Balloon valvotomy for pregnant patients with severe pliable mitral stenosis using the Inoue technique with total abdominal and pelvic shielding. Balloon valvotomy by means of the Inoue technique was attempted in seven pregnant (5 to 9 months) patients with severe mitral stenosis; the mean age of the patients was 32 +/- 8 years, and all had a two-dimensional echocardiographic mitral valve score of < 8. Indications for Inoue balloon valvotomy included severe symptomatic mitral stenosis with a Doppler mitral valve area < or = 1 cm2 and heart failure refractory to medical therapy, or absolute contraindications for the use of beta-blockade; Inoue valvotomy was also indicated for patients who lived a long distance from the hospital. Inoue balloon valvotomy was performed with no angiography and total pelvic and abdominal shielding; the balloon catheter was introduced into the right atrium without the aid of fluoroscopy, which was used for the transseptal puncture. Stepwise two-dimensional echocardiographic Doppler mitral valve dilatation was done. After Inoue balloon valvotomy the mean Doppler mitral valve area increased from 0.8 +/- 0.1 to 2.0 +/- 0.3 cm2 (p < 0.01) and by two-dimensional echocardiography from 0.8 +/- 0.2 to 1.9 +/- 0.3 cm2 (p < 0.01), with no significant Doppler residual stenosis (defined as mitral valve area < or = 1.5 cm2). The mean total fluoroscopy time was 16 +/- 7 minutes. The degree of mitral regurgitation increased in two patients from grade 1+/4+ to grade 2+/4+ and from grade 0+/4+ to grade 2+/4+, respectively. There was no mortality or significant morbidity. Pregnancy was uneventful in all patients, and all were delivered of normal babies without complications.(ABSTRACT TRUNCATED AT 250 WORDS)


Percutaneous mitral balloon valvuloplasty--a comparative evaluation of two transatrial techniques. The efficacy and safety of two different percutaneous transfemoral mitral balloon valvuloplasty procedures were evaluated in 45 patients. A double-balloon technique with Mansfield balloons was applied in the first 22 patients (group A), and an Inoue single-balloon technique was used in the subsequent 23 patients (group B). Mean diastolic gradient decreased from 17 +/- 7 mm Hg to 8 +/- 3 mm Hg (p < 0.001) in group A and from 13 +/- 4 mm Hg to 8 +/- 3 mm Hg (p < 0.001) in group B. The mitral orifice area increased from 1.1 +/- 0.3 cm2 to 2.2 +/- 0.8 cm2 (p < 0.001) in group A and from 1.2 +/- 0.4 cm2 to 1.7 +/- 0.7 cm2 (p < 0.001) in group B. The length of the total procedure and the total fluoroscopy time were considerably shorter in group B (86 +/- 24 minutes and 18 +/- 7 minutes) compared with group A (128 +/- 38 minutes and 35 +/- 14 minutes; p < 0.001). Mitral regurgitation (grade 3/4) was observed after the procedure in two patients in group A but in nine patients in group B. Cardiac tamponade occurred in two patients in group A, but no major complications were seen in group B. The Inoue single-balloon technique seemed to be safe, easier to perform, and equally effective.


The effect of aspirin on the risk of stroke in patients with nonrheumatic atrial fibrillation: The BAATAF Study. Recent randomized trials have consistently demonstrated the marked efficacy of warfarin in reducing the risk of stroke caused by nonrheumatic atrial fibrillation. These trials have provided conflicting evidence on the effect of aspirin. We report the aspirin analysis from the BAATAF study, a trial in which control patients could choose to take aspirin. There we two strokes in 446 person-years with warfarin (annual rate of 0.45%); eight strokes in 206 person-years with aspirin, most at 325 mg per day (annual rate of 3.9%); and five strokes in 271 person-years among patients taking neither aspirin nor warfarin (annual rate of 1.8%). Simultaneously controlling for the other significant determinants of stroke in the BAATAF study (age, mitral annular calcification, and clinical heart disease), the relative rates (95% confidence interval) of stroke were: (1) warfarin/aspirin = 0.135 (0.029 to 0.64); (2) aspirin/(no aspirin and no warfarin) = 1.95 (0.64 to 5.97); and (3) warfarin/(no aspirin and no warfarin) = 0.263 (0.051 to 1.36). Our "treatment received" analysis argues that warfarin is strikingly more effective than aspirin in preventing stroke in nonrheumatic atrial fibrillation.


Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives. One hundred thirteen patients with essential hypertension receiving single or multiple antihypertensive agents were enrolled in the study. All had had mild to severe hypertension before treatment, but their diastolic blood pressure (DBP) at study entry was lower than 90 mm Hg for all measurements. In half of the subjects, non-thiazide diuretics (n = 35) or angiotensin-converting enzyme inhibitors (ACEI, n = 37) were discontinued, and their remaining drugs were maintained throughout the study. The other patients (n = 41) continued all their medications. Forty-one percent of subjects remained normotensive for 12 months after withdrawal of diuretics, and 37% of patients with ACEI discontinuation remained normotensive, although the recurrence of hypertension after withdrawal of ACEI tended to be earlier than its recurrence after withdrawal of diuretics. Serum uric acid and creatinine concentration decreased after diuretic withdrawal, but not after ACEI withdrawal. Diuretic withdrawal resulted in an increase in serum potassium, but ACEI withdrawal induced a decrease in serum potassium. Withdrawal of diuretics or ACEI both significantly reduced plasma renin activity. The present study may be indicative of the ability to withdraw some medications in many patients being treated with multiple antihypertensive agents.


The treadmill exercise score revisited: coronary arteriographic and thallium perfusion correlates. The treadmill exercise score has been used to stratify patients into low-, moderate-, and high-risk groups. This score is derived from ST segment depression, angina, and exercise duration. To determine the coronary arteriographic and exercise thallium perfusion correlates of the score, we examined the extent of coronary artery disease and exercise single photon emission computed thallium-201 results in 834 patients for whom cardiac catheterization data were available. Of those, 174 had no coronary artery disease, 195 had one-vessel, 246 had two-vessel, and 219 had three-vessel disease. Based on the treadmill exercise score, 369 were in the low-risk, 384 in the moderate-risk, and 81 in the high-risk group. The extent of coronary artery disease was 2.1 +/- 1 diseased vessels in the high-risk, 1.7 +/- 1 in the moderate, and 1.4 +/- 1.1 in the low-risk group (p < 0.01). The extent of the thallium abnormality (maximum number of abnormal segments 120/patient) was 10 +/- 6 in the high-risk, 7 +/- 6 in the moderate, and 6 +/- 5 in the low-risk group (p < 0.05). Based on the extent of coronary artery disease and results of thallium imaging, patients were reclassified into three groups: group 1 had three-vessel disease and/or > or = 10 abnormal segments (n = 387), group 3 had no coronary artery disease or one-vessel disease and less than five abnormal segments (n = 212), and the remaining patients were in group 2 (n = 235).(ABSTRACT TRUNCATED AT 250 WORDS)


Radiation-induced coronary artery disease. Excessive unprotected radiation to the heart appears to lead to the development of CAD, even in the absence of significant cardiovascular risk factors. The coexistence of such factors may enhance the probability of CAD. The presence of hypercholesterolemia and concomitant or sequential use of chemotherapeutic agents (especially doxorubicin) could further increase this risk. Therapeutic decisions, as with any other manifestation of CAD, relate to the extent of myocardium at jeopardy and to the overall diffuseness of CAD. Management options possible are PTCA or coronary artery bypass surgery. The latter may be required in left main artery stenosis and complicated ostial lesions. Use of shielding should decrease the associated risk of radiation-induced CAD in future years. However, clinicians should continue to have a high degree of suspicion of CAD in patients treated with thoracic radiation without cardiac shielding.


Single photon emission computed tomographic teboroxime imaging with a preprocessing masking technique. We previously reported that single-head SPECT imaging with teboroxime is feasible. However, excessive hepatic uptake in some patients may interfere with image interpretation. This study examined the feasibility of improving image quality by use of a preprocessing masking technique to subtract hepatic activity. A band of 10 pixels in width adjacent to the inferior cardiac silhouette was marked on the raw planar images, and then SPECT reconstruction was done with the Butterworth filter with a frequency cutoff of 0.3 cycles/cm and the power of 10. The stress and rest images were compared before and after masking in 10 patients who underwent SPECT teboroxime imaging during adenosine-induced coronary hyperemia (140 micrograms/kg/min for 6 minutes). SPECT imaging with a single-head detector was performed with the use of a 180-degree anterior arc (from the 45-degree left posterior oblique projection to the 45-degree right anterior oblique projection); 32 images at 8 seconds per stop were obtained (total imaging time = 6.8 minutes). All images were considered subjectively better after the masking technique was used, especially for assessment of inferior wall perfusion pattern. The maximum count in any pixel was in the hepatic region of interest before masking and in the cardiac region of interest after masking (303 +/- 110 counts vs 166 +/- 55 counts; p < 0.001). The difference was especially pronounced in the images that were obtained when patients were at rest (366 +/- 102 counts vs 184 +/- 64 counts; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Survival of implantable cardioverter-defibrillator recipients: role of left ventricular function and its relationship to device use. The quantitative benefit of ICD therapy in patients with malignant ventricular tachyarrhythmia with different degrees of left ventricular dysfunction is unclear. We evaluated patterns of ICD use and survival in 112 patients with moderate to severe left ventricular dysfunction. Group 1 included 57 patients with moderate left ventricular dysfunction (defined as left ventricular ejection fraction greater than 30%) and group 2 comprised 55 patients with severe left ventricular dysfunction (defined as ejection fraction equal to or less than 30%). The follow-up period ranged from 1 to 78 months. Age, incidence of coronary artery disease, and presenting arrhythmia in the two groups were similar. The mean left ventricular ejection fraction in group 1 was 44.6 +/- 8.2% and in group 2 was 21.6 +/- 6% (p < 0.0001). At 3 years of follow-up 65% of the patients in group 1 and 71% in group 2 (p = NS) had ICD activation for presumed ventricular tachycardia. Survival was calculated by means of actuarial analysis. Arrhythmia or sudden death mortality at 4 years of follow-up was 5% in group 1 and 9% in group 2 (NS). Cardiac mortality was higher in patients with severe left ventricular dysfunction reaching levels of statistical significance at 2 years of follow-up. At 2 years of follow-up it was 12% in group 1 and 40% in group 2 (p = 0.05), and at 4 years of follow-up it was 15% in group 1 and 43% in group 2 (p < 0.01). In both groups there was no difference in cardiac mortality in patients who did and did not have appropriate ICD shocks.(ABSTRACT TRUNCATED AT 250 WORDS)


