The effect of early hypoxy upon the development of rats and mice. 1. Preimplantation effects. The effect of temporary hypoxy obtained by uterine vascular clamping during the preimplantation developmental period, was controlled on rats and mice (on the last day of preimplantation development). The following main effects were detected: retarded preimplantation development in rats; increased number of pathologically modified embryos and retarded oviduct-uterus migration in both species. The changes of the uterine wall due to vascular clamping disappear two days after the experimental intervention. The existence of an experimental hypoxic blastopathy is attested (at least its early, preimplantation aspect).


The effects of thymomodulin and thymolymphotropin on the stress response of neuroendocrine system by gamma-irradiated Wistar rat. Thymomodulin and Thymolymphotropin, biologically active thymus derivative peptides exert recovery effects on the functionality of some membrane bound, mitochondrial and lysosomal enzymes (monoamine oxidase, ATPase, phosphatases, cytochrome oxidase, succinate oxidase) affected by gamma-irradiation. These drugs exert antistress effect by re-establishing the function of hypothalamus-pituitary-adrenal axis and that of lymphoid organs.


Intragastric infection of conventional and germfree mice with Giardia lamblia. The effects of experimental infection with Giardia lamblia were studied in 30-day old conventional and germfree CFW mice (7 animals in each group) of both sexes. Cysts were observed in the feces of both groups 6 to 7 days after intragastric infection of each animal with about 2.5 x 10(5) G. lamblia trophozoites. Fecal cyst level was statistically higher in germfree mice (about 10(5) cysts/g feces) when compared with the conventional group (about 10(4) cysts/g feces). The peak of infection in the conventional group apparently occurred on the 10th day after infection as indicated by an increase of fecal weight and by histopathological examination. Intense infiltration of the lamina propria and high reactional hyperplasia of the lymphoid component were observed in the conventional group. There was no infiltration or hyperplasia in germfree infected mice and fecal weight was relatively constant throughout the experiment. These results suggest that, as is the case for other intestinal pathogenic protozoa, the intestinal microflora is indispensable for the expression of the pathogenicity but not for the multiplication of G. lamblia.


Hepatic morphology changes after hepatic artery ligation in extrahepatic cholestasis. The present study was performed to correlate changes in hepatic morphology with hepatic artery ligation (HAL) in the presence of extrahepatic cholestasis (EHC). The study was conducted on 36 male Wistar rats weighing 350 to 400 g, divided at random into four groups of 9 animals each: group I, sham operation (control); group II, HAL; group III, bile duct ligation (BDL); group IV, HAL plus BDL. After seven days, liver fragments were obtained for morphological study. The relative volume of the bile ducts was I > II < III and III > IV (P < 0.05). These data indicate that arterial irrigation is important for the nutrition of the biliary tree. Seventy-six percent of the animals submitted to HAL plus BDL showed hepatic necrosis. In general, the liver probably becomes more dependent on HA flow in the presence of EHC.


A freeze-etch study of the central myelin. The intramembranous organization of the interparanodal myelin lamellae in CNS was investigated by means of the freeze-etching technique. The density of the IMPs is about equal on both P- and E-fracture faces of every myelin sheath but varies between the myelin sheaths. The morphology of the myelin tight junctions was also described. The nature of the IMPs and the functional significance of their mode of distribution were discussed.


Comparison of counterimmunoelectrophoresis, latex agglutination and bacterial culture for the diagnosis of bacterial meningitis using urine, serum and cerebrospinal fluid samples. 1. Urine, serum and cerebrospinal fluid (CSF) samples from 98 children with clinical and laboratory diagnosis of bacterial meningitis were evaluated by counterimmunoelectrophoresis (CIE) and latex agglutination (LA) methods and the results compared to those obtained with bacterial cultures of the CSF samples. Antigens of Neisseria meningitidis groups A, B and C, Haemophilus influenzae type b and Streptococcus pneumoniae were determined by both immunological methods. Serum was diluted (1:4) with 0.1 M sodium EDTA, pH 7.5, and held at 80 degrees C for 10 min before assay. Polysaccharide of the urine samples was precipitated overnight using an equal volume of 1:1 ethanol-acetone followed by a heat-treatment with 0.1 M sodium EDTA, pH 7.5, at 80 degrees C for 10 min.. 2. Sensitivity indices were 0.772 (CSF), 0.595 (urine) and 0.317 (serum) for CIE, and 0.914 (CSF), 0.930 (urine) and 0.683 (serum) for LA in relation to the 42 positive bacterial cultures. 3. The optimal diagnostic efficacy reached 52% for CIE and 72% for LA when urine was concentrated 20- to 30-fold. 4. These data show that immunological tests of urine samples were more effective than bacterial culture for diagnosing bacterial meningitis and may be indicated when negative results are obtained for CSF tested by bacterial culture and immunoassay methods.


Effect of medium- and long-chain triglycerides on human neutrophil migration. There is some controversy concerning the effect of intravenous long-chain triglyceride (LCT) emulsions on the phagocytic system and little is known about the effect of medium-chain triglyceride (MCT)-containing emulsions. We evaluated the chemotaxis and random migration of human neutrophils from 18 healthy adults after preincubation with the following fat emulsions: LCT, MCT and a mixture of 50% MCT and 50% LCT (MCT/LCT). Leukocyte-rich plasma (4 x 10(6) cells/ml) was diluted 4:1 (v/v) with commercial fat emulsions (LCT, MCT, or MCT/LCT, 1:1) or saline and tumbled at 20 cycles/min for 30 min at 37 degrees C. The final composition of the emulsion was 20 mg/ml fat, 0.24% egg yolk lecithin, and 0.5% glycerol and the dispersion was made isotonic by adding NaCl. In a second set of experiments, the LCT and MCT concentrations were adjusted to be equimolar. Leukocyte viability was > or = 95% after exposure to the treatment with fat emulsions. For emulsions with the same weight of each fat, random migration and chemotaxis of neutrophils were unaffected by the LCT emulsion but there was a significant decrease in both chemotaxis and random migration in MCT-(79 and 74%) or MCT/LCT-treated (60 and 56%) neutrophils. Similar results were obtained when LCT and MCT were equimolar. These results demonstrate an inhibitory effect of MCT on two human neutrophil functions which may be dose dependent.


