We have previously found that dimethyl sulfoxide (DMSO), a known inducer of differentiation in several kinds of myeloid cells, arrests proliferation of human lymphoid cells including Raji and Akata ...Burkitt's lymphoma cells at the G1 phase. We investigated whether DMSO affects cell proliferation and differentiation of the lymphoid cell line SKW6-CL4, which is capable of differentiating terminally into IgM-producing cells. As in the case of Raji, Akata, and Molt-4, the proliferation of SKW6-CL4 was reversibly arrested at the G1 phase by treatment with 2% DMSO for 5 days even in the presence of interleukin-6 (IL-6). DMSO inhibited spontaneous IgM secretion as well as IL-6-induced IgM production in SKW6-CL4 at a concentration lower than that affecting cell proliferation. Of the cell-surface differentiation markers CD10, CD20, CD21, and CD23, the expression of CD20 was suppressed by DMSO treatment, and partial restoration of the expression was observed 24 to 48 h after release from DMSO. The level of IL-6 receptor protein was not affected by DMSO treatment. These results indicate that DMSO not only arrests the cell cycle of a human lymphoid cell line SKW6-CL4 at the G1 phase but also inhibits the differentiation into IgM-secreting cells at a concentration lower than that affecting cell proliferation and that DMSO overcomes the effect of IL-6 on terminal differentiation of SKW6-CL4. As a whole, proliferation of human lymphoblastoid cell lines was revealed to be reversibly arrested at the G1 phase by DMSO, which is known to induce differentiation in several myeloid cells, without inducing cell differentiation.
Secondary extramammary Paget disease (s‐EMPD) represents anal canal and rectal, bladder, and gynecological cancers, which horizontally extend within the epidermis of the anal and vulvar skin. It is ...necessary to distinguish this condition from primary extramammary Paget disease (p‐EMPD), which occurs primarily in genital and perianal areas. This study aimed to investigate the clinical and histopathological features of these two conditions in the perianal skin and to identify useful features for differentiation. We retrospectively analyzed 16 patients who visited Shinshu University Hospital from 2009 to 2022 and presented with perianal skin lesions and suspected EMPD. Six patients had p‐EMPD and 10 had s‐EMPD derived from anal canal adenocarcinoma. Regarding clinical features, nine of 10 (90%) of the s‐EMPD cases had symmetric skin lesions, whereas all of the p‐EMPD cases had asymmetrical lesions (p = 0.0004). Furthermore, assessment of symmetry around the anus showed that s‐EMPD had a significantly smaller coefficient of variation than p‐EMPD (0.35 and 0.62, respectively; p = 0.048), suggesting that s‐EMPD was more symmetric around the anus. The frequency of raised lesions, such as foci or nodules, was nine of 10 (90%) for s‐EMPD and one of six (16%) for p‐EMPD (p = 0.003). Well‐defined tumor borders on the lateral margins were identified in s‐EMPD (5/10, 50%); however, they were not identified in p‐EMPD (0/6, 0%). The borders tended to be clearer in s‐EMPD; however, the difference was not significant (p = 0.078). Based on these findings, we recommend consideration of s‐EMPD when anal skin lesions are symmetrical, well‐defined, or raised.
•Inhibition of CRMP2 phosphorylation delays progression of the motor symptoms of SOD1G93A-Tg mice.•Inhibition of CRMP2 phosphorylation maintains the survival of motor axons in SOD1G93A-Tg ...mice.•Inhibition of CRMP2 phosphorylation maintains innervation of NMJs in SOD1G93A-Tg mice.•Phosphorylation of CRMP2 may promote dying back axonal degeneration in motor neurons in ALS.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by the selective degeneration of motor neurons leading to paralysis and immobility. Missense mutations in the gene coding for the Cu2+/Zn2+ superoxide dismutase 1 (SOD1) accounts for 15–20% of familial ALS, and mice overexpressing ALS-linked SOD1 mutants have been frequently used as an animal model for ALS. Degeneration of motor neurons in ALS progresses in a manner called “dying back”, in which the degeneration of synapses and axons precedes the loss of cell bodies. Phosphorylation of collapsin response mediator protein 2 (CRMP2) is implicated in the progression of neuronal/axonal degeneration of different etiologies. To evaluate the role of CRMP2 phosphorylation in ALS pathogenesis, we utilized CRMP2 S522A knock-in (CRMP2ki/ki) mice, in which the serine residue 522 was homozygously replaced with alanine and thereby making CRMP2 no longer phosphorylatable by CDK5 or GSK3B. We found that the CRMP2ki/ki/SOD1G93A mice showed delay in the progression of the motor phenotype compared to their SOD1G93-Tg littermates. Histological analysis revealed that the CRMP2ki/ki/SOD1G93A mice retained more intact axons and NMJs than their SOD1G93A-Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS.
Abstract
OBJECTIVES
We aimed to identify predictors of postoperative permanent neurological deficits (PNDs) and evaluate the early management of cerebral perfusion in patients undergoing surgical ...repair of acute type A aortic dissection with cerebral malperfusion.
METHODS
Between October 2009 and September 2018, a total of 197 patients with acute type A aortic dissection underwent aortic replacement. Of these, 42 (21.3%) patients had an imaging cerebral malperfusion (ICM). ICM was assessed preoperatively, which also revealed whether dissected supra-aortic branch vessels were occluded or narrowed by a thrombosed false lumen. After September 2017, early reperfusion and extra-anatomic revascularization were performed in cases with ICM.