Flecainide acetate for treatment of tachyarrhythmias in children: review of world literature on efficacy, safety, and dosing. A review of all published experience with flecainide in infants, children, and fetuses was performed to evaluate the appropriate place of the drug in pediatric practice and to determine dosing guidelines. A total of 704 case references was generated. Flecainide appeared to be safe (no deaths with usual oral dosing, < 1% serious proarrhythmia) and effective (73% to 100% control, depending on mechanism) in children with supraventricular tachycardia. The drug was very effective for treatment of fetal tachyarrhythmias. Flecainide may not be safe for children who have structurally abnormal hearts and atrial flutter or ventricular arrhythmias. The safety of flecainide for patients with ventricular arrhythmias and normal hearts requires further investigation. Pharmacokinetic data reveal an age-dependent change in elimination half-life. Patients younger than 1 year of age have a plasma elimination half-life that is similar to that in children older than 12 years (i.e., 11 to 12 hours). Children aged 1 to 12 years have a mean elimination half-life of 8 hours. The effective flecainide dose is 100 to 200 mg/m2/day or 1 to 8 mg/kg/day. Toxicity may occur with doses in excess of these ranges, especially when high doses are accompanied by low serum trough levels. Milk blocks flecainide absorption, and toxicity may become manifest when milk products are removed from the diet.


Evidence that hepatitis D virus needs hepatitis B virus to cause hepatocellular damage. Serial liver biopsy specimens from 11 patients who had liver transplants after hepatitis D virus (HDV)-related end-stage liver disease developed were examined, allowing a novel opportunity to study the evolution of HDV infection in relation to hepatitis B virus (HBV) infection from the earliest stages. Hepatitis D virus antigen was detected in liver tissue in the absence of either tissue or serologic evidence of HBV recurrence within 3 months in all eight patients biopsied at that time. After serologic evidence of recurrent HBV infection in nine patients, there was a massive increase in hepatic expression of hepatitis D virus antigen and this was associated with the transient appearance of serum hepatitis D virus antigen in four patients. Coexpression of both HBV and HDV antigens in the liver was associated with the onset of lobular hepatitis, which progressed to chronic hepatitis in five patients. These findings indicate that HDV can survive and synthesize HDAg in the absence of detectable HBV, but when HBV replication increased to a detectable level, HDV replication was enhanced massively. Contrary to current thinking, the data suggest that HDV is not directly cytopathic and that HBV is an essential cofactor in the evolution of hepatocellular damage.


Pasteurella multocida endocarditis.

Pasteurella multocida endocarditis. Human infection with Pasteurella multocida is the leading cause of animal bite wound infection. Life-threatening infection may occur in patients with a variety of underlying disorders and an immunocompromised state. Infective endocarditis with P. multocida is very rare and only a few clinically diagnosed cases have been reported. Described here is an autopsy case of a 61-year-old man with polycystic kidney disease who had P. multocida bacteremia and acute infective endocarditis with multiple bacterial clumps involving bicuspid aortic valve. The organisms were gram negative. Apparently the sepsis with P. multocida was acquired via licking of leg ulcers by his pet dog, establishing an animal-related causal relationship. Because P. multocida is a very common flora of many animals, infection with this organism probably occurs more frequently than is commonly appreciated. High index of suspicion and early diagnosis, especially in immunocompromised patients, are warranted because the disease is potentially life threatening, yet is a readily treatable infection.


Helicobacter pylori-related gastritis and gastric ulcer. A continuum of progressive epithelial degeneration. One hundred forty-five consecutive gastric biopsy specimens showing colonization by Helicobacter pylori (HP) were studied. Biopsy specimens were obtained from patients with the following conditions: gastric ulcer (GU; 76), active chronic gastritis (ACG; 52), GU with duodenal ulcer (DU; 10), and ACG with DU (7). The mean age of the patients in the ACG group was 8.6 years less than the patients in the GU group. Helicobacter pylori colonization and HP-induced epithelial degeneration (ED) were quantified by a grading system (grades 0 to 6) comprising both focal and global scores for bacterial density (HP grade) and severity of ED (ED grade). The ED grade was directly proportional to the HP grade in all biopsy specimens. Gastric ulcer biopsy specimens were associated with higher HP grades: HP grade more than 5 in 25 cases (32.9%) and ED grade more than 5 in 18 cases (23.6%) of GU compared with similar respective scores in 9 cases (17.9%) and 2 cases (3.8%) of ACG. The difference was due primarily to a higher global score of bacterial density and higher focal score of ED in the GU biopsy specimens. These results support the hypothesis that HP-positive ACG and HP-positive GU are lesions within a single disease spectrum. Heavy HP colonization and severe HP-induced epithelial damage are predisposing factors in ulcerogenesis. Because HP-positive ACG is probably a preulcerative state, eradication of the bacteria in HP-positive ACG might prevent subsequent GU.


The characteristics of mitotic figures in jejunal mucosa of patients with celiac disease. The morphologic characteristics of the mitotic figures present in the jejunal mucosa of 23 pediatric patients having gluten enteropathy were recorded. Of the 851 mitoses found, 4.9% were in prophase, 39.9% in prometaphase, 29.5% in metaphase, 22.3% in anaphase, and 3.3% in telophase. Of the 851 mitoses found, 98.8% were considered to be morphologically normal and the remaining 1.2% were considered atypical. The occurrence of atypical mitoses in the jejunal mucosa of pediatric patients was unexpected. However, because jejunal adenocarcinomas in celiac patients are known to be rare, the plausible explanation for the present findings is that the occurrence of atypical mitoses may mirror morphologic variations from the normal mitotic pattern occurring in a rapidly proliferating mucosa, such as that of patients with gluten enteropathy.


Renal oncocytoma and granular renal cell carcinoma. A comparative clinicopathologic and DNA flow cytometric study. Twenty-three renal oncocytomas and 18 granular renal cell carcinomas (GRCC) were comparatively studied clinicopathologically and by DNA flow cytometry to delineate their differences. Of the patients with renal oncocytomas, 15 were men and 8 were women, and their ages ranged from 42 to 81 years (mean, 64 years). The gross appearance of renal oncocytomas was characteristically homogeneous tan-brown, with variable scarring, without areas of large hemorrhage, and with no apparent necrosis. Twenty-two renal oncocytomas were confined within the kidney (Robson stage I) and one tumor extended into the renal vein (stage IIIa). Twenty-two renal oncocytomas, including the stage IIIa tumor, manifested diploid DNA content and only one neoplasm showed a feature suggestive of near-diploid DNA aneuploidy. Of the 17 patients with renal oncocytomas who had adequate follow-up, none developed metastasis or died of disease. Of the patients with GRCC, 13 were men and 5 were women, and their ages ranged from 30 to 73 years (mean, 53 years). The gross appearance of GRCC was variegated, yellow to tan, and punctuated with geographic areas of necrosis. Eleven patients with GRCC were stage I, 4 were stage II, 2 were stage IIIa, and 1 patient had metastases at initial examination (stage IV). Seven GRCCs were DNA diploid, one was DNA tetraploid, and 10 tumors were DNA aneuploid. Twelve patients were alive with no evidence of disease (12 to 36 months; median, 26 months). All patients with DNA diploid neoplasm pursued benign clinical courses. One patient was alive with metastatic disease and two patients developed metastases and died of their disease; all three patients had DNA aneuploid tumors. Two patients died of other causes and one patient was lost to follow-up. Our data indicate that renal oncocytoma is a distinct clinicopathologic disease with characteristic gross, histologic, DNA flow cytometric, and biologic features that are different from GRCC.


Osteolysis after silicone arthroplasty.

Osteolysis after silicone arthroplasty. A young woman with a silicone lunate prosthesis for avascular necrosis developed painful lytic lesions in the distal ulna and the triquetrum. At reoperation, abundant reactive synovitis was found extending into those bone lesions. Histologic examination of the curetting samples revealed granulation tissue with histiocytes and many multinucleated giant cells containing refractile particles consistent with silicone. The authors report a giant cell lesion of the bone that radiographically and microscopically mimicked a neoplasm.


Evaluation of the CELL-DYN 3000 differential. The CELL-DYN 3000 (Unipath Corp., Mountain View, CA) differential was evaluated in a tertiary care hospital using samples with a broad range of distributional and morphologic abnormalities. Particular attention was directed to the performance of the instrument-generated suspect flags that occur as an aid to identify samples with abnormal leukocytes, as well as the estimates of abnormal cells that are made by the instrument. The CELL-DYN 3000 showed excellent quantitative results for the white blood cell differential compared with a 400-cell manual differential, in which morphologic abnormalities were absent or occurred in low numbers (< or = 5%). Specificity of the BLAST, VARIANT LYMPH, NRBC, WBC, or DIFF suspect flags (with the requirement that the blast estimate and variant lymphocyte estimate by the instrument be > or = 1%) was 82.6%. Sensitivity of these flags to detection of more than 5% "abnormal" leukocytes (blasts, malignant lymphoid cells, grossly dysplastic neutrophils, nucleated red blood cells, or reactive lymphocytes) or significant platelet clumping was 81.6%. The primary deficiency was the inability of the CELL-DYN 3000 to flag samples with small numbers (< or = 5%) of nucleated erythrocytes, lymphoid blasts, or hairy cells, or more than 5% reactive lymphocytes. Specificity of the IG flag (with immature granulocyte estimate > or = 3%) for immature granulocytes (metamyelocytes, myelocytes, or promyelocytes) was 94.9%. Sensitivity of the immature granulocyte flag varied from 41.7% for identifying IG > or = 1% to 100% for the three samples with immature granulocytes > or = 3%. Calculation of sensitivity and specificity to varying percentages of bands showed poor flagging performance, with many false-positive and false-negative results at all levels.


