The erythrocyte sedimentation rate in congestive heart failure

BACKGROUND AND METHODS. Physicians have long believed that the erythrocyte sedimentation rate is low in patients with congestive heart failure, but this concept is based on a misinterpretation of the results in a single report published in 1936. To reevaluate this concept in the modern era, we measured the sedimentation rate in 242 patients who were referred for treatment of chronic heart failure. RESULTS. The sedimentation rate was low (less than 5 mm per hour) in only 24 patients (10 percent) but was increased (above 25 mm per hour) in 50 percent. Patients with low or normal sedimentation rates (less than or equal to 25 mm per hour) had more severe hemodynamic abnormalities than patients with elevated rates: lower cardiac index (mean +/- SEM, 1.7 +/- 0.1 vs. 2.0 +/- 0.1 liters per minute per square meter of body-surface area) and higher mean right atrial pressure (mean +/- SEM, 12 +/- 1 vs. 9 +/- 1 mm Hg) (both P less than 0.0001). New York Heart Association functional class IV symptoms were present in 66 percent of the patients with a low or normal sedimentation rate, as compared with 42 percent of those with elevated rates (P less than 0.0001). After one to three months of therapy, patients whose sedimentation rates decreased showed little hemodynamic or clinical response to treatment, whereas both cardiac performance and functional status improved in patients whose rates increased (P less than 0.02 for the comparison between groups). The sedimentation rate was correlated with the plasma fibrinogen level (r = 0.64, P = 0.0025), and changes in the sedimentation rate during treatment were correlated inversely with changes in mean right atrial pressure (r = -0.57, P = 0.0002). During long-term follow-up, patients with low or normal sedimentation rates had a worse one-year survival than patients with elevated rates (41 vs. 66 percent, P = 0.01). CONCLUSIONS. These data indicate that the erythrocyte sedimentation rate is correlated with the severity of illness in patients with chronic heart failure. Because of its lack of discriminatory power, however, the test is of limited value in the clinical management of this disorder.     

The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial

We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.     

Common principles underlying the control of rapid, single degree-of-freedom movements at different joints

Studies of rapid, single degree-of-freedom movements have shown different changes in electromyographic patterns for movement tasks that appear very similar (e.g., movements over different ranges of distance). However, it is not clear whether these differences are a result of joint-specific control schemes or whether they are instead due to the limited range of task parameters studied relative to the mechanical constraints of each joint (e.g., short compared with long movements relative to the range of motion of a particular joint). In this study, we measured and compared the kinematic trajectories and electromyograms recorded during various movement tasks at the wrist, elbow, and ankle. Subjects performed movements over a wide range of distances “as fast as possible,”“at a comfortable speed,” and against two inertial loads (at the elbow only), and they performed movements over a fixed distance at three different speeds at the wrist and ankle. For fast movements we show that, in spite of some joint-specific differences, the basic pattern of electromyographic (EMG) modulation is similar at all three joints; for example, the agonist EMG burst transitions from a fixed duration to an increasing duration with increasing movement distance at all three joints. Moreover, the distance at which this transition occurs in one joint relative to the distance at which this transition occurs in the other two joints is consistent across subjects. The transition occurs at the shortest distance at the ankle and the longest distance at the wrist. In general we suggest that the data are consistent with a single set of control rules applied at all three joints, with the biomechanical constraints at each joint accounting for the differences in the EMG and kinematic patterns observed across joints. Received: 3 September 1996 / Accepted: 10 June 1997     

Increased CD8+ T Cell Apoptosis in Scleroderma Is Associated with Low Levels of NF-κB

Our objectives were (1) to compare lymphocyte subpopulation apoptosis rates in SSc patients versus healthy controls and (2) to compare Bcl-2 and NF-kappa B expression in cultured CD8 lymphocytes of SSc patients versus controls. Peripheral blood samples were obtained from 27 SSc patients meeting the American College of Rheumatology criteria for SSc and 28 healthy individuals. Mononuclear cells were isolated by Ficoll-Hypaque density gradient separation and cultured for 48 hr. For determination of apoptosis within specific cell populations, samples were labeled with PE-conjugated monoclonal antibody to CD8, CD4, and a FITC-conjugated monoclonal antibody to Annexin V. Flow cytometry was carried out with a FACS operating with Cellquest software. CD8+ lymphocytes were positively selected with magnetic microbeads conjugated to antihuman CD8. CD8 T cells were separated, then incubated with activation for 48 hr, and NF-kappa B and Bcl-2 analysis was carried out using Western immunoblotting. The CD4:CD8 ratio was increased in SSc compared to controls (2.6 +/- 1.13 vs.1.87 +/- 0.76; P = 0.018). The spontaneous apoptosis rate of SSc CD8 lymphocytes was increased compared to that of controls of (21.9 +/- 13.7 vs. 13.3 +/- 9.9; P = 0.019). No difference was found in the rate of CD4 apoptosis of SSc patients versus controls (9.8 +/- 5.2 vs. 7.18 +/- 4.89%; P = ns). The expression of NF-kappa B in SSc CD8 lymphocytes was decreased compared with that of CD8 lymphocytes from healthy controls (144 +/- 13 vs. 188 +/- 11; P = 0.018). Whereas expression of Bcl-2 was similar in activated CD8+ T cells of SSc patients and healthy controls, CD8+ T cell apoptosis rate was found to be in reverse correlation with expression of NF-kappa B in these cells ( r = - 0.53, P = 0.029). The increased CD4:CD8 ratio in SSC may result from increased CD8+ T cell apoptosis. Increased SSc CD8 T cell apoptosis is associated with low levels of NF-kappa B.     