Preliminary report on the application of the coagglutination test for rapid diagnosis of cholera in the upper Solimöes River area in the Brazilian Amazon region. The conventional diagnosis of cholera depends on complex bacteriological procedures. Coagglutination is a simple, rapid, inexpensive and efficient technique for the presumptive diagnosis of cholera. Of 840 fecal samples from suspected cases of cholera examined at Tabatinga (State of Amazonas, Brazil) 31 (3.6%) were confirmed by culture and 29 of them were also positive by the coagglutination test performed directly on the fecal enrichment broth (alkaline peptone water). About 90% of the positive coagglutination results were obtained after 5-h incubation at 37 degrees C and the sensitivity, specificity and accuracy of the method were 93.5%, 99% and 98.8%, respectively. Relative to the culture results, coagglutination yielded two false-negative and eight false-positive results. The coagglutination test for cholera can provide a rapid and reliable tool for epidemiological studies and for the planning of more effective measures against cholera.


Comparative pharmacokinetics of different oral nifedipine preparations in healthy Brazilian volunteers. 1. The pharmacokinetics of different pharmaceutical preparations of oral nifedipine--Adalat (capsule), Oxcord and Cardalin (tablets)--was determined after administration of single oral doses of 10 mg to nine healthy young Brazilian volunteers (7 men). 2. There were no significant changes in heart rate or systolic and diastolic blood pressure measured in the sitting position within 8 h of nifedipine administration to these normotensive volunteers. No side effects were reported by the volunteers or observed by the attending physicians during the study. 3. No significant differences were observed among the three preparations in relation to the following pharmacokinetic parameters obtained from the plasma concentration-time curves: area under the curve (AUC), slope (beta) and half-life (T1/2) of the elimination phase, volume of distribution (Vd/F) and total body clearance (CL/F), both expressed as functions of the oral bioavailability (F) of nifedipine. 4. The peak plasma concentration of nifedipine (Cmax) and the time to reach Cmax (Tmax) were not different for the two tablet preparations. However, Cmax was significantly higher, and Tmax was significantly shorter for the capsule. These data indicate that the capsule and the tablet preparations are not bioequivalent.


Effect of anesthesia on the propagation of cortical spreading depression in rats. The effect of ip anesthesia with urethane+chloralose (U+C, 1.0 g/kg + 40.0 mg/kg) or thionembutal (TH, 40.0 mg/kg) on the velocity of propagation of cortical spreading depression was studied in adult Wistar rats. We also describe a technique for measuring the spreading depression propagation rate based on implanting insulated silver wires into the right parietal region, whose silver chloride tips are in contact with the cortical surface. The propagation rate was measured in the same animals during (mean +/- SEM, mm/min: 2.69 +/- 0.17 for U+C, N = 9, and 2.60 +/- 0.09 for TH, N = 7) and after (3.23 +/- 0.13 for U+C and 3.84 +/- 0.18 for TH) anesthesia. The rate was significantly higher for rats in the awake condition. The second administration of anesthesia to the same rats decreased the velocity of spreading depression again (2.01 +/- 0.38 for U+C, N = 7, and 2.96 +/- 0.18 for TH, N = 7). The effects of TH and U+C on the rate of propagation were reversed 24 and 48 hours after anesthesia, respectively. We conclude that the technique proposed is adequate for measuring the velocity of spreading depression in unanesthetized rats and that U+C and TH reduce the propagation velocity.


Mechanisms underlying the genesis of post-rest contractions in cardiac muscle. 1. Post-rest potentiation reflects basic cellular mechanisms that control cardiac muscle contraction. Transmembrane calcium influx, the Na+/Ca2+ exchange and the function of intracellular stores that liberate activator calcium upon activation are some of the mechanisms involved. 2. Three aspects of the post-rest potentiated phenomenon were investigated, using isometrically contracting rat papillary muscles and toad ventricle strips: dependence on 1) inotropic state of steady-state contractions, 2) pause duration and Na+/Ca2+ exchange activity, and 3) the extent of transmembrane calcium influx. 3. The results suggest that the potentiated state of post-rest contractions increases linearly with the inotropic state of preceding steady-state control contractions. As the pause duration increases from 5 to 240 s, the post-rest potentiation also increases, attaining a steady level after 30-s pauses. During the pause, the Na+/Ca2+ exchange mechanism operates at an activity level that can alter the amount of activator calcium used for post-rest contractions. Interventions that increase intracellular Na+, such as the increase of the stimulation rate from 0.5 to 1 Hz or the increase of extracellular NaCl concentration to 160 mM, reduce the Na+/Ca2+ activity, increasing intracellular Ca2+ and post-rest potentiation. The decrease of transmembrane Ca2+ influx during activation increases the relative participation of the sarcoplasmic reticulum in the development of post-rest potentiation. Reduction of extracellular Ca2+ concentration from 1.25 mM to 0.25 mM or the use of 1 microM verapamil and 2 mM manganese increases the relative potentiation of post-rest contractions. This is particularly observed in toad ventricle strips since post-rest potentiation, which does not develop under control conditions, is observed after verapamil or manganese treatment. The results suggest that the excitation-contraction coupling process operating for post-rest contraction activation, unlike that operating for steady-state contraction activation, depends more on the calcium stored at intracellular sites than on transmembrane calcium influx.


Reduced lipogenesis in rats fed a high-protein, carbohydrate-free diet: participation of liver and four adipose depots. 1. Rates of in vivo fatty acid (FA) synthesis were assessed with 3H2O in carcass, liver, intestine, muscle and four adipose depots from rats fed a high-protein, carbohydrate-free diet (70% casein, 8% fat, w/w) or a balanced diet (66% carbohydrate, 17% casein, 8% fat) for 25-30 days. 2. Rats adapted to the high protein (HP) diet showed a marked reduction of total FA synthesis from all carbon sources, which was due to a decreased synthesis of triacylglycerols. Rates of phospholipid-fatty acid synthesis in both carcass and liver were not affected by the diet. Rates of triacylglycerol-fatty acid (TAG-FA) synthesis were markedly reduced in adipose tissue from four different sites: epididymal (79%), retroperitoneal (78%), subcutaneous (65%) and intermuscular (82%). 3. In rats fed the balanced control diet, TAG-FA synthesis in adipose tissue accounted for about 75% of synthesis in whole carcass, whereas it was reduced to 36% in rats under the HP regimen. 4. Although hepatic lipogenesis was also reduced in HP-fed rats, the contribution of the liver to total TAG-FA synthesis was approximately the same in HP (24%) and control (20%) rats, whereas the contribution of adipose tissue was only 26% in HP-fed animals compared to 57% in controls. 5. Force-feeding fed rats with components of their own diets resulted in a significant (100%) increase of liver TAG-FA synthesis in animals fed the control diet, but did not significantly affect liver lipogenesis in HP rats.