A method for the independent assessment of the accuracy of hematology whole-blood calibrators. An independent assessment of the accuracy with which a large manufacturer assigned values to hematologic calibrators was performed. Data were collected from 1,767 hospitals and clinics distributed over North America. Statistical analysis of the mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration of these patient data confirmed the accuracy of the values for hemoglobin, erythrocyte count, hematocrit, and erythrocyte indices for the calibrators manufactured and released during a 9-month period. This approach proved both workable and effective in detecting inaccuracies of less than 1%. Few technologist-users have the time or the equipment to verify independently the accuracy of hematologic calibrators. The manufacturers should perform ongoing, independent assessments of the accuracy of their products. The statistical analysis of patient data provides manufacturers with a suitable method.


Multiple myeloma with tadpolelike cells and rosette formation. A 65-year-old man with lower back pain was found to have multiple myeloma. Unique findings in the marrow aspirate smears of this patient were tadpolelike plasma cells and cellular rosettes simulating those seen in neuroblastoma. This case documents yet another facet of the broad morphologic spectrum of neoplastic plasma cells in multiple myeloma.


Report of a case of localized Castleman's disease with progression to malignant lymphoma. Patients with multicentric Castleman's disease have an increased risk of developing non-Hodgkin's lymphoma. However, development of lymphoma in the localized form of Castleman's disease has not been previously reported. This case study describes a patient with localized Castleman's disease, hyaline vascular type, whose course was complicated by follicular non-Hodgkin's lymphoma.


Magnetic fields of video display terminals and spontaneous abortion. The aim of this study was to examine whether work with a video display terminal and exposure to the magnetic fields of video display terminals are related to spontaneous abortion. The study was conducted among women employed as bank clerks and clerical workers in three companies in Finland. The cases (191 spontaneous abortions) and controls (394 births) were identified from Finnish medical registers for the years 1975-1985. Use of video display terminals was defined using the workers' own reports and information provided by the companies. The assessment of exposure to the magnetic fields was based on measurements of the fields of video display terminals. The odds ratio for spontaneous abortion for working with video display terminals was not increased (odds ratio = 1.1, 95% confidence interval 0.7-1.6). However, the odds ratio for workers who had used a video display terminal with a high level of extremely low frequency magnetic fields (> 0.9 microT) was 3.4 (95% confidence interval 1.4-8.6) compared with workers using a terminal with a low level of these magnetic fields (< 0.4 microT). Adjustment for ergonomic factors and mental work load factors changed the odds ratio for magnetic field exposure only very slightly. The findings suggest the need for future studies with assessment of exposure to the magnetic fields in the actual working environment to confirm the possible risk.


Pregnancy and lactation as determinants of bone mineral density in postmenopausal women. The relation of pregnancy and breast feeding to bone mineral density of the wrist, radius, hip, and spine was examined in a white, upper middle-class, homogeneous sample of 741 postmenopausal women ranging in age from 60 to 89 years. Number of pregnancies ranged from 0 to 14, with a mean of 2.0 pregnancies and 1.5 live births. Almost two thirds of the women who had had a live birth reported breast feeding. Unadjusted comparisons indicated that bone mineral density of the wrist, radius, and hip increased with increasing numbers of pregnancies, and women who had breast-fed had higher bone mineral densities at these sites. However, after adjustment for age or age and body mass index, these associations were no longer significant. Multiple regression analyses adjusted for age, age at menopause, obesity, cigarette smoking, and estrogen and thiazide use also indicated that number of pregnancies and breast feeding were not significantly associated with bone mineral density at any of the four sites measured. Results of the present study suggest that reproductive history and breast feeding are not long-term determinants of bone mineral density.


Lipoprotein(a) concentrations in Mexican Americans and non-Hispanic whites: the San Antonio Heart Study. There is considerable evidence that lipoprotein(a) (Lp(a)) is a strong independent risk factor for coronary heart disease. Based on their risk factor profile, Mexican Americans have an increased risk of coronary heart disease, yet Mexican Americans have coronary heart disease mortality similar to or lower than that of non-Hispanic whites. The authors therefore attempted to determine whether Mexican Americans had decreased Lp(a) concentrations relative to non-Hispanic whites in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Lp(a) concentrations (mg/dl) were significantly lower in Mexican Americans (n = 316) than in non-Hispanic whites (n = 242) (men: 10.4 vs. 16.3; women: 11.5 vs. 16.4). In addition, the proportion of persons with Lp(a) concentrations of > or = 30 mg/dl (the threshold at which increased risk of coronary heart disease is believed to occur) was significantly higher in non-Hispanic whites than in Mexican Americans (18.6% vs. 7.6%; Mantel-Haenszel odds ratio (adjusted for sex) = 2.79). Age, obesity, body fat distribution, cigarette smoking, alcohol consumption, and glucose and insulin concentrations were not significantly related to Lp(a) levels. Decreased Lp(a) concentrations may account in part for Mexican Americans' relative protection from coronary heart disease mortality.


Short-term intraindividual variability in lipoprotein measurements: the Atherosclerosis Risk in Communities (ARIC) Study. Much epidemiologic research is based on estimation of an association between a putative risk factor and a health outcome--for example, plasma concentration of lipoproteins and ischemic heart disease. Since the repeatability of a risk factor measurement determines, in part, the ability to ascertain its association in populations, the Atherosclerosis Risk in Communities (ARIC) Intraindividual Variability Study was conducted to estimate various components of variation in analyte data and to estimate the repeatability of these measurements. A total of 40 subjects (17 males and 23 females) from Forsyth County, North Carolina, Minneapolis, Minnesota, Jackson, Mississippi, and Washington County, Maryland, were studied in 1988. Fasting blood was collected three times from each subject, with a 1- to 2-week interval between each visit. The contributions of between-person variability, within-person variability, and processing and assay variability were estimated. From these components, the reliability coefficient, R, the correlation between measures made at repeat visits, was estimated. R was above 0.85 for total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, and lipoprotein(a). Low repeatability was obtained for apolipoprotein A-I (R = 0.60). High density lipoprotein subfractions 2 and 3 were intermediate in repeatability. Reliability coefficients from the ARIC Intraindividual Variability Study are generally higher than those found in other studies, and this is related to relative variability in populations studied, to the time between measurements, and to differences in laboratory variability. Only for apolipoprotein A-I would the findings strongly suggest the need to adjust for measurement variability in estimation using one of these analytes as an independent variable.


Serum ceruloplasmin level and the risk of myocardial infarction and stroke. The associations between serum ceruloplasmin level and the subsequent incidence of myocardial infarction and stroke were studied in a nested case-control study in Finland (baseline examination 1968-1972). Ceruloplasmin levels were measured in stored serum samples from 104 myocardial infarction or stroke cases occurring during a median follow-up of about 11 years and from 104 individually matched controls. High serum ceruloplasmin levels were significantly associated with higher future odds of myocardial infarction but not of stroke. The odds ratios for myocardial infarction and stroke comparing the highest and lowest tertiles of serum ceruloplasmin, adjusted for smoking, serum cholesterol, body mass index, hematocrit, hypertension, and diabetes, were 3.1 and 0.7, respectively. The results of the present study support the hypothesis that a high serum ceruloplasmin level is a risk factor for myocardial infarction.


Blood lead as a cardiovascular risk factor. Many epidemiologic and experimental animal studies support the hypothesis of there being a causal association between lead exposure and increased blood pressure/cardiovascular disease. This study includes 1,052 men and women from Copenhagen County, Denmark, who were examined in 1976 and 1981; in 1987, only the men were examined. Blood lead fell by approximately 40% for the men during the 11-year period and by approximately 30% for the women during the first 5-year period. There was a univariate association between systolic blood pressure and blood lead for both sexes in 1976, but it disappeared at the following examinations. For women, there was also a significant association with diastolic blood pressure, even after confounders were controlled for at the two examinations. Moreover, the authors found a significant univariate association between changes in blood lead and changes in systolic blood pressure from 1976 to 1987 in the males. All participants taking part in the study in 1976 were followed regarding hospital admissions and deaths throughout a follow-up period lasting for 14 years. There was a significant univariate association with total mortality, coronary heart disease, and cardiovascular disease. However, with regard to coronary heart disease and cardiovascular disease, the associations disappeared when confounders were controlled for. Blood lead was a significant predictor of total mortality after control for relevant confounders. This study supports the hypothesis of there being a weak causal association between blood lead and blood pressure, total mortality, coronary heart disease, and cardiovascular disease. The importance of this association is very modest for the individual, but the population attributable risk may be considerable.


The roles of insulin, obesity, and fat distribution in the elevation of cardiovascular risk factors in impaired glucose tolerance. The San Luis Valley Diabetes Study. The objective of this study was to determine whether a less favorable risk factor pattern for cardiovascular disease among persons with impaired glucose tolerance could be explained by fasting insulin, obesity, and/or a central distribution of body fat. Between 1984 and 1988, cardiovascular risk factors were examined cross-sectionally in Hispanic and non-Hispanic white participants in the San Luis Valley Diabetes Study who had either impaired (n = 173) or normal (n = 1,107) glucose tolerance. Sex-specific analysis of covariance models were constructed to adjust risk factor levels for age, age and insulin, and age, insulin, body mass index, and centrality index. Both males and females with impaired glucose tolerance had higher age-adjusted mean diastolic blood pressures, heart rates, uric acid levels, and triglyceride levels and lower levels of high density lipoprotein (HDL) cholesterol and HDL3 cholesterol than normal subjects; differences were significant for all risk factors except HDL cholesterol and HDL3 cholesterol in males. Differences in diastolic blood pressure in males, and differences in heart rate and triglyceride in both sexes, remained significant after adjustment for all covariates. However, differences in uric acid in males and differences in diastolic blood pressure and HDL3 cholesterol in females were attenuated to borderline significance levels. Differences in uric acid and HDL cholesterol in females were diminished to nonsignificant levels, especially after adjustment for obesity-related measures. With few exceptions, fasting insulin did not appear to play a major role in accounting for differences in these risk factors. With adjustment, ethnic differences (Hispanic vs. non-Hispanic white) were smaller and were statistically significant less often than differences observed between impaired and normal glucose tolerant groups. The authors concluded that hyperinsulinemia, obesity, and a central body fat distribution accounted for some, but usually not all, of the less favorable cardiovascular risk factor pattern found in subjects with impaired glucose tolerance.


