Ribavirin: efficacy in the treatment of murine autoimmune disease.

Ribavirin, a drug with known antiviral activity, was given to mice with established lupus nephritis. Ribavirin was effective in prolonging survival, reducing the titer of antibodies to DNA, and reversing proteinuria. Other antiviral agents were not effective in the dosages used.

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.

Weighted criteria for the diagnosis of systemic lupus erythematosus.

The preliminary American Rheumatism Association (ARA) criteria for classification of systemic lupus erythematosus (SLE) were evaluated for sensitivity and specificity in 87 patients with SLE and 73 without SLE from a rheumatology population. Using these data, Bayes' theorem was employed to weight the criteria so that a scoring system could be developed, allowing more accurate use of the criteria in diagnosis. Combinations of serologic test results were evaluated in a similar manner. Comparison of weighted scores with criteria counts showed greater sensitivity and specificity of the former whether the 1971 or modified 1982 ARA criteria were used. Weighted criteria may be more useful in clearly defining patient populations for studies of SLE.

Physiological variables and diabetic status. Findings in Tecumseh, Mich.

A random sample of 568 participants in the Tecumseh, Mich, study, aged 30 to 59 years, was stratified according to blood glucose concentration to select a high proportion of diabetics. Subjects were categorized as overt diabetics, chemical or probable diabetics, or nondiabetics. Diabetic groups and nondiabetics were compared for levels of blood glucose, plasma insulin, serum cholesterol, serum triglyceride, blood pressure, and contours of glucose and insulin curves. Overt diabetics had high mean fasting blood glucose levels. Challenged diabetics had significantly higher concentrations of all variables except cholesterol than nondiabetics, even after adjustment for age and adiposity. Glucose intolerance, adiposity, and sex influenced variables independently. Risk of atherosclerosis is partly attributable to persistent hyperglycemia and related metabolic abnormalities in overt diabetics. Postchallenge diabetics have subtle hyperglycemia but a high frequency of other risk factors. Recent developments suggest that control of blood glucose may become feasible and useful in the prevention of cardiovascular disease in overt and challenged diabetics.

Relative diagnostic value of cerebrospinal fluid kappa chains in MS: comparison with other immunoglobulin tests.

We used receiver operating characteristic (ROC) curve analysis to determine the relative performance of different CSF IgG parameters as diagnostic markers for multiple sclerosis. We quantitated CSF and serum IgG and albumin to determine an IgG albumin ratio, IgG index, Tourtellotte's synthesis rate, and Schuller's formula; CSF free kappa light chains were measured by radioimmunoassay. We compared a group of patients with clinically definite MS with a group of patients with a variety of other neurologic diseases. Tourtellotte's formula, IgG albumin ratio, IgG index, and free kappa chains distinguished the MS group from the comparative group of patients. ROC curve analysis demonstrated that CSF free kappa light chains were more closely linked to MS than the other measures. Multiple logistic regression analysis demonstrated no advantage of adding any single IgG measure or combination of measures to free kappa light chain analysis. Our results strongly suggest that free kappa light chains in CSF are the single best quantitative assay to support a clinical diagnosis of MS.

Interobserver variability in EEG interpretation.

A random sample of 100 active electroencephalographers in the United States evaluated 10-second samples of 12 selected EEGs. The evaluations consisted of multiple-choice questions related to the age of the patient, EEG finding, artifact, and consciousness of the patient. The rate of reporting the "correct" response was examined in terms of various respondent characteristics such as EEG board certification, age, percent of time in clinical EEG work, and number of recordings interpreted annually. This study indicates that, even today, there is considerable variability in EEG interpretation, and that this variability is influenced by specific reader characteristics.

Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus.

The validity of the hypothesis that some of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) are mediated by the direct effects of antibody binding to neuronal cell membranes is dependent on the demonstration of antineuronal activity within the central nervous system of patients with active central nervous system disease. Using a radiolabelled staphylococcal protein A assay, we tested cerebrospinal fluid from 27 patients with SLE and central nervous system manifestations, and cerebrospinal fluid from 18 additional patients with SLE but free of central nervous system disease for antibody reactive with the cultured human neuronal cell line SK-N-SH. Cerebrospinal fluid from 20 of 27 patients with active lupus central nervous system disease had increased immunoglobulin G (IgG) antineuronal activity compared with cerebrospinal fluid from two of 18 patients with SLE without central nervous system disease. Ninety percent of the patients with psychosis, organic brain syndrome or generalized seizures had increased IgG antineuronal activity as compared with only 25 percent of the patients who presented with hemiparesis or with chorea/hemiballismus. Antineuronal activity per microgram of IgG was concentrated eightfold in the cerebrospinal fluid of patients with active central nervous system disease as compared with the serum activity. Patients with or without active central nervous system disease did not differ significantly in the amount of serum antineuronal binding activity. The results are consistent with the hypothesis that the more diffuse central nervous system manifestations of SLE are a direct result of the interaction of antibody with neuronal cell membranes.

