Clinical Features of 544 Patients With Ruptured Aortic Aneurysm　- A Report From the Tokyo Acute Aortic Super Network Database.

BACKGROUND: Epidemiological data on ruptured aortic aneurysms from large-scale studies are scarce. The aims of this study were to: clarify the clinical course of ruptured aortic aneurysms; identify aneurysm site-specific therapies and outcomes; and determine the clinical course of patients receiving conservative therapy.Methods and Results: Using the Tokyo Acute Aortic Super Network database, we retrospectively analyzed 544 patients (mean [±SD] age 78±10 years; 70% male) with ruptured non-dissecting aortic aneurysms (AAs) after excluding those with impending rupture. Patient characteristics, status on admission, therapeutic strategy, and outcomes were evaluated. Shock or pulselessness on admission were observed in 45% of all patients. Conservative therapy, endovascular therapy (EVT), and open surgery (OS) accounted for 32%, 23%, and 42% of cases, respectively, with corresponding mortality rates of 93%, 30%, and 29%. The overall in-hospital mortality rate was 50%. The prevalence of pulselessness was highest (48%) in the ruptured ascending AA group, and in-hospital mortality was the highest (70%) in the ruptured thoracoabdominal AA group. Multivariable logistic regression analysis indicated in-hospital mortality was positively associated with pulselessness (odds ratio [OR] 10.12; 95% confidence interval [CI] 4.09-25.07), and negatively associated with invasive therapy (EVT and OS; OR 0.11; 95% CI 0.06-0.20). CONCLUSIONS: The outcomes of ruptured AAs remain poor; emergency invasive therapy is essential to save lives, although it remains challenging to reduce the risk of death.

Severe Left Ventricular Failure Unmanageable by Impella 5.0.

Mechanical circulatory support can be beneficial for patients with cardiogenic shock. Of these, the Impella has recently become the first-line device due to its feasibility, minimal invasiveness, and efficacy. We had a 58-year-old male with acute myocardial infarction followed by cardiogenic shock. We initially placed the patient on intra-aortic balloon pumping, which was switched to Impella 2.5 and could stabilize him. Unfortunately, the Impella 2.5 device suddenly stopped on the fifth day, thus, we tried to manage him by inotropes. However, his condition gradually deteriorated, so we applied Impella 5.0. Although his systemic circulation could be maintained, severe pulmonary hypertension persisted on Impella 5.0. He developed flash pulmonary edema, thus, we emergently added venoarterial extracorporeal membrane oxygenation on Impella 5.0 (ECPELLA). Then, we removed Impella 5.0 and changed peripheral venoarterial extracorporeal membrane oxygenation to central venoarterial extracorporeal membrane oxygenation. In this central venoarterial extracorporeal membrane oxygenation, we inserted the cannulas in the pulmonary artery and the left ventricle in addition to the usual cannulas in the ascending aorta and the right atrium. We aimed to control pulmonary arterial blood flow for lung protection as well as left ventricular unloading by this modification. However, his cardiac function showed no signs of recovery, and his lung condition showed further exacerbation. He was complicated by fungal sepsis and finally died of multi-organ failure. Although the Impella is an option, it is crucial to evaluate patients' condition carefully and to escalate the device, if needed, without delay.

Outcomes of type A acute aortic dissection with cardiopulmonary arrest: Tokyo Acute Aortic Super-network Registry.

OBJECTIVES: Preventing loss of life in patients with type A acute aortic dissection (AAD) who present with cardiopulmonary arrest (CPA) can be extremely difficult. Thus, we investigated the early outcomes in these patients. METHODS: Patients with type A AAD who were transported to hospitals belonging to the Tokyo Acute Aortic Super-network between January 2015 and December 2019 were considered for this study. We assessed the early mortality of these patients presenting with CPA and also investigated the differences in outcomes between patients with out-of-hospital and in-hospital CPA. RESULTS: A total of 3307 patients with type A AAD were transported, 434 (13.1%) of whom presented with CPA. The overall mortality of patients presenting with CPA was 88.2% (383/434), of which 94.5% (240/254) experienced out-of-hospital CPA and 79.4% (143/180) experienced in-hospital CPA (P < 0.001). Multivariable analysis revealed that aortic surgery [odds ratio (OR), 0.022; 95% confidence interval (CI), 0.008-0.060; P < 0.001] and patient age over 80 years (OR, 2.946; 95% CI, 1.012-8.572; P = 0.047) were related with mortality in patients with type A AAD and CPA. Between in-hospital and out-of-hospital CPA, the proportions of DeBakey type 1 (OR, 2.32; 95% CI, 1.065-5.054; P = 0.034), cerebral malperfusion (OR, 0.188; 95% CI, 0.056-0.629; P = 0.007), aortic surgery (OR, 0.111; 95% CI, 0.045-0.271; P = 0.001), age (OR, 0.969; 95% CI, 0.940-0.998; P = 0.039) and the time from symptom onset to hospital admission (OR, 1.122; 95% CI, 1.025-1.228; P = 0.012) were significantly different. CONCLUSIONS: Patients with type A AAD presenting with CPA exhibited extremely high rates of death. Patient outcomes following in-hospital CPA tended to be better than those following out-of-hospital CPA; however, this difference was not significantly different. To prevent deaths, aortic surgery, when possible, should be considered in patients with type A AAD who sustained CPA.

