Presenting features and outcomes in patients undergoing temporal artery biopsy. A review of 98 patients.

Although temporal arteritis is a well-recognized syndrome, controversy still exists regarding the optimal approach to diagnosis and treatment of this condition. We undertook this review to further define the spectrum of presenting features and outcomes of patients undergoing temporal artery biopsy. We reviewed the records of all patients undergoing temporal artery biopsy over a 5-year period. Presenting features were compared in biopsy-positive and biopsy-negative patients. In patients with positive biopsy specimens, treatment regimens, disease, treatment-related morbidity, and outcomes were recorded. Alternative diagnoses and therapy were reviewed in biopsy-negative patients. Of 98 patients, 30 had positive and 68 had negative biopsy specimens. Biopsy-positive patients had an increased incidence of headache (93% vs 62%), jaw claudication (50% vs 18%), and prior polymyalgia rheumatica (23% vs 3%), but the sensitivity and specificity of these indicators were relatively low. Other clinical and laboratory parameters, including prior steroids and erythrocyte sedimentation rate, were similar between the two groups. In 30 patients with positive biopsy specimens, response to initial high-dose steroid was excellent. Serious manifestations after initial treatment were not seen, but mild flares were common after 1 year of therapy. Steroid-related morbidity was common, and steroids were seldom discontinued (0/22 patients at 1 year, 6/19 patients at 2 years, 5/11 patients at 3 years). In 68 patients with negative biopsy specimens, alternative diagnoses included neurologic diseases (15 patients), "pure" polymyalgia rheumatica (14 patients), and other inflammatory rheumatologic diseases (10 patients). Fourteen patients with negative biopsy specimens were treated for temporal arteritis, and were similar to biopsy-positive patients. Temporal arteritis remains a challenging condition to diagnose and to treat. Presenting features are seldom helpful in predicting biopsy results. Initial treatment is effective but frequently toxic. Although late disease-related complications are rare, most patients continue to take long-term low-dose steroid therapy.


Cough and ACE inhibitors.

To assess the prevalence of cough as a side effect of angiotensin-converting enzyme inhibitor antihypertensive therapy, we reviewed 300 consecutive patient charts from a private practice and 200 consecutive patient charts from a university-based referral center for hypertension. Incidence of definite angiotensin-converting enzyme inhibitor-induced cough in the private practice was 25% and in the university practice, 7%, with an additional 6% of university-practice patients reporting a possible angiotensin-converting enzyme-inhibitor induced cough. This incidence is considerably greater than listed in the Physicians' Desk Reference. Reasons for the variability in incidence as reported in the literature are explored. Clinicians must be aware of this potentially disturbing side effect of angiotensin-converting enzyme inhibitors to avoid expensive and unnecessary diagnostic evaluations.


Clostridium difficile diarrhea induced by cancer chemotherapy.

Four patients had diarrhea due to Clostridium difficile after receiving chemotherapy for cancer. None of the patients had received antibiotics for at least 4 weeks before the onset of diarrhea. At the time of admission of any of these four patients no outbreak of diarrhea was noted on the ward. Each patient was admitted with the acute onset of diarrhea after receiving chemotherapy, at different times of the year. Diarrhea was clinically important and was associated with dehydration, toxemia, and blood in the stool in all cases. Diagnosis of C difficile was confirmed by endoscopic examination, positive biopsy specimen, and positive test for toxin in the stool. All patients recovered after undergoing specific treatment. Drugs not believed to carry serious risk to the bowel mucosa may facilitate proliferation of C difficile. Patients with severe diarrhea after receiving chemotherapy, particularly those with blood in the stool, should be promptly tested for C difficile even in the absence of a history of antibiotic administration. Early and specific treatment can prevent additional morbidity and reduce cost of care.


[Validation of axillary temperature measurement as a biorhythm marker. Study of the sex variable].

This paper analyses the relationship between oral and axillary temperatures in the waking part of the day, and verify the existence of sex differences within both parameters. We selected 20 healthy subjects (10 men and 10 women) aged 22 to 30, controlling environmental and subject variables. The women's group does show greater thermic values for axillary temperature (8 of the 13 recordings). There was a highly correlation between sex groups (r = 0.854, p less than 0.001), axillary temperature rhythms between sexes are coupled and any differences are only of degree. For oral temperature the women's group showed higher values in 3 recordings (15.00, 18.00 and 21.00), and there was no correlation between men and women throughout the day. These results evidence sex differences in rhythmic patterns of oral temperature. Correlations between temperatures were highly positive for the whole sample, men and women. Our study presents empirical data on the validity of using axillary temperature as alternative measurement of body temperature. We expect the use of axillary temperature to be increasingly employed in chronobiological field studies.


[Acetylcholinesterase activity during the cortical development of the cat brain].

Acetylcholinesterase (AChe) hydrolyses acetylcholine to choline and acetate, thereby inactivating the neurotransmitter. However, the possible non-cholinergic function of this enzyme has been recently suggested. In the present work, changes in AChe activity during the postnatal development of the cat brain are described, in order to show if the enzyme could play a part in the maturing processes of the CNS. The study was performed in the frontal and parietal cortices, area 17 and areas 18 and 19 as a whole in the 15 and 30 days postnatal stages. Significant increases with age were observed in all the brain areas under study. It is suggested that this enzyme activity play a part in the maturation of the cat brain cortices, possibly in the cholinergic development and/or as a cell growth regulatory factor.


[Treatment of adenosine deaminase deficiency with adenosine deaminase combined with polyethylene glycol].

Adenosine deaminase (ADA) deficiency is one the causes of severe combined immunodeficiency syndrome. Treatment was, until now, based on bone marrow transplantation. HLA identical bone marrow transplantation yields excellent results while those of HLA haploidentical bone marrow transplantation are not so good. A new therapeutic approach was developed recently, consisting of the intramuscular infusion of ADA enzyme covalently linked to polyethylene glycol (PEG-ADA). We report the results of this treatment in a 14 month-old child presenting with a partial form of ADA deficiency revealed by an opportunistic infection. This treatment corrected the immunodeficiency and the biochemical abnormalities as well. PEG-ADA infusions were well tolerated. The onset of an immunization against the ADA enzyme led to a drop in immunologic functions, which could be partially overcome by more frequent (biweekly) administration of the product. After a 18 month-follow-up the child is doing well, living normally at home. PEG-ADA represents a possible alternative for children presenting with ADA deficiency without any available HLA identical donor.


[Subtypes of muscarinic acetylcholine receptor following the experimental denervation of the cholinergic pathway ascending to the neocortex].

Use of an experimentally induced neurotoxic lesion of the ascending cholinergic pathway to the neocortex, in rat brain, to study the postulated selective loss of muscarinic receptor subtypes (mAChR) presynaptically located (autoreceptors). Stereotaxic lesion of n. basalis magnocellularis was induced by 25 nmol Ibotenic acid injection in the right brain hemisphere of adult, male, Wistar rats. The contralateral hemisphere served as control. Antagonist (quinuclidinyl-benzilate) and agonist (carbachol) specific binding to mAChR receptors at equilibrium was studied 7 days post-lesion on a P2 fraction of brain cortex homogenate. Displacement of antagonist binding by carbachol was analyzed by "one-point" and "two-point" model fits. Muscarinic receptors on the control hemisphere show no sign of lesion related changes as compared to data for intact rat brain: Bmax = 0.896 pmol/mg protein and Kd = 0.25 nM. In the lesioned hemisphere a -10.3% loss of antagonist binding (not statistically significant) was observed, with an increase in receptor affinity. Heterogeneity of agonist binding was found; receptor subtype analysis showed that the proportion M2/M1 was unchanged but an increase in carbachol (M2 selective affinity) did appeared. We found no evidence of a selective presynaptic localization of muscarinic receptor sub-types on terminals of the cholinergic ascending pathway to the neocortex. A receptor loss related to the intensity of the neurotoxic lesion is suggested as well as the presence of regulative mechanisms (hypersensitivity) for receptors.


[Value of MRI in various forms of idiopathic growth hormone deficiency].

Magnetic resonance imaging (MRI) of the sellar and juxta sellar area was performed in 40 children with idiopathic hypopituitarism. MRI was normal in the 17 patients with partial growth hormone (GH) deficiency and in the 5 patients with GH neurosecretory dysfunction. Among the 18 patients with complete GH deficiency, the 10 with pituitary stalk transection presented more often with perinatal abnormalities, had the most severe GH deficiencies and more frequently multiple hormone deficiencies, in particular TSH deficiency. Pituitary gland size studies showed that the small size of the residual glandular tissue was responsible for these particularities. If MRI is of no great interest for functional GH deficiency, in half of the primary complete GH deficiencies, it enables to visualize a pituitary stalk transection with regeneration of neurohypophysis.


[Modulatory capability of the somatosensory afferents through acupuncture reflexotherapy].

This paper concerns the influence of the acupuncture on the somatic afferent volley. As the main used points in experimental acupuncture, we stimulated 4GI and 7H. The results confirm the modulatory influence of the acupuncture on the somesthetic afference and, also, its different mode of action related with the nature of the point stimulated.


[Hemodynamic and renal adaptation of newborn infants of hypertensive mothers treated with acebutolol].

A prospective study of the hemodynamic and renal changes was undertaken in 11 neonates whose mothers were treated with acebutolol for hypertension during pregnancy, compared with a control group of 11 infants born to normotensive mothers. Monitoring of the cardio-respiratory system was performed for a period of 4 days. Renal function was studied during 2 periods (12-36, 60-84 hours of life). Hemodynamic failure was observed in 5 of 11 children from treated mothers. The data concerning the renal function of treated group showed: 1) a diuresis significantly lower during the first period (p less than 0.05); 2) the absence of significant rise in the glomerular filtration rates during the second period; 3) a lower sodium balance during the 1st and 2nd periods (p less than 0.02 and p less than 0.05), a lower calcium balance during the 1st period (p less than 0.01). No relationship was found between the renal changes and the hemodynamic disturbances. The direct effect of the drug on the glomerular and tubular functions and/or the renal arteriolar vasomotricity could explain these changes in the renal function in the newborns prenatally exposed to acebutolol.


