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PubMed1998

Long-term survival of VDD pacing.

UNLABELLED: All patients with VDD systems implanted at a tertiary pacing center were identified from a computer database and data collected on pacing indications, follow-up duration, rate response, reasons for programming changes, and implant P wave amplitudes. RESULTS: 366 implants were identified for which complete data were available for 335 leads implanted in 316 patients. The mean follow-up period was 24.1 months, and age at implant was 73.5 +/- 11.8 years. During follow-up, 19 patients died (6%) and 62 (19.6%) were followed elsewhere. Indications for pacing were complete heart block, 56.6%; intermittent AV block, 21.8%; postablation complete heart block, 5.4%; 2:1 AV block, 13%; and others, 3.2%. Two groups: no mode change (NMC, n = 280) and mode change (MC, n = 36) were identified. Reasons for reprogramming in the MC group were as follows: atrial sensing, 11; AF/atrial flutter, 18; chronotropic incompetence, 3; and others 4. Significantly more MC patients had rate response programmed ON (44.4% vs 22.1%, P < 0.05). No significant differences between the two groups were found in other variables, including male gender (55.5% vs 54.6%), length of follow-up (27.1 +/- 17.8 vs 23.8 +/- 20.6 months), age at last follow-up (72 +/- 12.3 vs 75.9 +/- 11.9 years), and P wave amplitude (1.7 +/- 0.9 vs 1.8 +/- 0.9 mV). CONCLUSION: Reprogramming of VDD systems is infrequent. When necessary, it is usually prompted by atrial arrhythmias or failure of atrial sensing. When adequate atrial chronotropy has been verified, VDD is an acceptable alternative to DDD pacing and survives well over the long term.

Aged↗
PubMed1999

Late retesting of system performance in ICD patients without spontaneous shocks.

UNLABELLED: One hundred five implantable cardioverter defibrillator (ICD) patients (71 +/- 9 years of age, 83% men) without spontaneous ICD discharges for > or = 12 months were tested to assess high voltage (HV) circuit integrity and the system's ability to recognize and terminate ventricular fibrillation (VF). Indications for ICD implantation were sustained ventricular tachycardia (VT) (35%), cardiac arrest (27%), and inducible VT (38%). Eighty-two percent of the patients had coronary artery disease (CAD), and the mean left ventricular ejection fraction (LVEF) was 36% +/- 13%. RESULTS: One hundred patients had inducible VF and five did not. Testing led to ICD reprogramming in 50 (49%) patients. Two (1.9%) patients required ICD replacement: (1) a 45-year-old patient with a Ventritex 110 ICD implanted for 13 months interfaced with a CPI 0062 lead implanted for 46 months could not be defibrillated internally (impedance nonmeasurable); (2) an 82-year-old patient with a 23-month-old Medtronic 7219 ICD interfaced with 6936 and 6933 leads whose defibrillation threshold (DFT) had doubled since implantation (24 J from 12 J). Lead fractures were found in both cases (proximal coil of the 0062, and subcutaneously in the 6933). Based on DFT determinations, the first shock output was programmed lower in 37 patients and higher in 10 patients. Shock pulse width was changed in one patient and the ventricular refractory period in another. No programming changes were made in 54 (51%) patients. CONCLUSIONS: (1) Late testing of HV circuit integrity in ICD patients without an ICD shock in > or = 12 months identifies previously unsuspected HV lead fractures; (2) chronic DFT testing resulted in HV output reprogramming in one-half of the patients.

Adult↗
PubMed2005

Value of pre-hospital discharge defibrillation testing in recipients of implanted cardioverter defibrillators.