Post-challenge glucose concentration, impaired glucose tolerance, diabetes, and cancer mortality in men. The possibility that diabetes is associated with an elevated risk of cancer mortality has been discussed for many years. Recently, Levine et al. (Am J Epidemiol, 1990; 131:254-62) approached this issue by relating post-load plasma glucose concentration to cancer mortality. For men, there appeared to be a positive association between post-load glucose and mortality from cancer for all sites combined and for some specific sites. However, that analysis was based on only 298 cancer deaths among 11,521 men followed for 12 years. The current authors explored this issue in a cohort of 18,274 male civil servants, among whom there were 1,282 cancer deaths over 18-20 years of follow-up. There was no association between post-load glucose and cancer mortality, except for pancreatic cancer. A role for asymptomatic hyperglycemia in the etiology of cancer is not supported by the results of the present study.


Sexual transmission of hepatitis C virus among female prostitutes and patients with sexually transmitted diseases in Fukuoka, Kyushu, Japan. The authors investigated the prevalence of antibody to hepatitis C virus (anti-HCV) in 404 female prostitutes, 428 clinic patients with a history of at least one episode of sexually transmitted disease, and 8,944 blood donors who served as the controls. All subjects were Japanese, and all studies were carried out in Fukuoka, Kyushu, Japan, in 1989. The prevalence of anti-HCV was significantly higher in the prostitutes (6.2%), in the female patients with sexually transmitted diseases (6.1%), and in the male patients with sexually transmitted diseases (2.9%) than in the controls (1.5%). Prevalence of anti-HCV increased with age in prostitutes and in the controls. The prevalence of anti-HCV in those who had been involved in prostitution for 1 year or more (8.1%) was higher than in those who had been involved in prostitution for less than 1 year (1.4%), but the difference was not statistically significant. One of the 152 anti-HCV negative prostitutes seroconverted between 1 and 2 years later. Among the subjects with sexually transmitted diseases, patients with a history of at least one episode of syphilis had a significantly higher prevalence of anti-HCV (4.4%) than the controls. Patients with acute urethritis and cervicitis also showed a high prevalence of anti-HCV (3.6% and 6.7%, respectively). These data support the possibility of sexual transmission of hepatitis C virus.


Familial aggregation of a disease consequent upon correlation between relatives in a risk factor measured on a continuous scale. Correlation between relatives in one or more risk factors for a disease will contribute to the risk in relatives of an affected individual, irrespective of the cause(s) of the correlation. In this paper, a model is proposed to quantify the relation between 1) the correlation (rho) between a random pair of relatives in a quantitative risk factor, 2) the dependence of the probability of being affected on a risk factor, assumed to be a logistic function and summarized by a risk ratio (RR) between upper and lower quartiles, and 3) the resultant disease association between relatives, represented as an odds ratio. For one risk factor, the odds ratio is almost independent of disease frequency across the range 0.001-0.1, and is approximately linearly related to rho on a logarithmic scale. An odds ratio between relatives of about 2 occurs if rho = 1 and RR = 9, if rho = 0.6 and RR = 20, or if rho = 0.3 and RR = 100. For two independent risk factors with the same risk ratio and rho, the resultant odds ratio exceeds unity by about twice as much as when there is one risk factor. That is, even moderate familial aggregation of a disease is consistent with there being one or more strong familial (genetic and/or environmental) risk factors. Illustrations of the model are discussed.


Sample size for studying intermediate endpoints within intervention trails or observational studies. An intermediate endpoint is a biologic event or marker that is a precursor to a given health outcome. Examples of potential intermediate endpoints include serum cholesterol for coronary heart disease, endogenous steroid hormones for breast cancer, and CD4 count for acquired immunodeficiency syndrome. When one is studying a potential intermediate endpoint in the context of an intervention trial, five types of questions may be investigated: 1) Does the intervention affect the intermediate endpoint? 2) Is the intermediate endpoint associated with prognostic or risk factors? 3) Is the intermediate endpoint associated with the main outcome? 4) Is the intervention effect on the main outcome mediated by the intermediate endpoint? 5) Are the prognostic or risk factor effects mediated by the intermediate endpoint? In this paper, the authors show that each of these questions had different sample size requirements, and they illustrate their point with a discussion of an ancillary study of large bowel epithelial proliferation in the National Cancer Institute's Polyp Prevention Trial. The same methods may be used in an observational study, in which case questions 2, 3, and 5 are relevant. However, much larger numbers than those used in the Polyp Prevention Trial example will be required when the main outcome is rare.


Leave no stone unturned.

Leave no stone unturned. The need for locating patients lost to follow-up is well known in epidemiologic research projects. This paper provides for the reader the basic tools, techniques, and methods that can be used to locate these patients.


Diabetic nephropathy in insulin-dependent patients. Diabetic nephropathy is a serious complication of insulin-dependent diabetes mellitus (IDDM) that affects 30% to 40% of IDDM patients with a predictable time of onset. Epidemiologic data suggest that either a genetic susceptibility, perhaps for hypertension (HTN), or an environmental exposure selects out that subset of IDDM patients and destines them to develop diabetic nephropathy. Hopefully, assessing glomerular hyperfiltration, urinary albumin excretion rate (AER), glycemic control, mean arterial pressure (MAP), and perhaps early morphologic changes will allow early identification of this high-risk group of IDDM patients before overt nephropathy is present. Once nephropathy appears, renal function inexorably declines, although the natural history of this progression may be changing with earlier therapeutic intervention. IDDM patients with nephropathy suffer a high mortality rate compared with IDDM patients without nephropathy or with nondiabetic end-stage renal disease patients. This is primarily due to malignant atherosclerotic disease manifested as coronary, peripheral, and cerebral arterial disease. Therapeutic interventions of demonstrated benefit in slowing the rate of decline of glomerular filtration rate (GFR) include blood pressure control and low-protein diets. Strict blood sugar control or treatment with aldose reductase inhibitors, converting enzyme inhibitors (CEIs), or inhibitors of advanced glycosylation end-product formation are of possible benefit, but are awaiting clinical trial results.


An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Clinical diabetic nephropathy in man is the consequence of the development of a specific constellation of glomerular, tubular, vascular, and interstitial structural abnormalities accompanied by highly characteristic immunohistochemical alterations that, together, are unique to diabetes. Because changes resembling the specific pathology of diabetes do not develop in patients with conditions that lead to long-standing glomerular hyperfunction (such as unilateral nephrectomy), it is unlikely that glomerular hemodynamic abnormalities per se can be the cause of diabetic nephropathy. Whether hemodynamic abnormalities represent a risk factor that, in the presence of the diabetic state, can accelerate the rate of development of the basic lesions of diabetic nephropathy is currently unclear. However, there is considerable evidence that when the renal lesions of diabetes are far advanced, factors such as systemic hypertension can determine the rate of renal functional deterioration in diabetes as in other disorders. Although the diabetic rat may be a useful model for the study of aspects of the pathogenesis of diabetic nephropathy, much confusion has resulted from the inclusion of focal segmental glomerular sclerosis as a diabetic lesion. Similarly, the acceptance of all increases in urinary protein excretions in this model as resulting from or reflecting of diabetic nephropathology can be misleading. It is concluded that treatment aimed at manipulating renal hemodynamics in diabetic patients without evidence of renal disease should remain in the realm of clinical research.


Captopril acutely lowers albuminuria in normotensive patients with diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors decrease albuminuria in patients with diabetic nephropathy. To study the change in albuminuria in relation to changes in systemic and renal hemodynamics, nine normotensive patients with type 1 (insulin-dependent) diabetes mellitus and persistent proteinuria were given a single oral dose of 25 mg of the ACE inhibitor captopril. Blood pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and albumin excretion rate (AER) were measured in two periods of 40 minutes before and in four periods of 40 minutes after administration of captopril. A constant water diuresis was maintained. Blood pressure did not decrease significantly (130/79 +/- 4/3 v 124/74 +/- 4/3 mm Hg; mean +/- SEM), median AER decreased from 403 (interquartile range [IQR], 812) micrograms/min to 333 (707) micrograms/min (P < 0.01). GFR did not change (123 +/- 13 v 117 +/- 14 mL/min), but ERPF increased significantly from 609 +/- 56 to 714 +/- 55 mL/min (P < 0.01). Consequently, the filtration fraction (FF; quotient of GFR and ERPF) decreased from 0.20 +/- 0.014 to 0.17 +/- 0.014 (P < 0.01). A strong correlation was found between the decrease of AER and the decrease of FF (rs = 0.75; P < 0.02). No correlation was found between the decrease in AER and changes in GFR or blood pressure. In the normotensive patient with diabetic nephropathy, captopril causes an acute reduction of AER, which is probably mediated by a lowering of the intraglomerular pressure.


Renal replacement therapy in type 2 diabetic patients: 10 years' experience. The objective of this study was to determine the impact of renal transplantation and hemodialysis treatment on outcome of elderly diabetic patients with end-stage renal disease (ESRD) among other factors related to survival. Results of treatment of ESRD in 78 patients with non-insulin-dependent diabetes mellitus (type 2) showed a survival rate of 58% at 1 year and 14% at 5 years, independent of treatment modality. Patients who received a renal allograft had a higher survival rate as compared with patients on hemodialysis treatment (5-year survival, 59% v 2%; P < 0.005). Diabetic patients with a history of myocardial infarction, stroke, or peripheral gangrene before onset of renal replacement therapy had a worse prognosis in comparison to patients without vascular complications (5-year survival, 2% v 21%; P < 0.05). Analysis of patients who survived less than 6 months and more than 24 months was performed. Long-term survivors were slightly younger, had diabetes for a shorter period, and showed a better metabolic control of diabetes mellitus. Sixteen long-term survivors received a renal allograft. In contrast, only three short-term survivors were transplanted. Furthermore, short-term survivors also had a greater than 70% incidence of severe vascular complications before renal replacement therapy. A history of myocardial infarction, stroke, or peripheral gangrene is an independent predictor of decreased survival, irrespective of whether the patients were transplanted or maintained on chronic hemodialysis treatment. In contrast, renal transplantation improved survival of elderly diabetic patients without vascular complications and should be the treatment of choice in this specific group of patients.


