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Ventricular Arrhythmias in Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Antonis S. Manolis, Antonis A. Manolis, Theodora A. Manolis
Particularly for patients with NICM, optimal HF therapy should precede the decision for ICD implantation by ≥3 months. The SCD-HeFT trial (n=792) provided clear evidence that favored ICD over amiodarone in prevention of SCD in NICM (hazard ratio 0.77, p=0.007).78 Recently, the DANISH trial (n=1,116, LVEF <35%) raised concerns about the role of ICDs in primary prevention of SCD in patients with NICM. ICDs reduced SCD from 8.4% to 4.3% over a mean of 5.6 years, but with no difference in all-cause mortality.98 However, this trial differed from previous trials as over 50% (58%) of patients in both (ICD and medical) arms received CRT (CRT-D or CRT-P). Subsequent meta-analyses that included the DANISH trial did confirm survival benefit from ICD implantation in NICM patients (22–25% relative risk reduction in mortality).99,100 The majority of data involved patients with NYHA class II–ambulatory IV patients; hence, there is uncertainty about the utility of ICD in NICM patients with class I or class IV HF symptoms. Finally, a special group of familial NICM patients includes patients with laminopathies caused by mutations mainly in the lamin A/C gene, who appear to have a high risk of SCD, especially when they are men and have NSVT on Holter monitor, LVEF <45%, and non-missense mutations.101 However, even lamin A/C patients with preserved (>45%) LVEF are at high risk of malignant ventricular arrhythmias in the presence of significant conduction disorders (hazard ratio 5.20; p=0.03).102
Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Autosomal dominant (EMD2) and autosomal recessive (EMD3) presentations are linked to mutations in the LMNA gene encoding lamin A/C. Mutations in lamin A/C can also result in other clinical phenotypes that include dilated cardiomyopathy with conduction defects, familial partial lipodystrophy, autosomal recessive axonal neuropathy (CMT2B1), and Hutchinson–Gilford progeria syndrome.
Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
Lamin B1 is a protein which comprises part of the nuclear lamina and helps in maintaining proper nuclear structure and function (Camps, Erdos, and Ried 2015). Senescent cells induced through MiDAS have lower expression of lamin B1 relative to dividing and undifferentiated cells (Wiley et al. 2016). Lamin B1 loss is also observed in RS and OIS (Freund et al. 2012). Cells induced to senesce by DNA-damaging agents, such as UV and X-ray irradiation, also exhibit decline in lamin B1 (Freund et al. 2012; Wang et al. 2017). Loss of lamin B1 in senescent cells is linked to the formation of SAHF (Sadaie et al. 2013) and nuclear blebs (Shimi et al. 2011).
Ambient PM2.5 exposure causes cellular senescence via DNA damage, micronuclei formation, and cGAS activation
Published in Nanotoxicology, 2022
Tao Wu, Shengmin Xu, Biao Chen, Lingzhi Bao, Jie Ma, Wei Han, An Xu, Kwan Ngok Yu, Lijun Wu, Shaopeng Chen
It was puzzling that although cGAS accumulated on most MNs, there was no cGAS accumulation on a tiny minority of MNs following PM2.5 exposures. Research from a previous study demonstrated that NE rupture in primary nuclei was associated with disorganization in the nuclear lamina of cells (Hatch et al. 2013). According to the previous finding, those MNs gathered cGAS might have defects in the nuclear lamina assembly. To detect the integrity of lamina, we labeled cGAS and lamin A/C in fibroblasts exposed to PM2.5, and found that although cGAS gathered in most MNs with the discontinuous nuclear rim of lamin A/C, indicating disruption of MNs, a few MNs with the continuous nuclear rim of lamin A/C still accumulated cGAS. Further labeling of lamin B1 showed that almost every MN with discontinuous nuclear rim of lamin B1 gathered cGAS. Co-staining of laminB1 and lamin A/C showed that MNs with continuous nuclear rim of lamin A/C presented discontinuous nuclear rim of lamin B1. Statistical results showed that both lamin B1 (about 90%) and lamin A/C (about 40%) had different degrees of rupture, and the rate of lamin B1 disorganization was closely related to the rate of cGAS gathering (about 80%). Consistent with the localization of lamina, the protein levels of lamin B1 decreased significantly and lamin A/C did not downregulate that much. Thus, we demonstrated that disrupted MNs were a source of cGAS activation to aggravate cellular senescence and lamin B1 triggered MNs disruption upon PM2.5 exposures.
Pseudo Pelger-Huët anomalies as potential biomarkers for acute exposure radiation dose in rhesus macaques (Macaca mulatta)
Published in International Journal of Radiation Biology, 2022
Joshua M. Hayes, John D. Olson, Yuiko Chino, J. Daniel Bourland, J. Mark Cline, Thomas E. Johnson
There is a distinction between the Pelger-Huët Anomaly (PHA) and the pseudo Pelger-Huët anomaly (PPHA); PHAs are naturally occurring while PPHAs are induced morphologies. PHAs were first described in 1928 by the German physician, Karl Pelger, and were believed to be a sign of poor prognosis for tuberculosis (Pelger 1928). However, in 1932 G.J Huët discovered PHAs were linked to an autosomal dominant mutation on the long arm of chromosome 1 (Huët 1931). The mutation was in a gene that encodes for the lamin-B receptor, which is a membrane-associated protein embedded in the inner nuclear membrane of the nuclear envelope. The lamin-B receptor has two functions that can be described by its location on the protein. The carboxyl terminus performs C14 sterol reductase activity which involves the breaking of carbon double bonds in cholesterol synthesis, while the amine terminus of the lamin-B receptor binds to an intermediate filament called lamin-B. Lamin-B in turn binds to the chromatin and provides structure to both the chromatin and the nucleoplasm (Holmer et al. 1998). The structure of the nucleus is incredibly important to granulocytes because a hyper-segmented nucleus makes it much easier for these cells to exit the blood vascular compartment via diapedesis. The structure of the nucleus also allows for ease in movement throughout tissues as the cell is migrating to areas undergoing the inflammation response (Colella and Hollensead 2012). An image of the lamin-B receptor with the sterol reductase carboxyl terminus and the chromatin tethering amino terminus can be seen in Figure 1.
Arg1201Gln mutation of insulin receptor impairs tyrosine kinase activity and causes insulin resistance: a case report
Published in Gynecological Endocrinology, 2020
The heterozygous mutation was also present in her mother but was absent in her father, indicating an autosomal dominant pattern of inheritance. In addition, the genetic trait of TAIRS can also be transmitted in an autosomal recessive pattern [24]. In general, missense mutations in the tyrosine kinase domain of the INSR are frequently inherited in a dominant form [15]. Although homozygous or compound-heterozygous mutations in the INSR are frequently associated with leprechaunism and Rabson-Mendenhall syndrome, they can also be detected in patients with TAIRS [10,24–26]. To clarify, the majority of individuals affected with TAIRS do not have mutation in INSR gene [7]. What’s more, Jacques Young et al. reported a case of a woman with TAIRS associated with a heterozygous missense mutation in the lamin A/C gene rather than INSR gene [27]. These lend support to the genetic heterogeneity of TAIRS.