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PubMed1985

Noninvasive evaluation of retrograde conduction times to avoid pacemaker-mediated tachycardia.

Pacemaker-mediated tachycardia is a potential complication of atrioventricular (AV) universal DDD pacemakers when retrograde ventriculoatrial (VA) conduction is slower than the postventricular-atrial refractory period of the pulse generator. The propensity for pacemaker-mediated tachycardia was noninvasively assessed in 17 patients with a unipolar DDD pacemaker using chest wall stimulation. Low amplitude stimuli were delivered to chest wall electrodes through a programmed stimulator. Using this method, 13 of the 17 patients were found to have absent VA conduction or VA conduction time less than the postventricular-atrial refractory period. In the four patients with noninvasively measured VA conduction time greater than the postventricular-atrial refractory period, sustained pacemaker-mediated tachycardia was induced. Reprogramming of pacemaker parameters prevented repeat induction of pacemaker-mediated tachycardia in only one of four patients. The three remaining patients had clinical pacemaker-mediated tachycardia and underwent pacemaker programming to the DVI mode. A total of 13 patients continue to use DDD mode after a mean follow-up period of 9.5 +/- 5.4 months. Invasive measurement of VA conduction was performed in 13 of the 17 patients. The noninvasive method accurately predicted the invasive measurement in each case. Noninvasive evaluation of VA conduction accurately predicts the propensity for pacemaker-mediated tachycardia under a variety of clinical conditions. Serial testing can be performed after pacemaker reprogramming or drug intervention. Noninvasive evaluation of retrograde VA conduction should predict most clinical episodes of pacemaker-mediated tachycardia.

Adult↗
PubMed2002

Epigenetics wins over genetics: induction of differentiation in tumor cells.

Malignant cells are genetically abnormal, but can the malignant phenotype revert to a non-malignant phenotype without correcting these genetic abnormalities? It has been found that this reversion can be achieved by reprogramming tumor cells by epigenetic changes induced by differentiation. The epigenetic suppression of malignancy by inducing differentiation bypasses the genetic abnormalities in tumor cells. Studies with myeloid leukemic cells have shown that some leukemic cells can be induced to differentiate by cytokines that control normal hematopoiesis, and that myeloid leukemic cells resistant to normal cytokines can be induced to differentiate by compounds that use alternative differentiation pathways. The epigenetic reprogramming of tumor cells by inducing differentiation has also been found with other types of tumors and can be used for tumor therapy. By this reversion of the malignant to non-malignant phenotype, epigenetics wins over genetics.

Animals↗
PubMedDate not supplied

Effect of donor cell age on the efficiency of nuclear transfer in rabbits.

The ability of rabbit fibroblasts of different ages to be reprogrammed following nuclear transfer (NT) to aged recipient oocytes was evaluated. The rate of NT blastocysts reconstructed with presumptive G1 stage morula cells or fetal fibroblasts was significantly higher (41.5% and 51.4%) than was those of cloned embryos reconstructed with fibroblasts from young (4-month-old) or aged (5-year-old) animals (16.7% and 7.1%, respectively, P < 0.025). Serum starvation significantly increased the development of NT embryos to the morula-blastocyst stage (67.6% versus 22.9%, P < 0.025). Transfer of 168 NT embryos derived from nuclei of morula cells and 106 control embryos into 21 recipients resulted in 10 pregnancies, 2 NT and 18 control pups, respectively. In the first experiment, transfer of 142 cleaved NT embryos reconstructed with fetal fibroblasts and 86 control embryos into eight recipient does resulted in five pregnancies and the birth of 20 control pups. In the second experiment, after transfer of 112 NT embryos derived from fetal fibroblasts into six recipients, 10 (8.9%) sites of implantation were revealed in two does (33.3%) on day 14 of gestation. This study provides evidence that nuclei of morula cells and fetal and adult fibroblasts differ in their ability to be reprogrammed by recipient cytoplasm following nuclear transfer.

Animals↗
PubMed1997

The 26S-proteasome: regulation and substrate recognition.

There is extensive reprogramming of the ATPase regulators of the 26S proteasome before the programmed elimination of the abdominal intersegmental muscles (ISM) after eclosion in Manduca sexta [1]. This extensive ATPase reprogramming only occurs in ISM which are destined to die and not in flight muscle (FM). The MS73 ATPase also increases in the proleg retractor muscles which die at a developmentally different stage to ISM. The non-ATPase regulator S5a shows a similar increase to the ATPase regulators. We have cloned the Manduca SUG2 ATPase and shown that this ATPase is a component of the 26S proteasome. This ATPase shows a similar increase in concentration to the other ATPases in 26S proteasomes before muscle death. The SUG2 ATPase is also associated with other smaller complexes besides the 26S proteasome which act as activators of the 26S proteasome. Finally, in a yeast two-hybrid genetic screen we have identified a protein in human brain which interacts with the MS73 ATPase (and human S6). The interacting protein contains 6 ankyrin repeats and is co-immunoprecipitated with anti-MS73 antiserum after in vitro transcription/translation. The ankyrin repeat protein may interact with the MS73 ATPase as part of the substrate recognition process by the 26S proteasome. Many proteins degraded by the 26S proteasome contain ankyrin repeats, e.g. IkB and some cyclins: binding through ankyrin repeats to an ATPase regulator may complement protein ubiquitination and S5a binding as recognition signals by the 26S proteasome.

Abdominal Muscles↗
PubMed2001

Ordered biochemical program of gene expression in cancer cells.

Our introduction of the molecular correlation concept and the key enzyme concept and the use of biologically meaningful tumor models and control systems resulted in the discovery of an ordered pattern of enzymic and metabolic imbalance and the elucidation of the linkage with transformation and progression. We showed that the biochemical and enzymic pattern of alterations was the result of a reprogramming of gene expression that was both quantitative and qualitative and was characteristic to neoplasia, since no similar pattern of imbalance was observed in any of the control normal, regenerating, or differentiating tissues. Important aspects of gene logic were identified. These include demonstration of operation of reciprocal control of activities of opposing key enzymes and antagonistic pathways of synthesis and catabolism in pyrimidine, purine, ornithine, and carbohydrate metabolism and recently in signal transduction. The extent of increase in the activities of key enzymes of pyrimidine and purine biosynthesis related to the absolute activity of the enzymes in resting liver. The qualitative alterations in gene expression included the isozyme shift of key regulatory enzymes. We identified a segment of gene expression that is essential for neoplasia. We pointed out the selective advantages that reprogramming of gene expression confers to cancer cells. Understanding these alterations in the enzymology and biochemistry of cancer cells made it possible to identify potentially sensitive targets for anticancer chemotherapy. In recent clinical studies we targeted the increased IMP dehydrogenase activity in leukemic blast cells by an inhibitor drug, tiazofurin, and achieved 77% responses, including complete remissions.

Animals↗
PubMed2003

Cloning adult farm animals: a review of the possibilities and problems associated with somatic cell nuclear transfer.

In 1997, Wilmut et al. announced the birth of Dolly, the first ever clone of an adult animal. To date, adult sheep, goats, cattle, mice, pigs, cats and rabbits have been cloned using somatic cell nuclear transfer. The ultimate challenge of cloning procedures is to reprogram the somatic cell nucleus for development of the early embryo. The cell type of choice for reprogramming the somatic nucleus is an enucleated oocyte. Given that somatic cells are easily obtained from adult animals, cultured in the laboratory and then genetically modified, cloning procedures are ideal for introducing specific genetic modifications in farm animals. Genetic modification of farm animals provides a means of studying genes involved in a variety of biological systems and disease processes. Moreover, genetically modified farm animals have created a new form of 'pharming' whereby farm animals serve as bioreactors for production of pharmaceuticals or organ donors. A major limitation of cloning procedures is the extreme inefficiency for producing live offspring. Dolly was the only live offspring produced after 277 attempts. Similar inefficiencies for cloning adult animals of other species have been described by others. Many factors related to cloning procedures and culture environment contribute to the death of clones, both in the embryonic and fetal periods as well as during neonatal life. Extreme inefficiencies of this magnitude, along with the fact that death of the surrogate may occur, continue to raise great concerns with cloning humans.

Animals↗
PubMed1996

Urothelial transformation into functional glandular tissue in situ by instructive mesenchymal induction.

It is generally believed that adult tissue is terminally differentiated. The ureter is derived from the metanephric diverticulum which, along with the derivatives of the metanephric mesoderm, forms the kidney. In our experiments, the left ureters of adult male athymic mouse hosts were severed below the kidney, and mesenchyme from neonatal rat seminal vesicles (SVM) was grafted to the cut end of the ureter, thus bringing adult mouse ureter epithelium (URE) in contact with neonatal rat SVM. After four to eight weeks, the in situ tissue recombinants were harvested, and the epithelial secretory proteins recovered. In 5 of 11 cases, an induction occurred, resulting in an in situ transformation of the non-glandular transitional epithelium of the adult mouse ureter into the simple columnar epithelium of the seminal vesicle (SV). Functional cytodifferentiation was examined in these neonatal rat SVM + adult mouse URE tissue recombinants using antibodies against SV-specific secretory (SVS) proteins of the mouse and rat. From the cut end of the ureter, the adult URE was induced to undergo SV morphogenesis, to express SV cytodifferentiation, and to produce the complete spectrum of major SVS proteins characteristic of the mouse. The induced seminal vesicle epithelium (SVE) also expressed androgen receptors (AR) which are not seen in urothelial tissue. Staining with Hoechst dye 33258, which can distinguish cells of mouse and rat origin, further demonstrated that the induced SVE was indeed of mouse origin and not a contaminant of the inducing rat SVM. in addition, neonatal mouse vaginal mesenchyme was grafted in situ beneath the bladder mucosa of adult male mice, and the host animals were killed after three months. The vaginal mesenchyme implanted into the bladders induced prostate-like acini, indicating that the above reprogramming of adult organs in situ is not an isolate occurrence. These results set a precedent for the "recreation" of new vital organs, such as the kidney, in situ by demonstrating that adult epithelial cells retain a developmental plasticity equivalent to their undifferentiated fetal counterparts and are capable of being reprogrammed in situ to express a completely new morphological, biochemical, and functional phenotype.

Animals↗
PubMed2002

Monoclonal mice generated by nuclear transfer from mature B and T donor cells.

Cloning from somatic cells is inefficient, with most clones dying during gestation. Cloning from embryonic stem (ES) cells is much more effective, suggesting that the nucleus of an embryonic cell is easier to reprogram. It is thus possible that most surviving clones are, in fact, derived from the nuclei of rare somatic stem cells present in adult tissues, rather than from the nuclei of differentiated cells, as has been assumed. Here we report the generation of monoclonal mice by nuclear transfer from mature lymphocytes. In a modified two-step cloning procedure, we established ES cells from cloned blastocysts and injected them into tetraploid blastocysts to generate mice. In this approach, the embryo is derived from the ES cells and the extra-embryonic tissues from the tetraploid host. Animals cloned from a B-cell nucleus were viable and carried fully rearranged immunoglobulin alleles in all tissues. Similarly, a mouse cloned from a T-cell nucleus carried rearranged T-cell-receptor genes in all tissues. This is an unequivocal demonstration that a terminally differentiated cell can be reprogrammed to produce an adult cloned animal.

Animals↗
PubMed2003

Developmentally regulated usage of Physarum DNA replication origins.

To determine the extent to which eukaryotic replication origins are developmentally regulated in transcriptionally competent cells, we compared origin use in untreated growing amoebae and plasmodia of Physarum polycephalum. At loci that contain genes transcribed in both developmental stages, such as the ribosomal RNA genes and two unlinked actin genes, we show that there is a similar replicational organization, with the same origins used with comparable efficiencies, as shown by two-dimensional agarose-gel electrophoresis. By contrast, we found cell-type-specific replication patterns for the homologous, unlinked profilin A (proA) and profilin P (proP) genes. proA is replicated from a promoter-proximal origin in amoebae, in which it is highly expressed, and is replicated passively in the plasmodium, in which it is not expressed. Conversely, proP is replicated passively and is not expressed in amoebae, but coincides with an efficient origin when highly expressed in the plasmodium. Our results show a reprogramming of S phase that is linked to the reprogramming of transcription during Physarum cell differentiation. This is achieved by the use of two classes of promoter-associated replication origins: those that are constitutively active and those that are developmentally regulated. This suggests that replication origins, like genes, are under epigenetic control associated with cellular differentiation.

Actins↗
PubMed2001

Modulation in vitro of H-ras oncogene expression by trans-splicing.

In man, activated N-, K- and H-ras oncogenes have been found in around 30% of the solid tumours tested. An exon known as IDX, which has been described previously and is located between exon 3 and exon 4A of the c-H-ras pre-mRNA, allows an alternative splicing process that results in the synthesis of the mRNA of a putative protein named p19. It has been suggested that this alternative pathway is less tumorigenic than that which results in the activation of p21. We have used the mammalian trans-splicing mechanism as a tool with which to modulate this particular pre-mRNA processing to produce mRNA similar to that of mature p19 RNA. The E4A exon of the activated H-ras gene was found to be a good target for external trans-splicing. We reprogrammed the rat carnitine octanoyltransferase exon 2 to specifically invade the terminal region of H-ras. Assays performed with this reprogrammed trans-exon showed that the trans-splicing product was obtained in competition with cis-splicing of the D intron of the H-ras gene, and was associated with concomitant down-modulation of D intron cis-splicing. We also found that the exon 4A of the human c-H-ras gene underwent successive trans-splicing rounds with an external exon.

Animals↗
PubMed2001

Bilateral extracorporeal shock wave lithotripsy in a spinal cord injury patient with a cardiac pacemaker.

OBJECTIVES: To review the precautions to be observed before and during extracorporeal shock wave lithotripsy (ESWL) in spinal cord injury (SCI) patients with a cardiac pacemaker and the safety of bilateral ESWL performed on the same day. DESIGN: A case report of bilateral ESWL in a SCI patient with a permanent cardiac pacemaker. SETTING: The Regional Spinal Injuries Centre, Southport, the Lithotripsy Unit, the Royal Liverpool University Hospitals NHS Trust, Liverpool, and the Department of Cardiology, Manchester Royal Infirmary, Manchester, UK. SUBJECT: A 43-year-old male sustained a T-4 fracture and developed paraplegia with a sensory level at T-2. During the post-injury period, he developed episodes of asystole requiring implantation of a dual chamber (DDD) permanent pacemaker. Twenty-one months later, he developed a right ureteric calculus with hydronephrosis. A radio-opaque shadow was seen in the left kidney with no hydronephrosis. During right ureteric stenting, the ureteric stone was pushed into the renal pelvis. 1,500 shock waves were delivered to this stone on the right side, followed by ESWL to the left intra-renal stone with 1250 shock waves. RESULTS: The patient tolerated ESWL to both kidneys. The pacemaker was reprogrammed to a single chamber ventricular pacing mode at 30 beats per minute with a reduced sensitivity during lithotripsy. There were no untoward cardiac events during or after lithotripsy. The serum creatinine was 45 micromol/l before lithotripsy and 44 micromol/l two weeks after ESWL. CONCLUSION: SCI patients with a cardiac pacemaker may be able to undergo extracorporeal shock wave lithotripsy following temporary reprogramming of the pacemaker. Bilateral, simultaneous ESWL is safe in the vast majority of patients provided that there is no risk of simultaneous ureteric obstruction by stone fragments. However, it should be remembered that a decrease in renal function could occur following bilateral ESWL of renal calculi.

Adult↗
PubMed2002

Gene expression profiling of Escherichia coli growth transitions: an expanded stringent response model.

When conditions cause bacterial growth to stop, extensive reprogramming of physiology and gene expression allows for the cell's survival. We used whole-genome DNA arrays to determine the system response in Escherichia coli cells experiencing transient growth arrest caused by glucose-lactose diauxie and H2O2 treatment, and also entry into stationary phase. The results show that growth-arrested cells induce stringent control of several gene systems. The vast majority of genes encoding the transcription and translation apparatus immediately downregulate, followed by a global return to steady state when growth resumes. Approximately one-half of the amino acid biosynthesis genes downregulate during growth arrest, with the notable exception of the his operon, which transiently upregulates in the diauxie experiment. Nucleotide biosynthesis downregulates, a result that is again consistent with the stringent response. Likewise, aerobic metabolism downregulates during growth arrest, and the results led us to suggest a model for stringent control of the ArcA regulon. The stationary phase stress response fully induces during growth arrest, whether transient or permanent, in a manner consistent with known mechanisms related to stringent control. Cells similarly induce the addiction module anti-toxin and toxin genes during growth arrest; the latter are known to inhibit translation and DNA replication. The results indicate that in all aspects of the response cells do not distinguish between transient and potentially permanent growth arrest (stationary phase). We introduce an expanded model for the stringent response that integrates induction of stationary phase survival genes and inhibition of transcription, translation and DNA replication. Central to the model is the reprogramming of transcription by guanosine tetraphosphate (ppGpp), which provides for the cell's rapid response to growth arrest and, by virtue of its brief half-life, the ability to quickly resume growth as changing conditions allow.

Amino Acids↗
PubMed2002

Chromatin remodeling in nuclear cloning.

Nuclear cloning is a procedure to create new animals by injecting somatic nuclei into unfertilized oocytes. Recent successes in mammalian cloning with differentiated adult nuclei strongly indicate that oocyte cytoplasm contains unidentified remarkable reprogramming activities with the capacity to erase the previous memory of cell differentiation. At the heart of this nuclear reprogramming lies chromatin remodeling as chromatin structure and function define cell differentiation through regulation of the transcriptional activities of the cells. Studies involving the modification of chromatin elements such as selective uptake or release of binding proteins, covalent histone modifications including acetylation and methylation, and DNA methylation should provide significant insight into the molecular mechanisms of nuclear dedifferentiation and redifferentiation in oocyte cytoplasm.

Acetylation↗
PubMed2001

Er:YAG laser resurfacing using combined ablation and coagulation modes.

BACKGROUND: The two main laser types used in resurfacing, the CO2 and the Er:YAG lasers, have their supporters and detractors, and each system has clear advantages and disadvantages. OBJECTIVE: The Er:YAG laser can be used in the usual efficient ablative mode, followed by reprogramming to achieve nonablative deeper dermal coagulation associated with the CO2 laser, thereby achieving the main advantages of both laser types. PATIENTS AND METHODS: Twenty-three female patients, ages 42-72 yrs, skin types I-IV, were treated. The epidermis was first removed in the ablative settings in a single pass with 50% overlap. The Er:YAG laser was reprogrammed for the subablative mode, and several passes produced controlled residual thermal damage (RTD) without further ablation. RESULTS: At 2 months postresurfacing the results were assessed. Thirteen patients were rated "very good," eight as "good," and two as "fair." CONCLUSION: The dual mode Er:YAG laser can first be used in the ablative mode to remove the epidermis with minimal RTD, following which, in the subablative mode, the same laser induces a controlled layer of dermal RTD, stimulating the dermis to achieve collagenesis and collagen remodeling and giving good long-term results.

Adult↗
PubMedDate not supplied

Developmental drive: an important determinant of the direction of phenotypic evolution.

Over any period of evolutionary time, the prevailing ontogenetic trajectory within a lineage may either recur unchanged from generation to generation (stasis) or alter (developmental reprogramming). A key question about reprogramming is whether it exhibits intrinsic biases in favor of some sorts of change and against others, which may be referred to respectively as "drive" and "constraint." A simple logical argument suggests that both drive and constraint should be common, and conversely that cases of equiprobable modification in various phenotypic directions should be relatively rare. These proposals, that drive and constraint exist and that they are common, appear to be widely accepted, even among neo-Darwinians, who are sometimes portrayed as rejecting them. What is more controversial is that developmental drive (and constraint) can have a powerful influence on the direction of evolutionary change. It is argued that such an influence will occur, and indeed may be pervasive.

Developmental Biology↗
PubMed2002

Pacemaker-mediated tachycardia: management by pacemaker interrogation/reprogramming in the ED.

We report a case of a patient with symptomatic pacemaker-mediated tachycardia (PMT). PMT should be suspected when asynchronous pacing induced by magnet application causes temporary resolution of an unknown tachycardia in a patient with a pacemaker. The underlying mechanism of PMT is either reentrant tachycardia or atrial triggering. PMT is better discerned with an intracardiac electrocardiogram (ECG) obtained through pacemaker interrogation (PI) than the standard 12-lead ECG. In the case reported, the interrogator was used to demonstrate that the initiating dysrhythmia was atrial flutter. Next, the programmer was used to overdrive the atrium restoring normal sinus rhythm. After pacemaker reprogramming, the patient was discharged from the emergency department (ED) in improved condition. We believe this to be the first reported case of a patient with PMT diagnosed, treated, and discharged effectively after PI, overdrive pacing and reprogramming from the ED. The pacemaker interrogator/programmer is a rapid noninvasive device that has practical applications in the ED.

Aged↗
PubMed1999

Significant improvement of quality of life following atrioventricular synchronous pacing in patients with hypertrophic obstructive cardiomyopathy. Data from 1 year of follow-up. PIC study group. Pacing In Cardiomyopathy.

AIMS: Atrioventricular synchronous pacing exerts beneficial effects, including reduction of left ventricular outflow tract gradients, in patients with hypertrophic obstructive cardiomyopathy. The Pacing in Cardiomyopathy study was initiated to explore the effects of pacing in a double-blind randomized crossover fashion. The aims were to ascertain the beneficial effects of pacing in a controlled study and to rule out a placebo effect by pacing. This paper deals with the outcome of pacing on quality of life during 1 year of follow-up. METHODS: Quality of life was evaluated with the Karolinska questionnaire, validated for patients paced for bradyarrhythmias and ischaemic heart disease. Drug-refractory patients with hypertrophic obstructive cardiomyopathy were recruited for the study and after a temporary pacing procedure implanted with permanent pacemakers. Patients were randomized to two study arms defining the sequence of pacemaker programming. In one arm the pacemaker was inactive, in the other active. After 3 months the pacemaker was reprogrammed to the alternate mode and a further 3 months followed. After this period subsequent pacemaker programming corresponded to the mode preferred by the patient. A last assessment was made 1 year after baseline examinations. RESULTS: Eighty patients completed the first crossover period and 75 completed the full 1 year of follow-up. Active pacing induced significant quality of life improvements, in the order of 9-44%, regardless of programming sequence. Discontinuation of pacing after a first active period resulted in the return of symptoms. Fourteen patients requested early reprogramming after having been programmed to inactive pacing after a first period of active pacing. Seventy-six patients preferred active pacing after the crossover period. A further 6 months of pacing induced progressive improvement in symptoms already favourably influenced. CONCLUSION: Atrioventricular synchronous pacing has a profound beneficial effect on most domains of quality of life in patients with hypertrophic obstructive cardiomyopathy refractory to drug treatment.

Adult↗
PubMed2003

The first half-century of nuclear transplantation.

Fifty years after Briggs and King first succeeded in obtaining normal tadpoles from transplanted embryo nuclei in vertebrates, two general principles have emerged from work in amphibia and mammals. One is the conservation of the genome during cell differentiation. A small percentage of adult or differentiated cells have totipotent nuclei, and a much higher percentage of cells committed to one pathway of cell differentiation have multipotent nuclei. The other is the remarkable reprogramming capacity of cell, and especially egg, cytoplasm. The eventual identification of reprogramming molecules and mechanisms could facilitate a route toward cell replacement therapy in humans.

Amphibians↗