THE EFFECT OF DIGITALIS ON THE NORMAL HUMAN ELECTROCARDIOGRAM,WITH ESPECIAL REFERENCE TO A-V CONDUCTION

Digitalis was given by mouth to five normal young male adults in amounts ranging from 2.0 to 3.0 gm. of standardized leaves in the course of 7 to 10 days. The As-Vs interval was prolonged in four of the five subjects, the greatest prolongation occurring in the case of the subject who received the most digitalis and none at all in one who received only 2.0 gm. There was no prolongation to so great an interval as 0.2 second until 2.7 gm. had been taken. The effects of the digitalis on conduction time began 5 to 6 days after the drug had been started and after 1.5 to 1.8 gm. had been taken. The effects persisted for 1 to 2 weeks after the drug had been stopped. Atropine removed completely the effect of digitalis on A-V conduction. The slowing heart rate after exercise was accompanied by an enhancement of the defect in conduction. The change in conduction through digitalis was therefore almost entirely, if not entirely, due to increase of vagal tone and irritability. Digitalis did not affect to an appreciable extent the Q-end of S and the Q-end of T intervals. Exercise and atropine both shortened the ventricular complex Q-end of T while the subject was under digitalis. The amplitude of the T wave, especially in Lead II, was changed within 48 hours after digitalis had been started, a decrease then beginning which became greater as the drug was continued and which persisted until 10 to 19 days after the digitalis had been stopped. The change in the T deflection preceded by several days the change in conduction time. The T wave, therefore, in the normal subject as well as in the patient gives us the earliest indication of digitalis action. The amplitudes of P, Q, R, and S were not materially influenced by the amounts of digitalis given. The pulse rate in two subjects became lower than usual at night as the result of the digitalis; otherwise there was no evidence of vagal action on the sino-auricular node. Blood pressure was uninfluenced by the digitalis. Mild subjective sensations occurred in all the subjects during the administration of the drug. A curious, hitherto undescribed, digitalis arrhythmia consisting of blocked auricular premature beats occurred in one subject after 3.0 gm. of digitalis had been taken.     

Interleukin-3, GM-CSF, and TPA induce distinct phosphorylation events in an interleukin 3-dependent multipotential cell line

The mechanism of action of the hemopoietic growth factor, murine interleukin-3 (mIL-3), was investigated using an mIL-3-dependent multipotential hematopoietic cell line, B6SUtA1. Murine granulocyte- macrophage colony-stimulating factor (mGM-CSF) was as potent as mIL-3 in stimulating these cells. In addition, sodium orthovanadate, an inhibitor of phosphotyrosine phosphatase, and 12-O-tetradecanoyl- phorbol-13-acetate (TPA), a known activator of protein kinase C, also stimulated DNA synthesis in these cells, suggesting that protein phosphorylation might be involved in the mechanism of action of mIL-3 and mGM-CSF. To assess this possibility, intact B6SUtA1 cells exposed for brief periods to mIL-3, mGM-CSF, and TPA were analyzed for changes in phosphorylation patterns using metabolic 32P-labeling and antibodies to phosphotyrosine. Both mIL-3 and mGM-CSF induced the serine-specific phosphorylation of a 68-Kd cytosolic protein, whereas all three agents stimulated the serine-specific phosphorylation of a 68-Kd membrane protein. Furthermore, mIL-3 stimulated tyrosine phosphorylation of the 68-Kd membrane protein, as well as of 140-, 90-, 55, and 40-Kd proteins. The 90-Kd protein was also tyrosine phosphorylated in response to mGM-CSF. These phosphotyrosine containing proteins were not detected in TPA-treated cells. These results indicate that protein phosphorylations on tyrosine and serine residues occur in B6SUtA1 cells following short-term incubation with mIL-3 or mGM-CSF and that most of these phosphorylation events are mediated by kinases other than protein kinase C (PkC).     

Extracellular truncations of h beta c, the common signaling subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5, lead to ligand-independent activation

The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony- stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c- derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid- specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling.     