[Study of serum kinetics of vancomycin during the "antibiotic-lock" technique].

The serum kinetics of vancomycin was studied in two patients aged 3 and 15 years during antibiotic therapy for catheter related sepsis associated with Staphylococcus epidermidis. Vancomycin was administered, simultaneously, by parenteral conventional doses (30 mg/kg/day div q 8 h) and using the antibiotic-lock technique in the infected catheter at a high concentration (150 mg/ml) during one hour, 3 hours after each infusion. Pharmacokinetics data did not show any significant change in the serum kinetics of the antibiotic. The results suggest that delivering a high concentration of vancomycin in the infected catheter using the lock technique may be useful to sterilize infected catheter without toxic effect.


[Insulin resistant diabetes, acanthosis nigricans and Bartter's syndrome, a fortuitous association?].

The authors have followed during 10 years a girl with Bartter's syndrome who developed severe insulin resistance with acanthosis nigricans. In this rare association, hypokalemia and renal failure did not appear to be relevant factors triggering the onset of diabetes. The therapeutic difficulties in this case have still not been resolved.


[Duodenal atresia with bifid termination of the common bile duct].

A new case of duodenal atresia with gas below the obstruction is reported. This apparently contradictory feature is due to a bifid termination of the common bile duct in the duodenum, air by-passing the atretic area. The anomaly was proven by operative cholangiography.


[Striatal involvement with abnormal movements in hemolytic-uremic syndrome].

Two children with hemolytic-uremic syndrome (HUS) presented with alteration of consciousness and severe abnormal movements related to striatal involvement. They required dialysis and controlled ventilation. Steady improvement in neurologic function was seen during the following weeks, and abnormal movements disappeared. It is suggested that the pathogenesis of neurological dysfunction in these two children was related to intracerebral microangiopathy, because neither systemic arterial hypertension, nor metabolic disturbances were present. This hypothesis is supported by the cerebral blood flow study in one patient. Neuropathologic studies of patients with HUS who presented with CNS symptoms showed vascular thromboses within the CNS: CT scan demonstrated multiple small areas of infarction, particularly in the basal ganglia. The prognosis of HUS is generally worsened in case of severe CNS involvement, but abnormal movements may disappear without sequelae.


[Cardiac tamponade secondary to umbilical venous catheterization accident in a premature infant].

Cardiac tamponade is a rare and sometimes severe complication of umbilical venous catheterization. A premature newborn (gestational age: 30 weeks, birth weight: 1,215 g) required assisted ventilation and umbilical venous catheterization for respiratory distress. Subsequent chest X-ray showed the ascending tip of the catheter lying in the left atrium, inside the auricle. At the age of 16 hours, the infant presented with episodes of bradycardia. Despite a second endotracheal intubation, a sudden vascular collapse necessitated cardiac massage plus sodium bicarbonate and epinephrine. An ultrasound examination was performed because of the persistence of the vascular collapse; it showed a clear echo-free space between the epicardium and pericardium, suggesting pericardial effusion. The patient responded dramatically to pericardial aspiration, providing hemorrhagic fluid containing 20 g per liter glucose. Cardiac tamponade probably occurred in this patient as a result of perforation of the atrial wall. Ultrasonography showed no local thrombus, but confirmed the cardiac compression by pericardial fluid and the localization of the tip of catheter in contact with the atrial wall. This case led us to review the mechanical complications of umbilical venous and/or percutaneous catheterization and the rules for their use. This complication must be suspected in all patients having a central venous catheter that present with vascular collapse.


[Brainstem lesion in multiple sclerosis, blink reflex, and brainstem auditory evoked potentials].

Blink reflex (BR) and brainstem auditory evoked potentials (BAEP) were recorded from 168 patients with several diagnostic categories of multiple sclerosis, from which 98 complained brainstem symptoms (BSS+). From the whole group, the BR showed a higher degree of abnormality (45.75%) than BAEP (27.95). This range increased in the group BSS+ (52.15% for the BR and 34.9% for the BAEP) and even more when sings or symptoms of brainstem were present at the time of exploration (BSS+P) 60.4% for the BR and 41.3% for BAEP. Among patients who never complained brainstem symptoms, the BR disclosed a subclinical lesion in the 33.3% and the BAEP in the 16.9%. The combination of BR and BAEP were more useful than an isolated test. The localization of the lesion both clinically and in the BR were mostly on the pons. Light correlation between the presence of isolated or multiple symptoms and the disorder in the BR were present. Facial myokymia and internuclear ophthalmoplegia were most often associated with disorder in the BR, in both, the commonest localization was on the pons, and in the former about the motor nucleus of the facial nerve.


Literature review of research related to the Clinical Laboratory Improvement Amendments of 1988.

In conjunction with a 1990 Report to Congress on the studies required by the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88), the Centers for Disease Control, Atlanta, Ga, prepared a summary of the existing scientific literature related to the five studies listed in Section 4 of the Act. Over 800 articles were identified that, by title, seemed to deal with subjects that have been assumed to be associated with the quality of clinical laboratory testing. Although our search was not exhaustive, we believe that the articles included in our search are representative of the scientific evidence that exists. Most of the articles collected in our initial search were later eliminated from additional review because they were determined to be evaluations of laboratory analytic methods, contained only anecdotal evidence, were primarily descriptions of methods or programs, or were opinion articles without specific scientific data to support the opinions. This review reports the conclusions drawn by the research investigators of the 90 referenced articles; it does not analyze each article to assess the scientific validity of the research nor does it critique each article that is included. The review points to the need for additional research to answer questions raised by CLIA '88.


Quantification of errors in laboratory reports. A quality improvement study of the College of American Pathologists' Q-Probes program.

Over a 3-month period, 61,496 errors were detected in clinical laboratory reports by 631 participants in the College of American Pathologists' 1990 Q-Probes program. Each error detected was defined as an opportunity for improvement. Almost 4% of the detected errors were attributed to nonlaboratory personnel and approximately 4% (A errors) had a major impact on patient care. Rates of B (serious errors, but unlikely to affect patient care) and C errors (minor clerical errors) were approximately equal. When expressed in terms of measures of laboratory work loads, four of six measures of mean errors were lowest in blood banking, intermediate in chemistry and microbiology, and highest in hematology. Thirteen percent of participants did not have an error detection system in place. We conclude that many errors go undetected, and we recommend that an effective system for error detection in patient reports should be employed in all laboratories.


Determination and validation of reference intervals.

A brief overview of the concept of the reference interval and its application in medical practice is presented. The populations from whom it is possible to derive reference intervals are discussed. Procedures used to develop reference intervals from both a selected healthy population and from hospitalized patients are discussed, and the influence of statistical method on presented reference intervals is reviewed. However, the weakness of using a reference interval derived from a population of individuals to facilitate interpretation of test results is illustrated in relationship to the variability of test results within an individual. In spite of the efforts that are made within the clinical laboratory through development of reference intervals to provide maximum guidance to clinicians to facilitate their proper interpretation of test values in patients, it is apparent that much of the carefully derived scientific information is ignored in actual practice.


Determination of reference intervals in the clinical laboratory using the proposed guideline National Committee for Clinical Laboratory Standards C28-P.

The Subcommittee on Reference Intervals of the National Committee for Clinical Laboratory Standards (NCCLS) has recently completed a proposed guideline, NCCLS Document C28-P, entitled "How to Define, Determine, and Utilize Reference Intervals in the Clinical Laboratory." This guideline document is an attempt to combine a concise set of procedures and recommendations, largely taken from the original literature, to form a standard, uniform, and reasonable protocol for determining population-based reference intervals. The intent of the guideline is to set forth the minimum requirements for the determination of a reliable and clinically useful reference interval. The subcommittee hopes the document will set a standard that upgrades the quality of reference intervals to a level worthy of their use in clinical medicine.


The concept of establishing vs verifying analytic claims in method evaluations.

The establishment of analytic claims occurs during the method development stage. For commercial methods, the thorough characterization of analytic performance is the responsibility of the manufacturer. The manufacturer establishes performance claims with a high degree of certainty by utilizing statistically sound experimental protocols with sufficient degrees of freedom. The manufacturer should establish performance claims that state the expected performance of the method for the intended spectrum of patients and laboratory environment. The verification of analytic claims occurs by the end-user of the method. The end-user should not have to necessarily repeat the extensive protocol testing of the manufacturer that was used to establish the performance claims. The goals of the method verification study are not to establish analytic performance or to determine if the analytic performance is clinically acceptable, but, simply, to confirm or verify the stated established performance claims of the manufacturer. This implies an abbreviated method evaluation with statistical confirmation that analytic performance is acceptable. Analytic parameters that should be verified are imprecision, inaccuracy (bias), and linearity including analytic sensitivity. Reference ranges should be determined if the patient population is unique, or if the reference range of the analyte is relatively new or unstudied. Principles of method evaluation are discussed.


Establishing and maintaining performance claims. A manufacturer's viewpoint.

Performance claims are the vehicle by which a manufacturer communicates the analytic capabilities of its methods to laboratory users and to regulatory agencies. Claims describe the expected performance of an analytic system. To be useful, claims must be meaningful, achievable, and verifiable. To ensure consistent interpretation, they must be stated in clear, unambiguous terms. There are no specific guidelines for stating claims. Consequently, comparing the performance of one system to another is difficult. Claims fall into three categories: clinical utility, analytical performance, and boundary conditions. This article focuses on the three basic analytical performance characteristics, precision, accuracy, and specificity, and describes how they are established, validated, maintained, and monitored by manufacturers and how they can be verified by end users. Precision claims describe the inherent variability of the system. They differ in the components of variance included, ranging from the short-term variables within a single run to the long-term variables experienced over time, such as lot changes, calibrations, instrument drift, and environmental fluctuations. Precision may be stated either as typical user experience or as the minimum performance expected. Accuracy claims describe the degree to which the results will approximate the true values. They are more difficult to establish and verify, given the lack of objective standards for many analytes. For this reason, few manufacturers make true accuracy claims, relying instead on comparisons with other marketed methods. A notable exception is cholesterol, for which a model reference system has been established to help laboratories ensure accuracy. External proficiency testing is handicapped by matrix effects from imperfect survey fluids. Specificity claims describe the method's freedom from interference and cross-reactivity. They are based on screening tests by the manufacturer, augmented by feedback from users. There are no agreed-on criteria for what constitutes clinically significant interference, and no consistent approach for disclosing interference information. The National Committee for Clinical Laboratory Standards, Villanova, Pa, is beginning to develop guidelines to promote greater consistency in performance claim statements.


