Electrically injected VCSEL with a composite DBR and MHCG reflector.

We achieve the continuous-wave (CW) lasing of electrically-injected, first-of-their-kind vertical-cavity surface-emitting lasers (VCSELs) that use a subwavelength monolithic high-refractive-index-contrast grating (MHCG) mirror. The MHCG, unlike the well-known high-refractive-index-contrast grating (HCG) is neither a membrane suspended in the air nor a structure that requires a cladding layer. The MHCG is patterned in a semiconductor material atop the VCSEL cavity creating an all-semiconductor laser. Static measurements show CW operation of the VCSELs from room temperature up to 75 °C. The VCSEL with a 13.5 µm current oxide aperture diameter operates with quasi-single mode emission from threshold to rollover. Our results open a way to produce all-semiconductor surface emitting lasers emitting at wavelengths from the ultraviolet and the visible (GaN-based) to the infrared (InP- and GaSb-based) with a reduced vertical thickness and thus we believe the manufacturing costs potentially will be reduced by approximately up to about 90% in comparison to the typical DBR VCSELs. Our VCSELs have immediate and emerging applications in optical communication, illumination, sensing, and as light sources in photonic integrated circuits.

Serum enzyme determinations in the diagnosis of acute myocardial infarction: an update.

Serum CK-MB and LD-1 have proved extremely useful in the diagnosis and differential diagnosis of acute myocardial infarction. However, CK-MB is present in skeletal muscle and can be released during ischemic attacks; thus, abnormal serum CK-MB activities cannot be equated with myocardial injury. Even wider is the distribution of LD-1, which is found particularly in erythrocytes and renal cortex; hence, an abnormal LD-1 level also cannot be equated with myocardial injury. The method of choice and the final arbiter for the CK and LD isoenzymes is electrophoresis. The possibility of interpreting the results visually fulfills, in part, quality-control needs, and makes the technique suitable for small and large laboratories. Extreme analytic sensitivity is not needed, and electrophoresis provides clinically useful and acceptable results.

An interlaboratory comparison of analyses of clinical specimens.

A pilot study was conducted to identify some of the benefits and limitations of making interlaboratory comparisons of clinical assays. Sixteen laboratories that participated in a regional quality control program and used similar instrumentation each provided analyses of specimens from three male and three female healthy subjects, 25 male and 25 female clinical subjects, and several control specimens. Analysis of the data revealed that the derived normal ranges agreed well with those provided by the instrument manufacturer, and that for some analytes the laboratories produced comparable clinical assays. The control specimens were found to be indicators of the presence of analytic bias that affected the clinical assays, but they did not always correctly indicate the kind or magnitude of bias. Using pattern recognition technics, it was shown that a laboratory's clinical assays had characteristic distributions that were apparently related to the populations served, as well as to analytic precision. The results demonstrate that useful information may be gleaned from interlaboratory surveys of clinical assays.

Intralaboratory survey of alkaline phosphatase methods.

Three sets of interrelated specimens containing alkaline phosphatase (ALP) were analyzed: CAP 1977 Enzyme Survey serum, human serum supplemental with calf intestinal ALP, and human serum with increased human liver ALP. Five quite distinct ALP methods were used. In addition, fresh serum from volunteer blood donors and serum from patients with increased serum ALP activities were examined by each of these five methods. Conversion factors for the five different methods based on results from calf-intestine-supplemented interrelated specimens could not be used to interconvert results for fresh human serum. However, the interrelated specimens with increased human liver ALP made interconversion of results for fresh human serum possible.

Interlaboratory survey of Enzyme Analyses iii. Does College of American Pathologists' survey serum mimic clinical specimens?

Participants in the last College of American Pathologists Enzyme Surveys in 1978 were asked that they provide results for lactate dehydrogenase (LD), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK), for the six interrelated Enzyme Survey serum specimens, and were also asked to provide results for the same enzymes from six healthy persons and from 50 patients. Extensive data analysis revealed that porcine LD and CK in the Survey serum had kinetic properties similar to the native enzymes in fresh human serum. On this basis, we were able to merge the normal data from laboratories using diverse methods and to establish a "universal" reference range for these two enzymes. Survey serum may serve as a bridge for the clinical comparison of very diverse methods for determining LD and CK, possibly for AST and ALT, but not for ALP.