The pho-2A mutant of Neurospora crassa which is deficient in Pi-repressible alkaline phosphatase (EC 3.1.3.1) is also defective in Pi-repressible acid phosphatase (EC 3.1.3.2). 1. The mycelial Pi-repressible acid phosphatase presented p-nitrophenylphosphatase activity with negative cooperativity and Michaelian behavior when synthesized by the wild-type and pho-2A mutant strains of Neurospora crassa, respectively. 2. The major acid phosphatase present in cell extracts of the pho-2A mutant of N. crassa grown in low Pi medium is more thermolabile (t1/2 = 4 min at 54 degrees C, pH 5.4) than that of the wild strain (stable for at least 80 min at 54 degrees C, pH 5.4). 3. The pho-2A mutant of N. crassa secreted a more thermolabile acid phosphatase (t1/2 = 30 min at 50 degrees C, pH 5.4) than the wild strain (t1/2 of at least 80 min at 50 degrees C, pH 5.4). 4. The pho-2A mutant of N. crassa synthesized a more thermolabile acid phosphatase (t1/2 = 37 min at 54 degrees C, pH 5.4) than the wild strain in high Pi medium (t1/2 = 14 min at 54 degrees C, pH 5.4). 5. The pleiotropic nature of the pho-2 locus and its possible involvement in the mechanism of phosphatase secretion by N. crassa are proposed.


Do impaired glucose tolerance and diabetes mellitus interfere with the interpretation of the growth hormone response to the oral glucose tolerance test? 1. The ability of glucose to suppress growth hormone (GH) secretion is well known and the glucose test is widely used for the diagnosis of acromegaly. However, when suspected acromegaly is associated with diabetes mellitus (DM) or impaired glucose tolerance (IGT) the interpretation of the GH response to the oral glucose tolerance test (OGTT) may be difficult. Recently, Hattori et al. (Journal of Clinical Endocrinology and Metabolism, 70: 771-778, 1990), using a highly sensitive (1.5 ng/l) polyclonal antibody-based immunoenzymometric assay, found no differences in the GH response to glucose load among control, IGT and DM patients. 2. We employed a less sensitive (100 ng/l) but monoclonal antibody-based immunoenzymometric assay to measure the serum GH levels of 19 normal subjects, 11 patients with DM and 11 patients with IGT to determine the effect of glucose intolerance on the GH response to the OGTT. 3. Complete suppression of GH (< 0.1 microgram/l) was achieved in 73% of the controls with a mean nadir of 0.17 +/- 0.16 microgram/l (range, < 0.1-0.6 microgram/l). GH was completely suppressed in 82% of the diabetics with a mean nadir of 0.58 +/- 1.21 micrograms/l (range, < 0.1-4.0 micrograms/l). However, complete suppression occurred in only 27% of the IGT patients with a nadir of 1.09 +/- 2.08 micrograms/l (range, < 0.1-7.0 micrograms/l), which was statistically higher than observed for controls and diabetics. 4. We conclude that plasma GH levels after glucose loading of IGT patients should be interpreted with caution because an abnormal response can be detected when some sensitive immunometric assays are employed.


Effect of cutaneous cell-mediated immune response to rIFN gamma on Mycobacterium leprae viability in the lesions of lepromatous leprosy. 1. Studies were carried out to determine the effect of intra-dermal injections of recombinant human interferon-gamma (rIFN gamma) on the viability of Mycobacterium leprae. Twenty-three untreated and 4 treated multibacillary patients, 12 with lepromatous leprosy (LL) and 15 with borderline lepromatous leprosy (BL), were selected for intradermal administration of rIFN gamma or PPD. Treated patients (LL and BL) had received multi-drug therapy according to the recommendations of the World Health Organization, i.e., rifampicin (600 mg/month), dapsone (100 mg/day) and clofazimine (50 mg/day and 300 mg/month) for 1-4 months. Three daily doses of 10 or 30 micrograms rIFN gamma induced local induration and mononuclear leucocyte accumulation. Bacteria isolated from a punch biopsy of the site 21 days after lymphokine administration were injected into mouse foot pads and evaluated for viability and growth. 2. The local response to rIFN gamma (specific activity 2 x 10(7) units/mg protein) induced a delay or total inhibition of M. leprae growth in the mouse foot pad, indicating that the cellular response to the antigen reduced local M. leprae viability. The extent of reduction in viability depended on the dose of rIFN gamma injected and the extent of local induration induced by the lymphokine. With a vigorous cell-mediated immune response growth was fully inhibited. 3. A similar but less extensive effect on M. leprae viability was observed in response to the local injection of 5 units in 0.1 ml of purified protein derivative of tuberculin (PPD).


Chemical and biological properties of endotoxin from Leptospira interrogans serovars canicola and icterohaemorrhagiae. 1. Endotoxin-like activity was extracted with phenol-chloroform-petroleum either (PCP) from Leptospira interrogans serovars icterohaemorrhagiae and canicola. Chemical analysis of leptospiral cells obtained from the PCP extract indicated the following distribution of lipopolysaccharide (LPS), protein and polysaccharide in mg/ml: 3.0, 4.5 and 1.0 for icterohaemorrhagiae and 3.3, 5.6 and 1.5 for canicola. 2. The preparations presented several biological activities: positive Limulus test (1.0 pg/ml) for icterohaemorrhagiae and canicola PCP extract and 0.5 pg/ml for E. coli O111:B4 LPS, lethality for chicken embryos (LD50 45, 25 and 1.0) for icterohaemorrhagiae, canicola and E. coli O111:B4 LPS, pyrogenicity in rabbits with an average increase in rectal temperature of 0.6 degrees C, 0.9 degrees C and 2.2 degrees C for canicola, icterohaemorrhagiae and E. coli O111:B4 LPS, reacted with complement inhibiting the lysis of sheep red blood cells, 62%, 75% and 90% for 2.0 micrograms/ml of icterohaemorrhagiae, canicola PCP extract and E. coli O111:B4 LPS. The PCP extract showed no cytotoxicity on chicken embryo fibroblasts and epithelial cells. 3. These results demonstrate that Leptospira endotoxin activity is similar to E. coli O111:B4 lipopolysaccharide.