Opinions vary regarding the need to perform defibrillation testing prior to hospital discharge in recipients of state-of-the-art cardioverter defibrillators (ICDs). Our protocol is to perform predischarge ICD testing 1 day after implant. This report includes 682 consecutive implants. Adverse observations at testing were grouped into (1) risk of defibrillation failure, (2) surgical complications, (3) sensing/pacing issues or narrow defibrillation margin warranting closer follow-up, or (4) findings correctable by device reprogramming. Among the 682 patients, 63% had single-chamber and 37% dual-chamber or biventricular ICDs. In 48 patients (7%) there were 69 concerns and/or interventions, with overlaps among the four categories, including one failure to defibrillate (0.15%), and six other patients at risk. Surgical complications included 11 hematomas (1.6%), and six lead dysfunctions. Closer follow-up was indicated in 19 patients (2.7%), for high pacing thresholds in seven, sensing issues in seven, and <10 J defibrillation margin in five. Device reprogramming was needed in 31 patients (4.5%), for tachycardia detection and therapy settings in 12, and for pacing/sensing functions in 22 patients. In eight patients ventricular fibrillation could not be induced. There was no morbidity or mortality due to testing. The state-of-the-art ICDs delivering biphasic shocks are remarkably reliable. The routine pre-hospital discharge defibrillation testing of such ICDs may be optional and left to the physicians' discretion.

Defibrillators, Implantable↗
PubMed2005

Strategies for the safe magnetic resonance imaging of pacemaker-dependent patients.

OBJECTIVE: To determine if strategies used to safely scan nonpacemaker-dependent patients could be applied to facilitate safe MRI of pacemaker-dependent patients. INTERVENTIONS: Ten pacemaker-dependent patients underwent a total of 11 MRI scans of the head and neck. Screening, reprogramming VOO or DOO at 60 ppm, and monitoring strategies were used to facilitate MRI. A transmit-receive coil was used and MRI pulse sequences were modified to limit the whole-body specific absorption rate (SAR). RESULTS: All scans proceeded uneventfully. No difficulties in post-MRI telemetry or interrogation were seen and no post-MRI programming changes were noted. No patient experienced arrhythmia or symptoms during or immediately after MRI. Battery status remained unchanged. No patient experienced post-MRI change in sensing thresholds. Three patients showed no change in the atrial or ventricular pacing thresholds when the pre-MRI values were compared to the immediate post-MRI values and the 3-month follow-up values. All other patients showed a rise or fall of 0.5 V in their chamber threshold values when the pre-MRI, post-MRI, and 3-month follow-up values were compared. More patients showed a fall in their pacing thresholds than a rise post-MRI. CONCLUSION: While clearly a higher risk group, like nonpacemaker-dependent patients, MRI might be performed in pacemaker-dependent patients if appropriate pacemaker reprogramming, patient monitoring, and MRI scanning techniques are implemented.

Humans↗
PubMed2005

Outcome of magnetic resonance imaging (MRI) in selected patients with implantable cardioverter defibrillators (ICDs).

OBJECTIVE: To determine if simple strategies used to safely scan pacemaker patients could be applied to implantable cardioverter defibrillator (ICD), patients undergoing MRI allowing ICD patients to undergo MRI as well. INTERVENTIONS: Screening, reprogramming, and monitoring strategies were used to facilitate MRI. RESULTS: Seven patients underwent eight MRI scans at 1.5 T. Post-MRI, all devices demonstrated no change in pacing, sensing, impedances, charge times, or battery status. The patient undergoing a lumbar spine scan experienced a "power-on-reset" of his ICD without permanent impairment of his device. CONCLUSION: Scanning of ICD patients might be performed if appropriate reprogramming and monitoring is implemented.

Defibrillators, Implantable↗
PubMedDate not supplied

Stemness, fusion and renewal of hematopoietic and embryonic stem cells.

Development of replacement cell therapies awaits the identification of factors that regulate nuclear reprogramming and the mechanisms that control stem cell renewal and differentiation. Once such factors and signals will begin to be elucidated, new technologies will have to be envisaged where uniform differentiation of adult or embryonic stem cells along one differentiation pathway can be induced. Controlled differentiation of stem cells will require the engineering of niches and extracellular signal combinations that would amplify a particular signaling network and allow uniform and selective differentiation. Three recent advances in stem cell research open the possibility to approach engineering studies for cell replacement therapies. Fusion events between stem cells and adult cells or between adult and embryonic stem cells have been shown to result in altered fates and nuclear reprogramming of cell hybrids. Hematopoietic stem cells were shown to require Wnt signaling in order to renew. The purification of Wnt proteins would allow their use as exogenous purified cytokines in attempts to amplify stem cells before bone marrow transplantation. The homeodomain protein Nanog has been shown to be crucial for the embryonic stem cell renewal and pluripotency. However, the cardinal question of how stemness is preserved in the early embryo and adult stem cells remains opened.