Interlaboratory survey of enzyme analyses: V. A simplified method of reporting participants' data.

The College of American Pathologists' Enzyme Survey continues to provide a valuable measure of the analytic quality of clinical enzymology for its participants and for the laboratory community. An updated reporting format for the participants simplifies the interpretation of Enzyme Survey data and should make it more valuable for detecting short- and long-term changes in accuracy and precision. A short-term CV of 3% and a long-term CV of 6% are recommended as analytic goals for the five enzymes described here. The upper limit of normal used by many laboratories is appropriate for a given enzyme yet remains as an area requiring urgent further study.

Interlaboratory survey of enzyme analyses IV. Human versus porcine tissue as source of creatine kinase for survey serum.

A special enzyme survey was carried out in 185 laboratories on specimens fortified with either porcine heart or human skeletal muscle creatine kinase (CK). All analytical systems were examined to see if they gave different results for porcine and human CK as compared with analysis of the same specimens on the duPont ACA. Analytical differences were found. However, these differences were small, and, with some exceptions, do not prevent interconversion of units based solely on specimens fortified with porcine CK. Both types of specimens serve equally well in estimating bias and variability of CK analyses. Based on the results for the human material, many laboratories appear to use inappropriate reference ranges for CK.

Further improvement of the enzyme-linked antiglobulin test (ELAT) for erythrocyte antibodies.

The enzyme-linked antiglobulin test (ELAT) was found to be nine times more sensitive than the direct antiglobulin test (DAT) in detecting erythrocytes sensitized by IgG antibody in vitro. The release of hemoglobin and other interfering substances from the erythrocytes gave falsely high absorbance values which were corrected by the use of a hemolysis bland with each test. ELAT results showed good precision. With the use of the hemolysis blank, the ELAT should prove to be a useful tool for hospital blood blanks in the detection of weakly reactive allo- and autoantibodies.

Changes in serum enzymes, lactate, and haptoglobin following acute physical stress in international-class athletes.

Skeletal muscle is rich in creatine kinase (CK), lactate dehydrogenase (LD), and other enzymes. Many reports describe changes in serum CK and LD following exercise. In our study, 11 male international-class medium-distance runners were followed over a 10-month period prior to the 1984 US Olympic Trials. Cardiorespiratory fitness, evaluated through repetitive treadmill testing, was unchanged in our athletes. Total CK increased significantly during the course of training, and the CK-MB activity was higher than that of sedentary individuals; CK-MB never rose to more than 3% of the total CK. Total LD also rose following acute exercise; however, the proportions of the five isoenzymes were unaltered. There was no change in the LD-1/LD-2 ratio from normal. The origin of the increased serum enzymes was believed to be primarily skeletal muscle. A decrease of serum haptoglobin following acute stress was attributed to intravascular hemolysis and binding of hemoglobin. As expected, serum lactate was dramatically increased immediately postexercise.

Assay of creatinine using the peroxidase activity of copper-creatinine complexes.