Estimating total analytical error and its sources. Techniques to improve method evaluation.

The process of method evaluation starts with identifying goals either to demonstrate the clinical validity of an assay or to identify assay error sources that require improvement. Taguchi's idea of continual quality improvement vs the notion of meeting or failing specification has been applied to clinical chemistry. In this article, I propose a model of assay performance that includes the terms random interferences and protocol-specific biases (a series of systematic errors). I explain these terms, as well as the consequences of failing to consider them. To validate an assay clinically, I recommend direct estimation of total analytical error from a method comparison. To identify assay error sources that require improvement, I recommend a multifactor protocol (in addition to a method comparison). Individual error sources are related to total analytical error with the use of an error propagation technique. Much of the proposed data analysis techniques are straightforward but not routinely practiced. I demonstrate principles with the use of a cholesterol assay.


Foundations for validation of quantitative analytical methods in the clinical laboratory.

This article explores federal requirements for validation of analytical methods and available resources. We focus on the contributions of the National Committee for Clinical Laboratory Standards to the problems of method validation. Illustrations are selected from the Committee's EP5-T Evaluation of Precision, EP10-T Preliminary Evaluation of Clinical Chemistry Methods, EP11 Uniformity of Claims, and the National Reference System for the Clinical Laboratory. We also include a list of applicable national and international organizations. Calcium assay by atomic absorption spectrometry using an imprecise diluter illustrates the application of the evaluation protocols as a method validation tool.


College of American pathologists experience with the linearity surveys, 1987-1991.

The Instrumentation Resource Committee has offered a survey since 1988 to perform and evaluate linearity. The survey uses a serum-based material and satisfies federal regulations that require linearity evaluations in the clinical laboratory. Both statistical and empirical methods to determine linearity were developed for the survey. Participant results have shown a high rate of nonlinear methods that may be due to our inability to accurately determine linearity or may reflect the true state of clinical assays. The survey shortcomings and future projects are discussed.


Alternative statistical techniques to evaluate linearity.

With the increase in demand for linearity assessment, a wide variety of analysis techniques have been advocated. There is no consensus on optimal techniques. This article reviews different approaches that have been advocated by the College of American Pathologists, by the National Committee for Clinical Laboratory Standards, and by manufacturers of diagnostic methods and controls. This is not a review of all statistical techniques proposed for linearity assessment. I discuss four basic categories of methods, with the first and simplest being visual review. The second general approach includes the conventional statistical techniques based on least-squares regression; this includes an equation for the line and statistical tests for linearity and for curvature. The third general approach involves comparison of slopes for line segments, or "deltas." This approximates the visual assessment of linearity. The fourth approach involves comparing observed and expected values, with some allowance for differences. Comparisons can be made for observed single results, means of replicates, or components of variance. Allowances for error can be internal goals or goals that are recommended for clinical usefulness. Each approach has strengths in different aspects of linearity assessment, including intuitive appeal, statistical rigor, and objectivity. Similarly, each approach has limitations that are not always obvious.


Linearity and calibration. A clinical laboratory perspective.

This article discusses the relationship of calibration and linearity using the example of glutaraldehyde assayed by high-performance liquid chromatography. Assuming adequate precision and a lack of interference, the relationship of calibration to a method's linear range becomes all important to achieving quality analytical results. Linearity is an objective description of the relationship between a quantitative method's final answer and true analyte concentration. Calibration brings this relationship into correspondence with calibrator concentration. The reportable range is that range within which a specified method produces results within defined allowable error without resorting to dilution of the specimen. The reportable range assumes a linear relationship between true analyte concentration and analytical results.


Correspondence of linearity evaluations to the performance of clinical chemistry instrument and reagent systems.

The importance of demonstrating linearity for a clinical chemistry analytical system has caused considerable debate. Disagreement about the way linearity is demonstrated has led to some misunderstanding about just what linearity means to the analytical goals. In many cases where linearity is evaluated by statistical means, the outcome will indicate a nonlinear condition. A subsequent graph plot of the same data usually produces a line that is virtually straight. Confusion over which linearity evaluation outcome to accept creates a lack of confidence in either approach owing to the sometimes obvious disagreement between the two outcomes and the ill-defined impact linearity has on analytical error or clinical usefulness. Models of analytical performance can be constructed in such a way that the paradox of conflicting linearity evaluations can be examined through their effects on the analytical goals.


Assuring analytical quality through process planning and quality control.

United States governmental regulations describe quality assurance as a system in which quality control (QC) and proficiency testing are to be used to substantiate that routine tests conform to specified performance criteria. Careful planning of analytical processes is necessary to guarantee that routine tests will achieve the analytical performance defined by the Health Care Financing Administration proficiency testing criteria. These proficiency testing criteria are analytical "total error" requirements that need to be translated into operational process specifications for the allowable imprecision, allowable inaccuracy, and the QC procedure (decision rules, number of control measurements) necessary to provide a known or specified level of analytical quality assurance. The level of assurance will depend on the QC procedure's probability for detecting critical sized errors that would cause the quality requirement to be exceeded. Analytical quality can be guaranteed by applying statistical QC to verify, with a specified probability, that a desired quality requirement is actually achieved in routine laboratory testing. Analytical quality assurance, applied in this way, can be a quantitative approach for guaranteeing quality through process planning and QC.


Health Care Financing Administration's new proficiency testing rules. Use of a statistical approach to predict long-term performance using the categories 'successful,' 'probation,' and 'suspended'.

Under the Clinical Laboratory Improvement Act of 1967 (CLIA-67) and the Medicare Act, the Health Care Financing Administration's proficiency testing rules apply uniformly to all hospital and reference laboratories. We examined the relationship between internal laboratory performance as characterized by bias and coefficient of variation and proficiency testing performance, categorized as "successful," "probation," and "suspended." Under the March 14, 1990, final rule, a laboratory with suspended testing for even one analyte may be required to cease testing in the entire subspecialty, eg, routine chemistry, unless it ceases testing for that analyte. Analyzing this regimen as a Markov process, we obtained the steady-state solution for performance for one to 27 analytes. While 1.1% of laboratories testing for five analytes with internal or day-to-day coefficients of variation at 50% of the CLIA-67 proficiency testing limit would be suspended, 19.5% of laboratories having biases of 50% and coefficients of variation of 33% would be suspended. We conclude that after eight events, there will be an unacceptably high rate of suspensions.


Selection of measurement and control procedures to satisfy the Health Care Financing Administration requirements and provide cost-effective operation.

The basic principles of method evaluation and quality control system design have been extensively studied and described. However, the interaction among the various independent variables comprising the complete analytical system is not so well known. In this article, a model of a generalized analytical system is presented and the nature of the interaction among analytical method parameters and quality control system parameters is explored. Implications of recent Health Care Financing Administration regulations for allowable total error are also discussed.


Achieving the Health Care Financing Administration limits by quality improvement and quality control. A real-world example.

With the enactment of the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88), the federal government is now using proficiency testing as the primary indicator of laboratory quality. Laboratories with proficiency test failures are now at risk of a variety of harsh penalties including large monetary fines and suspension of operations. To minimize the risk of failed proficiency testing, we initiated a continuous quality improvement program in our general chemistry laboratory in conjunction with the use of a new survey-validated quality control product. This article describes the quality improvement program and our success in reducing the long-term random error in general chemistry. Despite our improvement program, significant analytical errors (greater than 30% of the CLIA limits) still exist in analytes measured by our chemistry analyzer. These errors are present in nearly the same analytes measured by other common chemistry analyzers indicating the need for improvement in their design and manufacture.


Laboratory staff qualifications and accuracy of proficiency test results. A national study.

In the last quarter of 1988, laboratories from across the country that participated in the College of American Pathologists (Northbrook, Ill) proficiency testing program were asked to complete a questionnaire describing their staffing pattern and submit it with their test results. Laboratories were then divided into two groups, those employing 100% American Society of Clinical Pathologists (Chicago, Ill) certified technologists and those employing 0% American Society of Clinical Pathologists certified technologists. The nonparametric Wilcoxon significance test was used to determine differences in accuracy of test results for laboratories in each group. Significant differences were found for the basic laboratory survey, comprehensive diagnostic immunology, comprehensive blood banking, comprehensive hematology, and comprehensive chemistry. chi 2 Analysis revealed that laboratories employing 100% American Society of Clinical Pathologists certified technologists had a significantly higher probability of achieving 80% accuracy across all surveys. These results present a strong argument that staffing with qualified technologists contributes to maximizing the quality of laboratory services offered to the public.


Within-subject biological variation of hematological quantities and analytical goals.

For several common hematological quantities, the within-subject biological variation during a 1-year period was estimated in a group of 39 apparently healthy volunteers: 19 women and 20 men. All measurements were performed with a hematological analyzer (Toa E-5000, Toa Medical Electronics, Kobe, Japan). The means of the within-subject biological coefficients of variation, separated by sex when significant difference was shown, were as follows: 2.8% for hemoglobin concentration; 3.0% for erythrocyte concentration; 2.9% for erythrocyte volume fraction; 1.1% for mean erythrocyte volume; 1.9% for arbitrary SD of erythrocyte volume; 1.6% for mean erythrocyte hemoglobin concentration; 1.3% for mean erythrocyte hemoglobin; 10.8% in men and 15.7% in women for leukocyte concentration; and 6.7% in men and 8.6% in women for platelet concentration. The desirable between-day imprecisions for the measurement of each quantity were established as one half of the average of within-subject biological variation.