Gamma globulin inhibition of fibrin clot formation.

Myeloma gamma globulins have been reported to interfere with fibrinogen-fibrin conversion. A patient with multiple myeloma is described with a gamma globulin IgG1lambda concentration of 11 g per dl, prolonged thrombin time and poor clot retraction. Purified gamma globulin from the patient's serum and from normal serum caused prolongation of the thrombin time and reptilase clotting time assays in both normal plasma and in solutions of bovine fibrinogen. In addition, fibrin clots formed during the thrombin time assays were found to be ultrastructurally abnormal. This data suggests that the interaction of gamma globulin in the polymerization of fibrin may, in at least some cases, be due to nonspecific protein interaction.     

Glucose turnover values in the dog obtained with various species of labeled glucose.

Recent studies proposed that [2T]glucose is preferable to [14C]-glucose as a tracer for the measurement of glucose turnover. However, higher values for glucose turnover were obtained using [2T]glucose than with [14C]glucose. The present study explores the merit of another species of tritiated glucose, [3T]glucose. Utilizing isotope-dilution principles, comparison is made of glucose turnover values determined by use of [2T]glucose, [3T]glucose, and [6-14C]glucose. Glucose turnover using [2T]glucose was 1.51 +/- 0.07 times greater than that using [6-14C]glucose, after correction for recycling of 14C. However, glucose turnover values obtained with [3T]glucose were similar to those obtained with [6-14C]glucose. There were no temporal or quantitative differences in appearance of tritium (T) in plasma water after injection of [2T]- and [3T]glucose. A methylprednisolone regimen in the normal dog increased glucose turnover as determined by all three tracers, but the increase observed using [2T]glusoce was significantly greater than that using that two other tracers. Thiement for [6-14C]glucose for measurement of glucose turnover in the dog.     

Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus reactivation and infection post-allogeneic hematopoietic stem cell transplant continue to cause morbidity and mortality. Current pharmacologic therapies are limited by side effects. Adoptive transfer of ex vivo generated cytomegalovirus-specific T cells has the potential to restore immunity, prevent cytomegalovirus, and circumvent the need for pharmacologic therapies. We have generated donor-derived cytomegalovirus-specific cytotoxic T cells using dendritic cells pulsed with the HLA-A2 restricted nonapeptide NLVPMVATV (NLV) derived from the cytomegalovirus-pp65 protein. These cytotoxic T cells have been given prophylactically to 9 recipients aged 4 to 65 years on or after day 28 post-allogeneic hematopoietic stem cell transplant. Only 2 of 9 recipients received T cell depletion in vivo or in vitro. There were no immediate adverse reactions to the infusions. During 97-798 days of follow-up, 2 recipients developed cytomegalovirus reactivation; neither developed cytomegalovirus disease or required pharmacotherapy. Three recipients developed acute graft versus host disease after infusion. Two recipients died, 1 from thrombotic thrombocytopenia purpura secondary to cyclosporine, 1 from complications of graft versus host disease. A transient increase in numbers of cytomegalovirus-specific T cells demonstrated by NLV-tetramer binding was seen in 6 recipients. Prophylactic adoptive transfer of NLV-specific T cells is safe and may be effective in preventing cytomegalovirus reactivation.     

Differential reactivities of carcinoembryonic antigen (CEA) and CEA-related monoclonal and polyclonal antibodies in common epithelial malignancies.