OBJECTIVES: It was our goal to develop a urine dipstick that could measure creatinine with a peroxidase reaction. The simultaneous measurement of albumin and creatinine permits the estimation of the 24-h albumin excretion, an important value in judging existing or likely development of renal failure. A highly sensitive dye-binding dipstick method for albumin exists, and a suitable dipstick for the assay for urine creatinine is described here. METHODS: Copper-creatinine and iron-creatinine complexes have peroxidase activity. With 3,3',5,5'-tetramethylbenzidine (TMB), and diisopropyl benzene dihydroperoxide (DBDH); the peroxidase activity of copper-creatinine and iron-creatinine complexes can be demonstrated. This reaction was used in the assay of urine creatinine either in solution or by a suitably impregnated urine dipstick. RESULTS: Our method based on the peroxidase activity of the copper-creatinine complex has an analytical range for creatinine of 100 mg/L (0.884 mmol/L) to 3000 mg/L (26.52 mmol/L). The creatinine assay is free from most interfering compounds that may be present in urine. Hemoglobin is an interferent, and its effects can be reduced but not eliminated by the addition of 4-hydroxy-2-methyl quinoline. We do not recommend using the dipsticks when visible blood is present or if the dipstick blood test is positive. The copper-creatinine complex oxidizes ascorbic acid; however, we were able to modify the reaction conditions so that ascorbic acid at < 4.4 g/L does not interfere. We found good agreement on fresh urines between the creatinine dipstick results and those by a standard rate-Jaffe cuvet method for creatinine. DISCUSSION: With the simultaneous measurement of creatinine and albumin in urine, the albumin/creatinine ratio can be determined effectively reducing or eliminating the occasional false-negative and false-positive result in those with dilute or concentrated urines, respectively. The dipstick test for these analytes permits the simple identification of individuals with possible albuminuria and could serve well in a point-of-care setting.

The importance of objective data in the diagnosis of pancreatitis.

In 78 patients with likely pancreatitis, we used laparotomy, computerized tomography, ultrasonography and other information to make an objective diagnosis of pancreatitis. Laboratory studies included serum amylase, amylase isoenzymes and lipase. We found that both amylase and lipase are highly sensitive tests and P3 amylase by electrophoresis on agarose to be specific; a combination of these tests is recommended to assist in the diagnosis of pancreatitis. The frequent occurrence of an abnormal amylase and lipase in patients without pancreatitis is suggested as the cause of overdiagnosis of this disorder. A markedly increased amylase or lipase was always associated with pancreatic disease.

Urinary protein and albumin excretion corrected by creatinine and specific gravity.

Timed urine collections are difficult to use in clinical practice owing to inaccurate collections making calculations of the 24-h albumin or protein excretion questionable. One of our goals was to assess the 'correction' of urinary albumin and (or) protein excretion by dividing these by either the creatinine concentration or the term, (specific gravity-1)x100(1). The 24-h creatinine excretion can be estimated based on the patients' gender, age and weight. We studied the influence of physiological extremes of hydration and exercise, and protein and creatinine excretion in patients with or suspected kidney disorders. Specimens were collected from healthy volunteers every 4 h during one 24-h period. We assayed the collections individually to give us an assessment of the variability of the analytes with time, and then reassayed them after combining them to give a 24-h urine. For all volunteers, the mean intra-individual CVs based on the 4-h collections expressed in mg/24 h were 80.0% for albumin and 96.5% for total protein (P0.2). The CVs were reduced by dividing the albumin or protein concentration by the creatinine concentration or by the term, (SG-1)x100. This gave a CV for mg albumin/g creatinine of 52% (P<0.1 vs. albumin mg/g creatinine); mg protein/g creatinine of 39% (P<0.05 vs. mg protein/g creatinine); mg albumin/[(SG-1)x100] of 49% (P<0.1 vs. albumin)/[(SG-1)x100]; and mg protein/[(SG-1)x100] of 37% (P<0. 05 vs. mg protein)/[(SG-1)x100]. For the 68 subjects in the study, the strongest correlation was between the creatinine concentrations and the 24-h urine volume: r=0.786, P<0.001. The correlation of (SG-1)x100 vs. the 24-h urine volume was: r=0.606, P<0.001; for (SG-1)x100 and the creatinine concentration, the correlation was: r=0.666, P<0.001. Compared to the volunteers, the albumin and protein excretion in mg/24 h were more variable in the patients. The same was true if the albumin or protein concentrations were divided by the creatinine concentration or by (SG-1)x100. Protein and albumin concentrations were lower in dilute urines. Dividing the albumin or protein concentrations by the creatinine concentration reduced the number of false negative protein and albumin results. Dividing the albumin or protein values in mg/24 h by (SG-1)x100 eliminated fewer false negatives. Albumin concentrations increased significantly after vigorous exercise. The increase was almost eliminated when the albumin result was divided by the creatinine concentration suggesting that a decreased urine flow and not increased glomerular permeability causes an increase of post-exercise albuminuria. The same was true for proteinuria. A dipstick test plus an optical strip reader that can measure urine protein, albumin, and creatinine and calculate the appropriate ratios provides a better screening test for albuminuria or proteinuria than one measuring only albumin or protein.

