Mobilized blood cells vs bone marrow harvest: experience compared in 171 donors with particular reference to pain and fatigue.

This prospective study compared the donor experience of blood cell (BC) mobilization and leukapheresis (n=116) with that of bone marrow (BM) harvest (n=55). Internal jugular catheters were inserted electively in 89% of BC donors. Most (80%) BM donors had a harvest with general anesthesia; 20% had epidural or spinal anesthesia. Pain and fatigue were frequent with both procedures and were compared in responses to questionnaires. A total of 85% of BM donors reported moderate or severe pain compared with 68% of BC donors (P=0.02). The median duration of pain was 14 days for BM donors compared with 3 days after BC mobilization (P<0.0001). More BM donors had pain for more than 7 days (75% vs 0%, P<0.0001). Severe fatigue was experienced by more BM donors (49 vs 16%, P<0.0001). Fatigue lasted significantly longer in BM donors (median 11 vs 4 days, P<0.0001) and more BM donors were fatigued for more than 1 week (69 vs 0%, P<0.0001). A total of 11 donors had both BM and BC collection; seven preferred the latter. Simply considered with respect to pain and fatigue, BC donation appears better tolerated by donors. However, there are other sequelae of both influencing the acceptability for individual donors.

CpG-A oligonucleotides induce a monocyte-derived dendritic cell-like phenotype that preferentially activates CD8 T cells.

Human B cells and plasmacytoid dendritic cells recognize CpG motifs within microbial DNA via Toll-like receptor 9. Two functionally distinct types of CpG motif containing oligonucleotides (CpG ODN) have been described, CpG-A and CpG-B. In contrast to CpG-B, CpG-A induces high amounts of type I IFN (IFN-alpha and IFN-beta) in plasmacytoid dendritic cells. In the present study, we examined the effects of CpG-A on human primary monocytes. In PBMC stimulated with CpG-A and GM-CSF, monocytes showed excellent survival, increased in size and granularity, and within 3 days developed a dendritic cell-like phenotype that was characterized by down-regulation of CD14, partial up-regulation of CCR7, and an increased surface expression of costimulatory and Ag-presenting molecules. This effect could be inhibited by a combination of blocking Abs to type I IFN, and no such CpG-A-induced changes were observed in purified monocytes. Although IL-12 production by this dendritic cell-like phenotype required additional stimulation with CD40 ligand, this cell type spontaneously up-regulated IL-15 expression. Consistent with the known effect of IL-15 on effector and memory CD8 T cells, the frequency of CCR7(-)/CD45RA(-) CD8 T cells was selectively increased in allogeneic T cell assays. Furthermore, this dendritic cell type was more potent to support both the generation and the IFN-gamma production of autologous influenza matrix peptide-specific memory CD8 T cells as compared with dendritic cells generated in the presence of GM-CSF and IL-4. In conclusion, monocytes exposed to the cytokine milieu provided by CpG-A rapidly develop a dendritic cell-like phenotype that is well equipped to support CD8 T cell responses.

Image-guided central venous catheter placement for apheresis in allogeneic stem cell donors.

Peripheral blood stem cell harvest by apheresis is an increasingly important procedure utilized in the treatment of many malignancies. Whether autologous or allogeneic, it is frequently performed via peripheral access because of concern over major complications associated with central venous catheter placement. This study was to determine the safety and success, complications and premature failure rates for radiolocally placed ultrasound-guided non-tunneled central venous catheters placed for apheresis in a donor (allogeneic) population. One hundred central venous catheters were placed in ninety-one individuals for allogeneic stem cell harvest. Procedural success and complications relating to placement were noted in all. In 97 cases the number of needle passes required for venous cannulation and whether this was achieved with a single wall puncture was noted. Duration of catheterization and reason for removal were recorded in all cases. All catheters were placed by a right transjugular route. Venous cannulation and functioning line placement was achieved in every case; 92/97 (95%) required only a single needle pass and 84/97 (87%) only a single wall puncture. There were no placement related complications; 94 catheters were removed the same day with the remainder removed within 48 hr. All completed apheresis. Our study demonstrates the safe use of central venous catheters for apheresis in normal donors if ultrasound guidance is used for the puncture and the duration of catheterization is short.

Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina.

BACKGROUND: Transmyocardial revascularization involves the creation of channels in the myocardium with a laser to relieve angina. We compared the safety and efficacy of transmyocardial revascularization performed with a holmium laser with those of medical therapy in patients with refractory class IV angina (according to the criteria of the Canadian Cardiovascular Society). METHODS: In a prospective study conducted between March 1996 and July 1998 at 18 centers, 275 patients with medically refractory class IV angina and coronary disease that could not be treated with percutaneous or surgical revascularization were randomly assigned to receive transmyocardial revascularization followed by continued medical therapy (132 patients) or medical therapy alone (143 patients). RESULTS: After one year of follow-up, 76 percent of the patients who had undergone transmyocardial revascularization had improvement in angina (a reduction of two or more classes), as compared with 32 percent of the patients who received medical therapy alone (P<0.001). Kaplan-Meier survival estimates at one year (based on an intention-to-treat analysis) were similar for the patients assigned to undergo transmyocardial revascularization and those assigned to receive medical therapy alone (84 percent and 89 percent, respectively; P=0.23). At one year, the patients in the transmyocardial-revascularization group had a significantly higher rate of survival free of cardiac events (54 percent, vs. 31 percent in the medical-therapy group; P<0.001), a significantly higher rate of freedom from treatment failure (73 percent vs. 47 percent, P<0.001), and a significantly higher rate of freedom from cardiac-related rehospitalization (61 percent vs. 33 percent, P<0.001). Exercise tolerance and quality-of-life scores were also significantly higher in the transmyocardial-revascularization group than in the medical-therapy group (exercise tolerance, 5.0 MET [metabolic equivalent] vs. 3.9 MET; P=0.05); quality-of-life score, 21 vs. 12; P=0.003). However, there were no differences in myocardial perfusion between the two groups, as assessed by thallium scanning. CONCLUSIONS: Patients with refractory angina who underwent transmyocardial revascularization and received continued medical therapy, as compared with similar patients who received medical therapy alone, had a significantly better outcome with respect to improvement in angina, survival free of cardiac events, freedom from treatment failure, and freedom from cardiac-related rehospitalization.

Transmyocardial revascularization in patients with refractory, unstable angina.

BACKGROUND: Previous reports of transmyocardial revascularization (TMR) indicate a significant mortality in patients with refractory, unstable angina. We hypothesized that TMR with a holmium laser would result in significant angina relief with acceptable mortality in this patient population. METHODS AND RESULTS: Patients were defined as unstable if they were unweanable from intravenous antianginal medications or were too unstable for a persantine thallium scan. Patients had a left ventricular ejection fraction (LVEF) of > 25% and were not amenable to CABG or PTCA. Before treatment, all patients had class IV angina. TMR was performed in 85 patients, with a mean of 35 +/- 11 transmural laser channels. Mean age was 63 +/- 10 years. Mean LVEF was 48 +/- 11%. Of these patients, 79% were men. Prior CABG and/or PTCA had been performed in 87% of patients, and 72% of patients had a history of prior MI. Operative mortality was 12% (10 of 85). There were 2 deaths between discharge and 3 months after surgery and 7 late deaths from 6 to 12 months after surgery. Twelve-month mortality was 22.4% (19 of 85). At 3 months, 86% of patients had class II angina or better. At 6 and 12 months, 77% and 75% of patients, respectively, had class II angina or better. Mean angina class at 6 and 12 months' follow-up was 1.5 +/- 1.1 and 1.6 +/- 1.3, respectively. CONCLUSIONS: In patients with refractory unstable angina, TMR with a holmium laser provided significant angina relief. Moreover, 30-day operative mortality and 12-month mortality were acceptable, especially given this subset of unstable patients with refractory angina.