Detection of beta-endorphin in human blood. A study of performance characteristics of different radiometric systems.

beta-Endorphin, an opioid peptide that contains 31-amino acids derived from proopiomelanocortin, has been implicated in a variety of disorders. To understand its role in pathophysiological states, its levels have been determined in body fluids, particularly in serum or plasma, with the use of commercially available radiometric assay kits. Because the circulating levels of this endogenous opioid peptide are small and antibodies can cross-react with chemically related peptides to different degrees and give rise to faulty interpretation of the data, the performance characteristics of the available radioimmunoassay kits for beta-endorphin from the Immuno Nuclear Corporation, Stillwater, Minn, the New England Nuclear Corporation, Boston, Mass, and the Nichols Institute, San Juan Capistrano, Calif, were evaluated. In overall performance, the Nichols kit was found to be the most reliable in this laboratory, even though the sensitivity of the Immuno Nuclear kit was better at lower concentrations of beta-endorphin. Serum was better than plasma in terms of recovery of beta-endorphin. When collected on ice, no significant loss in beta-endorphin immunoreactivity was observed at 1 hour. The use of edetic acid (EDTA), siliconized edetic acid, and aprotinin (Trasylol)-added siliconized edetic acid tubes was not helpful in improving the performance of the assay. The optimal condition to collect the specimen was to use glass tubes, place the glass tubes on ice immediately, separate the serum, and freeze the sample within 1 hour of collection.


Very high values of serum high-density lipoprotein cholesterol.

Little is known about individuals who have very high values of serum high-density lipoprotein cholesterol (HDL-C) with the exception of those who have very rare genetic conditions, eg, familial hyperalphalipoproteinemia or hypobetalipoproteinemia. During a period of 60 months of testing for HDL-C, we found 46 individuals (of whom 43 were women) who had an HDL-C level equal to or higher than 2.58 mmol/L (greater than or equal to 100 mg/dL) (range, 2.58 to 6.15 mmol/L [100 to 238 mg/dL]). Sixteen of these individuals were treated with estrogens or ranitidine or were alcoholic, and several had evidence of coronary heart disease. We conclude that very high values of HDL-C can be found in the general population mostly in women, and this is often related to environmental causes, eg, the use of H2-blockers, estrogens, and alcohol. The finding of very elevated HDL-C levels in serum is probably not always due to a genetic condition and does not always signify absence of coronary heart disease and increased life expectancy.


Activated partial thromboplastin time reagent sensitivity to the presence of the lupus anticoagulant.

The lupus anticoagulant (LA) is an acquired abnormality that is associated with a prolonged activated partial thromboplastin time (aPTT). It is one of the most frequent coagulation abnormalities seen in the routine clinical laboratory. The sensitivity of various commercial aPTT reagents varies in their ability to detect the LA. We undertook this evaluation by using a single coagulation instrument to determine the sensitivity of five different commercial aPTT reagents to the presence of the LA. We evaluated 23 patients with known LA using five different reagents, two of which were marketed as having enhanced LA sensitivity. All samples and testing were performed under the same conditions in a timely manner. Based on these data, essentially all of the commercial reagents that were tested could detect patients with known LA by at least minimally prolonging the aPTT. Some reagents were slightly better than others in their ability to detect the LA. For most hospitals, the detection of the LA is not the highest priority for the use of the aPTT assay. In most cases, heparin anticoagulation monitoring is the most common use of the aPTT assay. Since all five reagents are sensitive to the LA, then the best overall reagent will be the one with the best sensitivity to the most important need for the laboratory (usually heparin monitoring). Therefore, a reagent should be chosen based on the primary monitoring requirements of the aPTT assay, and greater than 90% of the patients with the LA will be detected.


Fine-needle aspiration cytology of the adrenal gland. Fifty biopsies in 48 patients.

Fine-needle aspiration biopsy of 50 adrenal masses from 48 patients was performed between 1984 and 1991. The series consisted of 28 males and 20 females, with an age range of 12 months to 79 years (mean age, 55 years). Clinical and/or pathologic follow-up was available in 37 patients. Fine-needle aspiration was diagnostic in all 29 malignant cases having follow-up, with no false-positive diagnoses. There were six primary malignancies (three neuroblastomas, two pheochromocytomas, and one adrenal cortical carcinoma) and 23 metastatic lesions. Of these, the lung was the most frequent primary malignancy (60%), followed by melanoma and renal cell carcinoma (8.6% each). The remaining nonmalignant fine-needle aspiration diagnoses were adrenal cortical neoplasms (most likely adenoma), adrenal cortical hyperplasia, myelolipoma, benign adrenal tissue, and abscess. Based on clinical follow-up, three other adrenal adenomas were not diagnosed by fine-needle aspiration. Six biopsy specimens (12%) were insufficient for diagnosis. Ancillary studies including electron microscopy and/or immunocytochemistry were performed on 13 malignant aspirates and provided additional confirmation of the cytology diagnosis in 12 cases. This study confirms that fine-needle aspiration is a sensitive and highly specific procedure for the evaluation of primary and metastatic malignancies involving the adrenal gland. The technique is less useful in the workup of benign processes but, in some instances, can provide specific diagnostic information.


Rhabdomyosarcoma. A new classification scheme related to prognosis.

We classified 159 cases of rhabdomyosarcoma (RMS) according to the conventional scheme adopted by the World Health Organization and a modified conventional scheme established at the National Cancer Institute (NCI), Bethesda, Md. The major modification in the NCI scheme was the inclusion of compact round-cell RMS with scant myogenesis in the group of alveolar RMS despite lack of an alveolar architecture. These tumors were previously considered to be embryonal RMS, but their cytologic features are quite different from those seen in embryonal RMS and are indistinguishable from those encountered in alveolar RMS. These tumors are referred to as "solid alveolar RMS." Survival curves were constructed with the method of Kaplan-Meier and compared with the unstratified and stratified methods of Mantel-Haenszel (with stratification factors being stage, site, and age) and with the Cox regression analysis. Both histologic schemes showed a statistically significant prognostic value in unstratified analyses, but the NCI scheme demonstrated prognostic value even in stratified analyses and in the Cox regression analysis in our series of cases. The data indicate that the NCI scheme can serve as a highly predictive, independent prognostic factor in RMS and that the alveolar category should be expanded to include the solid round-cell RMS, even in the absence of a classic alveolar architecture.


Lack of prognostic value of histopathologic parameters in Hodgkin's disease, nodular sclerosis type. A study of 123 patients with limited stage disease who had undergone laparotomy and were treated with radiation therapy.

The value of histopathologic parameters in predicting the long-term overall survival probabilities was studied in a series of 123 patients with pathologic stage IA, IB, IIA, IIB, or IIIA Hodgkin's disease, nodular sclerosis type who were treated with curative radiation therapy. The parameters that were studied included the relative proportion of atypical vs reactive cells, amount of eosinophils, presence of necrosis, degree of mitotic activity, intensity of different types of mesenchymal reactions, classification in three subtypes (ie, lymphocyte predominance, mixed cellularity, and lymphocyte depletion) or in two grades (ie, grades 1 and 2), and identification of the syncytial variant. For each parameter, the association with clinical risk factors was also analyzed. The results of this study show that there are no pathologic features that carry a significant predictive value of the overall survival.


Abdominal visceral peliosis associated with bacillary angiomatosis. Ultrastructural evidence of endothelial destruction by bacilli.

Peliosis involving solid internal organs is a rare entity, and it has been reported in association with chronic debilitating diseases. Bacillary angiomatosis (BA), on the other hand, is a recently identified lesion found virtually only in individuals infected by the human immunodeficiency virus. We describe herein two cases of visceral BA and peliosis in human immunodeficiency virus-infected patients. Based on light and electron microscopic findings, we conclude that (1) BA bacilli present in the hepatic sinusoidal endothelial cells, in a suitable host milieu, may be the causative agents of peliosis hepatis; (2) BA bacilli can be found both intracellularly and extracellularly; and (3) peliosis is also identified in association with BA in abdominal lymph nodes.


Angiokeratoma of the clitoris.

A 25-year-old woman, multigravida, presented with a dark ulcerated tumor of the clitoris. Histologic examination demonstrated an angiokeratoma, a benign telangiectatic vascular tumor. To our knowledge, this is the first report of angiokeratoma of the clitoris and only the fifth describing vascular tumor of this organ. The clinical differential diagnosis of angiokeratoma and of clitoral tumors includes malignant neoplasms such as melanoma. Biopsy with histologic examination is, therefore, recommended to ensure appropriate treatment of these unusual tumors.


Pol André Bouin, MD (1870-1962). Bouin's fixative and other contributions to medicine.

Pol André Bouin was a distinguished French scientist who gained international reputation at the turn of the century for his work in histology and reproductive endocrinology. His name has been retained eponymously in the fixative he described in 1897, today known as "Bouin's fixative." The fixative that bears his name is only one of many contributions he made to academic medicine.


Sexual behavior patterns of customers of male street prostitutes.

Information about male customers of male prostitutes, including sociodemographic and life-style characteristics, sexual and drug use behaviors, and knowledge about HIV infection were collected from a convenience sample of 211 male street prostitutes and a convenience sample of 15 male customers as part of a feasibility study. Data from these two groups indicate that despite knowledge of HIV infection and its transmission, customers engage in high-risk sexual and drug use behaviors with prostitutes. Because there is a high HIV infection rate within the male prostitute sample (175/1000) and because these customers for the most part describe themselves as bisexual or heterosexual, it is likely that male customers of male prostitutes serve as a vector of transmission of HIV infection to their other partners including the heterosexual population.


Divorce and sex.

Studies on the sex lives of the divorced are relatively few and somewhat dated. Although they give a rather optimistic view of the subject, this research is flawed by high respondent refusal rates and poor representativeness of samples. Further, a major gap in this literature is that the possible predictors of sexual activity of the divorced remain largely unexplored. The present study, using national data on 340 divorced people, indicates a much lower level of sexual activity than found in past research. Regression analyses find that both number of partners and sex frequency are related to religiosity, education, and political liberality. Future research can explore the impact of low sexual activity among the divorced on indicators of emotional well-being.


The relationship of sexual daydreaming to sexual activity, sexual drive, and sexual attitudes for women across the life-span.