Dexmedetomidine for dyspnoea.

Dexmedetomidine is a selective α2-adrenoreceptor agonist with a broad range of effects, including easily controllable sedation, analgesia and anxiolysis. Because of these favorable features, it has replaced traditional sedatives, such as benzodiazepines, and is becoming the first-line sedative for the patients in intensive care units. Terminally ill patients often need sedatives for symptom management, especially for dyspnoea. However, the use of dexmedetomidine in a palliative care setting has rarely been recognised to date. We experienced a patient nearing the end of life due to uncontrollable pulmonary haemorrhage on ventilator, whose dyspnoea was successfully managed by dexmedetomidine in addition to continuous intravenous infusion of oxycodone.

Sex Differences in DeBakey Type I/II Acute Aortic Dissection Outcomes: The Tokyo Acute Aortic Super-network.

Background: Sex differences in the clinical presentation and outcomes of DeBakey type I/II (Stanford type A) acute aortic dissection (AAD) remain unclear. Objectives: The authors aimed to determine the impact of sex on the clinical presentation and in-hospital outcomes of surgically or medically treated patients with type I/II AAD. Methods: We studied 3,089 patients with type I/II AAD enrolled in multicenter Japanese registry between 2013 and 2018. The patients were divided into 2 treatment groups: surgical and medical. Multivariable logistic regression was used to examine the association between sex and in-hospital mortality. Results: In the entire cohort, women were older and more likely to have hyperlipidemia, previous stroke, altered consciousness, and shock/hypotension at presentation than men. Women had higher proportions of intramural hematomas and type II dissections than men. In the surgical group (n = 2,543), men had higher rates of preoperative end-organ malperfusion (P = 0.003) and in-hospital mortality (P = 0.002) than women. Multivariable analysis revealed that male sex was associated with higher in-hospital mortality after surgery (OR: 1.71; 95% CI: 1.24-2.35; P < 0.001). In the medical group (n = 546), women were older and had higher rates of cardiac tamponade (P = 0.004) and in-hospital mortality (P = 0.039) than men; no significant association between sex and in-hospital mortality was found after multivariable adjustment (OR: 0.95; 95% CI: 0.56-1.59; P = 0.832). Conclusions: Male sex was associated with higher in-hospital mortality for type I/II AAD in the surgical group but not in the medical group. Further research is needed to understand the mechanisms responsible for worse surgical outcomes in men.

In-Hospital Mortality of Patients With Acute Type A Aortic Dissection Hospitalized on Weekends Versus Weekdays.

Background: In acute aortic dissection, weekend admissions are reported to be associated with increased mortality compared with weekday admissions. Objective: This study aimed to determine whether patients with acute type A aortic dissection (ATAAD) admitted on weekends had higher in-hospital mortality than those admitted on weekdays in the Tokyo metropolitan area, where we developed a patient-transfer system for aortic dissection. Methods: Data were collected during the first year after our transfer system began (cohort I) and in the subsequent years from 2013 to 2015 (cohort II). Results: We studied 2,339 patients (500 in cohort I; 1,839 in cohort II) with ATAAD. Patients with weekend admissions had higher in-hospital mortality than those with weekday admissions in cohort I. In association with increased interfacility transfer during weekends and reduced mortality at non-high-volume centers, the in-hospital mortality in the weekend group improved from 37.2% in cohort I to 22.2% in cohort II (P < 0.001). After inverse probability weighting adjustment, weekend admission was associated with higher in-hospital mortality in cohort I (odds ratio: 2.28; 95% confidence interval: 1.48 to 3.52; P < 0.001), but not in cohort II (odds ratio: 0.96; 95% confidence interval: 0.75 to 1.22; P = 0.731). On multivariable analyses, weekend admission was associated with higher in-hospital mortality in combined cohort I+II; the associations between weekend admission and mortality were not significant in cohort II. Conclusions: We found a significant reduction in in-hospital mortality in patients with weekend admissions for ATAAD. No mortality difference between weekend and weekday admissions was observed in the later years of the study.