Animals↗
PubMed2004

Transcriptional response of Candida albicans upon internalization by macrophages.

The opportunistic fungal pathogen Candida albicans is both a benign gut commensal and a frequently fatal systemic pathogen. The interaction of C. albicans with the host's innate immune system is the primary factor in this balance; defects in innate immunity predispose the patient to disseminated candidiasis. Because of the central importance of phagocytic cells in defense against fungal infections, we have investigated the response of C. albicans to phagocytosis by mammalian macrophages using genomic transcript profiling. This analysis reveals a dramatic reprogramming of transcription in C. albicans that occurs in two successive steps. In the early phase cells shift to a starvation mode, including gluconeogenic growth, activation of fatty acid degradation, and downregulation of translation. In a later phase, as hyphal growth enables C. albicans to escape from the macrophage, cells quickly resume glycolytic growth. In addition, there is a substantial nonmetabolic response imbedded in the early phase, including machinery for DNA damage repair, oxidative stress responses, peptide uptake systems, and arginine biosynthesis. Further, a surprising percentage of the genes that respond specifically to macrophage contact have no known homologs, suggesting that the organism has undergone substantial evolutionary adaptations to the commensal or pathogen lifestyle. This transcriptional reprogramming is almost wholly absent in the related, but nonpathogenic, yeast Saccharomyces cerevisiae, suggesting that these large-scale and coordinated changes contribute significantly to the ability of this organism to survive and cause disease in vivo.

Animals↗
PubMed1996

Low-dose lipopolysaccharide (LPS) pretreatment of mouse macrophages modulates LPS-dependent interleukin-6 production in vitro.

Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of cytokines and other inflammatory mediators. Our laboratory previously reported that LPS-dependent macrophage-derived tumor necrosis factor alpha (TNF-alpha) production could be significantly potentiated by pretreatment with LPS at substimulatory LPS priming doses. The observed potentiation was shown to be coincident with a down-regulation of LPS-dependent nitric oxide (NO) production (X. Zhang and D. C. Morrison, J. Exp. Med. 177: 511-516, 1993). In order to determine whether these LPS reprogramming effects in mouse macrophages were selective for these two macrophage-derived mediators, we have examined the effects of LPS pretreatment on LPS-dependent interleukin 6 (IL-6) production. Thioglycolate-elicited mouse peritoneal macrophages were pretreated with various subthreshold stimulatory concentrations of LPS for 6 h, washed three times, and then stimulated with an effective stimulatory concentration of smooth LPS for 18 h. In confirmation of earlier studies, pretreatment of mouse macrophages with substimulatory doses of LPS inhibited the subsequent LPS-dependent NO production. This down-regulation was accompanied by a coordinate up-regulation of LPS-dependent IL-6 production, similar to what was shown earlier for TNF-alpha production. These priming effects with the substimulatory dose of smooth LPS are shown to be independent of doses of LPS used for subsequent activation and are not restricted to specific LPS stimulation. Moreover, the enhancement of the IL-6 response by LPS pretreatment is still observed in the presence of neutralizing antibody to TNF-alpha. These findings, therefore, provide further support for the conclusion that LPS-dependent macrophage reprogramming is likely to involve common regulatory pathways that control the secretion of both IL-6 and TNF-alpha.

Animals↗
PubMed2002

Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities.