The association among sexual daydreaming and sexual attitudes and activity was examined in a cross-sectional life-span sample of women (N = 117, 26 to 78 years). Sexual daydreaming was measured using the Imaginal Processes Inventory (IPI) while sexual history measures of sexual activity, sexual drive, and sexual attitudes were derived from a comprehensive personal interview. A factor analysis and varimax rotation of the sexual history variables, age, and the Sexual Daydream Scale of the IPI revealed three primary factors representing dimensions of sexual activity and drive, attitudes toward sexual activity, and sexual satisfaction. Age was associated with less sexual daydreaming, less sexual drive, less sexual activity, and more negative sexual attitudes. Sexual daydreaming varied directly with sexual drive and sexual activity and with a positive sexual attitude.


Vibrotactile stimulation enhances sexual response in sexually functional men: a study using concomitant measures of erection.

The role of vibrotactile stimulation on the penis in producing erection was investigated in 34 sexually functional men. Subjects were presented with three stimulus segments: erotic video (VID); vibrotactile stimulation (VT) applied to the underside of the penis; and combined vibrotactile and erotic video stimulation (VID+VT). Maximum erectile response was recorded to each stimulus using both an erectiometer and a Barlow strain gauge. Self-reported sexual arousal and affective response to each stimulus segment were also obtained. Results indicated significant variation in erectile response and self-reported arousal over the stimulus segments. Erectile response was lowest to VT alone and highest to VID+VT for both erectile measures, although the pattern of change across stimuli was different for each measure. Self-reported sexual arousal was consistent with erectile measures, but the difference between VID and VID+VT was not statistically significant. VT stimulation alone was perceived as somewhat unpleasant; both VID and VID+VT were perceived as more pleasant than VT, but VID and VID+VT did not differ significantly from each other. This study demonstrates that, while not perceived as more pleasurable or arousing, VT stimulation on the penis combined with erotic video stimulation augments erectile response in functional men in a controlled laboratory situation. The possible use of this methodology for the improved study of men with sexual dysfunctions is discussed.


Buspirone hydrochloride in the treatment of an atypical paraphilia.

A case report involving buspirone hydrochloride in the successful treatment of a patient with an atypical paraphilia and transvestic fetishism is presented. Treatment outcome was assessed by the patient's self-report as well as by retrospective examination of detailed notes about paraphilia fantasies which unknown to the therapists, had been kept by the patient. Preliminary evidence indicates that buspirone appears to effectively treat some paraphilias.


Effects of cigarette smoke on the antibody responses to thymic independent antigens from different lymphoid tissues of mice.

The influence of cigarette smoke on the humoral immune response of mice was investigated in lymphocytes derived from the spleen, bone marrow (BM) and mesenteric lymph nodes (MLN). Mice of the DBA/2J or C57BL/6 strain were exposed to cigarette smoke of a standard research cigarette, 2R1, twice a day, ten puffs each in morning and afternoon for 20, 40 or 60 weeks. At the end of the smoking period, animals were immunized intraperitoneally with the thymic independent antigens polyvinyl pyrrolidone (PVP) or trinitrophenyl (TNP)-Ficoll. The antibody responses were analyzed using sheep red blood cells coated with PVP or TNP, in a plaque forming cell (PFC) assay. The results indicate a statistically significant inhibition of the antibody response induced by PVP but not by TNP-Ficoll in splenic B cells of smoke exposed mice compared to sham controls. When tested in other lymphoid organs, there was higher anti-TNP PFC response from the BM and MLN cells of smoke exposed animals compared to sham controls.


Oral and dermal application of 2,4-dichlorophenoxyacetic acid sodium and dimethylamine salts to male rats: investigations on absorption and excretion as well as induction of hepatic mixed-function oxidase activities.

Absorption and urinary excretion of 2,4-dichlorophenoxyacetic acid sodium (sodium 2,4-D) and 2,4-dichlorophenoxyacetic acid dimethylammonium (2,4-DMA) salts were examined after single oral and mid-dorsal skin applications of the herbicides to male rats. Doses of 2.6 mg 2,4-D/kg body wt (sodium 2,4-D) and 1.9 mg 2,4-D/kg body wt (2,4-DMA) were applied. Quantitatively, with both salts, most of the orally administered herbicide (over 90%) was excreted in urine within 28 h. However, 2,4-D urinary peak concentrations were measured 4.5 and 20.5 h after dosing with 2,4-DMA and sodium 2,4-D, respectively. Additionally, the volume of urine in the oral study was significantly increased with both salts when compared with the controls or the dermal exposure. After topical application, 2,4-D absorption was much lower than in the oral study. Urinary excretion only reached about 10 and 15% of the applied dose for sodium 2,4-D and 2,4-DMA, respectively, by 5 days post-treatment. Further, we found some elevations in hepatic cytochrome P-450 activities. Ethylmorphine N-demethylase was only slightly induced by the herbicides while ethoxyresorufin O-deethylase activity was increased nearly 2-fold by sodium 2,4-D.


Inhibition of ferrochelatase and accumulation of porphyrins in mouse hepatocyte cultures exposed to porphyrinogenic chemicals.

The ability of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (EDDC) and griseofulvin to induce porphyria in primary cultures of mouse hepatocytes has been examined. Exposure of cultured mouse hepatocytes to DDC, EDDC or griseofulvin resulted in a marked inhibition of ferrochelatase which was sustained over the 4-day exposure period. Maximal concentrations of DDC (25 microM), EDDC (25 microM) and griseofulvin (25 microM) resulted in 14-fold, 30-fold and 9-fold increases, respectively, in total porphyrin in the culture medium. Analysis of the porphyrins accumulating indicated a predominance of protoporphyrin with all three xenobiotics. Addition of 5-aminolaevulinic acid (ALA) to mouse hepatocyte cultures (10-1000 microM) resulted in much larger increases (up to 164-fold) in porphyrin accumulation in the medium and the porphyrin accumulating was predominantly uroporphyrin. These studies have demonstrated that primary cultures of mouse hepatocytes provide a valid mechanism-based in vitro model of the hepatic porphyrias produced by the dihydropyridines and griseofulvin in mice.


Studies on the hepatotoxicity induced by bis (tributyltin) oxide.

The toxic effects of bis (tributyltin) oxide (TBTO) on the rat liver were studied with an electron microscope and the accumulation sites of tin were determined with an X-ray microanalyzer. The activities of serum enzymes and the concentration of serum bilirubin were also analyzed. Male Wistar rats received an intramuscular injection of 0.5 ml/kg of TBTO. Marked swelling of the mitochondria appeared in the hepatocytes 4 h after injection of TBTO. Cytoplasmic vacuoles, which contained degenerated mitochondria, gradually increased in number in these hepatocytes. This in turn may have caused a decrease in the volume of hepatic cell cords and an enlargement of sinusoids in the entire hepatic lobule. However, fine structures of intrahepatic bile ducts were not altered. By X-ray microanalysis, tin peaks were preferentially obtained from swollen mitochondria of the hepatocytes. By polarographic analysis of the respiratory responses of mitochondria, it was demonstrated that rates of state 4 respiration and respiratory control ratio were significantly disturbed in TBTO-treated rats in comparison with those of controls. The activities of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) were significantly increased after TBTO treatment, but those of ALP (alkaline phosphatase), LAP (leucine aminopeptidase) and total bilirubin were not changed. These results indicated that parenterally administered TBTO accumulated in the liver cell mitochondria and disturbed oxidative phosphorylation. Mitochondrial dysfunction might induce severe damage of the hepatocytes. Four days after injection of TBTO, hepatic structures and chemical indices were almost restored by the regeneration of hepatocytes.


Developmental toxicity evaluation of gallium nitrate in mice.

Gallium nitrate, a drug with antitumor activity, is presently undergoing clinical trials as a chemotherapeutic agent for the treatment of certain malignancies. Since there are very limited published animal toxicity data available, this study was conducted to investigate the potential adverse developmental effects of this drug. Pregnant Swiss mice were administered intraperitoneally gallium nitrate at 12.5, 25, 50, and 100 mg/kg/day on days 6, 8, 10, 12, and 14 of gestation. Monitors for maternal toxicity were body weight, food consumption and clinical signs. At sacrifice (day 18) maternal weight, liver and kidney weights, and gravid uterine weights were measured. Gestational parameters monitored were numbers of total implants, resorptions, postimplantation losses, and dead fetuses. Live fetuses were sexed, weighted, and examined for external, internal and skeletal malformations and variations. Maternal toxicity was noted in all the gallium nitrate-treated groups. Embryo/fetal toxicity was evidenced by a decrease in the number of viable implants, a reduction in fetal weight, and an increase in the number of skeletal variations (12.5, 25, 50 and 100 mg/kg). No significant increase in the incidence of malformations was observed at 12.5, 25, or 50 mg/kg. The no-observable-adverse-effect level (NOAEL) for both maternal and developmental toxicity of gallium nitrate was less than 12.5 mg/kg.


Teratogenicity of arotinoids (retinoids) in the rat whole embryo culture.

Structural modifications of the arotinoid molecule RO 13-7410 led to a difference in the teratogenic potencies of more than five orders of magnitude in mice in vivo and in micromass cultures of rat embryonic limb bud cells (Kistler et al. 1990). Five of these retinoids were selected and tested in rat whole embryo culture to determine the suitability of this in vitro test system for the identification of potentially non-teratogenic derivatives among this class of chemicals. The highest concentrations of the compounds with no effects (NOAEL) on general conceptus growth, on differentiation and on the frequency of dysmorphogenic embryos in vitro were compared with the lowest effective teratogenic doses in vivo (LOAEL) or with the concentrations leading to 50% inhibition of limb bud cell differentiation (IC50) in vitro. NOAEL's for the parameters of conceptus development ranged from 10(-5) micrograms/ml (0.03 nM) to 10 micrograms/ml (28.7 microM) for the compounds tested. These correlated very well with LOAEL and IC50 (R greater than 0.95). The types of dysmorphogenesis in vitro were those typical for retinoids, and for the most part resembled the malformations found in vivo. We conclude that the whole embryo culture system is a useful tool for the preliminary testing of retinoids.


Effects of megadoses of pyridoxine on spermatogenesis and male reproductive organs in rats.