Sex-Related Differences in Clinical Features and In-Hospital Outcomes of Type B Acute Aortic Dissection: A Registry Study.

Background The association between female sex and poor outcomes following surgery for type A acute aortic dissection has been reported; however, sex-related differences in clinical features and in-hospital outcomes of type B acute aortic dissection, including classic aortic dissection and intramural hematoma, remain to be elucidated. Methods and Results We studied 2372 patients with type B acute aortic dissection who were enrolled in the Tokyo Acute Aortic Super-Network Registry. There were fewer and older women than men (median age [interquartile range]: 76 years [66-84 years], n=695 versus 68 years [57-77 years], n=1677; P<0.001). Women presented to the aortic centers later than men. Women had a higher proportion of intramural hematoma (63.7% versus 53.7%, P<0.001), were medically managed more frequently (90.9% versus 86.3%, P=0.002), and had less end-organ malperfusion (2.4% versus 5.7%, P<0.001) and higher in-hospital mortality (5.3% versus 2.7%, P=0.002) than men. In multivariable analysis, age (per year, odds ratio [OR], 1.06 [95% CI, 1.03-1.08]; P<0.001), hyperlipidemia (OR, 2.09 [95% CI, 1.13-3.88]; P=0.019), painlessness (OR, 2.59 [95% CI, 1.14-5.89]; P=0.023), shock/hypotension (OR, 2.93 [95% CI, 1.21-7.11]; P=0.017), non-intramural hematoma (OR, 2.31 [95% CI, 1.32-4.05]; P=0.004), aortic rupture (OR, 26.6 [95% CI, 14.1-50.0]; P<0.001), and end-organ malperfusion (OR, 4.61 [95% CI, 2.11-10.1]; P<0.001) were associated with higher in-hospital mortality, but was not female sex (OR, 1.67 [95% CI, 0.96-2.91]; P=0.072). Conclusions Women affected with type B acute aortic dissection were older and had more intramural hematoma, a lower incidence of end-organ malperfusion, and higher in-hospital mortality than men. However, female sex was not associated with in-hospital mortality after multivariable adjustment.

Perforation of the right atrial appendage during implantation of a leadless pacemaker.

We report a case of perforation of the right atrial appendage during implantation of a leadless pacemaker in a 94 years old woman. We performed emergency surgery to repair the perforation site. To our konwledge, there are few reports of right atrial perforation during a leadless pacemaker indwelling.

Usefulness of hybrid veno-arterial extracorporeal membrane oxygenation for lung ischemia-reperfusion injury after biventricular assist device implantation.

We experienced a case of fulminant myocarditis complicated by severe lung ischemia-reperfusion injury after switching from veno-arterial extracorporeal membrane oxygenation to biventricular assist device. We controlled lung blood flow by hybrid veno-arterial extracorporeal membrane oxygenation, which was established by modifying the biventricular assist device circuit without resternotomy, blood delivery to the pulmonary artery and blood removal from the left ventricle in addition to central veno-arterial extracorporeal membrane oxygenation, and accelerated lung recovery. The patient's lung damage and cardiac function were restored, and she completely recovered and was discharged without any complications. Regulation of lung blood flow is important and effective for lung ischemia-reperfusion injury after biventricular assist device implantation.

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.

Subcellular dynamics of estrogen-related receptors involved in transrepression through interactions with scaffold attachment factor B1.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, ß, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRß, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics.

Risk analysis for early mortality in emergency acute type A aortic dissection surgery: experience of Tokyo Acute Aortic Super-network.