Cellular infection by cytomegalovirus (CMV) is associated with very early G-protein-mediated signal transduction and reprogramming of gene expression. Here we investigated the involvement of human CMV (HCMV)-encoded US27, US28, and UL33 receptors as well as murine CMV-encoded M33 transmembrane (7TM) receptors in host cell signaling mechanisms. HCMV-encoded US27 did not show any constitutive activity in any of the studied signaling pathways; in contrast, US28 and M33 displayed ligand-independent, constitutive signaling through the G protein q (Gq)/phospholipase C pathway. In addition, M33 and US28 also activated the transcription factor NF-kappaB as well as the cyclic AMP response element binding protein (CREB) in a ligand-independent, constitutive manner. The use of specific inhibitors indicated that the p38 mitogen-activated protein (MAP) kinase but not the extracellular signal-regulated kinase 1/2-MAP kinase pathway is involved in M33- and US28-mediated CREB activation but not NF-kappaB activation. Interestingly, UL33-the HCMV-encoded structural homologue of M33-was only marginally constitutively active in the Gq/phospholipase C turnover and CREB activation assays and did not show any constitutive activity in the NF-kappaB pathway, where M33 and US28 were highly active. Hence, CMVs appear to have conserved mechanisms for regulating host gene transcription, i.e., constitutive activation of certain kinases and transcription factors through the constitutive activities of 7TM proteins. These data, together with the previous identification of the incorporation of such proteins in the viral envelope, suggest that these proteins could be involved in the very early reprogramming of the host cell during viral infection.

Animals↗
PubMed2005

Interactions with pocket proteins contribute to the role of human papillomavirus type 16 E7 in the papillomavirus life cycle.

Human papillomaviruses (HPVs), most commonly the HPV16 genotype, are the principle etiological determinant for cervical cancer, a common cancer worldwide resulting in over 200,000 deaths annually. The oncogenic properties of HPVs are attributable in part to the virally encoded protein E7, best known for its ability to bind to and induce the degradation of the retinoblastoma tumor suppressor, pRb, and related "pocket proteins" p107 and p130. Previously, we defined a role for E7 in the productive stage of the HPV16 life cycle, which takes place in stratified squamous epithelia. HPV perturbs the normal processes of cell growth and differentiation of stratified squamous epithelia. HPVs reprogram cells to support continued DNA synthesis and inhibit their differentiation in the suprabasal compartment of the epithelia, where cells normally have withdrawn from the cell cycle and initiated a well-defined pattern of terminal differentiation. These virus-induced perturbations, which contribute to the production of progeny HPVs, are dependent on E7. In this study, we define the mechanism of action by which E7 contributes to the productive stage of the HPV16 life cycle. We found that the ability of HPV16 to reprogram suprabasal cells to support DNA synthesis correlates with E7's ability to bind pocket proteins but not its ability to induce their degradation. In contrast, the ability of HPV16 to perturb differentiation correlated with both E7's binding to and degradation of pocket proteins. These data indicate that different hallmarks of the productive stage of the HPV16 life cycle rely upon different sets of requirements for E7.

Animals↗
PubMed1995

Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems.