Reported alcohol consumption and the serum carbohydrate-deficient transferrin test in third-year medical students.

The serum carbohydrate-deficient transferrin (CDT) test was performed on 143 third-year medical students along with questionnaires for the self-reporting of alcohol consumption during the last 2 weeks, the last 6 months, and questions on any alcohol-related untoward events. We found that the CDT test has poor sensitivity for detecting binge drinking in our population of students, despite some likely under-reporting of drinking. Self-reporting of drinking is commonly unreliable, and we found no significant correlation between the CDT concentrations in serum and the magnitude of self-reported alcohol use during 2-week and 6-month periods. Hangover was by far the commonest self-reported untoward event, and there was a highly significant relationship (P < 0.001) between drinking and untoward events. From a small population of non-drinkers, we estimated the reference ranges for CDT to be <27 U/l for men and <35 U/l for women.

Differential diagnosis of patients with abnormal serum creatine kinase isoenzymes.

For the diagnosis of myocardial injury, particularly AMI, CK-MB has become the gold standard. Changing CK-MB activities in serially collected blood from patients with suggestive signs and symptoms of AMI is almost pathognomonic for infarction. Nevertheless, an increased CK-MB cannot be equated with AMI owing to the many other types of inflammatory, traumatic, and miscellaneous forms of injury to the heart and the trace activities of CK-MB in skeletal muscle. Other enzyme tests for AMI are less efficient. In order of decreasing efficiency, the tests are CK-MB, CK, LD1 greater than LD2 or LD1/LD2 greater than 0.76, AST and LD; the latter two tests are not cost effective and add little or nothing when results for CK-MB, CK, and LD isoenzymes are available. The value of the isoforms of CK-MM and CK-MB remains to be established. Early evidence suggests that they could be helpful in the diagnosis of AMI; however, owing to the greater technical difficulties in performing these tests, their use is necessarily more restricted. Enzyme testing on admission and then every 12 hours for 2 days is sufficient and effective in making the initial diagnosis. In patients presenting early after an attack, CK and CK-MB are often normal. Decisions on AMI cannot be made on blood tests collected in the emergency department. Clot-lysing agents like streptokinase, urokinase, and tPA have changed the therapy of AMI dramatically. Enzyme tests clearly separate patients with and without successful therapeutic or spontaneous reperfusion. With successful reperfusion, the uniform finding has been a "washout" phenomenon with significantly earlier peaking times for CK and CK-MB. The isoforms of CK and myoglobin give the earliest peaks after successful reperfusion. With faster turnaround times for these tests, they may become important tools in patient management.

Creatine kinase isoenzymes.

Creatine kinase (CK), a widely distributed enzyme in the body, has its highest activities in skeletal muscle and myocardium; when serum CK activities are abnormally increased, injury to these organs must be part of the differential diagnosis. The isoenzyme CK-MB is the most important biochemical test in the diagnosis of acute myocardial infarction.

Proficiency testing of serum enzymes based on medical-needs criteria.

Proficiency testing goals for serum enzymes have been set by statistical methods, by the ex cathedra statements of experts, based on the intraindividual variation of healthy people, and based on responses from the users of enzyme data, ie, clinicians in practice. Clinicians consider small changes in serum enzyme values to be medically unimportant. Medical-needs criteria are probably the most relevant in setting proficiency testing goals for enzymes. The enzyme values that most modern clinical analyzers are capable of producing are more precise than appears to be medically necessary. We surveyed clinicians for their perceived needs; based on their responses, we conclude that tight proficiency testing limits for enzyme tests are inappropriate.

Determination of reference ranges for serum enzymes via a large interlaboratory survey.