Mesangial overload in experimental membranous nephropathy. 1. The distribution and amount of ferritin in the glomeruli following intravenous injection of radiolabeled ferritin (125I-ferritin) was studied in 25 normal rats and in 25 rats with membranous nephropathy. The animals used were male Sprague-Dawley rats weighing 180-200 g at the beginning of the experiment. Membranous nephropathy was induced by repeated iv injections of 1.0 mg cationic bovine serum albumin during 28 days. 2. At the end of the experiment the animals received 125I-ferritin iv and were sacrificed 2, 6, 12, 24 and 36 h later, and the glomeruli were isolated. 3. Mean (+/- SEM) levels of 125I-ferritin in the glomeruli reported as cpm/mg protein in rats injected with cationic bovine serum albumin were: 731.8 +/- 155.6 after 2 h, 946.4 +/- 268.2 after 6 h, 565.4 +/- 143.5 after 12 h, 251.8 +/- 26.5 after 24 h, and 202 +/- 29.1 after 36 h. Mean (+/- SEM) 125I-ferritin in normal rats were: 2 h: 256.2 +/- 44.6; 6 h: 214.2 +/- 8.78; 12 h: 198.2 +/- 32.2; 24 h: 51.5 +/- 3.57; 36 h: 40.6 +/- 5.48. 125I-ferritin levels in the glomeruli isolated from rats injected with cationic bovine serum albumin were significantly higher than in control rats at 2, 6, 24 and 36 h. 4. The distribution of ferritin in the glomeruli was studied by a direct immunofluorescence technique. Normal and nephrotic rats showed ferritin in the glomerular mesangium only, with similar pattern and intensity. 5. These data show that rats with membranous glomerulonephritis induced by cationic bovine serum albumin presented an increased macromolecule uptake by the glomerular mesangium. However, the mechanism underlying this mesangial overloading is still unknown.


The acute phase of experimental infection with Trypanosoma cruzi is more severe in mice monoassociated with strict anaerobic bacteria. 1. The influence of some components of the normal human intestinal flora on the acute phase of experimental infection with strain CL of Trypanosoma cruzi was studied in 30-day-old germ-free or gnotobiotic CFW (LOB) mice monoassociated with Bacteroides fragilis, Peptostreptococcus sp or Clostridium sp by intragastric inoculation of 10(6) bacteria 10 days before the intraperitoneal infection with 5 x 10(3) trypomastigotes/g body weight. 2. Significantly earlier parasitemia peak and mortality were observed in Bacteroides fragilis- and Clostridium-associated mice (16.75 +/- 0.96 and 15.00 +/- 1.15 days, respectively) when compared with germfree animals (18.83 +/- 1.17 days). More precocious mortality (10.40 +/- 2.06 days) and, curiously, much lower blood parasitemia were observed in Peptostreptococcus-associated mice than in other gnotobiotic mice. 3. The extent of cardiac tissue parasitism decreased in the following order: germfree, B. fragilis-associated, Clostridium-associated, and Peptostreptococcus-associated animals. The levels of inflammatory reaction decreased in the following order: germfree, Peptostreptococcus-associated, Clostridium-associated, and B. fragilis-associated mice. 4. These results show that the acute phase of experimental infection with T. cruzi was more severe in mice associated with strict anaerobic bacteria when compared with germfree animals. This suggests that a normal intestinal flora may be another factor, in addition to nutritional and genetic factors, responsible for the different susceptibility of organisms of the same species infected with T. cruzi.


Type I collagen synthesis by rats fed beans (Phaseolus vulgaris, L.) as the protein source. Type I collagen synthesis was studied in 12 female Wistar rats weighing 60 +/- 5 g at the beginning of the experiment. The animals were fasted for 24 h and then injected ip with 10 microCi uniformly labeled [14C]-glycine. Two hours later, groups of 4 animals each were fed balanced diets (10.7 +/- 0.4% protein) containing raw beans (Phaseolus vulgaris, L.), cooked beans or casein (control) as the single protein source, ad libitum. The animals were killed after 4 days and collagen was extracted from the tail and calcaneal tendons. Food intake and weight gain of rats fed raw beans (22 g, 0 g) were considerably less than rats fed cooked beans (38 g, 9 g) and casein (44 g, 22 g). Collagen was quantitated on the basis of hydroxyproline and corresponded to 0.1, 0.2 and 0.2% rat body weight, with specific radioactivity of 1.2, 1.6 and 4.2 microCi/g, for the rats fed raw beans, cooked beans and casein, respectively. The results indicate that rats fed either bean protein synthesized less collagen than those fed casein (P < 0.05). Although the food intake and extractable collagen of rats fed cooked beans were similar to those of casein-fed rats, weight gain and collagen specific radioactivity were less.


Comparison of indirect immunofluorescence with agar gel immunodiffusion for the diagnosis of bluetongue virus infection. 1. Sera from 190 cows and from 72 sheep were examined to compare the results obtained with the agar gel immunodiffusion (AGID) and indirect immunofluorescence (IIF) tests for the diagnosis of bluetongue (BT) disease. 2. In the AGID test, 96 of 190 (50.5%) cattle serum samples and 38 of 72 (52.7%) sheep serum samples were positive, for a total of 134 out of 262 (51.1%) sera. In the IIF test, 98 of 190 (51.6%) cattle serum samples and 39 of 72 (54.2%) sheep serum samples were positive, for a total of 137 out of 262 (52.3%) sera. 3. The fluorescence of the IIF test presented a granular cytoplasmic aspect, which in some cells was observed only on the cell membranes. 4. Statistical analysis of the data showed close agreement between the two techniques, regardless of the kind of sera examined. The IIF test showed high sensitivity (93.8% and 92.1%), specificity (91.4% and 88.2%) and positive (91.8% and 89.7%) and negative (93.48% and 90.9%) predictive values for cattle serum and sheep serum, respectively. 5. The results obtained with IIF were comparable to those obtained with the AGID test, indicating that both techniques can be used routinely in epidemiologic studies of BT. However, the IIF offers the additional advantages that it can be used for antibody quantification and for the detection of viral antigens in BT-infected cell lines.


Differential modulatory effect of IL-5 on MHC class II expression by macrophages and B cells. The present study examines the effect of interleukin 5 on the expression of class II major histocompatibility complex (MHC) in macrophages and B cells. Treatment of splenic adherent cells, a population that contains mostly macrophages and dendritic cells, with 100 U/ml of recombinant interleukin 5 resulted in a decrease of 10 to 30% in cell surface MHC class II expression by macrophages. The treatment had no effect on class I MHC expression, or on the mRNA synthesis as evaluated by tritiated-uridine incorporation. The same treatment of B cells resulted in the delineation of two groups with regard to class II MHC expression in a previously more homogeneous population. One group had an increase in surface Ia expression and the other had a decrease in the expression of this molecule. These results suggest that interleukin 5 has a role in MHC class II regulation.