Renal scanning 99mTc diethylene-triamine pentaacetic acid glomerular filtration rate (GFR) determination compared with iothalamate clearance GFR in diabetics. The Collaborative Study Group for The study of Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy. Traditionally, creatinine clearance is used as an estimation of the glomerular filtration rate (GFR) because of its relative ease and low cost. Errors in collection limit its usefulness. Estimation of GFR using 99mTc diethylene-triamine pentaacetic acid (Tc-DTPA) by direct scintigraphic determination of fractional radionuclide accumulation within each kidney does not require blood or urine sampling, takes 10 to 15 minutes to perform, and has been reported to give a GFR that correlates with 24-hour urinary creatinine clearance (CC) in hospitalized patients (r = 0.95). To assess its usefulness in the outpatient diabetic with nephropathy, 24 patients with type I diabetes underwent 56 iothalamate clearances during water diuresis and 56 simultaneous Tc-DTPA GFR estimations. GFR was also estimated from 24-hour urinary CC, 100/creatinine, and by the formula of Cockcroft and Gault. Tc-DTPA GFR estimation by direct renal scanning correlated relatively poorly with iothalamate GFR (r = 0.74) in this patient population when all levels of iothalamate GFR were compared (n = 56), but improved (r = 0.80) when iothalamate GFR values greater than or equal to 120 mL/min were excluded from analysis (n = 45). Given all levels of iothalamate GFR, the best correlation was obtained with the estimation using the equation of Cockcroft and Gault (r = 0.86).


The diagnosis of Helicobacter pylori infection in uremic patients. Two urease-based tests--the urease slide test and the radiolabeled urea breath test, are commonly used for the diagnosis of Helicobacter pylori infection of the stomach. The reliability of these tests in chronic uremia was compared with serological tests for H pylori antibodies, and with direct detection of the organism by microscopy or culture of gastric antral biopsies. Twenty-seven patients with chronic renal failure and dyspepsia underwent upper gastrointestinal endoscopy. Twelve of these patients (46%) were judged to be infected with H pylori on the basis of identification of the organism on microscopy or culture of antral biopsy. Both urease-based tests were able to determine H pylori status, despite the markedly increased concentrations of urea in the gastric juice found in chronic renal failure. The urease slide test performed on antral biopsies obtained at endoscopy proved reliable in determining H pylori status with no false-positive nor false-negative results after 20 minutes and 24 hours of incubation. The 14C-urea breath test also differentiated the infected from the uninfected patients. The 20-minute 14CO2 excretion (kg %dose/mmol CO2 x 100) ranged from 50 to 834 in the H pylori-infected patients, compared with 0.3 to 27 in the H pylori-noninfected patients (P < 0.0001); the 90-minute values ranged from 88 to 398 in the former, compared with 1 to 79 in the latter (P < 0.0001). The excretion of 14CO2 (derived from bacterial hydrolysis of ingested 14C-urea) was higher in all the uremic patients compared with nonuremic controls, and in half of the H pylori-noninfected uremic patients there was a late increase in 14CO2 excretion.(ABSTRACT TRUNCATED AT 250 WORDS)


Iron accumulation in human chronic renal disease. Iron, which has been shown to accumulate within proximal tubule lysosomes in proteinuric models of renal disease, may play a role in the progression of chronic renal disease by the generation of reactive oxygen species. Therefore, renal biopsies from humans with proteinuria and/or chronic renal failure were examined at an ultrastructural level for iron by energy dispersive analysis and compared with normal biopsies. Iron accumulated in proximal tubular lysosomes in renal disease (P < 0.05 v normals), accompanied in some cases by phosphorus and silicon. Both the number of iron-containing lysosomes per tubular cross-section (1.86 +/- 0.41 v 0.66 +/- 0.22, P < 0.05) and the mean concentration of lysosomal iron (254.5 +/- 73.4 mg/dL v 81.2 +/- 23.8, P < 0.001) was greater in patients with nephrotic syndrome (n = 12) than in those without (n = 8). Iron accumulation (number of iron-containing lysosomes/tubule) correlated with protein excretion (r = 0.68, P = 0.003, n = 20), but not with glomerular filtration rate. Damaged tubules contained greater amounts of iron than tubules with less damage (288.5 +/- 68.5 mg/dL v 80.4 +/- 13.9, P < 0.01). Further studies are needed to define the possible role of iron in causing tubular damage and progression of renal disease.


Uremic pancreopathy: impaired secretory function in vitro. Abnormalities of the exocrine pancreas have long been described in uremia. The present study was performed to determine whether these abnormalities occur as a result of derangements in protein synthesis or disturbances in protein secretion. Pancreatic acini obtained from rats with renal failure and their pair-fed shams were studied in vitro by the method of radiolabeled leucine incorporation and secretory response to carbachol. In vitro protein synthesis, as reflected in radiolabeled leucine incorporation per DNA content was increased in uremic acini compared with control. However, the secretory response to carbachol was impaired. These results suggest that the impairment in exocrine pancreatic function is likely due to abnormalities in protein secretion, rather than protein synthesis.


Eating behavior in continuous ambulatory peritoneal dialysis and hemodialysis patients. Three groups consisting of 12 subjects each (continuous ambulatory peritoneal dialysis [CAPD] patients, hemodialysis patients, and healthy controls) matched for age, sex, and body weight were invited to a test meal for the study of hunger, fullness, and food preferences. They were served an excess portion of hash served on a plate placed on a hidden scale ("VIKTOR"), which was connected to a computer registering the eating process on-line. The patients filled in visual analogue scales (VAS) concerning appetite and food preferences before and after the test meal. Mean total intake of food (+/- SD) was significantly higher for healthy controls (357 +/- 175 g) compared with hemodialysis patients (295 +/- 105 g), which in turn was higher than in CAPD patients (206 +/- 70 g). Eating velocity was lower in both dialysis groups compared with controls. CAPD patients experienced less hunger and desire to eat compared with hemodialysis patients and controls. The reason for the low eating drive in CAPD patients despite their great need for protein and calories is unknown, but might be explained by gastric retention, insufficient dialysis, metabolic effects of the high sugar load from the dialysate, or combinations of these factors.


The determination of hemodialysis blood recirculation using blood urea nitrogen measurements. The determination of blood recirculation using blood urea nitrogen (BUN) measurements in hemodialysis patients is a standard technique. The accuracy and reproducibility of these calculations have never been determined. Two pairs of recirculation studies (study A and study B) were performed in 13 patients during a single dialysis treatment. Blood samples were analyzed for BUN and recirculation was calculated. The first recirculation study (study A) was performed within 1 hour of the initiation of dialysis, with a duplicate test of recirculation performed within 15 minutes. In study B, the dialyzer blood lines were reversed in an attempt to enhance blood recirculation. After 15 minutes, duplicate tests of recirculation were again performed. Calculated recirculations before the line reversal (study A) ranged from -3.3% to 11.9% in the first test and -2.9% to 12.2% in the second test. In study A, there was no correlation (P > 0.05, r = 0.09) between the first and second calculated recirculations. In study B, an increase in recirculation was observed. Calculated recirculations ranged from 16.3% to 53.5% for the first test and 5.4% to 58.1% for the second test. A significant relationship was observed in the calculated recirculation in study B (P < 0.05, r = 0.81). The results from the present study show that the use of BUN measurements may not provide a consistent indicator of access recirculation in a patient with a low recirculation. This lack of consistency should be considered when determining further clinical treatment.


Antilymphocyte globulin versus OKT3 induction therapy in cadaveric kidney transplantation: a prospective randomized study. Different induction therapies have been used in renal transplantation to avoid cyclosporine (CsA) nephrotoxicity and early acute graft rejection. This study compares the efficacy of a short course of prophylactic OKT3 to that of antilymphocyte globulin (ALG) in preventing acute renal allograft rejection when administered concomitantly with CsA and steroids. Between March 1988 and December 1990, 140 first-cadaver renal transplant recipients were randomly allocated to two immunosuppression groups--ALG group (n = 68): ALG 15 mg/kg just before transplant surgery, ALG 12 mg/kg the first day after transplant, followed by four doses of 10 mg/kg on alternate days; and OKT3 group (n = 72): OKT3 5 mg just before transplant, followed by four doses of 5 mg/d. Both groups included low-dose CsA and steroids. The incidence of rejection during the first 3 months after transplantation was 15% in the ALG group and 19% in the OKT3 group (NS). Kaplan-Meier estimates of patients free of rejection at 2 years was 85% in the ALG group and 77% in the OKT3 group (NS). The 3-year actuarial graft survival was 82% and 85% (NS), and 3-year patient survival was 97% and 98% (NS), in the ALG and OKT3 groups, respectively. These results indicate that the concomitant association of CsA and ALG or OKT3 constitutes a safe and effective therapeutic strategy that provides a low incidence of rejection and gives good results for patient and graft survival.


Cytokine-induced immunoglobulin production in primary IgA nephropathy. Increased IgA synthesis probably plays a role in the pathogenesis of IgA nephropathy (IgAN). We investigated whether an increased sensitivity to the effect of various growth factor combinations leads to increased immunoglobulin synthesis by peripheral blood mononuclear cells (PBMC) from IgAN patients, in comparison to healthy controls. Although none of the growth factors studied (pokeweed mitogen [PWM], interleukin [IL]-2, IL-6, transforming growth factor-beta [TGF-beta], and combinations) led to greater IgA synthesis in IgAN patients than in controls, the IgA subclass ratio was shifted in favor of IgA1. In controls, but not in IgAN patients, IL-2 enhanced the production of IgA and IgA1 compared with media alone. This possibly reflects previous in vivo activation by IL-2 in IgAN patients. The suppressive effect of TGF-beta on immunoglobulin synthesis was modestly greater in IgAN patients than in controls. Increased production of IL-2 and perhaps other cytokines by T cells in vivo may be responsible for the elevated IgA immune response in these patients.