Functional endothelial progenitor cells from cryopreserved umbilical cord blood

Umbilical cord blood (UCB) is recognized as an enriched source of endothelial progenitor cells (EPCs) with potential therapeutic value. Because cryopreservation is the only reliable method for long-term storage of UCB cells, the clinical application of EPCs depends on our ability to acquire them from cryopreserved samples; however, the feasibility of doing so remains unclear. In this study we demonstrate that EPCs can be isolated from cryopreserved UCB-derived mononuclear cells (MNCs). The number of outgrowth EPC colonies that emerged in culture from cryopreserved samples was similar to that obtained from fresh UCB. Furthermore, EPCs obtained from cryopreserved MNCs were phenotypically and functionally indistinguishable from freshly isolated ones, including the ability to form blood vessels in vivo. Our results eliminate the necessity of performing cell isolation procedures ahead of future clinical needs and suggest that EPCs derived from cryopreserved UCB may be suitable for EPC-related therapies.     

Interpreting regulatory authority guidance on immunosuppressive therapy for renal transplantation: a response to the UK's National Institute for Clinical Excellence (NICE)

AIMS: A group of UK consultant transplant physicians and surgeons (the Consensus Group) met to consider the implications and interpretation of the National Institute for Clinical Excellence's (NICE) Technology Appraisal No. 85 on the use of immunosuppressive therapy for renal transplantation in adults. METHODS: This group considered what the implications of these guidelines might be for clinical practice and consensus was developed on those areas which were potentially open to different interpretations. A wider survey of nephrologists and transplant surgeons throughout the UK was also performed to gauge the impact of the NICE recommendations. RESULTS AND CONCLUSIONS: The outcome of the discussions of the Consensus Group are presented with particular reference to the recommendations of how to respond to calcineurin inhibitor (CNI) intolerance. The survey suggested that the publication of this NICE guidance has resulted in relatively few changes in prescribing practice: UK transplant centers continue to use a wide range of locally developed protocols for immunosuppressive therapy. These include the use of agents such as mycophenolate mofetil (MMF) and sirolimus, despite the fact that both drugs appeared to receive only conditional acceptance in the NICE Guidelines.     

Cervical spine computed tomography utilization in pediatric trauma patients

Background

Guidelines for evaluating the cervical spine in pediatric trauma patients recommend cervical spine CT (CSCT) when plain radiographs suggest an injury. Our objective was to compare usage of CSCT between a pediatric trauma center (PTC) and referral general emergency departments (GEDs).

Methods

Patient data from a pediatric trauma registry from 2002 to 2011 were analyzed. Rates of CSI and CSCT of patients presenting to the PTC and GED were compared. Factors associated with use of CSCT were assessed using multivariate logistic regression.

Results

5148 patients were evaluated, 2142 (41.6%) at the PTC and 3006 (58.4%) at the GED. Groups were similar with regard to age, gender, GCS, and triage category. GED patients had a higher median ISS (14 vs. 9, p < 0.05) and more frequent ICU admissions (44.3% vs. 26.1% p < 0.05). CSI rate was 2.1% (107/5148) and remained stable. CSCT use increased from 3.5% to 16.1% over time at the PTC (mean 9.6% 95% CI = 8.3, 10.9) and increased from 6.8% to 42.0% (mean 26.9%, CI = 25.4, 28.4) at the GED. Initial care at a GED remained strongly associated with CSCT.

Conclusions

Despite a stable rate of CSI, rate of CSCT increased significantly over time, especially among patients initially evaluated at a GED.     

Morbidity and mortality after peritoneovenous shunt surgery for refractory ascites.

A prospective analysis of the morbidity and mortality after peritoneovenous shunting was carried out in 25 patients who had a total of 27 shunts for refractory ascites. Major complications were limited to the patients in whom ascites was secondary to hepatic rather than peritoneal disease. Immediate postoperative complications followed 17 out of the 23 shunts carried out in patients with liver disease and included septicaemia (two), profound hypotension (two), pulmonary oedema (one), and clinically evident disseminated intravascular coagulation (14). Long term morbidity was again limited to the patients with liver disease and included chronic shunt infection (two) and major venous thrombosis (two). Shunt associated mortality was only seen in the patients with liver disease. Despite late shunt blockage in five long term survivors with alcoholic liver disease fluid retention was easily controlled by simple medical means probably because of improved liver function associated with abstinence from alcohol. It is concluded that: (1) patients with hepatic and malignant ascites respond differently to the insertion of a peritoneovenous shunt; (2) Shunt patency should be monitored regularly in patients with liver disease and, because of the potential for septic and thrombotic complications, if blocked the shunt should be removed and; (3) because of the morbidity and mortality of peritoneovenous shunt surgery in patients with liver disease and refractory ascites, an alternative mode of therapy, such as repeated ultrafiltration and reinfusion of ascitic fluid, may be a more effective initial therapeutic approach especially in patients in whom there is a reversible element to their underlying liver disease.