Chemical lesion of the circumventricular organs with monosodium glutamate reduces the blood pressure of spontaneously hypertensive but not of one kidney-one clip hypertensive rats. Subcutaneous injection of monosodium glutamate (MSG) on days 1, 5 and 9 of the experiment (5 g/kg per day) significantly reduced the blood pressure of a group of 10 spontaneously hypertensive rats (SHR) measured 7 and 14 days after treatment (200 +/- 7 mmHg vs 172 +/- 8 mmHg or 185 +/- 3 mmHg, respectively), without affecting that of 11 age-matched Wistar Kyoto (WKY) rats (127 +/- 7 mmHg vs 123 +/- 5 mmHg and 119 +/- 5 mmHg, respectively). Using autoradiographic methods and 125I-Sar1-angiotensin II, receptor binding was shown to be higher in the subfornical organ (SFO) of SHR (332 +/- 31 fmol/mg protein) when compared to WKY rats (240 +/- 30 fmol/mg protein) and similar (222 +/- 21 vs 170 +/- 14 fmol/mg protein) in the paraventricular nucleus (PVN). Binding to angiotensin-converting enzyme (ACE) was evaluated using the ACE inhibitor 125I-351A as ligand. Binding to ACE was lower in SHR in the PVN and the globus pallidus (GP) of SHR when compared to WKY rats (PVN: 111 +/- 9 vs 172 +/- 13 and GP: 163 +/- 2 vs 213 +/- 7 fmol/mg protein) and similar in the SFO, choroid plexus (ChP) and caudate nucleus (CD) of both strains (SFO: 779 +/- 107 vs 805 +/- 169; ChP: 2,780 +/- 210 vs 3,140 +/- 360 and CD: 461 +/- 42 vs 424 +/- 18 fmol/mg protein). No changes in angiotensin II (Ang II) receptor number or binding to ACE were detected in these brain areas after MSG treatment of SHR or WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Papaverine inhibits human platelet aggregation induced by ADP. 1. The in vitro and ex vivo effect of therapeutic levels of papaverine on human platelet aggregation induced by 3-5 microM adenosine-5'-diphosphate (ADP) was evaluated in platelet-rich plasma (PRP) by photometric and impedance aggregometry, and in whole blood by impedance aggregometry. 2. Platelet aggregation induced by 3-5 microM ADP in whole blood was significantly inhibited by 5.32 and 10.64 microM papaverine in vitro. This effect was also observed in PRP enriched with erythrocytes but not in PRP alone or enriched with leukocytes. 3. Papaverine (5.32 microM) significantly enhanced the antiplatelet activity of adenosine (0.75 microM) in human whole blood, an effect that was not observed in PRP. 4. A single oral dose of 100 mg papaverine hydrochloride, given to eight healthy human volunteers 1 h before the platelet aggregation evaluation, significantly inhibited the platelet aggregation induced by 3-5 microM ADP in whole blood. This effect was not observed in PRP. 5. Oral administration of the same dose at 8-h intervals (10 times) to seven additional healthy human volunteers led to a significant negative correlation (r = -0.55, P < 0.01) between the slope of platelet aggregation in whole blood and plasma papaverine levels (0.12-0.75 microM). 6. Papaverine and adenosine, alone or together, had no in vitro effect on whole blood platelet aggregation of male Wistar rats measured by impedance aggregometry. 7. These results suggest that papaverine inhibits human platelet aggregation in whole blood by an interaction with red blood cells.


Effect of exercise during pregnancy and dam age on maternal blood chemistry and fetal growth. In order to determine the effect of maternal exercise on maternal nutritional status and fetal growth, young (Y = 45-50 days old) Wistar rats were divided into 4 groups of 5 to 8 animals: control pregnant (CP), control non-pregnant (CNP), exercise-trained (swimming 1 h/day, 5 days/week, for 19 days) pregnant (TP) and exercise-trained non-pregnant (TNP). Four equivalent groups of adult rats (A = 90-100 days old) were also formed. Serum glucose, total protein, albumin, hematocrit and liver glycogen were determined in female rats and pups. There were no statistical differences in serum glucose, total protein and albumin levels, litter size or birth weight among exercise-trained animals, controls and their respective pups. Hematocrit was significantly lower in pups of exercise-trained young rats than in all other groups (YCP = 38.6 +/- 3.0; YTP = 32.6 +/- 2.1; ACP = 39.0 +/- 2.5; ATP = 39.2 +/- 2.9%). Liver glycogen levels were lower in pregnant than in non-pregnant rats but similar in exercise-trained and control rats of the same age and physiological status (YCNP = 4.1 +/- 0.2; YCP = 2.7 +/- 0.9; YTNP = 4.9 +/- 0.8; YTP = 2.7 +/- 0.4; ACNP = 6.1 +/- 0.6; ACP = 3.1 +/- 0.8; ATNP = 6.6 +/- 0.8; ATP = 2.2 +/- 0.9 mg/100 mg). We conclude that pups of adult female rats are spared from the effects of this kind of exercise training during pregnancy. On the other hand, it appears that maternal adaptations to exercise training in young rats are able to preserve only some aspects of pup metabolism.


Spectrophotometric determination of total proteins in blood plasma with p-benzoquinone. 1. In the present study we have documented the use of the reagent, p-benzoquinone (PBQ) for the spectrophotometric determination of total proteins in blood plasma. 2. Since the products of reaction are stable for several hours at room temperature after the 20-min boiling step, the time at which absorbance is measured is not a critical factor. 3. Common anticoagulants such as EDTA, citrate, or heparin do not interfere with the PBQ method at concentrations used in clinical laboratories. 4. The products of the reaction between PBQ and either plasma (specific absorbance 2.33 x 10(-3) +/- 0.20 x 10(-3) micrograms cm-2) or purified proteins (specific absorbance 2.61 x 10(-3) +/- 0.31 x 10(-3) micrograms cm-2) show an absorption band at 350 nm, which follows Beer's law, and therefore can be used for analytical purposes. 5. The PBQ method has a lower limit of detection (4 micrograms/ml) than that of the biuret method (45 micrograms/ml) for a final reaction mixture of 5.0 and 4.2 ml, respectively.


Interactions between vasodilator drugs and human hemoglobin. 1. The in vitro effect of the vasodilators papaverine, dipyridamole, nifedipine, prenylamine and glyceryl di-, tri- and tetranitrate on the oxygen saturation curve of human hemoglobin (Hb) was evaluated. The Hb dissociation curve was measured spectrophotometrically both for freshly obtained heparinized blood and for purified Hb A after incubation with the drugs. 2. For both purified Hb and whole blood samples, incubation with papaverine, dipyridamole and nifedipine modified P50 (PO2 for half saturation of the Hb/oxygen sites) at pH 7.4: 30.9 mmHg for 0.72 mM papaverine vs 23.9 mmHg for control; 23.9 mmHg for 1.43 mM dipyridamole vs 20.8 mmHg for control; 1.09 mmHg for 2.73 mM nifedipine vs 1.14 mmHg for control stripped Hb. The effects of the three vasodilators on Hb were correlated with pH, methemoglobin formation, temperature and incubation time. 3. P50 values were determined for Hb of the blood of angina patients treated with one of the vasodilators, and blood 2,3-diphosphoglycerate (2,3-DPG) levels were also measured. In contrast to the in vitro data, neither P50 nor 2,3-DPG levels were significantly modified in the blood of patients treated with one of the vasodilators. 4. These in vitro studies demonstrated that the vasodilators papaverine and dipyridamole decrease, and nifedipine increases the oxygen affinity of Hb in red blood cells or as a purified hemoglobin.


