome and in intratubular SC clusters. Our data demonstrate for the first time that cx43 expression in SCs is an absolute requirement for normal testicular development and spermatogenesis.     

Evaluating thyroid gland function in patients with protein anomalies

The euthyroid hyperthyroxinemia (EHT) is characterized on the one hand by a normal basal THS or TRH-TSH response but also by high plasma values of total thyroxine (TT4) on the other. However if only TT4 is assessed, "hyperthyroidism" may be diagnosed erroneously. EHT may be caused by an increase of specific thyroxine binding proteins which may be hereditary (permanent) or acquired (transient). The most frequent disturbance is due to an estrogen induced increase of thyroxine binding globulin (TBG) in the course of pregnancy, anticonceptive drugs or estrogen treatment. The albumin associated HT (FDH syndrome), first reported in 1979, has autosomal dominant traits. 144 patients with FDH syndrome were observed during the period between 1984 and 1990, i.e. 7% (1986) of all hyperthyroid patients explored. Family screening is required to prevent unjustified treatment. Additionally existing disturbances of thyroid function as well as other protein binding anomalies may both cause problems in differential diagnosis. Prealbumin associated hyperthyroxinemia (PAAH), first published in 1982, may be due to an inherited increase in affinity, but may also be the consequence of a true elevation of prealbumin plasma concentration in the course of an islet cell cancer; both conditions are extremely rare. Nearly as rare are patients with plasma autoantibodies directed against T4 and/or T3 (5 cases); yet, a reverse T3 autoantibody could be observed in merely 1 case. By means of our modified radio-thyroxine-agarosegel-iceelectrophoresis all such protein anomalies may be diagnosed and differentiated in 1 procedure. Moreover, all other types of EHT must be taken into consideration by differential diagnosis.