Factors influencing yields of progenitor cells for allogeneic transplantation: optimization of G-CSF dose, day of collection, and duration of leukapheresis.

Mobilization of hematopoietic progenitor cells by G-CSF was attempted on 89 occasions in 85 healthy donors. Three dose ranges of G-CSF were chosen for analysis: low (4-7.4 micrograms/kg), intermediate (7.5-10 micrograms/kg) and high (> 10 micrograms/kg). A target blood level for apheresis of 20 x 10(6)/L CD34+ cells was reached by day 3 in 75 patients (84%) and by day 4 in all but 1 (99%). Target yields above 2.5 x 10(6)/kg for 75 unmanipulated transplants were exceeded in a single collection in 73 donors (97%). Correlation of CD34+ cell yields to blood CD34+ cell level before leukapheresis was moderate only (r2 = 0.32). There was close linear correlation between processed volume and cumulative CD34+ cell yield, with a median r2 value of 0.98 (range 0.74-1.00). Yields of CD34+ cells achieved on day 3 were significantly lower after the high dose than after the intermediate G-CSF dose (21 +/- 3 versus 29 +/- 6 x 10(6)/L blood processed, p = 0.03). After the low dose of G-CSF, yields on day 4 were higher than on day 3 (48 +/- 10 versus 22 +/- 4 x 10(6)/L blood processed, p = 0.01). There was no difference between day 3 and day 4 yields with the intermediate G-CSF dose. In 73 of 93 (78%) leukaphereses, the CD34+ cell yield was more than 100% of the estimated intravascular CD34+ cells at the beginning of collection and ranged up to 342%. These data indicate that a daily dose of 7.5-10 micrograms/kg G-CSF, given as a multiple of 300 and 480 micrograms ampoules, is a convenient regimen giving adequate yields from a single collection on day 3 or 4 in most donors. Measuring blood CD34+ cell levels is of limited value in predicting yields, but monitoring CD34+ cell yields during leukapheresis may help to minimize unnecessary or inefficient collection.

Surgical intervention in acute myocardial infarction: an historical perspective.

Acute myocardial infarction is an evolving event that lends itself well to surgical intervention. An historical review of surgery of acute myocardial infarction, with specific emphasis on the Spokane data, shows that this can be done safely and efficiently with myocardial salvage. Those people who were operated on within 6 hours of the onset of symptoms of acute myocardial infarction had a clear reduction in hospital mortality incidence and a better long-term result. The conclusion of our review is that emergency coronary artery bypass grafting for acute evolving myocardial infarction should be considered as a therapeutic option in every patient. All other modalities of therapy should be compared with the results of acute bypass surgery.

Collection of progenitor cells for allogeneic transplantation from peripheral blood of normal donors.

Fourteen donors were given recombinant G-CSF to mobilize progenitor cells. Circulating CD34+ cells were monitored daily and leukapheresis was performed at 3-5 days when the level exceeded 20 x 10(6)/L. Monitoring of CD34+ cells collected at intervals during apheresis gave results within 20 min. Yields of 2.6-7.4 x 10(6) per kg recipient body weight were achieved in single aphereses of 2-4 h in all but two cases where the donor was substantially smaller than the recipient. These products were sufficient to establish engraftment, at least of granulocytes, in 11 five or six antigen matched recipients with high risk malignancy. Despite some complications donors tolerated the procedure well and the five individuals who had previously given marrow preferred these manoeuvres to bone marrow harvest. The ability to monitor CD34+ cells rapidly in the circulation and leukapheresis product facilitates an efficient collection technique for allogeneic BCT donors. Adequate yields could probably be achieved by a single harvest on days 2-4 in most donors.

Medical and surgical management of early Q wave myocardial infarction. I. Effects of surgical reperfusion on survival, recurrent myocardial infarction, sudden death and functional class at 10 or more years of follow-up.