An allergenic 2S storage protein from Ricinus communis seeds which is a part of the 2S albumin precursor predicted by c-DNA data. 1. A 1.9S albumin having allergenic activity and denoted Ric c III was isolated from an alcohol extract of defatted Ricinus communis seeds, CB-1A, as a homogeneous protein by ion-exchange chromatography on SP-Sephadex, gel filtration on Sephadex G-75 and preparative polyacrylamide gel electrophoresis (6 mg Ric c III/g CB-1A). 2. The protein contained approximately 98 amino acid residues distributed in 2 chains of 67 and 34 residues, a molecular weight of 11,239 based on amino acid composition and pI = 4.9 Ric c III can be aligned, on the basis of amino acid composition and partial amino acid sequence data, with residues 18 to 50 (51) and 66 to 130 of the 2S albumin precursor predicted by the cDNA data of S.D. Irwin, J.N. Keen, J.B.C. Findlay and J.M. Lord (Molecular and General Genetics, 222: 400-408, 1990). 3. The present data identify Ric c III as the second allergenic 2S storage albumin coded by this DNA.


Comparison of the Lowry and Coomassie Blue methods for the determination of protein concentration. 1. The Lowry and Coomassie Blue methods were compared for precision when applied to Schistosoma mansoni proteins, using bovine serum albumin (BSA) as standard. 2. The absorbance of five different concentrations was measured and the experiments were run in parallel to reduce bias in the comparison. Thus, for a given technique, all photometric data were obtained from reaction mixtures (BSA and test solutions) prepared and analyzed as simultaneously as possible. 3. To interpret the results, polynomial functions of different degrees--up to the third--were calculated to fit the absorbance values to the respective protein concentrations of BSA or worm protein present in the reaction mixtures, and the standard errors of all slopes were also calculated. 4. The protein concentration of worm extracts was calculated by two methods: 1) the ratio of the first-degree slopes of the polynomials applied to absorbance = f(x), with x being either mg BSA or ml worm extract, and 2) the utilization of the BSA function parameters to convert any worm absorbance value to protein concentration. 5. The results obtained with the slope ratio method were variable. However, the function method seemed to be reliable, especially when applied to Coomassie Blue data. When the results were derived from the BSA cubic function the concentration of soluble worm protein was calculated with a coefficient of variation of 1.20%.


Acute effect of the somatostatin analogue SMS-201995 on plasma glucose and triglycerides in insulin-dependent diabetic patients. 1. The effect of the long-acting somatostatin analogue SMS-201995 on diabetes control was assessed in 6 insulin-dependent diabetic patients (3 men and 3 women aged 19-38 years). 2. Plasma glucose and triglyceride profiles were obtained on 4 consecutive days, from 8:00 a.m. to 2:00 p.m. On the first 2 days the patients received their usual dose of insulin and ate at 8:00 a.m. and at noon. On the third and fourth days they received 1/3 of their usual insulin dose together with 100 micrograms SMS-201995 injected subcutaneously. 3. Postprandial glucose and triglyceride increases were blunted during the 360 min of observation on both days after SMS-201995 administration. The areas under the glucose-time plots fell from 23.72 +/- 12.29 (mean +/- SD) to 7.98 +/- 14.26 (P < 0.05) and the areas under the triglyceride-time plots from 10.51 +/- 9.01 to -3.15 +/- 4.30 g.min.dl-1 (P < 0.01). 4. No adverse reactions were observed after SMS-201995 administration for 2 days. 5. We conclude that administration of the somatostatin analogue SMS-201995 may be beneficial for insulin-dependent diabetic patients.


Antibodies to new cytoplasmic autoantigens: anti-JA, a potential marker for disease activity in systemic lupus erythematosus. 1. We describe new autoantibodies which recognize two cytoplasmic proteins of 30 and 26 kDa. They were detected by Western blot analysis in the sera of 6 of 79 randomly selected systemic lupus erythematosus (SLE) patients and are denoted anti-JA antibodies. This antibody specificity is different from the previously described lupus autoantibodies, anti-P and anti-S10. 2. The targeted autoantigens are trypsin sensitive, and resistant to RNase and DNase treatment. The binding to the antigens was not modified when reticulocyte ribosomes were prepared with protease inhibitors indicating that these are primary antigens and not degradation products. Several lines of evidence suggest that these proteins are almost certainly part of the ribosome. 3. Anti-JA reactivity was not observed in the sera from 60 patients with other autoimmune diseases or from normal individuals. In contrast, 55% of lupus sera selected for a high titer of anti-dsDNA (double stranded DNA) and LE cells were also anti-JA positive. 4. Anti-JA antibodies may be useful as a specific serological marker for disease activity in SLE. The strong association with anti-dsDNA antibodies and LE cell in the sera of SLE patients requires further study.


Reduced anti-Mycobacterium tuberculosis antibody response in tuberculosis patients with acquired immunodeficiency syndrome. 1. When the sera of patients with tuberculosis were tested for anti-Mycobacterium tuberculosis IgG using an indirect ELISA, the test was positive for 94.1% of the samples from patients not having AIDS (N = 51), but for only 37.5% of the samples from patients with AIDS (N = 16). 2. False-positive results were obtained for 7.3% of patients not infected with HIV (N = 96) and for 4.7% of patients infected with HIV (N = 64). 3. In most serum samples obtained from patients with tuberculosis and AIDS after the beginning of specific treatment there was a reduction of the ELISA absorbance at 490 nm with time. 4. These results indicate that serological tests for the detection of anti-M. tuberculosis IgG in patients with AIDS are of limited value for the diagnosis of tuberculosis, most likely as a consequence of the underlying immune defect of the patients.