OBJECTIVES: We investigated the various pre- and postoperative complications related to early (30-day) mortality after open surgery for acute type A aortic dissection. METHODS: Data from the Tokyo Acute Aortic Super-network database spanning January 2015 to December 2017 were retrospectively reviewed. Pre- and postoperative factors related to early postoperative mortality were assessed in 1504 of 2058 (73.0%) consecutive patients [age: 66.6 (SD: 13.5) years, male: 52.9%] who underwent acute type A aortic dissection repair. RESULTS: The early mortality rate following surgical repair was 8.9%. According to multivariable analysis, male sex [odds ratio (OR) 1.670, 95% confidence interval (CI) 1.063-2.624, P = 0.026], use of percutaneous circulatory assist devices (n = 116, 7.7%) including extracorporeal membrane oxygenators or intra-aortic balloon pumps (OR 4.857, 95% CI 2.867-8.228, P < 0.001), shock (n = 162, 10.8%) (OR 3.06, 95% CI 1.741-5.387, P < 0.001), cardiopulmonary arrest (n = 41, 2.7%) (OR 7.534, 95% CI 3.407-16.661, P < 0.001), coronary ischaemia (n = 36, 2.3%) (OR 2.583, 95% CI 1.042-6.404, P = 0.041) and cerebral ischaemia (n = 59, 3.9%) (OR 2.904, 95% CI 1.347-6.261, P = 0.007) were independent preoperative risk factors for early mortality, while cardiac tamponade (n = 34, 2.3%) (OR 10.282, 95% CI 4.640-22.785, P < 0.001), cerebral ischaemia (n = 80, 5.3%) (OR 2.409, 95% CI 1.179-4.923, P = 0.016) and mesenteric ischaemia (n = 15, 1.0%) (OR 44.763, 95% CI 13.027-153.808, P < 0.001) were independent postoperative risk factors. CONCLUSIONS: Not only critical preoperative conditions but also postoperative cardiac tamponade and vital organ ischaemia are risk factors for early mortality after acute type A aortic dissection repair.

Scaffold attachment factor B: distribution and interaction with ERα in the rat brain.

Scaffold attachment factor (SAFB) 1 and its homologue SAFB2 are multifunctional proteins that are involved in various cellular mechanisms, including chromatin organization and transcriptional regulation, and are also corepressors of estrogen receptor alpha (ERα). Both SAFBs are expressed at high levels in the brain. However, the distributions of SAFB1 and SAFB2 have yet to be characterized in detail and it is unclear whether both proteins interact with ERα in the brain. In this study, we investigated the expression and distribution of both SAFBs and their interaction with ERα in adult male rat brain. Immunohistochemical staining showed that SAFB1 and SAFB2 have a similar distribution pattern and are widely expressed throughout the brain. Double-fluorescence immunohistochemical and immunocytochemical analyses in primary cultures showed that the two SAFB proteins are localized in nuclei of neurons, astrocytes, and oligodendrocytes. Of note, SAFB2 was also found in cytoplasmic regions in these cell lineages. Both SAFB proteins were also expressed in ERα-positive cells in the medial preoptic area (MPOA) and arcuate and ventromedial hypothalamic nuclei. Co-immunoprecipitation experiments revealed that both SAFB proteins from the MPOA reciprocally interact with endogenous ERα. These results indicate that, in addition to a role in basal cellular function in the brain, the SAFB proteins may serve as ERα corepressors in hormone-sensitive regions.

Knee-Hip-Spine Syndrome: Improvement in Preoperative Abnormal Posture following Total Knee Arthroplasty.

An ergonomic upright body posture is maintained by the alignment of the spine, pelvis, and lower extremities, and the muscle strength of body trunk and lower extremities. The posture varies with age because of the degenerative changes in the involved structures and the weakening of the muscles. The compensatory mechanisms underlying these changes have recently been evaluated, and the loss of lumbar lordosis results in spinal kyphosis, pelvic retroversion, hip extension, knee flexion, and ankle dorsiflexion. These mechanisms are referred to as the hip-spine and knee-spine syndromes. The spine, hip, and knee are anatomically connected, and the pain and discomfort of the lower back, hip, and knee frequently arise due to degenerative changes of these structures. Thus, these mechanisms are considered as the knee-hip-spine syndrome. Spinal fusion, total hip arthroplasty, and total knee arthroplasty are the surgical procedures for severe degeneration, and their clinical outcomes for the affected sites are promising. However, despite surgeries, other structures may degenerate and result in complications, such as proximal junctional kyphosis and hip dislocation, following spinal fusion. Therefore, it is necessary to evaluate each patient under specific conditions and to treat each section while considering associations between the target structure and entire body. The purpose of this article is to introduce postural maintenance, variations with age, and improvements with surgical interventions of spine, hip, and knee as the knee-hip-spine syndrome.

Is systolic blood pressure high in patients with acute aortic dissection on first medical contact before hospital transfer?