Analysis of cytodiagnostic urinalysis findings in 77 patients with concurrent renal biopsies. We investigated the value of cytodiagnostic urinalysis in detecting and scoring the severity of the four types of renal lesions (glomerular, interstitial, tubular, and vascular). Both cytodiagnostic urinalysis and concurrent renal biopsy were performed in 77 patients (47 from native kidneys and 30 from transplants) and the scoring and findings assessed in a double-blinded fashion. Evaluation of the reproducibility for the counting of renal cells showed a low intraobserver and interobserver variation. Cytodiagnostic urinalysis correlated with the renal biopsy with respect to primary lesions in 42 (89%) of the native kidney cases, and in 23 (77%) of the transplant kidney cases. The accuracy of diagnosis of glomerular lesions in both native and transplanted kidneys was 0.91, and for acute rejection in transplanted kidneys, the accuracy of diagnosis was 0.73. Severity scores showed good correlation between cytodiagnostic urinalysis and renal biopsy in both transplanted and in native kidneys and cytodiagnostic urinalysis correlated well with the increase in creatinine levels. The most important components of cytodiagnostic urinalysis for the diagnosis of glomerular lesions were dysmorphic erythrocytes and proteinuria. The specificity and sensitivity of dysmorphic erythrocytes for a glomerular lesion were 0.89 and 0.88, respectively. In cases with biopsy-proven glomerular lesions, more severe changes were found by cytodiagnostic urinalysis when the biopsy showed proliferative lesions in the glomeruli than when normal glomeruli were found by light microscopy. Cytodiagnostic urinalysis has the advantage over renal biopsy that it can be repeated as often as necessary and thus allows observation of the development or regression of the renal lesion over time. We conclude that cytodiagnostic urinalysis is well correlated with the renal biopsy and that it provides valuable and quantitative information regarding the disease process in the kidney.


Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. In a review of the autopsies and medical records of 22 obese patients, focal segmental glomerulosclerosis (FSGS) was present in seven. The FSGS was mild in all but one patient. The FSGS of obese patients has similar features to idiopathic FSGS; however, our findings suggest that it lacks the hyperplasia of glomerular epithelial cells, shows no predilection for the corticomedullary junction, and is probably more often seen in the hilar region of the glomeruli. FSGS or glomerulomegaly was not associated with the degree of obesity. We demonstrated lipid deposition in the kidney of obese patients. Obese patients with FSGS, compared to those without FSGS, had higher blood cholesterol (P < 0.10) and higher triglyceride levels (P < 0.01). The mean heart weight of obese patients with FSGS was greater than that of patients without FSGS (P < 0.01). Also, obese patients with FSGS had larger glomeruli (246 +/- 33 microns) than obese patients without FSGS (218 +/- 16 microns) (P < 0.05). These findings suggest that cardiomegaly with hemodynamic changes and glomerular hyperfiltration may play a significant role in the glomerulomegaly and FSGS of obese patients. The secondary or contributory role of lipids in the development of the FSGS of obese patients remains to be determined.


Sclerosing peritonitis with gross peritoneal calcification: a case report. We report the case of a patient on dialysis for 13 years, including continuous ambulatory peritoneal dialysis (CAPD) for 11 years, who developed sclerosing peritonitis with gross peritoneal calcification. The patient first presented with abdominal pain in January 1990, when peritoneal calcification was detected for the first time. Her symptoms settled spontaneously and 1 year later she presented with acute peritonitis and adynamic ileus. The peritonitis settled with antibiotics and Tenchkoff catheter removal, but the ileus persisted. She was commenced on long-term parenteral nutrition, but never recovered useful bowel function. After 8 weeks of hemodialysis and total parenteral nutrition, a further laparotomy for an acute abdomen showed what appeared to be extensive bowel infarction and peritoneal calcification. She died several days later. Of significance, peritoneal calcification was first noted on x-ray and computed tomography (CT) scan while the patient was still largely asymptomatic and before peritoneal ultrafiltration capacity was significantly impaired. Unlike other reported cases of calcifying peritonitis, sclerosing peritonitis was present and calcification was far more extensive. It was not associated with factors such as frequent infective peritonitis or acetate dialysate. Calciphylaxis was not present nor was there any abnormality of calcium-phosphate metabolism. The outcome of this case suggests that patients with recurrent or persistent bowel symptoms on long-term CAPD should have early abdominal x-ray or CT scanning to exclude sclerosing peritonitis or bowel calcification. If present, consideration should be given to transferring the patient to another therapeutic dialysis modality if possible.


Acute skin and fat necrosis during sepsis in a patient with chronic renal failure and subcutaneous arterial calcification. Calcification of small subcutaneous arteries and arterioles is commonly found in patients with chronic renal failure (CRF), but the syndrome of acute ischemic necrosis of the skin and subcutaneous fat supplied by these vessels is relatively uncommon. The necrosis occurs during dialysis and after successful renal transplantation, and it is often fatal. Occlusion of the calcified arteries and associated microvessels by thrombi is reported infrequently, but it is relevant to the necrosis. However, the pathogenesis remains enigmatic. In the patient described here, who had CRF, bacteremia, and laboratory evidence of disseminated intravascular coagulation (DIC), the distribution of thrombi and necrosis was mainly that of the calcified arteries which, therefore, probably played a role in the localization of the thrombi. An increased susceptibility of the endothelium of calcified vessels to the procoagulant effects of sepsis may be a contributing factor.


Neurotoxicity of acyclovir in patients with end-stage renal failure treated with continuous ambulatory peritoneal dialysis. We report two cases of herpes-zoster in which the administration of acyclovir to patients with end-stage renal failure treated by continuous ambulatory peritoneal dialysis (CAPD) resulted in acyclovir neurotoxicity, even though the doses administered were within those recommended by the manufacturer's data sheet for patients with renal failure. Acyclovir removal was negligible with peritoneal dialysis and one patient died. The other patient was successfully treated with hemodialysis, which effectively reduced plasma concentrations, resulting in an improvement in conscious state. Acyclovir neurotoxicity should be considered in patients with renal failure who have been treated for viral infections, in whom the conscious state has deteriorated despite normal brain computed tomography (CT) scan and lumbar puncture investigations. Hemodialysis is the preferred treatment for the rapid removal of acyclovir.


Acetazolamide in hemodialysis patients: a rational use after ocular surgery. Acetazolamide is a weak diuretic used to decrease production of aqueous humor in the eye. Hemodialysis patients undergoing ocular surgery may benefit from acetazolamide; however, no pharmacokinetic data are available for this group of patients. We report a patient who received acetazolamide 250 mg every 6 hours after ophthalmic surgery and developed reversible neurological side effects associated with very high plasma concentrations. Using pharmacokinetic analysis, we suggest an alternate administration of acetazolamide for end-stage renal patients.


Segregation and manifestations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. We have studied the segregation and manifestations of the tRNA(Lys) A-->G(8344) mutation of mtDNA. Three unrelated patients with myoclonus epilepsy and ragged-red fibers (MERRF) syndrome were investigated, along with 30 of their maternal relatives. Mutated mtDNA was not always found in the offspring of women carrying the tRNA(Lys) mutation. Four women had 10%-33% of mutated mtDNA in lymphocytes, and no mutated mtDNA was found in 7 of their 14 investigated children. The presence of mutated mtDNA was excluded at a level of 3:1,000. Five women had a proportion of 43%-73% mutated mtDNA in lymphocytes, and mutated mtDNA was found in all their 12 investigated children. This suggests that the risk for transmission of mutated mtDNA to the offspring increases if high levels are present in the mother and that, above a threshold level of 35%-40%, it is very likely that transmission will occur to all children. The three patients with MERRF syndrome had, in muscle, both 94%-96% mutated mtDNA and biochemical and histochemical evidence of a respiratory-chain dysfunction. Four relatives had a proportion of 61%-92% mutated mtDNA in muscle, and biochemical measurements showed a normal respiratory-chain function in muscle in all cases. These findings suggest that > 92% of mtDNA with the tRNA(Lys) mutation in muscle is required to cause a respiratory-chain dysfunction that can be detected by biochemical methods. There was a positive correlation between the levels of mtDNA with the tRNA(Lys) mutation in lymphocytes and the levels in muscle, in all nine investigated cases. The levels of mutated mtDNA were higher in muscle than in lymphocytes in all cases. In two of the patients with MERRF syndrome, muscle specimens were obtained at different times. In both cases, biochemical measurements revealed a deteriorating respiratory-chain function, and in one case a progressive increase in the amount of cytochrome c oxidase-deficient muscle fibers was found.


A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON). The risk of developing the optic neuropathy shows strict maternal inheritance, and the ophthalmological changes in affected family members are characteristic of LHON. However, in contrast to the common form of the disease, members of these two families show a high frequency of vision recovery. To ascertain the mitochondrial genetic etiology of the LHON in these families, both (a) the the nucleotide sequences of the seven mitochondrial genes encoding subunits of respiratory-chain complex I and (b) the mitochondrial cytochrome b gene were determined for representatives of both families. Neither family carries any of the previously identified primary mitochondrial LHON mutations: ND4/11778, ND1/3460, or ND1/4160. Instead, both LHON families carry multiple nucleotide changes in the mitochondrial complex I genes, which produce conservative amino acid changes. From the available sequence data, it is inferred that the Vic2 and Tas2 LHON families are phylogenetically related to each other and to a cluster of LHON families in which mutations in the mitochondrial cytochrome b gene have been hypothesized to play a primary etiological role. However, sequencing analysis establishes that the Vic2 and Tas2 LHON families do not carry these cytochrome b mutations. There are two hypotheses to account for the unusual mitochondrial genetic etiology of the LHON in the Tas2 and Vic2 LHON families. One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses. Alternatively, the disease in these families may result from the cumulative effects of multiple secondary LHON mutations that have less severe phenotypic consequences.