To evaluate the role of carcinoembryonic antigen (CEA) in solving problems of tumor histogenesis in surgical pathology, monoclonal antibodies to four distinct epitopes of CEA (E-Z-EM) were applied to paraffin sections of 303 epithelial neoplasms from multiple sites. Two epitopes were CEA specific (D14 and B7.1), one was shared with nonspecific cross-reacting antigen (NCA) (B7.8), and the fourth (B18) was common to CEA, NCA, and biliary glycoprotein antigen (BGP). A sample of the tumors (n = 110) was also stained with a polyclonal anti-CEA (DAKO). Gastrointestinal adenocarcinomas, including esophageal and gastric (n = 19), small intestinal (n = 8), colorectal (n = 56), biliary tract (n = 8), and pancreatic adenocarcinomas (n = 14), were consistently positive with all five antibodies. Other predominantly gland-forming carcinomas tested, comprising lung (n = 22), ovary (n = 18), and endometrium (n = 12), were either invariably negative with all five antibodies (endometrial adenocarcinoma, non-mucinous ovarian adenocarcinoma) or demonstrated selective and variable positivity (lung: D14, 50%; ovarian mucinous: D14, 50%). Among large polygonal cell carcinomas (hepatocellular carcinoma, renal cell carcinoma, melanoma, and adrenal carcinoma), only hepatomas stained positively, showing a distinctive canalicular staining pattern with the B18 (BGP epitope) (55%) and polyclonal antibody (50%). In the small polygonal cell carcinoma category, true CEA positivity was rare in breast (D14, 10% and B7.1, 14%) and never seen in prostatic carcinomas and carcinoid tumors. A subset of these breast (8 of 42), prostate (4 of 22), and carcinoids (4 of 7) showed exclusive positivity for the B18 antibody (NCA/BGP epitope). Ovarian serous papillary carcinomas (n = 14), papillary carcinomas of thyroid (n = 12), transitional cell carcinomas of the bladder (n = 11), and mesotheliomas (n = 3) were negative with all monoclonal antibodies. Metastatic carcinomas (n = 74) showed a similar pattern of reactivity to primary tumors. The authors conclude that CEA immunostaining may assist in identifying the histogenesis of epithelial tumors in several morphologic categories; that differential reactivities of the CEA monoclonal antibody panel exceed those of the polyclonal antibody; and that the discriminating power of the monoclonal panel is related to whether (1) CEA is or is not produced or (2) NCA or BGP is produced without concomitant CEA production. There is little evidence to support a concept of site-specific CEA species.     

Ultrastructural characterization of the border zone surrounding early experimental myocardial infarcts in dogs.

The existence of a border zone composed of reversibly injured myocardium surrounding an evolving infarct has been the subject of controversy. In experiments designed to search for such a border zone by electron microscopy, 12 mongrel dogs underwent permanent ligation of the left anterior descending coronary artery (LAD). Two to 6.5 (average = 4.2) hours later, the hearts were excised, the area at risk (myocardium perfused by the LAD) was outlined by injection of fluorescent microspheres, and the myocardial infarct was demonstrated by the nitro blue tetrazolium (NBT) gross histochemical method. Myocardial samples for electron-microscopic study were obtained from the periphery of the infarct (tissues unstained by NBT) and serially from the immediately adjacent myocardium, which was stained deep blue by NBT. Grossly, the infarcts always involved the subendocardial myocardium, extended for a variable distance in the epicardial direction, and closely approximated the lateral margins of the area at risk. When examined by electron microscopy, the infarct periphery showed evidence of irreversible damage, thus confirming the ability of NBT to detect early myocardial necrosis. Multiple samples of the NBT-stained myocardium immediately adjacent to the infarct showed varying degrees of reversible ischemia, thus demonstrating, at the ultrastructural level, the existence of a border zone of intermediate myocardial injury. This border zone was substantial (3--4 mm in width) along the subepicardial aspect of the infarct and very thin (1--2 mm) laterally. In conclusion, a significant border zone was demonstrable by electron microscopy in the subepicardial myocardium of 8 out or 12 canine hearts with recent coronary artery occlusion. In the remaining 4 hearts, the infarcts had already reached the epicardium at the time of study, and only a thin lateral border zone was present.     

Patients' substance abuse and the primary care physician: patterns of practice

The Social Learning Theory concepts of self-efficacy and outcome expectations were used to study physician practice regarding patients' smoking, alcohol problems, OTC drug problems, and illicit drug use in a random sample of Texas primary care physicians. The highest proportion of physicians took histories and counseled patients regarding the abuse of cigarettes, followed by alcohol, OTC drugs, and illicit drugs. Outside referral was most likely for illicit drugs, followed by alcohol, OTC drugs, and smoking. Multivariate discriminant analysis showed year of graduation, specialty, self-efficacy, and outcome expectation for patient compliance to be predictive of many of the behavior/practice level combinations. More recently trained physicians, internists, and family practice specialists were more likely to practice in the substance abuse areas. Self-efficacy and outcome expectation were positively related to history-taking and counseling and negatively related to outside referral. Interventions to increase physicians' self-efficacy and expectations for patient compliance and to provide more realistic expectations for treatment "success" are needed, especially for physicians who are not recently trained. Further research to clarify the process by which physicians' cognitions of self-efficacy and outcome expectations influence their practice behavior is also recommended.