Haemophilus parainfluenzae mitral valve vegetation without hemodynamic abnormality. Demonstration by angiography and serial echocardiography.

The occurrence of Haemophilus parainfluenzae endocarditis on a previously normal mitral valve of a drug addict is described. A large mitral valve vegetation was demonstrated by serial echocardiography and cineangiography. The vegetation did not produce hemodynamic abnormalities preventing detection by physical examination. Multiple septic emboli to various organs, including brain, resulted in death. The role of serial echocardiography and the levophase of right heart cineangiography in detecting mitral valve vegetation in a patient suspected of having infective endocarditis is emphasized.

Pharmacology and autoradiography of human DP prostanoid receptors using [(3)H]-BWA868C, a DP receptor-selective antagonist radioligand.

1. A potent and highly selective DP prostanoid receptor antagonist radioligand, [(3)H]-cyclohexyl-N-BWA868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethyl-amino) hydantoin, ([(3)H]-BWA868C)), has been generated for receptor binding and autoradiographic studies. 2. Specific [(3)H]-BWA868C binding to human platelet membranes achieved equilibrium within 60 min at 23 degrees C and constituted up to 95% of the total binding. The association (K(+1)) and dissociation (K(-1)) rate constants of binding were 0.758+/-0.064 min(-1), mmol and 0.0042+/-0.0002 min(-1), respectively, yielding dissociation constants (K(D)s) of 5.66+/-0. 44 nM (n=4). 3. Specific [(3)H]-BWA868C bound to DP receptors with a high affinity (K(D)=1.45+/-0.01 nM, n=3) and to a finite, saturable number of binding sites (B(max)=21.1+/-0.6 nmol g(-1) wet weight). 4. DP receptor class prostanoids (e.g. ZK118182, BW245C, BWA868C, PGD(2)) exhibited high (nanomolar) affinities for [(3)H]-BWA868C binding, while prostanoids selective for EP, FP, IP and TP receptors showed a low (micromolar) affinity. 5. Specific DP receptor binding sites were autoradiographically localized on the ciliary epithelium/process, longitudinal and circular ciliary muscles, retinal choroid and iris in human eye sections using [(3)H]-BWA868C. While [(3)H]-PGD(2) yielded similar quantitative distribution of DP receptors as [(3)H]-BWA868C, the level of non-specific binding observed with [(3)H]-PGD(2) was significantly greater than that observed with [(3)H]-BWA868C. 6. It is concluded that [(3)H]-BWA868C is a high-affinity and very specific DP receptor radioligand capable of selectively labelling the DP receptor. [(3)H]-BWA868C may prove useful for future homogenate-based and autoradiographic studies on the DP receptor.

In vivo hemodynamic comparison of porcine and pericardial valves.

The bovine pericardial valve and the SupraAnnular valve have been developed to improve the hemodynamic function of tissue valves. Hemodynamic performances of the standard Carpentier-Edwards porcine valve, the Carpentier-Edwards SupraAnnular valve, and the Carpentier-Edwards bovine pericardial valve were compared in the aortic position. One hundred patients undergoing aortic valve replacement were studied intraoperatively. Mean gradient across the valve decreased for standard and pericardial valves as valve size increased. At the same flow rate, the 23 mm pericardial valve had larger valve orifice areas, higher performance indices, and lower gradients than the 23 mm SupraAnnular valve. The SupraAnnular valve is hemodynamically superior to the standard Carpentier-Edwards porcine bioprosthesis. The Carpentier-Edwards pericardial valve, however, is less obstructive in the aortic position than either of the porcine valves.

Reproducibility of syphilis serology results.