OBJECTIVE: To evaluate the incidence of intraoperative and early postoperative complications (up to two months after implant) of endocardial permanent pacemaker insertion in all patients under-going a first implant at a referral centre. METHODS: Prospective evaluation of all endocardial pacemaker implantation procedures performed from April 1992 to January 1994 carried out by completion of standard audit form at implant. Patients' demographic data, medical history, details of pacemaker hardware used, and any complications were noted. Follow up information was also collected prospectively onto standard forms at pacemaker outpatient clinic. SETTING: United Kingdom tertiary referral cardiothoracic centre. PATIENTS: 1088 consecutive patients underwent implantation of their first endocardial permanent pacemaker from April 1992 to January 1994. Implant and follow up data were available for 1059 (97.3%) patients at analysis. The median (range) age was 77 years (16-99); 51.2 % were male. RESULTS: Dual chamber units were implanted in 54.1% of patients, single chamber atrial in 5.2%, and ventricular in 40.7%. A temporary pacing lead was present at implant in 22.9% of patients. Most (93.6%) implants were performed via the subclavian vein. Immediate complications were rare: eight (0.8%) patients developed pneumothorax requiring medical treatment and 11 (1.0%) an insignificant pneumothorax. There was no significant difference in the pneumothorax rate for dual chamber (DDD) compared with single chamber systems. Arterial puncture without sequelae was documented in 2.7% of attempts at subclavian vein cannulation. A total of 35 patients (3.3%) required reoperation; the reoperation rate for dual chamber (3.5%) was similar to that for single chamber (3.1%) systems. Electrode displacement (n = 15, 1.4%) was the most common reason for reoperation. Atrial lead displacement (n = 10, 1.6% of atrial leads) was significantly more common than ventricular lead displacement (n = 5, 0.5% of ventricular leads, P = 0.047). There was no difference in electrode displacement rates for dual (1.6%) compared with single (1.2%) chamber systems. Pacemaker pocket infection led to reoperation in 10 patients (six dual, four single chamber, P = not significant) and was significantly more common in patients who had a temporary pacing lead in place at implant (2.9%) than in those who did not (0.4%, P = 0.0014). Five patients (0.5%) required reoperation for generator erosion (two dual, three single chamber, P = not significant). and a further five for drainage of haematoma or a serous fluid collection (three dual, two single chamber, P = not significant). Complications that did not require reoperation were also rare. Undersensing occurred in 10 patients (0.9%). Atrial undersensing (n = 8) was significantly more common than ventricular undersensing (n = 2, P = 0.017). All patients were successfully treated by reprogramming of sensitivity. Superficial wound infection was treated successfully with antibiotics in nine patients (six dual, three single chamber, P = not significant). Three patients with DDD generators developed sustained atrial fibrillation: two required reprogramming to VVI mode and one required cardioversion. CONCLUSIONS: Permanent pacing in a large tertiary referral centre with experienced operators carries a low risk. Infection rates are low, < 1% overall but significantly higher in patients who undergo temporary pacing before implantation. Lead displacement and undersensing are more likely to occur with atrial than ventricular leads. The overall complication rate for dual chamber pacing, however, is no higher than for single chamber pacing.

Adolescent↗
PubMed1993

Coding of movement direction and amplitude in Parkinson's disease: are they differentially impaired (or unimportant)?

A recent study suggested that the preparation of movement direction, but not amplitude, may be selectively impaired by Parkinson's disease (PD). The authors examined the reprogramming of direction only, amplitude only, and direction and amplitude together, and included a control condition in which neither parameter was reprogrammed. The findings suggested that neither direction nor amplitude coding was differentially impaired in PD. Thus the structures affected by PD may not be uniquely involved in specifying only the direction or the amplitude of future movements; these structures probably have more complex higher-level roles.

Aged↗
PubMed1998

How do monoclonal antibodies induce tolerance? A role for infectious tolerance?

One of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mild-1980s that CD4 antibodies can induce immunological tolerance without depleting CD4+ T cells has reawakened interest in the use of nondepleting monoclonal antibodies for reprogramming the immune system in autoimmunity and in transplantation. Since that time, antibodies to CD11a, CD4OL, CD25, CD3, and CTLA4-Ig have all been shown capable of facilitating tolerance. In order to apply to principle of reprogramming in the clinic, we have sought to understand the mechanisms that are involved in its induction and its maintenance. In a number of allogeneic transplant models (heart, skin, bone marrow) anti-CD4 (+/- CD8) antibodies can be shown to block the rejection process while selectively promoting the development of CD4+ regulatory T cells responsible for a dominant tolerance that is reflected in findings of linked suppression and infectious tolerance. In these models, T cells that have never been exposed to CD4 antibodies become tolerant to grafted antigens by experiencing antigen in the microenvironment of regulatory T cells. Dominant tolerance is not the only mechanism that can be facilitated by CD4 Mab therapy. If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion. The mechanism by which regulatory CD4+ T cell suppress is not yet defined but could be active or passive. We have proposed the "civil service model" to explain how tolerant T cells might interfere with the responses of competent T cells in such a way as to render them tolerant.