Acute aortic dissection (AAD) cases are thought to have high blood pressure (BP) on admission; however, little data are available on BP prior to admission. The purpose of this study was to investigate systolic blood pressure (SBP) very early after symptom onset and before hospital transfer in patients with AAD to determine whether SBPs were high, and also whether SBPs were higher or lower compared with SBPs at hospital admission. We obtained results using three-year data derived from the Tokyo Acute Aortic Super Network Database. First, we selected 830 patients with AAD for which the "duration from symptom onset to first medical contact by ambulance crews" (SO-FMC) was within 60 min. We examined the SBPs of such patients. Next, we selected 222 patients with AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, and compared SBPs at FMC with those at hospital admission. Among types A (n = 190) and B (n = 117), in patients with an SO-FMC ≤ 15 min, the median SBP was 100 mmHg and 178 mmHg (p < 0.001), respectively; 9% and 50% (p < 0.001) of such patients, respectively, exhibited an SBP ≥ 180 mmHg; and 43% and 10% (p < 0.001) of such patients, respectively, had an SBP < 90 mmHg. Of patients with types A (n = 124) and B (n = 98) AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, SBPs at FMC were higher than those at hospital admission for the SBP ≥ 180 mmHg subgroups of both type A (194 mmHg vs. 159 mmHg, p < 0.001) and type B (199 mmHg vs. 186 mmHg, p < 0.001). Approximately 10 min after symptom onset and before hospital transfer, the measured SBPs of many patients with type A AAD were not necessarily high. However, the SBPs of cases with type B AAD were high as previously reported for SBP on admission. In addition, for the subgroup of SBP ≥ 180 mmHg at FMC within 15 min after symptom onset, SBPs at FMC were significantly higher than those at hospital admission for both types A and B; the higher SBP at symptom onset may have been partially associated with being a trigger of AD.

A case of HeartMate II implantation in non-dilated left ventricle.

Left ventricular assist device is an established therapeutic option for the patient with end-stage heart failure. Recently, durable continuous-flow devices have replaced earlier generation of pulsatile devices and their desirable features are accelerating the utilization of these devices. However, their powerful performance could sometimes induce unfavorable complications such as sucking, especially in not so dilated left ventricle. Special maneuvers such as cannula position and lower pump speed may be reasonable for patients with non-dilated left ventricular, however, those managements have not been established yet to date. Right ventricular failure is also another concern in these devices. We experienced a patient who got a HeartMate II in spade-shaped, non-dilated left ventricle concomitant with right ventricular dysfunction, and successfully managed her.

Distribution of endogenous normal tau in the mouse brain.

Tau is a microtubule-associated protein (MAP) that is localized to the axon. In Alzheimer's disease (AD), the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. While the abnormal aggregated tau has been extensively studied in human patient tissues and animal models of AD, how normal tau localizes to the axon, which would be the foundation to understand how the mis-localization occurs, has not been well studied due to the poor detectability of normal unaggregated tau in vivo. Therefore, we developed immunohistochemical techniques that can detect normal mouse and human tau in brain tissues with high sensitivity. Using these techniques, we demonstrate the global distribution of tau in the mouse brain and confirmed that normal tau is exclusively localized to the axonal compartment in vivo. Interestingly, tau antibodies strongly labeled nonmyelinated axons such as hippocampal mossy fibers, while white matters generally exhibited low levels of immunoreactivity. Furthermore, mouse tau is highly expressed not only in neurons but also in oligodendrocytes. With super resolution imaging using the stimulated-depletion microscopy, axonal tau appeared punctate rather than fibrous, indicating that tau decorates microtubules sparsely. Co-labeling with presynaptic and postsynaptic markers revealed that normal tau is not localized to synapses but sparsely distributes in the axon. Taken together, this study reports novel antibodies to investigate the localization and mis-localization of tau in vivo and novel findings of normal tau localization in the mouse brain.

Intranuclear Mobility of Estrogen Receptor: Implication for Transcriptional Regulation.

The estrogen receptor (ER) is a ligand-dependent transcription factor that has two subtypes: ERα and ERß. ERs regulate transcription of estrogen-responsive genes through interactions with multiple intranuclear components, such as cofactors and the nuclear matrix. Live cell imaging using fluorescent protein-labeled ERs has revealed that ligand-activated ERs are highly mobile in the nucleus, with transient association with the DNA and nuclear matrix. Scaffold attachment factor B (SAFB) 1 and its paralogue, SAFB2, are nuclear matrix-binding proteins that negatively modulate ERα-mediated transcription. Expression of SAFB1 and SAFB2 reduces the mobility of ERα in the presence of ligand. This regulatory machinery is emerging as an epigenetic-like mechanism that alters transcriptional activity through control of intranuclear molecular mobility.