Although it has been indicated that many neurotoxicants also cause reproductive toxicity, the reproductive toxicity of megadoses of pyridoxine, which is a neurotoxicant, has not been studied. In this paper, we studied the effects of megadoses of pyridoxine on male reproductive organs. Pyridoxine hydrochloride, 125 mg/kg, 250 mg/kg, 500 mg/kg or 1000 mg/kg, daily, was intraperitoneally injected into Wistar male rats 5 days a week for 2 or 6 weeks, and its effects on the male reproductive organs were investigated. After 2 weeks of administration, absolute weights of the testis in the 500 and 1000 mg/kg epididymis in all the exposed groups and prostate gland in the 1000 mg/kg group decreased, and mature spermatid counts in the testis decreased in the 1000 mg/kg group. After 6 weeks administration, the absolute and relative weights of the testis, epididymis, prostate gland and seminal vesicle decreased in the 500 mg/kg and 1000 mg/kg groups, and mature spermatid counts in the testis and sperm counts in the epididymis decreased in these groups. Among the marker enzymes of the testicular cells, LDH-X activity decreased, and beta-glucuronidase activity, cytochrome P-450 content and cytochrome b5 content increased in the 1000 mg/kg group. Plasma testosterone concentration did not significantly alter in all the exposed groups. From these results, it was concluded that megadoses of pyridoxine affected the spermatogenesis and decreased reproductive organ weights in the rat.


Mechanism of soman-induced contractions in canine tracheal smooth muscle.

The actions of the irreversible organophosphorus cholinesterase (ChE) inhibitor soman were investigated on canine tracheal smooth muscle in vitro. Concentrations of soman greater than or equal to 1 nM increased the amplitude and decay of contractions elicited by electric field stimulation. The effect on decay showed a marked dependence on stimulation frequency, undergoing a 2.4-fold increase between 3 and 60 Hz. Soman also potentiated tensions due to bath applied acetylcholine (ACh). Little or no potentiation was observed for contractions elicited by carbamylcholine, an agonist that is not hydrolyzed by ChE. Concentration of soman greater than or equal to 3 nM led to the appearance of sustained contractures. These contractures developed with a delayed onset and were well correlated with ChE activity. Alkylation of muscarinic receptors by propylbenzilylcholine mustard antagonized the actions of soman on both spontaneous and electrically-evoked muscle contractions. The results are consistent with a mechanism in which the toxic actions of soman are mediated by accumulation of neurally-released ACh secondary to inhibition of ChE activity. An important factor in this accumulation is suggested to be the buffering effect of the muscarinic receptors on the efflux of ACh from the neuroeffector junction.


Interaction of obidoxime with sarin in aqueous solution.

The interaction of obidoxime (Toxogonin) with sarin was shown by different analytical methods. The UV spectrum of obidoxime at pH 7.4 yields two absorption maxima, lambda 1 = 284 nm and lambda 2 = 353 nm. The peak at lambda 2 = 353 nm is representative for the amount of zwitter-ionic obidoxime, i.e. the active form of obidoxime. By addition of sarin, lambda 1 shifts immediately to 278 nm and the intensity at lambda 2 decreases, thus indicating an interaction. TLC and 31P-NMR evidence shows that both mono-phosphonylated and diphosphonylated obidoximes are present. Decomposition of phosphonylated obidoxime in MOPS (3-[N-morpholino] propanesulfonic acid) buffered D2O at pH 7.4 occurs with t1/2 = 13.3 min at 24 degrees C. Decomposition of di-phosphonylated obidoxime is faster. It is suggested that decomposition of di-phosphonylated obidoxime occurs through the mono-phosphonylated form. Formation and decomposition of mono- and di-phosphonylated obidoxime is pH dependent. We conclude that obidoxime exerts a detoxifying effect by capturing free sarin molecules and thus increasing its polarity. Thereby the transition of sarin through the blood-brain barrier is restricted and its renal elimination facilitated.


Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice.

The toxicity and efficacy of two oximes, HLö-7 and pyrimidoxime, were evaluated in mice and compared to those obtained with HI-6. HLö-7 and pyrimidoxime produced 24 h LD50 values of 356 and 291 mg/kg (i.p.), respectively. In combination with atropine (17.4 mg/kg, i.p.), HLö-7 was a very efficient therapy against poisoning by 3 x LD50 dose of soman, sarin and GF and 2 x LD50 dose of tabun with ED50 values of 12.4, 0.31, 0.32 and 25.2 mg/kg, respectively. In contrast, pyrimidoxime was a relatively poor therapy which resulted in ED50 values of greater than 150, 5.88, 100 and 71 mg/kg against poisoning by soman, sarin, GF and tabun, respectively. HLö-7 produced significant (p less than 0.05) reactivation of phosphorylated acetylcholinesterase, in vivo, resulting in 47, 38, 27 and 10% reactivation of sarin, GF, soman and tabun inhibited mouse diaphragm acetylcholinesterase, respectively. HLö-7 also antagonized sarin-induced hypothermia in mice suggesting that it reactivated central acetylcholinesterase. The potential of HLö-7 as a replacement oxime for the treatment of nerve agent poisoning is discussed.


Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their constituents in human HepG2 cells.

Dose-response curves of the induction of P4501A1-dependent 7-ethoxyresorufin O-deethylase (EROD) were analyzed in human hepatoma HepG2 cells treated with defined mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their 2,3,7,8-substituted constituents, similar to previous studies with rat hepatocytes and H4IIE cells (Schrenk et al. 1991). PCDDs appear to act less potent in human HepG2 cells in comparison with rat cells. For example, EC50 values of 2,3,7,8-Cl4DD were 8-fold and 19-fold higher than in rat H4IIE cells and hepatocytes, respectively. EC50 values of PCDDs were compared with that of 2,3,7,8-Cl4DD and expressed as 2,3,7,8-Cl4DD equivalents (TEs). Although the rank order of PCDD potencies was similar, TEs for some PCDDs (1,2,3,7,8-Cl5DD; TE = 0.75 and 1,2,3,7,8-Cl6DD; TE = 0.61) were found to be higher than in the rat system. In contrast to rat cells no significant induction of EROD could be detected with Cl8DD in HepG2 cells up to its limit of solubility. Experimentally determined TEs of PCDD mixtures containing 49 constituents were found to be largely due to additive effects of their 2,3,7,8-substituted constituents.


Cytotoxicity of mebendazole against established cell lines from the human, rat, and mouse liver.

The direct cytotoxicity of mebendazole (MBZ) was investigated by using cell lines derived from human, mouse and rat liver. It was demonstrated that Chang liver cells (derived from human liver) were more sensitive to the cytotoxic effects of MBZ than the other two cell lines. Longer incubation of the cells with MBZ resulted in stronger toxicity, and the cytotoxicity was dependent on the MBZ concentration above a certain threshold value (0.25-0.50 mg/l in a 42-h culture). Inhibition of the proliferation of Chang liver cells by MBZ was detected at a concentration of 0.008 mg/l, a lower concentration than that having a cytotoxic effect. The other two cell lines were less sensitive to the inhibitory effect of MBZ. Proliferation of human mononuclear cells following stimulation by phytohemagglutinin (PHA) was inhibited by MBZ, and this inhibition was more extensive than that of cells stimulated with whole formalin-treated Pseudomonas aeruginosa. It is suggested that dividing cells may be more sensitive to MBZ cytotoxicity. This anti-proliferative effect may be related to its clinically known side effects, such as hepatotoxicity and bone marrow suppression.


Hematological toxicity of tetrachloroethylene in mice.

Female C57/BL/6 x DBA/2 hybrid mice were exposed to two concentrations (270 and 135 ppm) of tetrachloroethylene (PER) in inhalation chambers for 6 h/day, 5 days per week, up to 11.5 weeks (270 ppm) and 7.5 weeks (135 ppm), respectively, followed by a 3-week exposure-free period. In the peripheral blood a reduction of lymphocytes/monocytes and of neutrophils was observed with an almost complete regeneration in the exposure-free period. A reticulocytosis during and also after the exposure indicated a compensatory reaction in the erythroid cell system. Bone marrow pluripotent stem cells (CFU-S) were not affected up to 7.5 weeks. Erythroid committed cells (BFU-E and CFU-E) did react, with a reduction of CFU-E numbers at 7.5 and 11.5 weeks. A slight reduction of CFU-C numbers at 7.5 weeks indicated, in accordance with the peripheral blood data, a disturbance of the granulocytic cell series as well.


Gadolinium-pentetic acid magnetic resonance imaging in patients with relapsing remitting multiple sclerosis.

Ten patients with relapsing-remitting multiple sclerosis have been studied by serial gadolinium-pentetic acid magnetic resonance imaging (MRI) every 14 days for 3 months. At the end of the follow-up, seven relapses occurred in six patients; no therapy was administered during the study. Ninety-three enhancing lesions were collected in eight patients. With regard to the duration of the enhancement, 32 lesions were detected in only one MRI scan and 32 were found in more MRI scans (most of the lesions occurring in two serial examinations). Four old lesions increased their size with delayed enhancement. Correlation was found between the relapses and the gadolinium-pentetic acid-enhancing areas only for one brain-stem and two cervical spinal cord lesions. Gadolinium-pentetic acid MRI provides useful information about activity of the disease that cannot be obtained clinically even if the dynamic of the lesions may be undervalued in old plaques.


Effect of age on autonomic and cardiac responses in a rat stroke model.

The cardiovascular system and its responses change with increasing age. This has seldom been considered in experimental models of stroke, although most strokes occur in the elderly. We studied 57 male Wistar rats in three age groups: 47 to 70 days old (juvenile), 110 to 152 days old (young adult), and 186 to 245 days old (mature adult), each group being subdivided into experimental and sham operation groups. All rats underwent occlusion or sham occlusion of the left middle cerebral artery and monitoring of the mean arterial blood pressure, heart rate, sympathetic nerve activity, plasma catecholamine levels, and electrocardiogram. Eight of the 12 rats in the oldest group died within 6 hours of the middle cerebral artery occlusion; of these, the youngest was 186 days old. The mature adult rats that died before completion of the experiment showed the highest level of sympathetic nerve activity and the only significant increase in the QT interval of the electrocardiogram. Following middle cerebral artery occlusion, sympathetic nerve activity increased in the young adult rats but most strikingly in the mature adult rats that died before the end of the 6-hour experiments. Plasma norepinephrine levels were significantly elevated at 4 and 6 hours after middle cerebral artery occlusion in the oldest group and only at 6 hours in the juvenile rats. The results of this study are consistent with impaired sympathetic and cardiovascular regulation in the mature adult rat. High sympathetic activity may represent one mechanism leading to fatal cardiac arrhythmias. Age-related impairment of sympathetic regulation may contribute to the higher mortality seen among elderly patients with stroke.