We obtained enzyme data on normal individuals in conjunction with a large interlaboratory enzyme survey. For the 12 largest peer groups using unique methods, we found a simple relationship between the upper reference limits and the laboratories' results obtained from human-enzyme-supplemented survey serum. A conversion to a common base made possible the merging of data on the normal individuals and interconversion of results by diverse methods. We determined the upper reference limits for serum lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and creatine kinase for approximately 8000 adult men and women believed to be in good health. Using a technique described here, we believe that the results can be transformed to user-specific units, and that the large data base can be applied to the many diverse enzyme methods in current use. With these data, enzyme survey participants will be able to estimate appropriate reference intervals for their particular method.

Proficiency testing of enzymes. Charting the way toward standardization.

Laboratories participating in the College of American Pathologists Enzyme Survey (ES) and Comprehensive Chemistry Survey used diverse methods for the same analyte, resulting in a considerable range of values for the commonly performed enzyme measurements. Nevertheless, with the techniques developed for the ES, both the short-term (within-mailing) and long-term (between-mailings) coefficients of variation (CVs) can be determined. The ten-year experience of the ES has shown improvement in the short-term CV; however, long-term stability of enzyme testing requires more effort on the part of the instrument and reagent suppliers and participating laboratories. A reference material with an International Federation of Clinical Chemistry-established aspartate aminotransferase value, National Bureau of Standards RM 8430, is now available and was sent to three large peer groups as part of a special study. Correction of the results to the RM 8430 aspartate aminotransferase value resulted in reducing the range of data from peers using the duPont aca but not from those using the American Monitor KDA or Technicon SMAC. Based on our experience with the ES, goals of 5% for the short-term CV and 10% for the long-term CV are proposed; they are achievable by most laboratories and meet medical needs for biochemical screening. Fixed criteria for the evaluation of enzyme results appear to be appropriate given the way most enzyme data are used clinically.

Survey of serum enzyme analyses. Human tissues as a source of enzymes.

The College of American Pathologists' enzyme survey permits the evaluation of the quality of enzyme analyses in clinical laboratories. Animal source enzymes for lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and creatine kinase are satisfactory as supplements for enzyme survey serum, since they give results equivalent to human source enzymes. This finding makes the interconversion of results by different methods possible, and the estimation of the upper limit of normal based on the results obtained for the enzyme survey serum.

Use of continuous quality improvement to identify barriers in the management of hypertension.

We have made great strides in understanding the pathophysiology and medical management of hypertension, yet barriers to effective blood pressure control remain. The process of identifying the barriers within the health care system may be as important as the barriers themselves. Our primary purpose was to apply the widely accepted tool, Continuous Quality Improvement (CQI), to identify barriers to the management of hypertension. We wanted to identify the most important factors and (or) persons in effective blood pressure control and to compare costs, satisfaction, and blood pressure control among subgroups of patients to identify those most likely to benefit from interventions. We recruited patients with essential hypertension who came to a university-based clinic staffed by family physicians and residents; 181 patients with hypertension were identified and asked at the time of their visit to complete a questionnaire relating to the management of their blood pressure. Twenty-five physicians and 8 medical assistants were also asked to complete a similar questionnaire regarding their perceptions of barriers to blood pressure management. All other information came from the patients' medical records. Blood pressure control was based on a reading taken on the date the questionnaire was completed. Student's t test was used to determine if statistically significant differences existed in blood pressure control, patient satisfaction, and total costs for certain subgroups; regression analysis was used to determine correlations. We had completed questionnaires from 91 patients, 89 physicians, and 79 staff. The physicians and staff were of course involved; however, we found that the patients' gestalt was extremely important in blood pressure control. Our patients perceived that lifestyle modifications such as exercise and weight loss were the greatest barrier to better blood pressure control. The cost of certain antihypertensive drugs was an obstacle for some patients. African Americans had poorer blood pressure control, and their satisfaction of care was significantly lower than that of other races. Our patients taught us that the 2 major barriers to blood pressure control were changes in lifestyle and reducing the cost of medications. We also found that our African American patients showed the poorest blood pressure control and the greatest dissatisfaction with their care. We surmise that the greatest benefit of any intervention would be expected in this population. We demonstrated that CQI can be used to identify barriers to hypertension management and subgroups of patients likely to benefit from interventions.