Animals↗
PubMed2006

[Safety and effectiveness of single-lead VDD pacing].

INTRODUCTION AND OBJECTIVES: Single-lead VDD pacing provides the physiological benefits of atrioventricular synchrony with the convenience of a single-lead system. However, concern remains about the method's safety and effectiveness. METHOD: In total, 700 patients with single-lead VDD pacemakers were evaluated retrospectively. The following parameters were recorded: age, sex, etiology, the symptoms and electrocardiographic diagnosis that justified pacemaker implantation, the venous access route used for implantation, atrial sensing at implantation, atrial undersensing at follow-up, the occurrence of supraventricular tachyarrhythmias, and final pacing mode. RESULTS: Third-degree atrioventricular block was the main indication for pacemaker implantation (66.4%). The most commonly used venous access route was via the right cephalic vein (49.1%). At implantation, the mean atrial signal was 1.8 (4 1.15) mV. During follow-up, significant atrial undersensing occurred in 7.7% of patients; in 1.9%, it could not be corrected by device reprogramming. Uncontrollable supraventricular arrhythmias were observed in 6.4% of patients. Symptomatic sinus node disease was rare. By the end of follow-up, 91.4% of patients were still on VDD pacing, while, in 8.3%, the pacemaker had to be reprogrammed to the VVI mode. Only 0.3% required atrial lead implantation for DDD pacing. Left-side venous access during implantation was a independent predictora of atrial undersensing at follow-up. Low values of atrial detection at implant did not reach statistical signification although it showed a remarkable trend. CONCLUSIONS: Single-lead VDD pacing seems to be safe and effective when appropriately indicated. Our findings are consistent with those of previously published studies.

Adult↗
PubMed2006

Antiangiogenic antithrombin induces global changes in the gene expression profile of endothelial cells.

Antithrombin, a serpin family protease inhibitor crucial to hemostasis, acquires antiangiogenic properties on undergoing conformational alterations induced by limited proteolysis or elevated temperature. To better understand the biochemical mechanisms underlying antithrombin antiangiogenic activity, we did genome-wide expression profiling, coupled with quantitative reverse transcription-PCR, Northern blot, and Western blot analyses, to characterize the gene expression patterns that are induced by antiangiogenic antithrombin in cultured primary human umbilical vein endothelial cells. Overall, 35 genes with significantly increased expression and 93 genes with significantly reduced expression (> or =2-fold changes) due to antiangiogenic antithrombin treatment were identified. More than half of the down-regulated genes have well-established proangiogenic functions in endothelial cells, including cell-surface and matrix proteoglycans (e.g., perlecan, biglycan, and syndecans 1 and 3) and mitogenesis-related signaling proteins (e.g., mitogen-activated protein kinase 3, signal transducers and activators of transcription 2, 3, and 6, and early growth response factor 1). In contrast, most up-regulated genes (e.g., caspase-3, p21, tissue inhibitor of metalloproteinases 1, 2, and 3, and adenomatosis polyposis coli) are known for their antiangiogenic functions which include the promotion of cell apoptosis and cell cycle arrest and the inhibition of tumor growth and metastasis. These results show that the antiangiogenic activity of antithrombin is mediated at least in part by a global genetic reprogramming of endothelial cells and strongly implicate an endothelial cell ligand-receptor signaling mechanism in this reprogramming.

Angiogenesis Inhibitors↗
PubMed2025

Parkin Induces Ubiquitination and Large Extracellular Vesicle Release of HMGB1 to Activate Antitumor Immunity.