Asymmetry of sympathetic consequences of experimental stroke.

Asymmetries of sympathetic regulation at the level of the inferior cervical ganglia have long been recognized. Lateralization of autonomic representation may also occur in the brain, since inactivation of the left and right hemispheres by intracarotid amobarbital produces an increase and decrease in heart rate, respectively. However, this conclusion has remained tentative, since the differential effect of lateralized brain lesions on sympathetic activity has not been studied systematically. Forty-eight urethan-anesthetized Wistar rats were divided into three groups: a group given left middle cerebral artery occlusion, and a group given sham operation. Heart rate, mean arterial blood pressure, renal sympathetic nerve discharge, and electrocardiogram were monitored throughout the 4-hour experiments. Plasma epinephrine and norepinephrine levels were measured at baseline and 1 and 4 hours after occlusion or sham occlusion. The mean arterial pressure decreased in the group given sham operation and to lesser extent in the group given left middle cerebral artery occlusion. By contrast, mean arterial pressure did not fall in the group given right middle cerebral artery occlusion and at 4 hours was significantly higher than control values in the sham-occluded rats. Renal sympathetic nerve discharge was decreased in the sham-occluded group, increased significantly from 20 minutes to 2 hours in the group given left middle cerebral artery occlusion, and increased from about 20 minutes to the end of the experiment in the group given right middle cerebral artery occlusion. The plasma norepinephrine level was significantly elevated at 1 hour (93%) and 4 hours (44%) only in the group given right middle cerebral artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Thalamic stroke. Presentation and prognosis of infarcts and hemorrhages.

Thalamic strokes in 62 patients selected from the Stroke Data Bank were studied to determine differences among 18 infarctions (INF), 23 localized hemorrhages (ICH), and 21 hematomas with ventricular extension (IVH). Stupor or coma at onset occurred more frequently in the IVH (62%) than in the INF (6%) or ICH (13%) groups and was reflected in significantly lower median Glasgow Coma Scores in the IVH group (7) than in the INF (15) and ICH (14) groups. Although ocular movements were more frequently abnormal in the IVH group compared with the ICH and INF groups, no significant differences were found in the frequency of motor or sensory deficits. Among the 62 strokes, 32 had restricted lesions of the posterolateral (n = 9), anterior (n = 3), paramedian (n = 7), and dorsal (n = 13) portions of the thalamus. Differences in consciousness and in motor, sensory, and oculomotor deficits were found among the topographic subgroups. Stroke-related deaths occurred in 52% of IVH cases, 13% of ICH cases, and no cases of INF. Median lesion volume as detected with computed tomography was greater in hemorrhages (INF, 2 cm3; ICH, 10 cm3; IVH, 16 cm3), with mortality related to increasing hematoma size. Coma, Glasgow Coma Score lower than 9, weakness score greater than 15 of a possible 30, abnormal ocular movements, and fixed pupils were also associated with stroke-related mortality. We conclude that the initial neurologic syndrome does not discriminate infarcts from intrathalamic hemorrhages. Ventricular extension, however, causes significantly more severe deficits and higher mortality.


Biological significance of iron-related magnetic resonance imaging changes in the brain.

Iron, an essential element for basic cellular metabolism, regularly accumulates in certain brain areas in normal subjects and in patients with certain diseases. Magnetic resonance imaging can depict iron deposition, offering a singular opportunity to correlate the regional iron content with the functional status of the human brain in vivo. We studied the relationship between age and the iron-related signal loss on T2-weighted images in basal ganglia, and observed a strongly significant signal decrease in the globus pallidus at the age of brain development (first two decades of life), but we found no such decrease in later years. Moreover, in healthy adults, subject-to-subject variability was relevant in changes due to iron deposition in magnetic resonance imaging. We found increased signal loss to be associated with poor performance on motor and specific cognitive tasks, suggesting that these image changes can provide functional information with respect to the brain in normal subjects.


Local cerebral blood flow and its response to intravenous levodopa in progressive supranuclear palsy. Comparison with Parkinson's disease.

The local cerebral blood flow (LCBF) at steady state and after the intravenous administration of levodopa (1 mg/kg) was measured by the xenon-enhanced computed tomographic method in six patients with progressive supranuclear palsy (PSP) and in nine patients with idiopathic Parkinson's disease. The baseline LCBF values in most brain regions in patients with PSP were lower than those in patients with Parkinson's disease, and hyperfrontality of the LCBF was lost. In patients with Parkinson's disease, the injection of levodopa markedly increased LCBF, especially in the striatum, thalamus, and internal capsule (approximately 40%). In patients with PSP, however, levodopa did not increase the LCBF in all brain regions examined. The LCBF increases after the administration of levodopa in patients with Parkinson's disease may be secondary to metabolic activation of the dopaminergic system. The different LCBF responses to levodopa between patients with PSP and those with Parkinson's disease may reflect differences in pathologic features, such as in the degree of preservation of nigrostriatal dopaminergic neurons and the distribution and density of dopamine receptors, and are also related to the clinical effectiveness of levodopa therapy.


Increased metallothionein in the liver and kidney of patients with amyotrophic lateral sclerosis.

To evaluate the putative role of metals and trace elements in the pathogenesis of classic amyotrophic lateral sclerosis, we studied the metallothionein levels in liver and kidney samples obtained at autopsy from 24 patients with amyotrophic lateral sclerosis and 18 controls. To assay metallothioneins and copper, cadmium, and zinc bound to metallothioneins, we used high-performance liquid chromatography directly coupled to flame atomic absorption spectrometry. Total cadmium, zinc, and copper concentrations were determined separately with the use of graphite furnace atomic absorption spectrometry with Zeeman background correction. The median liver metallothionein level was 60.3 mg/kg (range, 9 to 318 mg/kg) in the patients with amyotrophic lateral sclerosis and 12.6 mg/kg (range, 0 to 104.5 mg/kg) in the controls. In the kidney, median metallothionein levels were 126.9 mg/kg (range, 44 to 387 mg/kg) in the patients with amyotrophic lateral sclerosis and 64 mg/kg (range, 13.1 to 187 mg/kg) in the controls. Total zinc, cadmium, and copper concentrations, as measured by atomic absorption spectrometry, were not significantly different in patients vs controls. Our finding of elevated metallothionein levels in organs from patients with amyotrophic lateral sclerosis may indicate an increased exposure to metals.


Cerebral brain metabolism in adult dyslexic subjects assessed with positron emission tomography during performance of an auditory task.

Ten dyslexic adults (aged 33.5 +/- 7.3 years, nine men, one woman) and 10 age-, sex- and handedness-matched control subjects (aged 33.6 +/- 5.8 years) performed an auditory syllable discrimination task during 18-fluoro-2-deoxyglucose uptake, and then underwent positron emission tomographic scans. A second normal control group performed an analogous visual discrimination task. Dyslexic subjects experienced greater difficulty and made significantly more errors in performing the auditory task. There were no differences in brain metabolic rates in lateral cortical areas (frontal, parietal, temporal, and occipital lobes). A significant difference emerged in the medial temporal lobe, with dyslexic subjects having significantly higher absolute and relative brain metabolism along an anterior-posterior gradient than normal adults. These data support the hypothesis of altered cerebral processing of auditory stimuli in patients with dyslexia.


Peripheral mechanical loading and the mechanism of the tremor of chronic alcoholism.

The tremor of chronic alcoholism, although clinically similar to essential tremor, has been considered a distinct syndrome. Its underlying mechanism was analyzed in five patients (none in the acute stages of alcohol withdrawal) hospitalized in an alcohol detoxification program. All five patients performed tracking tasks in which they pursued a linearly moving "target" light with a response light that they controlled by flexion-extension activity of the wrist. Stationary and dynamic targets were used with both isometric and unconstrained wrist mechanical interfaces. Frequency, torque, and displacement tremor characteristics were examined under varying inertial loading or isometric voluntary torque conditions. Two simultaneous tremor components were present in all patients: a prominent 4- to 7-Hz low-frequency peak and a smaller-amplitude 9.4- to 9.6-Hz high-frequency peak. As the inertia of the hand was augmented during unconstrained tasks, the low-frequency peak decreased, while the high-frequency peak was unaffected. As required voluntary effort was increased during isometric testing, the amplitude of the low-frequency peak increased. These findings suggest that the low-frequency peak represents the significant pathologic component of the tremor of chronic alcoholism and that it has a biomechanical reflex mechanism similar to that of the lower-amplitude normal physiologic tremor.


Spinal epidural abscess. Early detection with gadolinium magnetic resonance imaging.

To emphasize the importance of timely diagnosis of spinal epidural abscess, thirteen patients admitted to a single general hospital are presented. In 10 patients, diagnosis was not appreciated at the time of presentation. After treatment, four remained paraparetic and three died. Nine patients had predisposing factors, including seven with infections at sites other than the spinal canal. Staphylococcus aureus was the predominant organism. Outcome was equally devastating for the seven patients with acute and the six patients with chronic infections. Gadolinium-enhanced magnetic resonance imaging was the most useful diagnostic test, and we recommend that it be performed promptly in any patient with clinical features suggesting spinal epidural abscess since early surgical drainage and appropriate antibiotics may yield a favorable outcome.


Further observations on the pathology of subcortical lesions identified on magnetic resonance imaging.

We performed postmortem magnetic resonance imaging and pathologic examinations on the brains of seven consecutive patients older than 50 years of age who died of non-neurologic causes. Multiple hyperintense subcortical lesions were identified in each patient, and a total of 29 lesions were examined histologically (eight rims, six caps, six punctate lesions, and nine patches). Rims were characterized by subependymal gliosis and loss of the ependymal lining; caps were associated with myelin pallor, gliosis, and arteriosclerosis; punctate lesions were characterized by dilated perivascular spaces and perivascular gliosis; and patches were associated with myelin pallor and dilated perivascular spaces. The pattern of myelin pallor defined the size and shape of caps and patches. Arteriosclerosis was identified in six of six caps, three of six punctate lesions, and in three of nine patches. These data indicate that (1) each type of hyperintense subcortical lesion has a distinct pathologic correlate; (2) arteriosclerosis is not invariably associated with all types of hyperintense subcortical lesions on magnetic resonance imaging; and (3) myelin pallor appears to contribute to the magnetic resonance imaging signal at 1.5 tesla.