In order to evaluate the stability and reproducibility of syphilis serology qualitative results, the results reported on replicate specimens in the College of American Pathologists Quality Evaluation Program during 1978 were examined. There is evidence of good stability of syphilis serology specimens and reproducibility of qualitative results separated in time by as much as nine months for specimens that are nonreactive or highly reactive. However, there is evidence of lack of such stability and reproducibility of weakly reactive specimens. There is no striking difference in these results for the RPR card or VDRL test. The FTA-ABS test is more stable over time. There is some indication that the lack of stability and reproducibility of weakly reactive specimens is primarily a function of the stability of the specimen, with laboratory performance playing a secondary role.

Some statistical implications of rounding in the College of American Pathologists Survey.

Quantitative measurements of constituent concentrations of Survey specimens are generally recorded to the nearest integer or to the nearest tenth. Questions have arisen as to whether this degree of rounding of measurements is appropriate when available laboratory equipment can determine results more precisely. Statisticians have studied the effects of rounding off on an variety of standard statistical procedures. In this report biases that may result for estimates of the mean and variance from several typical data sets obtained in the 1975 College of American Pathologists (CAP) Survey are examined. The study indicates that the amount of bias in the sample mean and variance is generally minimal.

The distribution of selected hematology measurements in the CAP survey.

Investigation of the 1978 CAP Hematology Survey results for hemoglobin, hematocrit, erythrocyte count, leukocyte count, prothrombin time, and partial thromboplastin time with respect to the assumption of normality and the method for detecting outliers was performed. The findings indicate that the assumption of normality, while not exactly valid, is reasonable for the purposes of the Survey, but that the method of determining outliers may be too stringent in the case of hemoglobin, hematocrit, erythrocyte count, and leukocyte count, and not appropriate for prothrombin time and partial thromboplastin time. These findings are similar to those reported earlier for selected chemistry and immunology constituents in the CAP Survey.

Normality and other statistical considerations as they relate to selected quantitative measures in the CAP survey.

Investigation of the CAP statistical reports for quantitative tests with respect to the assumption of normality and the method for detecting outliers was performed. Specifically, laboratory measurements of several constituents from the Comprehensive Survey for 1975 were examined. The findings indicate that the assumption of normality, while not exactly valid, is reasonable and not deleterious to the purpose of the Survey, but that the method of determining outliers may be too stringent. A less strict, simpler outlier procedure is suggested as an alternative. It is also observed that other evaluation procedures would be available if more significant digits were reported for the laboratory measurements.

An evaluation of statistical procedures designed to detect outliers resulting from a light degree of contamination in random samples of moderate size.

The literature on statistical outlier procedures applicable to the CAP Survey program is briefly reviewed. Limited Monte Carlo evaluations of selected procedures were performed. For a light degree of contamination in random samples of moderate size, it is shown that the application of these procedures has little effect on estimates of measures of central tendency and spread. Moreover, in this situation these procedures detect a very small percentage of the outliners.

A blood ordering strategy for hospital blood banks derived from a computer simulation.

The ultimate goal of a hospital blood bank inventory control programs is to reduce wastage of blood products and unnecessary use of laboratory services without jeopardizing patient safety. The development of a practical blood ordering policy at the hospital level is an integral part of any such program. In order to explore various blood ordering options in detail, a computer simulation of a hospital blood inventory was used to assess the impact on blood band performance measures of reductions in group O and non-group-O levels from baseline levels, assuming both a 21-day and 35-day shelf life. On the basis of data derived from this study showing that such inventory reductions accompanied by partial protection of the group O inventory will not result in significant shortages, a practical strategy was developed for establishing optimal target inventory levels for a hospital on an empirical basis. These target levels can serve as a guide for subsequent blood ordering. A step-by-step approach for analyzing a hospital blood inventory control program is then suggested, accompanied by an action plan for implementing change which incorporates the experimentally-derived blood ordering strategy. Adherence to this plan should result in a low outdate rate, a reduction in unnecessary cross-matching, and greater availability of blood for those patients with a legitimate need for it.

Doppler velocimetry in concordant and discordant twin gestations.

Doppler blood flow studies in 63 pairs of concordant and 17 pairs of discordant twins were compared with those of 277 appropriate for gestational age singleton fetuses. Discordancy was defined as a more than 20% intra-pair actual birth weight difference. The data were divided into five groups: singletons and large and small concordant and discordant twins. Statistical comparisons of the regression lines for the large concordant and discordant twins and the singletons showed no significant differences among the three lines, either in slopes (P = .1) or intercepts (P = .08). Comparisons of the regression lines for small concordant and discordant twins and the singletons indicated a significant interaction among the three lines (P = .01). Additional analysis leads us to conclude that the systolic-diastolic ratio (S/D) decreases with advancing gestational age for all groups except small discordant twins. The S/D of small discordant twins differed significantly from that of singletons and tended to differ from that of small concordant twins.

Bimatoprost (Lumigan((R))) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracellular Ca(2+) mobilization studies.

Bimatoprost is the ethyl amide derivative of 17-phenyl-trinor prostaglandin F(2alpha). Here, we show that bimatoprost (K(i)=9250+/-846nM) and bimatoprost free acid (17-phenyl-trinor prostaglandin F(2alpha); K(i)=59+/-6nM) bind to the FP receptor and displace [(3)H]-travoprost acid, a selective FP agonist. Bimatoprost (EC(50)=3070+/-1330nM), Lumigan((R)) (bimatoprost 0.03% ophthalmic solution; EC(50)=1150+/-93nM) and bimatoprost acid (EC(50)=15+/-3nM) mobilized intracellular Ca(2+) ([Ca(2+)](i)) in <5s in HEK-293 cells expressing the cloned human ciliary body FP receptor on a fluorometric imaging plate reader (FLIPR). Furthermore, agonist effects of bimatoprost and bimatoprost acid were blocked by AL-8810 (11beta-fluoro-15-epi-15-indanyl prostaglandin F(2alpha); K(i)=0.7-2.1 MicroM), an FP receptor-selective antagonist. Therefore, the prodrug bimatoprost and its hydrolytic product, bimatoprost free acid, bind to and activate the human ocular FP prostaglandin receptor to mobilize [Ca(2+)](i), thus behaving as FP receptor agonists.

Intraoperative esophageal manometry: is it valid?

Forty-five patients undergoing a Collis-Nissen antireflux operation had preoperative, several intraoperative, and postoperative distal esophageal high-pressure-zone (HPZ) measurements. In 11 patients (24%), intraoperative manipulation of the esophagus alone, prior to beginning the repair, had a major effect upon the HPZ. The final mean intraoperative HPZ pressure (21.2 mm Hg) differed significantly (p less than 0.01) from that obtained postoperatively at 1 to 3 weeks (15.2 mm Hg), 6 months (11.2 mm Hg), and 12 mm Hg), and 12 months, (12.1 mm Hg). However, there was no significant statistical correlation between the final intraoperative HPZ pressures and those obtained after 6 and 12 months. Irrespective of the final intraoperative HPZ value, no patient undergoing acid reflux testing at 6 to 12 months after operation had any gastroesophageal reflux. It is concluded that esophageal manipulation (mobilization or dilation) results in variable intraoperative Hpz values that are not reliable predictors of HPZ values obtained late postoperatively. The rationale for altering the technique of an operation simply to obtain an "ideal" intraoperative HPZ value must be seriously questioned.

Thoracic surgery manpower: the fourth manpower study of thoracic surgery: 1985 report of the Ad Hoc Committee on Manpower of The American Association for Thoracic Surgery and The Society of Thoracic Surgeons.

Responding to a survey about their practice in 1985, 2,969 (70%) Board-certified thoracic surgeons provided data that were compared with data from manpower surveys in 1980 and 1976. (table; see text) Thoracic surgeons were most active between ages 35 and 54 years when they accomplished 61% of all general thoracic and 85% of cardiac operations. Surgeons older than 50 years performed significantly more general thoracic operations than younger surgeons, and the younger group performed significantly more cardiac operations than their older counterparts. Solo practice continued to decline. In smaller referral areas, the number of general thoracic procedures per surgeon increased, but the number of cardiac operations have decreased compared with 1980. Overall, general thoracic and cardiac operations increased, but peripheral vascular procedures and pacemaker insertions decreased in almost all nine census regions. Fewer general thoracic and cardiac operations were performed per thoracic surgeon in the western United States than in central and eastern regions. In response to questions about work load, 55% believed that their clinical activity was satisfactory, 42% operated too little, and 3% operated too much. The 363 non-Thoracic Board-certified surgeons who responded performed 14% of general thoracic and 8% of cardiac surgery in 1985. During the first half of the 1980s, our specialty certified an average of 134 thoracic surgeons annually, which is higher than the 120 surgeons per year estimated to meet the projected demand.