No significant effect of monosomy for distal 21q22.3 on the Down syndrome phenotype in "mirror" duplications of chromosome 21. Three Down syndrome patients for whom karyotypic analysis showed a "mirror" (reverse tandem) duplication of chromosome 21 were studied by phenotypic, cytogenetic, and molecular methods. On high-resolution R-banding analysis performed in two cases, the size of the fusion 21q22.3 band was apparently less than twice the size of the normal 21q22.3, suggesting a partial deletion of distal 21q. The evaluation of eight chromosome 21 single-copy sequences of the 21q22 region--namely, SOD1, D21S15, D21S42, CRYA1, PFKL, CD18, COL6A1, and S100B--by a slot blot method showed in all three cases a partial deletion of 21q22.3 and partial monosomy. The translocation breakpoints were different in each patient, and in two cases the rearranged chromosome was found to be asymmetrical. The molecular definition of the monosomy 21 in each patient was, respectively, COL6A1-S100B, CD18-S100B, and PFKL-S100B. DNA polymorphism analysis indicated in all cases a homozygosity of the duplicated material. The duplicated region was maternal in two patients and paternal in one patient. These data suggest that the reverse tandem chromosomes did not result from a telomeric fusion between chromosomes 21 but from a translocation between sister chromatids. The phenotypes of these patients did not differ significantly from that of individuals with full trisomy 21, except in one case with large ears with an unfolded helix. The fact that monosomy of distal 21q22.3 in these patients resulted in a phenotype very similar to Down syndrome suggests that the duplication of the genes located in this part of chromosome 21 is not necessary for the pathogenesis of the Down syndrome features observed in these patients, including most of the facial and hand features, muscular hypotonia, cardiopathy of the Fallot tetralogy type, and part of the mental retardation.


Analysis of chromosome 21 yeast artificial chromosome (YAC) clones. Chromosome 21 contains genes relevant to several important diseases. Yeast artificial chromosome (YAC) clones, because they span > 100 kbp, will provide attractive material for initiating searches for such genes. Twenty-two YAC clones, each of which maps to a region of potential relevance either to aspects of the Down syndrome phenotype or to one of the other chromosome 21-associated genetic diseases, have been analyzed in detail. Clones total approximately 6,000 kb and derive from all parts of the long arm. Rare restriction-site maps have been constructed for each clone and have been used to determine regional variations in clonability, methylation frequency, CpG island density, and CpG island frequency versus gene density. This information will be useful for the isolation and mapping of new genes to chromosome 21 and for walking in YAC libraries.


Nondisjunction of chromosome 21: comparisons of cytogenetic and molecular studies of the meiotic stage and parent of origin. In the present report, we summarize studies aimed at examining the reliability of chromosome heteromorphisms in analyses of chromosome 21 nondisjunction. We used two cytogenetic approaches--fluorescent in situ hybridization (FISH) to repetitive sequences on 21p and traditional Q-banding--to distinguish chromosome 21 homologues and then compared the results of these studies with those obtained by DNA markers. Using a conservative scoring system for Q-banding and FISH heteromorphisms, we were able to specify the parental origin of trisomy in 10% of cases; in contrast, DNA marker studies were informative for parental origin in almost all cases. The results of the molecular and cytogenetic studies of parental origin concurred in all cases in which assignments were made independently using both techniques. However, in 4 of 13 cases in which the molecular studies contributed to the interpretation of the cytogenetic findings, the two results did not agree with respect to the meiotic stage of nondisjunction. A relatively high frequency of crossing-over on either the short arm or proximal long arm of chromosome 21 could explain these results and may be a mechanism leading to nondisjunction.


Xp21 contiguous gene syndromes: deletion quantitation with bivariate flow karyotyping allows mapping of patient breakpoints. Bivariate flow karyotyping was used to estimate the deletion sizes for a series of patients with Xp21 contiguous gene syndromes. The deletion estimates were used to develop an approximate scale for the genomic map in Xp21. The bivariate flow karyotype results were compared with clinical and molecular genetic information on the extent of the patients' deletions, and these various types of data were consistent. The resulting map spans > 15 Mb, from the telomeric interval between DXS41 (99-6) and DXS68 (L1-4) to a position centromeric to the ornithine transcarbamylase locus. The deletion sizing was considered to be accurate to +/- 1 Mb. The map provides information on the relative localization of genes and markers within this region. For example, the map suggests that the adrenal hypoplasia congenita and glycerol kinase genes are physically close to each other, are within 1-2 Mb of the telomeric end of the Duchenne muscular dystrophy (DMD) gene, and are nearer to the DMD locus than to the more distal marker DXS28 (C7). Information of this type is useful in developing genomic strategies for positional cloning in Xp21. These investigations demonstrate that the DNA from patients with Xp21 contiguous gene syndromes can be valuable reagents, not only for ordering loci and markers but also for providing an approximate scale to the map of the Xp21 region surrounding DMD.


Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families. A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions--LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml)--to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The penetrance of the more dense LDL subfraction patterns, characterized by values of K < 0, was dependent on age, gender, and, in women, on oral contraceptive use and postmenopausal status. Furthermore, multiple regression analysis revealed that approximately 60% of the variation in the LDL subfraction pattern could be accounted for by alterations in age, gender, relative body weight, smoking habits, hormonal status in women, and lipid and lipoprotein levels. In conclusion, our results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease.


The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota. II. Regression relationships with concomitants. The influence of the apolipoprotein E (Apo E) polymorphism and gender on the regression relationships between each of nine plasma lipid and apolipoprotein traits (total cholesterol; ln triglycerides; high-density-lipoprotein cholesterol; apolipoproteins AI, AII, B, and CII; ln CIII; and ln E) and four concomitants (age, weight, waist-to-hip ratio, and smoking) was studied in 507 unrelated individuals representative of the adult population of Rochester, MN. Analyses are presented separately for females and males. Each lipid and apolipoprotein trait exhibited at least one Apo E genotype-specific regression relationship with the concomitants investigated in this study. In most cases the heterogeneity of regression was associated with differences between the epsilon 32 and epsilon 33 genotype. This study documents that the influence of Apo E genotype on average levels of plasma lipids and apolipoproteins varies among subdivisions of the population defined by age, body size, and smoking status.


Characteristics of polymorphism at a VNTR locus 3' to the apolipoprotein B gene in five human populations. We have analyzed the allele frequency distribution at the hypervariable locus 3' to the apolipoprotein B gene (ApoB 3' VNTR) in five well-defined human populations (Kacharis of northeast India, New Guinea Highlanders of Papua New Guinea, Dogrib Indians of Canada, Pehuenche Indians of Chile, and a relatively homogeneous Caucasian population of northern German extraction) by using the PCR technique. A total of 12 segregating alleles were detected in the pooled sample of 319 individuals. A fairly consistent bimodal pattern of allele frequency distribution, apparent in most of these geographically and genetically diverse populations, suggests that the ApoB 3' VNTR polymorphism predates the geographic dispersal of ancestral human populations. In spite of the observed high degree of polymorphism at this locus (expected heterozygosity levels 55%-78%), the genotype distributions in all populations (irrespective of their tribal or cosmopolitan nature) conform to their respective Hardy-Weinberg predictions. Furthermore, analysis of the congruence between expected heterozygosity and the observed number of alleles reveals that, in general, the allele frequency distributions at this locus are in agreement with the predictions of the classical mutation-drift models. The data also show that alleles that are shared by all populations have the highest average frequency within populations. These findings demonstrate the potential utility of highly informative hypervariable loci such as the ApoB 3' VNTR locus in population genetic research, as well as in forensic medicine and determination of biological relatedness of individuals.


The gene for familial Mediterranean fever in both Armenians and non-Ashkenazi Jews is linked to the alpha-globin complex on 16p: evidence for locus homogeneity. Familial Mediterranean fever (FMF) is a recurrent inflammatory disorder characterized by short episodes of fever, peritonitis, pleuritis, and arthritis. While FMF has been shown to be inherited in an autosomal recessive fashion in both non-Ashkenazi Jews and Armenian families, clinical differences have raised the possibility of genetic heterogeneity. As its pathogenesis is unknown, mapping of the gene for FMF may provide the first objective method for early and accurate diagnosis of this disease. After excluding 45% of the entire human genome, we studied 14 Armenian and 9 non-Ashkenazi Jewish families with FMF and tested linkage with the alpha-globin locus on chromosome 16. Analysis of the PvuII length polymorphism of the 3' HVR (hypervariable region) probe showed significant linkage with the FMF gene (maximum lod score [lodmax] = 9.76 at maximum recombination fraction [theta] = .076). In the Armenians, the lodmax = 3.61 at theta = .10; and for the non-Ashkenazi Jews, lodmax = 6.28 at theta = .06. There was no evidence for genetic heterogeneity between the Armenians and the non-Ashkenazi Jews (chi 2 = 1.28; P = .26) or within either ethnic group (chi 2 = .00; P = .50). Thus, the gene for FMF is linked to the alpha-globin complex on chromosome 16p in both non-Ashkenazi Jews and Armenians.


Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. The identification of polymorphic alleles at loci coding for functional genes is crucial for genetic association and linkage studies. Since the tryptophan hydroxylase (TPH) gene codes for the rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin, it would be advantageous to identify a polymorphism in this gene. By examining introns of the human TPH gene by PCR amplification and analysis by the single-strand conformational polymorphism (SSCP) technique, an SSCP was revealed with two alleles that occur with frequencies of .40 and .60 in unrelated Caucasians. DNAs from 24 informative CEPH families were typed for the TPH intron polymorphism and analyzed with respect to 10 linked markers on chromosome 11, between p13 and p15, with the result that TPH was placed between D11S151 and D11S134. This region contains loci for several important genes, including those for Beckwith-Wiedemann syndrome and tyrosine hydroxylase.


Study of large inbred Friedreich ataxia families reveals a recombination between D9S15 and the disease locus. Friedreich ataxia is a neurodegenerative disorder with autosomal recessive inheritance. Precise linkage mapping of the Friedreich ataxia locus (FRDA) in 9q13-q21 should lead to the isolation of the defective gene by positional cloning. The two closest DNA markers, D9S5 and D9S15, show very tight linkage to FRDA, making difficult the ordering of the three loci. We present a linkage study of three large Friedreich ataxia families of Tunisian origin, with several multiallelic markers around D9S5 and D9S15. Haplotype data were used to investigate genetic homogeneity of the disease in these geographically related families. A meiotic recombination was found in a nonaffected individual, which excludes a 150-kb segment, including D9S15, as a possible location for the Friedreich ataxia gene and which should orient the search in the D9S5 region.


Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus. Uniparental disomy for chromosome 7 has been described previously in two individuals with cystic fibrosis. Here, we describe a third case that was discovered because the proband was homozygous for a mutation in the COL1A2 gene for type I procollagen, although his mother was heterozygous and his father did not have the mutation. Phenotypically, the proband was similar to the two previously reported cases with uniparental disomy for chromosome 7, in that he was short in stature and growth retarded. Paternity was assessed with five polymorphic markers. Chromosome 7 inheritance in the proband was analyzed using 12 polymorphic markers distributed along the entire chromosome. Similar analysis of the proband's two brothers established the phase of the alleles at the various loci, assuming minimal recombination. The proband inherited only maternal alleles at five loci and was homozygous at all loci examined, except one. He was heterozygous for an RFLP at the IGBP-1 locus at 7p13-p12. The results suggest that the isodisomy was not complete because of a recombination event involving the proximal short arms of two maternal chromosomes. In addition, the phenotype of proportional dwarfism in the proband suggests imprinting of one or more growth-related genes on chromosome 7.


Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia. Argininemia is caused by a hereditary deficiency of liver-type arginase (E.C.3.5.3.1) and is characterized by psychomotor retardation and spastic tetraplegia. We examined findings in three Japanese patients with argininemia, by using the PCR, cloning, and sequencing procedures. We found three different mutations--G-to-A-365 in exon 4, G-to-C-703 in exon 7, and C-del-842 in exon 8--thereby leading to mutant arginase proteins of W122X, G235R, and L282FS, respectively. Patient 1 was a compound heterozygote, inheriting the allele with G-to-A-365 from his mother and the allele with G-to-C-703 from his father. Patients 2 and 3 were homozygotes of the allele with G-to-C-703 and of the allele with C-del-842, respectively. Expression tests of these mutant arginases in Escherichia coli indicated that the mutant arginase of W122X did not remain a stable product. The other two mutant arginases--G235R and L282FS--were detected by immunoblot analyses. There was no evidence of activity of the three mutant arginases expressed in E. coli. We tentatively conclude that argininemia is heterogeneous, at the molecular level.


Importance sampling. I. Computing multimodel p values in linkage analysis. In linkage analysis, when the lod score is maximized over multiple genetic models, standard asymptotic approximation of the significance level does not apply. Monte Carlo methods can be used to estimate the p value, but procedures currently used are extremely inefficient. We propose a Monte Carlo procedure based on the concept of importance sampling, which can be thousands of times more efficient than current procedures. With a reasonable amount of computing time, extremely accurate estimates of the p values can be obtained. Both theoretical results and an example of maturity-onset diabetes of the young (MODY) are presented to illustrate the efficiency performance of our method. Relations between single-model and multimodel p values are explored. The new procedure is also used to investigate the performance of asymptotic approximations in a single model situation.


Regulation of priority carcinogens and reproductive or developmental toxicants. In California, 370 carcinogens and 112 reproductive/developmental toxicants have been identified as a result of the State's Safe Drinking Water and Toxic Enforcement Act of 1986. They include pesticides, solvents, metals, industrial intermediates, environmental mixtures, and reactive agents. Occupational, environmental, and consumer product exposures that involve these agents are regulated under the Act. At levels of concern, businesses must provide warnings for and limit discharges of those chemicals. The lists of chemicals were compiled following systematic review of published data, including technical reports from the U.S. Public Health Service--National Toxicology Program (NTP), and evaluation of recommendations from authoritative bodies such as the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (USEPA). Given the large number of chemicals that are carcinogens or reproductive/developmental toxicants, regulatory concerns should focus on those that have high potential for human exposure, e.g., widely distributed or easily absorbed solvents, metals, environmental mixtures, or reactive agents. In this paper, we present a list of 33 potential priority carcinogens and reproductive/developmental toxicants, including alcoholic beverages, asbestos, benzene, chlorinated solvents, formaldehyde, glycol ethers, lead, tobacco smoke, and toluene.


Mortality studies of machining fluid exposure in the automobile industry I: A standardized mortality ratio analysis. Machining fluids are widely used in a variety of common industrial metalworking operations to lubricate and cool both the tool and the working surfaces. Previous studies have suggested elevated respiratory, digestive, and skin cancers in exposed populations. This cohort study was initiated to assess whether long-term exposure to machining fluids in the course of machining, grinding, and other cutting operations is associated with excess cancer mortality. The cohort includes more than 45,000 automobile production workers from 3 plants, almost 1 million years of follow-up, over 10,000 deaths, and an extensive exposure assessment component. Standardized mortality ratios (SMRs) have been estimated for each of the 3 plants, using both U.S. as well as local populations as reference. Relative risks of 1.2-3.1 have been observed for several specific respiratory and digestive cancers of a priori interest, including cancer of the stomach, large intestine, pancreas, lung, and larynx. In addition, elevated risks for leukemia and asthma were noted. Future exposure-response analyses will provide the opportunity to identify relatively modest excesses in cause-specific mortality risk associated with exposure to specific types (straight, soluble, or synthetic), additives, or components of machining fluids.


Cancer of the stomach and the colon-rectum among workers in a coke gas plant. Four thousand nine hundred and eight male workers of the Hamburg gas plant, employed for 10 or more years during the period from January 1, 1900 to December 31, 1989, have been traced for cancer mortality. Based on their jobs, they were grouped into three subcohorts: gas furnace workers, workers in other parts of the plant, and white-collar workers. Despite the general "healthy worker effect," gas furnace workers showed a significant incidence of cancer of all sites (standardized mortality ratio [SMR] = 186), particularly cancers of the lung (SMR = 288), stomach (SMR = 177), and the colon-rectum (SMR = 184). In comparison to the death rates of white-collar workers, the manual workers in other parts of the plant also showed an excess of cancer mortality for cancer of these sites. The reason for this excess in cancer mortality seems to be due to the working conditions. The results contribute to the current evidence that exposure to coal carbonization fumes causes not only lung cancer, but also cancers of the stomach and colon-rectum.


A case-control study of lung cancer at a dye and resin manufacturing plant. This case-control study evaluated the relationship between lung cancer and occupational factors among employees at a dye and resin manufacturing plant. The study included 51 lung cancer cases and 102 controls who were members of a cohort of workers investigated in a previous retrospective follow-up study. Information on area of employment and on potential exposure to certain chemicals was obtained from plant personnel and medical records and from interviews with long-term employees. Information on potential confounders, including cigarette smoking, was obtained by interviewing study subjects or their next-of-kin. The odds ratio (OR) for heavy smokers compared with light or nonsmokers was 5.9 (95% confidence interval (CI) = 2.4-15). An elevated OR for lung cancer was observed for subjects who worked in the anthraquinone dye and epichlorohydrin manufacturing area of the plant (OR = 2.4; 95% CI = 1.1-5.2) and for employees who were seen at the plant infirmary for acute exposure to chlorine (OR, adjusted for smoking = 27; 95% CI = 3.5-205). Pipefitters employed at the plant for five or more years also had an elevated OR (3.3; 95% CI = 0.8-14).


Fluorocarbon 113 exposure and cardiac dysrhythmias among aerospace workers. We investigated the cardiotoxic effects of 1,1,2-Trichloro-1,2,2- Trifluoroethane (fluorocarbon 113 or FC113) exposures among healthy workers cleaning rocket and ground support equipment for the National Aeronautic and Space Administration (NASA) programs. Exposure and ambulatory electrocardiographic (ECG) monitoring data were evaluated on 16 workers, each of whom was examined on exposed and nonexposed workdays. We examined whether there was a greater rate of dysrhythmias on an exposed workday relative to a nonexposed workday. Overall, we found no within subject differences in the rate of ventricular and supraventricular premature beats (number per 1,000 heart beats), fluctuations in the length of the P-R interval, or heart rate. We found that levels of FC113 exposures below the Occupational Safety and Health Administration (OSHA) 8-hour time-weighted-average (TWA) standard of 1,000 ppm did not induce cardiac dysrhythmias or subtle changes in cardiac activity. However, because fluorocarbons may sensitize the heart to epinephrine, this study's negative findings based on sedentary and fairly healthy workers may not be generalizable to other populations of workers who are not as healthy or engaged in more physically demanding work.


Outbreak of hypersensitivity pneumonitis among mushroom farm workers. Between April 1982 and August 1985, seven cases of mushroom worker's lung (MWL), a form of hypersensitivity pneumonitis, were diagnosed among workers at one mushroom farm in Florida. The cases suffered from episodic shortness of breath, cough, fever and chills, myalgia, malaise, and difficulty breathing. Pulmonary function testing revealed restrictive ventilatory impairment and reduced diffusing capacity; chest radiographs exhibited diffuse interstitial pulmonary infiltrates. The seven cases occurred among workers from different farm operations, suggesting that workers throughout the farm were exposed to the disease causing agent(s). Six of the affected workers left employment at the farm in order to remain free of symptoms. The other affected worker was able to continue working at the farm, but only by remaining in a maintenance shop which was physically separated from the rest of the farm facilities. An industrial hygiene survey demonstrated that farm workers from every work area were exposed to organic dust constituents suspected of causing MWL, but no specific antigens were identified as the cause of the cases. Of the remaining workers who participated in a cross-sectional respiratory morbidity survey at the farm, approximately 20% of the more heavily exposed workers reported occasionally experiencing symptoms consistent with MWL. Approximately 10% of the workers had below normal spirometry test results, but interpretation was hampered by the diverse racial makeup of the population and lack of an adequate comparison group. No abnormalities consistent with either acute or chronic MWL were seen on the chest radiographs. Serologic tests demonstrated that almost all workers had been exposed to antigens capable of causing MWL, but the results were not associated with health status. At the time of the cross-sectional survey, no workers were found to be suffering acute respiratory problems consistent with MWL.


Upper extremity symptoms in supermarket workers. Upper extremity symptoms in supermarket workers, particularly those who performed checking using laser scanners, were evaluated using a questionnaire administered by trained interviewers to 124 supermarket workers. Summary indices of exposure (short-term and long-term) as well as indices of past personal illnesses and personal activities were employed. Outcome data were summarized by four composite symptom indices. Chi square and logistic regression analyses demonstrated that hours of checking work in the preceding 2 weeks and cumulative weighted years of work were associated with adverse upper extremity symptoms. Symptoms involved both the proximal and distal parts of the upper extremities.