To define the outcome of patients given medical or surgical therapy for Q wave myocardial infarction, 387 patients were followed up for 10 to 13 years (mean 11.4). On study entry the groups had similar distributions for variables such as mean age, gender, previous myocardial infarction, abnormal creatine kinase activity, area of infarction, number of vessels diseased and clinical classification. The hospital mortality rate of the medical versus surgical group was 11.5% (23 of 200) versus 5.8% (11 of 187) (p = 0.07). Early reperfusion (that is, less than or equal to 6 h) resulted in a lower mortality rate than did medical therapy--2% (2 of 100) versus 11.5% (23 of 200) (p less than 0.05)--whereas the hospital mortality rate with late reperfusion was 10.3% (9 of 87). The long-term mortality rate of the medical and surgical groups was 41% (82 of 200) versus 27% (51 of 187) (p = 0.0007) with use of an adjusted Cox proportional hazards model. In the survivors, the differences between medical and surgical groups in recurrent myocardial infarction, mortality associated with reinfarction and sudden death were prospectively followed and evaluated by the life table method. Recurrent myocardial infarction was not prevented by surgical reperfusion or medical therapy (23% in both groups), however, the mortality rate in patients with recurrent infarction was higher in the medical therapy group--36.6% (15 of 41) versus 17.5% (7 of 40) (p = 0.04). The mortality difference did not depend on early or late surgical reperfusion. In the in-hospital survivors, the incidence of sudden death was 17.5% in the medical (31 of 177) versus 7.4% (13 of 176) in the surgical group (p = 0.01). This difference was much more pronounced in the early reperfusion group. Functional class was significantly lower than that for medical therapy in the early reperfusion but not the late reperfusion group. Thus, in comparable groups given medical and surgical therapy for acute myocardial infarction and followed up for greater than or equal to 10 years, surgical reperfusion appears to offer improved longevity in selected cases (when implemented early) but does not prevent recurrent myocardial infarction. The associated mortality with recurrent myocardial infarction is less as is the incidence of sudden death. Finally, lower functional class occurs most often in patients given early reperfusion.

Pituitary adenoma in McCune-Albright syndrome: MR demonstration.

The magnetic resonance (MR) demonstration of a pituitary adenoma associated with McCune-Albright syndrome is presented. A useful role for routine MR imaging of the sella turcica in all cases of clinically suspected McCune-Albright syndrome is suggested. This is especially important in patients with leontiasis ossea secondary to polyostotic fibrous dysplasia involving the craniofacial bones and skull base.

Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. A case report.

A 43-year-old woman with spontaneous episodes of neuroglycopenic hypoglycemia was found to have immune-mediated thrombocytopenic purpura and primary biliary cirrhosis. Hypoglycemia along with hyperinsulinemia suggested insulinoma. Serum c-peptide levels were disproportionately low, raising the possibility of factitious hypoglycemia. The patient's plasma contained circulating insulin receptor autoantibodies, thought to cause hypoglycemia by their insulin-like actions. With prednisone therapy, her other autoimmune features improved, and the hypoglycemia eventually resolved. Hypoglycemia mediated by insulin receptor autoantibodies should be considered in patients with fasting hypoglycemia and features suggesting an underlying autoimmune disorder before pursuing more invasive procedures. High-dose steroids may be life-saving in this disorder.

Effects of removing oxygen from patients with chronic obstructive pulmonary disease.

To determine the acute physiologic effects of removing oxygen from patients with chronic obstructive pulmonary disease (COPD) who are receiving long-term oxygen therapy, we made serial measurements in 20 patients during and after stopping low-flow oxygen therapy. Removing oxygen caused an increase in pulmonary vascular resistance, requiring 2 to 3 h to reach a new steady state. Removing oxygen therapy increased pulmonary vascular resistance index (PVRI) by 31% during rest (8.14 +/- 0.61 versus 6.23 +/- 0.51 units, p less than 0.001) and by 29% during exercise (8.11 +/- 0.9 versus 6.31 +/- 0.7, p less than 0.001). The increase in PVRI occurred because of an increase in pulmonary arterial pressure without a change in pulmonary capillary wedge pressure or cardiac index. At rest the increase in pulmonary arterial pressure caused by stopping oxygen correlated with the decrease in arterial oxygen saturation (r = 0.70, p less than 0.01). Removing oxygen decreased stroke volume index during rest and exercise. Although removing oxygen increased pulmonary vascular resistance, it did not affect systemic arterial pressure or vascular resistance. Stopping oxygen reduced arterial and mixed venous oxygen tension and oxygen delivery during rest and exercise. In patients who had a normal PaCO2 while breathing room air, removing oxygen therapy increased their oxygen consumption; conversely, in those patients who had an elevated PaCO2 while breathing room air, stopping oxygen therapy reduced oxygen delivery and oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologic therapy of cor pulmonale.