Effects of thermostable Escherichia coli enterotoxin peptide on the isolated rat kidney. In order to compare the function of sodium transport between the intestine and renal tubule, we studied the effect of thermostable E. coli enterotoxin on rat kidneys. Isolated kidneys from adult male hooded rats weighing 240-335 g were perfused with Krebs-Henseleit solution containing 60 mg/ml dialyzed bovine serum albumin. The effects of E. coli enterotoxin (STa; molecular weight approximately 2000; 18 amino acids with three disulfide bonds) were studied on glomerular filtration rate (GFR), net urinary flow rate (UF) and fractional sodium reabsorption (% TNa+). All experiments were preceded by a 30-min control period, and in some kidneys the time course of the variables was followed without toxin infusion, for a paired control. STa (0.1 microgram/ml) infused into the perfusate 30 min after the beginning of the experimental period promoted a significant decline in % TNa+ from 78.4 +/- 1.6 (control period) to 51.6 +/- 6.8 (P < 0.001) 90 min after the administration of the toxin. This effect was followed by an increase in net urinary flow (UF) in toxin-treated kidneys (UFSTa = 0.120 +/- 0.009 vs UFcontrol = 0.056 +/- 0.011 ml g-1 min-1, P < 0.008). The GFR of control and STa-treated kidneys did not change during the total time of perfusion and after toxin infusion. Our data demonstrate that STa promotes a specific decrease in tubular sodium transport in the rat kidney.


Cotransport of sodium with glutamine, alanine and glucose in the isolated rabbit ileal mucosa. To investigate the effect of substrates during oral rehydration therapy, we studied intestinal cation cotransport (ICC) with glutamine (Gln), alanine (Ala) and glucose (Glu). The specific aims were to determine the biological effects of these three different cotransport systems on intestinal function. Isolated rabbit ileal mucosa preparations mounted in Ussing chambers were studied. ICC was determined by measuring short-circuit current (Isc) and potential difference (PD) while monitoring tissue resistance (TR). The data are reported as the mean +/- SEM of 4-6 experiments for each amino acid concentration. Increasing concentrations of Gln (10(-5) to 10(-2) M), Ala (10(-5) to 10(-1) M) and Glu (10(-5) to 10(-2) M) caused a significant (P < 0.05) increase in ICC. Gln (30 mM) and Ala (0.1 M) had a maximal effect (Em(Gln) = 100% and Em(Ala) = 66%, P < 0.05) which was higher than that obtained with 30 mM Glu (Em(Glu) = 35%). When sodium was replaced with choline on the mucosal side, Ringer solution completely abolished the response with Gln, Ala and Glu. The presence of all three substrates (10(-2) M Gln, 10(-1) M Ala, and 10(-2) M Glu) in Ringer solution on the mucosal side caused a significant increase in ICC (delta increase of short circuit current = 111 +/- 43 microA, P < 0.05). These results demonstrate that Gln, Ala and Glu each increased sodium-dependent cation cotransport, and that sodium-dependent intestinal cation cotransport was higher with Gln than with Ala or Glu.


The effect of fasting on cell proliferation in the gastric mucosa of the 14-day-old suckling rat. 1. The effect of fasting on cell proliferation in the gastric mucosa was investigated in 14-day-old suckling Wistar rats. 2. The renewal of the epithelial cells of the corpus of the stomach was evaluated by DNA labelling and counting arrested metaphases in fifty 14-day old rats fasted for 18 to 21 h and in fifty control suckling rats of the same age. The animals were sacrificed at 3 h intervals over a 24-h period. 3. The metaphase arrest method was also used to estimate the rate of entry of cells into mitosis in the gastric glands of 26 rats under both feeding and fasting conditions. In addition to the proliferative indices, the number of epithelial cells, and the heights of the glands and mucosa were measured morphometrically in 20 rats. 4. No significant differences in the rate of entry of cells into mitosis (number of cells in fasted = 0.49 +/- 0.077 cells 100 cells-1 h-1), in the number of epithelial cells (fasted = 241.2 +/- 24.3 cells/0.023 mm2) or in the height of the gastric glands (fasted = 194 +/- 5.4 microns) of fasted and control rats were observed. Both labelling and metaphase indices (means +/- SEM) were significantly higher (P < 0.01) in the fasted (13.9 +/- 0.57% and 1.3 +/- 0.07%, respectively) suckling rats than in the controls (7.9 +/- 0.39% and 0.9 +/- 0.05%, respectively). 5. These data indicate that fasting stimulates cell proliferation in the gastric mucosa of suckling rats rather than decreasing proliferation, as is the case for adult rats.


Angiotensin-(1-7) is a potent antidiuretic peptide in rats. We have shown previously that angiotensin-(1-7) (Asp-Arg-Val-Tyr-Ile-His-Pro) is a biologically active endogenous angiotensin which is a major product of angiotensin I processing by an angiotensin converting enzyme (ACE)-independent pathway. Intense staining for angiotensin-(1-7) immunoreactivity was demonstrable in brain areas related to the maintenance of hydromineral balance, suggesting the involvement of this peptide in this process. In the present study we investigated the antidiuretic effect of angiotensin-(1-7) by determining its effect on the water diuresis produced by an ip water load (5 ml/100 g) in male Wistar rats. The peptide had a pronounced antidiuretic effect when administered peripherally in doses ranging from 5.5 to 22 pmol/100 g. In contrast, angiotensin II presented only a small effect with the highest dose used (20 pmol/100 g). Comparison of the potency of angiotensin-(1-7) and vasopressin (AVP) showed that both peptides act in the same molar range although AVP was slightly more potent than angiotensin-(1-7). Urine volumes for 22 pmol/100 g angiotensin-(1-7) were 0.85 +/- 0.26 and 3.47 +/- 0.36 ml for hours 1 and 2, respectively, whereas they were 0.54 +/- 0.40 and 2.38 +/- 0.64 ml for 10 pmol/100 g AVP. There was apparent additivity of effect when 10 pmol of each peptide were administered simultaneously (0.0 and 1.72 +/- 0.45 ml vs 2.58 +/- 0.45 and 3.85 +/- 0.35 ml for control for hours 1 and 2, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Chemical sensors for space applications. There will be a great need for a wide variety of chemical analyses, both for biomedical experimentation and for the monitoring of water and air recycling processes on Space Station Freedom and later long-term space missions. The infrequent logistics flights of the Space Shuttle will necessitate onboard analysis. Chemical sensors offer several advantages over conventional analysis onboard a spacecraft. They require less crew time, space, and power. A chemical sensor consists of a selector which selectively interacts with the analyte present in a mixture of substances, and a transducer which produces an electric signal in response to the interaction of analyte and selector. The transducer signal thus provides a quantitative and selective measurement of the analyte. Types and requirements for chemical sensors to be used in biomedical experimentation and monitoring of water recycling during long-term space missions are discussed. With chemical sensors, a wide variety of analytes can be determined selectively without separation steps. In principle, chemical sensors can provide (near) real-time monitoring of many important analytes. In some cases they can even provide continuous monitoring of such analytes. The sensors, and even the ancillary instruments, are small compared to conventional analytical instruments. Their power consumption is low. Sensor measurements do not require extensive sample treatment before analysis. In most cases a sensor can simply be inserted in, or be attached to, the organism; or be placed in the water flowing through the water recycling system. Since the sensor signal can usually be provided in digitized form, rapid transmission to the ground is possible. The use of sensors thus provides an efficient use of the scarce resources of crew time, pressurized volume, and power.