RESULTS
Hospital mortality rates for cases with ICM were 4.8% (2/42). Before September 2017, PND were observed in 6 patients (54.5%) with preoperative neurological symptoms (n = 11), and 7 patients (33.3%) without neurological symptoms (n = 21) in patients with ICM. Occlusion or severe stenosis of supra-aortic branch vessels (odds ratio, 7.66; P < 0.001), regardless of preoperative clinical neurological symptoms, was a risk factor for PND. After September 2017, 7 of 10 patients with ICM underwent early reperfusion and extra-anatomic revascularization. PND did not occur in any of these 7 patients.
CONCLUSIONS
Occlusion or severe stenosis of supra-aortic branch vessels is a predictor of PND risk in patients undergoing surgery for acute type A aortic dissection. Early reperfusion and extra-anatomic revascularization may reduce the risk of neurological complications in patients with ICM, with or without neurological symptoms.
Inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ release channels that regulate various vital processes. Although the ryanodine receptor type 2, another type of ...intracellular Ca2+ release channel, has been shown to play a role in embryonic cardiomyocytes, the functions of the IP3Rs in cardiogenesis remain unclear.
We found that IP3R1(-/-)-IP3R2(-/-) double-mutant mice died in utero with developmental defects of the ventricular myocardium and atrioventricular (AV) canal of the heart by embryonic day (E) 11.5, even though no cardiac defect was detectable in IP3R1(-/-) or IP3R2(-/-) single-mutant mice at this developmental stage. The double-mutant phenotype resembled that of mice deficient for calcineurin/NFATc signaling, and NFATc was inactive in embryonic hearts from the double knockout-mutant mice. The double mutation of IP3R1/R2 and pharmacologic inhibition of IP3Rs mimicked the phenotype of the AV valve defect that result from the inhibition of calcineurin, and it could be rescued by constitutively active calcineurin.
Our results suggest an essential role for IP3Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling.
Abstract Congenital heart defects (CHDs) occur in 0.5–1% of live births, yet the underlying genetic etiology remains mostly unknown. Recently, a new source of myocardial cells, namely the second ...heart field (SHF), was discovered in the splanchnic mesoderm. Abnormal development of the SHF leads to a spectrum of outflow tract defects, such as persistent truncus arteriosus and tetralogy of Fallot. Intracellular Ca2+ signaling is known to be essential for many aspects of heart biology including heart development, but its role in the SHF is uncertain. Here, we analyzed mice deficient for genes encoding inositol 1,4,5-trisphosphate receptors (IP3 Rs), which are intracellular Ca2+ release channels on the endo/sarcoplasmic reticulum that mediate Ca2+ mobilization. Mouse embryos that are double mutant for IP3 R type 1 and type 3 ( IP 3 R1 −/− IP 3 R3 −/− ) show hypoplasia of the outflow tract and the right ventricle, reduced expression of specific molecular markers and enhanced apoptosis of mesodermal cells in the SHF. Gene expression analyses suggest that IP3 R-mediated Ca2+ signaling may involve, at least in part, the Mef2C–Smyd1 pathway, a transcriptional cascade essential for the SHF. These data reveal that IP3 R type 1 and type 3 may play a redundant role in the development of the SHF.
Although skeletal muscle quantity is linked to surgical outcomes, quality remains unexamined. In this study, we evaluated whether skeletal muscle quality and quantity could predict surgical outcomes ...in acute type A aortic dissection (ATAAD).
Skeletal muscle quality and quantity were evaluated using computed tomography (CT) values and the psoas muscle mass index, respectively. From May 2004 to December 2017, 324 ATAAD patients underwent aortic replacement after CT scans and psoas muscle mass index measurements. Patients were grouped into intramuscular fat (IMF; n = 55) and non-IMF (n = 269) deposition groups.
The mean ages of the patients were 72.3 ± 9.7 and 66.8 ± 12.1 years (P = 0.002), and hospital mortality rates were 3.6% (2/55) and 7.4% (20/269; P = 0.393) for IMF and non-IMF deposition groups, respectively. IMF deposition was a risk factor for a deterioration in activities of daily living at discharge by multivariable analysis odds ratio 0.33, 95% confidence interval (CI) 0.16-0.69; P = 0.003. The mean follow-up was 43.9 ± 36.8 months. The 5-year survival was significantly worse for the IMF deposition group (IMF 73.8% vs non-IMF 88.2%; P = 0.010). The multivariable Cox proportional hazard analysis showed that IMF deposition significantly predicted poor survival (hazard ratio 3.26, 95% CI 1.47-7.24; P = 0.004), unlike psoas muscle mass index and age.
Skeletal muscle quality, defined by IMF deposition, was an independent predictor of overall survival and postoperative activities of daily living dependence risk in patients undergoing surgery for ATAAD. Thus, IMF deposition may be an additional risk factor for estimating late outcomes of ATAAD surgery.
A 62-year-old man with Marfan syndrome had a modified Bentall procedure and total arch replacement for annuloaortic ectasia, aortic insufficiency and thoracic aortic aneurysm fifteen years ago at ...another hospital. A follow-up CT revealed bilateral coronary artery aneurysms and an aortic root pseudoaneurysm, and thus he was referred to our hospital. The previous prosthetic valve was removed, followed by the re-Bentall procedure. Coronary artery aneurysms were resected and consequently coronary arteries were reconstructed directly. Although the shortcoming of the Bentall procedure was pseudoaneurysm, the outcomes of the modified Bentall procedure have shown some improvements. However, as there is still a high risk of postoperative complication in connective tissue diseases, long-term follow-up is required.
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