Meningiomas are not significantly associated with breast cancer.

We studied 283 meningiomas seen at the University of Kansas, Kansas City, from 1948 through 1984, identifying all additional nonmeningeal malignancies and primary brain tumors in these patients and calculating the expected number of additional tumors by the use of a person-year method from age and sex-matched cancer incidence data. We determined expected numbers of total neoplasms in our meningioma population as well as the expected numbers in each major organ system for the sexes independently and together. We then calculated standard morbidity ratios and 95% confidence intervals for each tumor type. The number of breast cancers did not reach statistical significance. We found a significantly increased number of second primary brain tumors in women (standard morbidity ratio, 8.0; 95% confidence interval, 2.2 to 20.4) and an increased number of thyroid cancers in both sexes (standard morbidity ratio, 7.5; 95% confidence interval, 1.5 to 21.9).


Developmental consequences of childhood frontal lobe damage.

A 33-year-old woman underwent neurologic and neuropsychological studies 26 years after she sustained damage to the frontal lobe. The findings of the neurologic examination were normal, and magnetic resonance imaging revealed a lesion in left prefrontal cortex and deep white matter. Cerebral blood flow studies showed an abnormal pattern in both left and right frontal regions. The patient exhibited striking neuropsychological defects in higher cognition, most notably in self-regulation of emotion and affect and in social behavior. Analysis of her behavioral development failed to yield a pattern of abrupt onset of defect immediately after the lesion occurred. On the contrary, there was a delayed onset of defects, followed by a period of seeming progression, and finally an arrest of development in adolescence. We suggest that this peculiar pattern is the natural consequence of the varied changes that occurred in brain development and social cognition during the patient's formative years. While certain long-term neuropsychological deficits in our case are similar to those following frontal damage in adults, the delayed onset and progression of deficits are different.


Asymmetric cortical degeneration syndromes. A proposed clinical classification.

Twenty-six patients presented with slowly progressive focal neurologic symptoms that conformed clinically to one of three categories: asphasia, perceptuomotor dysfunction, or neuropsychiatric dysfunction. Of 12 patients with progressive aphasia, seven were dysfluent and five were fluent. Nine patients had progressive perceptuomotor impairment due to bilateral parietal lobe atrophy, which also included frontal lobe signs in seven patients and occipital lobe signs in three patients. The right hemisphere was more severely involved in five patients and the left hemisphere in four. Five patients had a progressive neuropsychiatric syndrome, and there was also generalized spasticity in three patients due to frontal lobe atrophy. The clinically suspected anatomic localization of cortical atrophy or hypoperfusion in all three categories was confirmed with neuroimaging techniques. A brain biopsy specimen from one patient showed mild, nonspecific degenerative changes. A clinical classification scheme incorporating our observations as well as the observations of others is presented to aid in the recognition of these syndromes.


A randomized study of trabeculectomy and subconjunctival administration of fluorouracil in primary glaucomas.

Forty-one adult patients with primary open angle glaucoma and nine adult patients with chronic angle closure glaucoma underwent trabeculectomy in one eye each. Twenty-one eyes with primary open angle glaucoma and four with chronic angle closure glaucoma were randomly assigned to receive four to six subconjunctival injections of fluorouracil for 10 days after surgery. Twenty-five control eyes did not receive fluorouracil. Intraocular pressure was 20 mm Hg or lower in 24 eyes (96%) in the treatment group after mean follow-up of 17.8 months and in 19 control eyes (76%) after mean follow-up of 17.5 months (P less than .05). Encapsulated bleb developed in three (12%) of the fluorouracil-treated eyes vs two (8%) of the control eyes. A few injections of fluorouracil adequately inhibited scarring. This might be explained by its toxic effect on existing fibroblasts. Overall, trabeculectomy with injection of fluorouracil was found to be efficacious and relatively safe. Further studies regarding late complications are required.


Contrast sensitivity and reading through multifocal intraocular lenses.

Multifocal intraocular lenses are intended to increase depth of focus for patients with cataracts, but optical considerations predict reduced retinal-image contrast. We evaluated visual performance through multifocal intraocular lenses by measuring contrast sensitivity functions and reading speed for age-matched groups with multifocal and monofocal intraocular lenses and two normal control groups. Contrast sensitivity functions of the patients with multifocal lenses did not differ significantly for optical distances differing by 2.5 diopters, indicating substantial depth of focus. Normal and monofocal contrast sensitivity functions were nearly identical, and both were about a factor of two higher than multifocal contrast sensitivity functions. Patients with multifocal lenses showed deficits in reading speed only for low-contrast text (less than 30%) and small letters (0.2 degree and 1.0 degree).


The effect of early cataracts on glare and contrast sensitivity. A pilot study.

To establish the effect of cataracts on glare and contrast sensitivity, we graded type and amount of lens opacity in 110 subjects who underwent two glare tests (Brightness Acuity Tester and Berkeley glare test) and two contrast sensitivity tests (a sine-wave test and Pelli-Robson chart). Twenty-seven subjects (25%) had clear lenses (mean visual acuity of 20/20) and 83 subjects (75%) had early lens opacities (mean visual acuity of 20/40) in otherwise normal eyes. Multiple regression techniques were used to control for the effects of age and visual acuity. Glare test scores were significantly lower for nearly all patients with lens opacities than for patients with clear lenses and were the lowest for patients with lenses with posterior subcapsular opacity. Contrast sensitivity scores were lower for all patients with lens opacities than for patients with clear lenses at high frequencies only; all lens opacity groups scores similarly with each other. These results indicate reduced visual function among patients with cataracts whose visual acuity is only minimally impaired.


Visual acuity correlates with severity of retinopathy of prematurity in untreated infants weighing 750 g or less at birth.

Visual acuity was assessed in 72 patients who weighed 750 g or less at birth, had intact visual pathways as confirmed with computed tomography or magnetic resonance imaging, and had at least one eye evaluated for cicatricial sequelae after active, untreated retinopathy of prematurity without macular detachment (stage 4a or better). Visual acuities were obtained for 137 untreated, sighted eyes. Severity parameters for retinopathy of prematurity (stage of retinopathy of prematurity, refraction [in spherical equivalents], macular ectopia [in disc diameters], and vessel traction [in 30 degrees sectors]) was were significant predictors of visual acuity (P less than .0001) based on results of linear regression and stepwise regression analyses; however, parameters of retinal immaturity (birth weight, gestational age, and zone of retinopathy of prematurity) were not significant predictors of visual acuity. Visual acuity of the study eyes was good (median, 20/30; geometric mean, 20/33.58), with no statistical differences between eyes evaluated on last examination with linear Allen figures and those evaluated with linear Snellen test types.


Ocular cosmesis in retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group.

We report the externally apparent outcome in the natural history cohort (n = 4099) that was followed up prospectively in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. The overall incidence of an adverse cosmetic outcome in the survivors who were examined 12 months post term (n = 2759) was 15.1%. Adverse cosmetic outcomes included strabismus (12.8%), nystagmus (3.3%), total retrolental membrane (1%), epiphora (0.6%), corneal opacity (0.6%), cataract (0.3%), and episcleral hyperemia (0.3%). A comparable subgroup examined 24 months post term showed strabismus (14.4%), nystagmus (2.2%), epiphora (0.5%), corneal opacity (0.7%), cataract (0.5%), episcleral hyperemia (0.5%), lid fissure asymmetry (2.4%), and corneal diameter asymmetry (2.0%). The rate of adverse aesthetic outcome was greatest in eyes that had developed more severe acute retinopathy of prematurity and an unfavorable structural outcome. In patients with bilateral threshold retinopathy of prematurity who underwent no therapeutic ocular procedures, other than randomized assignment to undergo cryotherapy in one eye, more frequent adverse cosmetic outcomes were found in the untreated eyes.


Measurement of preretinal oxygen tension in the vitrectomized human eye using fluorine-19 magnetic resonance spectroscopy.

We obtained oxygen measurements from a human eye that contained small preretinal droplets of perfluorotributylamine (FTBA) by using fluorine-19 magnetic resonance spectroscopy. These droplets were the remainder of a larger volume of FTBA that was used as an intraoperative retinal tamponade during retinal detachment repair. The spin-lattice relaxation rate ([T1]-1) of the FTBA fluorine nuclide was obtained that could then be related, by direct proportionality, to droplet PO2. With the patient in a supine position, the droplets could be positioned over the macula in the preretinal vitreous space, whereon the FTBA PO2 could be influenced by the preretinal oxygen concentration. Preretinal PO2 values, derived from magnetic resonance spectroscopy, were in the range of 6 to 9 mm Hg, although multiple components were identified that were suggestive of a heterogeneous distribution of PO2 values in the population of droplets. To our knowledge, this investigation is the first to demonstrate the feasibility of this approach to performing long-term, noninvasive preretinal oxygen measurements in the vitrectomized human eye by using small droplets of a liquid perfluorochemical.


Magnetic resonance imaging. Diverse appearances of uveal malignant melanomas.

Fifteen patients with uveal malignant melanomas were studied by magnetic resonance imaging. The magnetic resonance imaging appearances varied from those that have been reported previously to be characteristic of these tumors. In our series, malignant melanomas were of high signal on the T1 sequence and of variable but usually also of high signal on the T2 and Short Tau Inversion Recovery (STIR) sequences, a signal combination rarely described before. We postulate that magnetic resonance imaging appearances may be dependent on variations in histologic factors and on the type and field strength of the scanner used. It is widely believed that the paramagnetic melanin in malignant melanomas gives these tumors characteristic magnetic resonance imaging appearances, but our finding of diverse magnetic resonance imaging appearances for proved malignant melanomas suggests that this may not always be the case. We advise caution in diagnosing malignant melanomas from magnetic resonance imaging appearances alone.