OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency

Studies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes.We identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample had two OBSCN mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with OBSCN mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control level).Obscurin levels in DCM controls, donor heart and myectomy samples were the same.OBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations

Tight p-fusion frames

Fusion frames enable signal decompositions into weighted linear subspace components. For positive integers p, we introduce p-fusion frames, a sharpening of the notion of fusion frames. Tight p-fusion frames are closely related to the classical notions of designs and cubature formulas in Grassmann spaces and are analyzed with methods from harmonic analysis in the Grassmannians. We define the p-fusion frame potential, derive bounds for its value, and discuss the connections to tight p-fusion frames

Re-expansion of balloon-expandable stents after growth

AbstractObjectives. The purpose of this study was to evaluate the feasibility of re-expansion of balloon expandable intravascular stents and to examine the gross and histologic effects of re-expansion on vascular integrity.Background. Intravascular stents have been used successfully as an adjunct to balloon dilation of congenital pulmonary artery branch stenosis and postoperative stenosis of the pulmonary arteries in children. However, use of rigid stents in children could result in development of relative stenosis at the site of stent implantation with subsequent growth of the child.Methods. Stainless steel “iliac” stents were placed in the thoracic aorta of 10 normal juvenile swine by a transcatheter technique. Angiography and re-expansion were performed at a mean of 11 weeks (n = 9) and again at 18 weeks (n = 5). After euthanasia, the aortic specimens were removed for gross and histologic examination.Results. Stents were successfully implanted in 10 swine. Re-expansion was successfully performed in each animal at 11 weeks and at 18 weeks. Aortic growth produced a relative constriction of the aorta of 20% ± 10% (mean ± SD) at the site of stent implantation at both 11 and 18 weeks. Re-expansion produced a significant increase in mean stent diameter from 10.1 ± 1 mm to 12.3 ± 1.2 mm at 11 weeks and from 11.2 ± 0.7 to 13.5 ± 1.1 mm at 18 weeks after implantation (p < 0.001). Balloon dilation produced a relative increase in stent diameter of 21% ± 7% at 11 weeks and 18% ± 4% at 18 weeks. Stent re-expansion was accompanied by plastic deformation of the neointima without neointimal dissection. Where neointima was thick, there was no evidence of neointimal abrasion, but where neointima was thin, areas of localized neointimal abrasion were observed with focal fibrin and platelet adherence to the stent struts. There was no evidence of medial or adventitial hemorrhage or dissection produced by re-expansion.Conclusions. Re-expansion of intravascular stents is feasible after growth in juvenile swine without significant injury to neointima, media or adventitia. The results of this study support careful and selective use of intravascular stents as an adjunct to balloon dilation of congenital stenoses in children

Acute Disseminated Encephalomyelitis with Seizures and Myocarditis: A Fatal Triad.

Autoimmune pathology of acute disseminated encephalomyelitis (ADEM) is generally restricted to the brain. Our objective is to expand the phenotype of ADEM. A four-year-old girl was admitted to the pediatric emergency room of a university medical center five days after a common upper respiratory tract infection. Acute symptoms were fever, leg pain, and headaches. She developed meningeal signs, and her level of consciousness dropped rapidly. Epileptic seizure activity started, and she became comatose, requiring intubation and mechanical ventilation. Serial brain magnetic resonance imaging (MRI) illustrated the fulminant development of ADEM. Treatment escalation with high-dose corticosteroids, immunoglobulins, and plasma exchange did not lead to clinical improvement. On day ten, the patient developed treatment-refractory cardiogenic shock and passed away. The postmortem assessment confirmed ADEM and revealed acute lymphocytic myocarditis, likely explaining the acute cardiac failure. Human metapneumovirus and picornavirus were detected in the tracheal secrete by PCR. Data sources-medical chart of the patient. This case is consistent with evidence from experimental findings of an association of ADEM with myocarditis as a postinfectious systemic autoimmune response, with life-threatening involvement of the brain and heart

A case series on the value of tau and neurofilament protein levels to predict and detect delirium in cardiac surgery patients

BACKGROUND: Delirium following cardiac surgery is a relevant complication in the majority of elderly patients but its prediction is challenging. Cardiopulmonary bypass, essential for many interventions in cardiac surgery, is responsible for a severe inflammatory response leading to neuroinflammation and subsequent delirium. Neurofilament light protein (NfL) and tau protein (tau) are specific biomarkers to detect neuroaxonal injury as well as glial fibrillary acidic protein (GFAP), a marker of astrocytic activation. METHODS: We thought to examine the perioperative course of these markers in a case series of each three cardiac surgery patients under off-pump cardiac arterial bypass without evolving delirium (OPCAB-NDEL), patients with a procedure under cardio-pulmonary bypass (CPB) without delirium (CPB-NDEL) and delirium after a CPB procedure (CPB-DEL). Delirium was diagnosed by the Confusion Assessment Method for the ICU and chart reviews. RESULTS: We observed increased preoperative levels of tau in patients with later delirium, whereas values of NfL and GFAP did not differ. In the postoperative course, all biomarkers increased multi-fold. NfL levels sharply increased in patients with CPB reaching the highest levels in the CPB-DEL group. CONCLUSION: Tau and NfL might be of benefit to identify patients in cardiac surgery at risk for delirium and to detect patients with the postoperative emergence of delirium

Probabilistic frames: An overview

Finite frames can be viewed as mass points distributed in $N$-dimensional Euclidean space. As such they form a subclass of a larger and rich class of probability measures that we call probabilistic frames. We derive the basic properties of probabilistic frames, and we characterize one of their subclasses in terms of minimizers of some appropriate potential function. In addition, we survey a range of areas where probabilistic frames, albeit, under different names, appear. These areas include directional statistics, the geometry of convex bodies, and the theory of t-designs

Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy