Automated health services--reprogramming the doctor.
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Cognitive prosthetics is a new frontier. It seeks to find an artificial substitute for injured brain processes by using computers and other technologies. In recent years, the Physicians' Health Programs of The Educational and Scientific Trust of the Pennsylvania Medical Society has been working with the Institute for Cognitive Prosthetics to develop innovative therapies to help physicians with brain injuries return to a productive life.
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Nuclear reprogramming induces global changes of epigenetic profile and confers pluripotency on specialized somatic nuclei. Embryonic stem (ES) cells retain nuclear reprogramming activity as shown by cell fusion with adult somatic cells. The reprogrammed somatic nuclei resemble ES cell nuclei in pluripotential competence. Changes of histone tail modifications in somatic cell-derived genome by cell fusion demonstrate that the molecular process of nuclear reprogramming is separable at least in two steps: erasure of somatic epigenetic modification (genome-wide reprogramming) and establishment of pluripotential epigenetic modification (gene-specific reprogramming). In the latter step, the newly identified transcriptional factor Nanog functions in maintaining pluripotency in cooperation with other key gene Oct4. Somatic-derived Nanog is reactivated in the reprogrammed nuclei in hybrid cells and also in cloned blastocysts. It is unclear which key molecules are responsible for the nuclear reprogramming. It is, however, evident that adult somatic cell nuclei are capable of being reprogrammed in vitro by cell fusion with ES cells. A technological innovation for eliminating ES-derived chromosomes from the hybrid nuclei could make the production of personalized pluripotential stem cells without the need for therapeutic cloning possible.
OBJECTIVES: The goal of this study was to investigate the possible role of transesophageal echocardiography in the evaluation of patients with clinical pacemaker syndrome. BACKGROUND: Several reports on transthoracic echocardiographic features of ventricular pacing were described; however, no previous study of transesophageal echocardiography has been undertaken in patients at the severe end of pacemaker syndrome who need reprogramming of dual-chamber pacing for symptom relief. METHODS: Twelve patients with ventricular-inhibited pacemakers (VVI) with clinical symptomatic pacemaker syndrome (group I) and 10 patients with VVI without pacemaker syndrome (group II) were prospectively studied. The two groups were pacemaker dependent and had persistent ventriculoatrial conduction. Transesophageal echocardiographic parameters were assessed in group II and within 6 hours before reprogramming to the DDD mode in group I. Follow-up transesophageal echocardiographic study was performed 28+/-5 days after reprogramming in group I. RESULTS: All patients in group I had subjective improvements of symptoms after DDD reprogramming. The atrial reverse flow velocities of pulmonary veins in group I before reprogramming were significantly higher in group II (39.3+/-11.4 versus 15.7+/-13.5 cm/sec, p < 0.0001). Spontaneous echo contrast in the descending aorta was detected in all patients from group I before reprogramming. The prevalence of significant mitral regurgitation (> or = moderate) was significantly higher in group I before reprogramming than in group II (67% versus 8%, p = 0.01). Significant mitral regurgitation and spontaneous echo contrast in the descending aorta in group I disappeared after reprogramming to the DDD mode. CONCLUSIONS: Transesophageal echocardiography provides physiologic, pacemaker-related hemodynamic changes in paced patients. Significantly higher atrial reverse flow velocities of pulmonary veins, increased frequency of spontaneous echo contrast in the descending aorta, and significant mitral regurgitation are peculiar echocardiographic findings in patients with VVI with clinical pacemaker syndrome.
Case reports were received of a fatal tachycardia caused by a malfunction of an implantable cardioverter defibrillator (ICD), a device that is subject to the tracking regulations of the Food and Drug Administration's Center for Devices and Radiological Health. The case reports led to a decision to notify 5,604 patients of the need for reprogramming of their ICDs to prevent the tachycordia. In the first 60 days, a total of 98.7% of the patients were successfully located and their devices reprogrammed. Multiple logistic regression analysis was conducted to examine an extensive array of factors that might have been related to the time to reprogramming. Patient-specific factors such as age, sex, and ejection fraction did not serve as a barrier to reprogramming in the first week (p = NS). Patients whose regular physician had >5 patients with the ICD subject to the recall were significantly more likely to have their ICDs reprogrammed in the first week (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.85 to 2.43, p<0.001). Patients who changed physicians were significantly less likely to undergo reprogramming in the first week (OR 0.73, 95% CI 0.63 to 0.86, p<0.001). The experience of the recall of this tracked device is highly encouraging because it demonstrates that most tracked device recipients can be successfully located and receive medical intervention. Although tracking devices is a manufacturer's responsibility, the clinical community plays a critical role in its success. This report highlights the importance of understanding that role among physicians.
We describe our experience with Sophy programmable valve shunts, compared with Codman-Hakim programmable shunts in cases with normal pressure hydrocephalus (NPH) after subarachnoid hemorrhage (SAH). A total of 147 consecutive patients underwent 204 shunt implantations (102 Sophy valves, 51 Codman-Hakim valves, 51 nonprogrammable valves). Of these, 23 Sophy and 25 Codman-Hakim valves respectively were implanted into patients with NPH after SAH. Comparison of reprogramming rate and frequency in cases with NPH after SAH between Sophy and Codman-Hakim valves revealed similar reprogramming rates (65.2 vs. 64.0%) but a higher frequency with the former (1.70 vs. 1.08 times/person). The mean difference between initial and final pressure was 65.3+/-45.8mmH(2)O in cases with Sophy valves, and 25.0+/-14.1mmH(2)O with Codman-Hakim valves. The average period which was required to determine the final pressures with Sophy and Codman-Hakim valves were 56.5+/-45.0 days and 43.3+/-45.7 days, respectively. Total incidence of complications of Sophy and Codman-Hakim valve shunt systems in cases with NPH after SAH were 26.1% (6/23) and 16% (4/25), respectively. Total instances requiring shunt revision with Sophy valves in cases of NPH after SAH were 6 of 23 (26.1%), while for Codman-Hakim valves the figure was 2 of 25 (8.0%). Sophy, as well as Codman-Hakim programmable valve shunts, allow alteration of opening pressure after the implantation according to patients' conditions, which may contribute to reduction of revision. Similar reprogramming rates but lower frequency, and smaller difference between initial and final pressure in Codman-Hakim valves may be ascribed to finer pressure ranges and ease of reprogramming, which facilitates earlier reprogramming and decisions regarding final optimal opening pressure.
Patients with ICDs might experience oversensing associated with inappropriate shock therapy when paced at low bradycardia rates or if they have a low intrinsic rhythm. The amplifier gain of automatic gain control is maximal at long RR intervals and might lead to oversensing of myopotentials. The hypothesis was that an individual adjustment of the sensitivity floor could reduce inappropriate ICD therapies. Fourteen patients implanted with the VENTAK MINI I/II and III in whom oversensing and/or inappropriate shocks had been documented were included in this evaluation based on stored episodes. Sensitivity was modified in all ICDs by means of noninvasive software downloading that allowed reprogramming of the maximum sensitivity from 0.14 mV in two steps to 0.27 mV ("Normal," "Less," "Least"). Provocation testing (deep inspiration, sit-ups, and abdominal pressing) was conducted at "Nominal" settings (0.14 mV) while the intracardiac electrogram with annotated event marker was running continuously and was repeated at 0.22 mV (Less) and 0.27 mV (Least). All patients evaluated had documented spontaneous episodes due to oversensing before the sensitivity floor was reprogrammed. During provocation testing at Nominal settings, oversensing could be documented in 9 of (64.3%) 14 patients. Provocation testing was repeated after the sensitivity selection was reprogrammed and oversensing could not be provoked in any of the 14 implanted devices. Sensitivity was reprogrammed in all 14 patients to a higher value (5 patients Less, 9 patients Least). After sensitivity adjustment, VF was induced in all patients to verify appropriate arrhythmia detection and termination. Sensitivity reprogramming in patients with documented oversensing eliminates the incidence of inappropriate shock therapy without compromising the ability to detect VF appropriately.
The objective of the investigation was to determine the pattern of use of the Hakim (Medos) programmable valve implanted in patients with complex hydrocephalus and their clinical outcome. A prospective audit of patients with complex hydrocephalus undergoing Hakim programmable valve implantation between 1989 and 1994 in the United Kingdom and Ireland, was followed-up for a minimum of 5 years. Surgical practice and complications were audited together with clinical outcome. One-hundred-and-thirty-nine patients (80 male, 59 female; mean age 43.4 years; median 47 years; range 1 month-84 years) with complex hydrocephalus due to a wide range of aetiologies were implanted with the Hakim programmable valve. Eighty-eight (63%) had large or massive ventricles prior to implantation; seven (5%) were slit. Fifty-five (40%) had previously been shunted with a fixed pressure system. One-hundred-and-thirty-one (94%) of the Hakim programmable shunts were ventriculoperitoneal; four (3%) ventriculoatrial; two (1.4%) cystoperitoneal; and two (1.5%) lumboperitoneal. The initial opening pressure selected ranged from 50 to 200 mmH2O (median 120). Valves were reprogrammed on average 1.7 times with 143 reprogrammings in the first year after implantation; 67 in the second; 19 in the third; three in the fourth; two in the fifth. Forty-nine (36%) valves were never reprogrammed after implantation. During the 5 years audit period, there were 70 (50%) shunt revisions, 40 of which were performed within 1 year of implantation. Thirty-six (27%) shunts were removed. There were 24 (18%) shunt infections. Subdural collections were identified in 37(27%) patients after Hakim programmable valve implantation; 10 (27%) required surgical drainage. Five (3.7%) patients developed symptomatic slit ventricles after Hakim programmable valve implantation. Headache was improved following reprogramming in 27(71%) of the 38 patients with refractory headache. After Hakim programmable valve implantation, patients underwent an average of 4.6 CT scans (range 1-25); 0.3 MRI (range 1-5) and 1.8 skull radiographs (range 1-20). The mean hospital stay per patient over 5 years was 26 days (range 1-110 days). Five years after implantation, the Glasgow Outcome scale was favourable in 64% of patients. The Hakim programmable valve is useful in the management of patients with complex hydrocephalus and may reduce the need for shunt revision for headache. Non-haemorrhagic, post-shunting, subdural collections identified on routine postoperative CT may be treated by reprogramming.
Ways of directly turning a somatic cell into another (a process known as transdifferentiation) would alleviate difficulties associated with current nuclear transplantation procedures and be beneficial for producing replacement cells for therapeutic purposes. Adult stem cells have been shown to display a broader differentiation potential than anticipated and may contribute to tissues other than those in which they reside. In addition, novel transdifferentiation strategies are being developed. We illustrate here a functional reprogramming of a somatic cell using a nuclear and cytoplasmic extract derived from another somatic cell type. Reprogramming of 293T fibroblasts in an extract from T cells is evidenced by nuclear uptake and assembly of transcription factors, induction of activity of a chromatin remodeling complex, changes in chromatin composition and activation of lymphoid cell-specific genes. The reprogrammed cells expressed T cell-specific surface molecules and a complex regulatory function. We propose that in vitro cell reprogramming may create possibilities for producing isogenic replacement cells for therapeutic applications. The system is also likely to constitute a powerful tool to examine the mechanisms of nuclear reprogramming as they occur in vitro.
Recent studies indicate that during tumorigenic transformations, cells may generate mutations by themselves as a result of error-prone cell division with participation of error-prone polymerases and aberrant mitosis. These mechanisms may be activated in cells by continuing proliferative and survival signaling in a sustained stress environment (SSE). The paper hypothesizes that long-term exposure to this signaling epigenetically reprograms the genome of some cells and, in addition, leads to their senescence. The epigenetic reprogramming results in: (i) hypermethylation of tumor-suppressor genes involved in the onset of cell-cycle arrest, apoptosis and DNA repair; (ii) hypomethylation of proto-oncogenes associated with persistent proliferative activity; and (iii) the global demethylation of the genome and activation of DNA repeats. These epigenetic changes in the proliferating cells associate with their replicative senescence and allow the reprogrammed senescent cells to overcome the cell-cycle arrest and to activate error-prone replications. It is hypothesized that the generation of mutations in the error-prone replications of the epigenetically reprogrammed cells is not random. The mutations match epigenetic alterations in the cellular genome, namely gain of function mutations in the case of hypomethylation and loss of functions in the case of hypermethylation. In addition, continuing proliferation of the cells imposed by signaling in SSE speeds up the natural selection of the mutant cells favoring the survival of the cells with mutations that are beneficial in the environment. In this way, a stress-induced replication of the cells epigenetically reprograms their genome for quick adaptation to stressful environments providing an increased rate of mutations, epigenetic tags to beneficial mutations and quick selection process. In combination, these processes drive the origin of the transformed mammalian cells, cancer development and progression. Support from genomic, biochemical and medical studies for the proposed hypothesis, and its implementations are discussed.
The low efficiency of somatic cell cloning is the major obstacle to widespread use of this technology. Incomplete nuclear reprogramming following the transfer of donor nuclei into recipient oocytes has been implicated as a primary reason for the low efficiency of the cloning procedure. The mechanisms and factors that affect the progression of the nuclear reprogramming process have not been completely elucidated, but the identification of these factors and their subsequent manipulation would increase cloning efficiency. At present, many groups are studying donor nucleus reprogramming. Here, we present an approach in which the efficiency of producing viable offspring is improved by selecting recipient oocytes and donor cells that will produce cloned embryos with functionally reprogrammed nuclei. This approach will produce information useful in future studies aimed at further deciphering the nuclear reprogramming process.