Oxygen remains the mainstay for the therapy of pulmonary hypertension and right ventricular failure in patients with COPD. Oxygen selectively vasodilates the pulmonary vascular bed, increases oxygen delivery and mixed venous oxygen tension, and reduces the elevated pulmonary vascular resistance and right ventricular work. Clinically, oxygen therapy improves neurologic function, exercise performance, and survival. Digitalis therapy is indicated only in patients with biventricular failure or supraventricular tachycardia. Diuretics should be used carefully. Two investigational therapies offer promise, but are unproven. Almitrine increases arterial PO2, and vasodilators lower pulmonary vascular resistance. Despite the proper use of the drugs reviewed in this chapter, the current therapy for the treatment of right ventricular hypertrophy and failure is limited. Improved therapy will require a better understanding of the pathophysiology that causes a hypertrophied ventricle to fail.

Use of calcium channel blockers in hypoxic lung disease.

COPD patients who are hypoxic develop pulmonary hypertension primarily because alveolar hypoxia induces muscular hypertrophy of pulmonary arteries. This muscular hypertrophy will regress in animals if they receive continuous oxygen therapy. Since many COPD patients refuse to use oxygen continuously, calcium channel blockers, which inhibit hypoxic pulmonary vasoconstriction, may be effective adjuvant therapy. Nifedipine lowers pulmonary vascular resistance during rest and exercise in hypoxic COPD patients.

Acute evolving myocardial infarction. A surgical emergency.

This is a report of 342 cases of acute evolving myocardial infarction treated with prompt coronary artery bypass. Myocardial infarction results from a time-related sequence of ischemic pathophysiological changes. The first hours constitute a rapidly progressive event. Prompt surgical revascularization partially prevents impending myocardial necrosis; occasionally it may even prevent it completely. The results are limited infarct size, decreased mortality and morbidity, and a striking absence of the complications associated with conventional therapy (ventricular aneurysm or perforation and septal and papillary muscle rupture).

Surgical intervention in acute myocardial infarction.

The goal of surgical reperfusion during the first hours of acute evolving myocardial infarction is to limit the extent of the infarction. This should be reflected by improved ventricular function and low mortality. Over the past 10 years, 440 patients with transmural myocardial infarction and 261 patients with nontransmural myocardial infarction underwent coronary artery bypass graft surgery within 24 hours of peak symptoms. The in-hospital mortality was 5.2% in the transmural group and 3% in the non-transmural group. In a 10-year study period, the mortality in the transmural group rose to 12.5%, while the mortality in the nontransmural group, followed for an 8-year period, rose to a total of 6.5%. The transmural myocardial infarctions in patients revascularized within 6 hours, showed a significantly improved in-hospital mortality of 3.8% compared to an in-hospital mortality of 12% for reperfusion after 6 hours. Anterior transmural areas of myocardial infarctions were reperfused within 6 hours of symptom onset, and demonstrated improved global ejection fraction and regional wall motion. Little improvement was seen if revascularization was instituted later than 6 hours from symptoms except in patients with adequate collateral perfusion of non-total left anterior descending coronary occlusion. Long-term follow-up of patients revascularized for acute myocardial infarction shows a low rate of subsequent reinfarction, incapacitating angina and sudden death. Left ventricular function at the time of cardiac catheterization correlates well with subsequent long-term mortality.