UNLABELLED: Parkin (PRKN) is a mitochondria-associated E3 ubiquitin ligase that mediates mitophagy and organelle quality control. More recently, PRKN has been implicated in stimulating antitumor immunity and reprogramming the tumor immune microenvironment. In this study, we showed that PRKN ubiquitinates the alarmin molecule, high-mobility group box-1 (HMGB1) on Lys146 (K146) using predominantly K48 linkages. By molecular modeling, the in-between-ring domain of PRKN (Gln326-Leu358) made extensive contacts with the amino-terminus A-box of HMGB1 (Met1-Ser42), forming a mitochondria-associated PRKN-HMGB1 complex that juxtaposes K146 to ubiquitin active site residues Gly76 and Arg74. Instead of proteasomal degradation, PRKN ubiquitination of K146 enabled the loading of HMGB1 but not HMGB1 K146A mutant, onto autophagy- and mitochondria-derived large extracellular vesicles (LEV). In turn, released PRKN-HMGB1-LEV stimulated a potent IFN and cytokine response in recipient cells, expanding CD8+ T-cell subsets with effector (CD69+/KLRG1+), self-renewal (TCF1+/PD-1+), and cytotoxic (KLRG1+/GrzB+) properties. Conditional expression of PRKN induced HMGB1 release, activated intratumoral CD8+ T cells, and suppressed syngeneic tumor growth in vivo in a response that was abolished by HMGB1 silencing. These data identify that PRKN-LEV-regulated release of HMGB1 reprograms antitumor immunity via stimulation of IFN signaling and expansion of specialized CD8+ T-cell subsets. SIGNIFICANCE: Parkin ubiquitinates the alarmin molecule HMGB1 to enable its regulated release in large extracellular vesicles that activate interferon signaling, expand specialized CD8+ T-cell subsets, and promote antitumor immunity.

HMGB1 Protein↗
PubMed2004

Maternal and environmental factors in early cloned embryo development.

Cloning by somatic cell nuclear transfer (SCNT) in mammals has revealed the remarkable ability of an oocyte to reprogram somatic cell nuclei and induce them to recapitulate the developmental program. Despite the success, cloning remains very inefficient. This review summarizes recent observations from cloning in mice that reveal some of the likely causes for the present inefficiency. One cause appears to be the slow pace of reprogramming combined with the early onset of genome transcription, which together cause cloned embryos to elaborate many somatic cell characteristics even before the first cleavage division. The altered phenotypes of cloned embryos render standard embryo culture conditions grossly sub-optimum. Another cause appears to be a hitherto unappreciated contribution of spindle-associated factors to early embryo development. As current procedures remove the spindle and associated factors, cloned embryos lack these factors. These observations are providing new insight into basic mammalian embryology. They also reveal possible changes to protocols that could improve the overall success of cloning.

Animals↗
PubMed1997

Dissociation of left ventricular hypertrophy, beta-myosin heavy chain gene expression, and myosin isoform switch in rats after ascending aortic stenosis.

BACKGROUND: Reexpression of the fetal beta-myosin heavy chain (beta-MHC) gene was reported to be a marker for phenotypic reprogramming and cardiac hypertrophy in rats. Recent in vitro studies strongly suggested a role of angiotensin II for phenotypic reprogramming. In the present investigation, beta-MHC gene expression was studied in an experimental model of pressure-over-load hypertrophy that is not associated with a concurrent activation of the circulating renin-angiotensin system. METHODS AND RESULTS: Hypertrophy was induced in rats by ascending aortic banding (n = 40). After 7 days, myosin contained 31% (P < .05) of the beta-MHC isoform in banded but < 5% in sham-operated animals. However, no specific elevation of beta-MHC mRNA levels was found in banded animals. In contrast, hearts of rats with abdominal aortic banding displayed a marked increase in beta-MHC mRNA levels (3-fold to 5-fold, P < .05). Both the left ventricular weight and left ventricular peak systolic pressure were significantly elevated compared with sham-operated animals (abdominal aortic banding, +13% and 164 +/- 7 mm Hg; ascending aortic banding, +27% and 191 +/- 9 mm Hg). Plasma renin activity was elevated in rats with abdominal aortic banding (2.5-fold, P < .05) but not in rats with ascending aortic banding. CONCLUSIONS: The results of the present work do not support the concept that increased beta-MHC gene expression is a general "stable late marker" of myocardial hypertrophy in rats. Our results suggest that the stimulation of the renin-angiotensin system is crucial for the activation of the beta-MHC gene.

Analysis of Variance↗