Triglycerides and blood glucose are the major coronary risk factors in elderly Swedish men. The study of men born in 1913. In 1980 we examined 707 67-year-old men, 656 of whom had no previous myocardial infarction. During 8 years of follow-up, 70 (10.7%) of the 656 men developed a first myocardial infarction or died from coronary heart disease (CHD). The incidence of CHD increased 1.6-fold from the lowest to the highest quintile of cholesterol levels, 2.7-fold from the lowest to the highest quintile of triglyceride levels, and 2.2-fold among those with diabetes. Blood pressure, smoking habits, and two measurements of obesity (body mass index and waist circumference) were not significantly related to the incidence of CHD. In multivariate analysis, serum triglyceride levels and blood glucose concentration remained as significant risk factors for CHD. This may reflect that disturbances in glucose and triglyceride metabolism (as part of a metabolic syndrome?) are more important CHD risk factors in older than in younger men.


Diabetes and coronary heart disease risk in Mexican Americans. Mexican Americans have a high prevalence of diabetes relative to non-Hispanic whites, but paradoxically experience a lower prevalence of myocardial infarction and lower cardiovascular mortality (at least in men). To determine whether Mexican Americans might be more resistant to the atherogenic effects of diabetes than non-Hispanic whites, we examined the associations between diabetes and myocardial infarction and selected coronary heart disease (CHD) risk factors in these two ethnic groups. The study population consisted of 5149 Mexican Americans and non-Hispanic whites who were 25 to 64 years old and recruited from the San Antonio Heart Study, a population-based study of cardiovascular risk factors and diabetes conducted between 1979 and 1988. Diabetic men were more than twice as likely to have an electrocardiography (ECG)-documented myocardial infarction than were nondiabetic men, while diabetic women were more than three times as likely to have a myocardial infarction than were nondiabetic women. In both sexes the association between myocardial infarction and diabetes was nearly identical between the two ethnic groups. In both ethnic groups diabetes was also more strongly associated with conventional CHD risk factors (e.g., triglycerides, systolic blood pressure, and high-density-lipoprotein cholesterol) in women than in men. Furthermore, these associations were at least as strong, if not stronger, in Mexican Americans as in non-Hispanic whites. Thus, these data provide no evidence to suggest that Mexican Americans are resistant to the lipid-altering effects of diabetes. We conclude that the protective effect against CHD conferred by Mexican American ethnicity may be obscured in part by the high prevalence of diabetes in this ethnic group.


The relationship of total serum cholesterol to coronary heart disease in older men. The Italian rural areas of the Seven Countries Study. The relationship of serum cholesterol to the development of major coronary events (CHD) was studied in Italian rural cohorts of adult men aged 40-59 (n = 1672) and of older men aged 65-79 (n = 752) followed up for 5 years. In adult men both univariate and multivariate analysis (the latter with 4 or 5 covariates fed into the Cox model) showed a direct and significant relationship of cholesterol to CHD. In older men the univariate analysis confirmed a direct and significant relationship; for the multivariate analysis none of the considered factors was significantly predictive.


Serum cholesterol in patients undergoing cardiac catheterization for suspected coronary artery disease: diagnostic and prognostic implications. The Duke Data Bank for Cardiovascular Diseases is an observational data bank capturing baseline, treatment, and follow-up information on patients referred for evaluation of suspected coronary artery disease. From 6829 patients referred between 1969 and 1990 for diagnostic angiography, baseline cholesterol levels were determined as part of the standard clinical procedure. Baseline total cholesterol values were found to be related to the presence of coronary disease in men and women, although in the elderly little evidence for a significant relationship was found. Formal tests for interactions revealed a significant interaction between age and cholesterol but not between gender and cholesterol. In subgroup analyses using the Cox proportional hazards model, no relationship was found between cholesterol and either cardiovascular death or total cardiac events (death or nonfatal myocardial infarction) in 2038 medically treated patients with 5 to 20 years of follow-up. In the subgroup of 1798 surgically treated patients, there was also no relationship between baseline cholesterol level and these end points. Finally, detailed lipid analysis was done at baseline and 6-month angiography in a second population of 759 patients undergoing percutaneous coronary angioplasty between 1986 and 1989. No substantial relationship between baseline or follow-up cholesterol, low-density or high-density lipoproteins, or triglyceride levels and restenosis was found.


Cholesterol and carotid atherosclerosis in older persons: the Framingham Study. We studied the relationship between extracranial carotid atherosclerosis as measured by high-resolution carotid sonography and serum total cholesterol and high-density-lipoprotein cholesterol (HDL-C) levels which were determined at the time of carotid sonography and 8 years previously in 1189 members of the Framingham cohort, aged 66 to 93 years. Among participants, no carotid disease was found in 30%; 1 to 49% stenosis, in 62%; 50 to 74% stenosis, in 5%; 75 to 99% stenosis, in 2%; and 100% stenosis, in 1%. Total cholesterol measured 8 years prior to the carotid examination showed a strong positive association with the occurrence of stenosis in both men and women. There was no association between concurrently measured cholesterol levels and stenosis for either men or women. For women there was a strong association between both the 8-year HDL-C level and the concurrently measured HDL-C level and the degree of carotid stenosis. For men, neither concurrent nor 8-year HDL-C measurements were significantly related to carotid stenosis. These results suggest that there is a time lag between the observation of an elevated cholesterol level and its expression as an increased degree of carotid atherosclerosis.


Blood lipid distributions in older persons. Prevalence and correlates of hyperlipidemia. Distributions of blood total cholesterol, triglyceride, low-density-lipoprotein (LDL) cholesterol, and high-density-lipoprotein (HDL) cholesterol levels are presented for a geographically defined cohort of rural elderly Iowans, 71 to 102 years old. Cross-sectionally, women had higher levels of total and LDL cholesterol than men did, levels that declined with increasing age. Mean HDL cholesterol levels were also higher in women than in men, but remained relatively constant across the age range. Age- and sex-specific total, LDL, and HDL cholesterol levels were lower among participants residing in long-term-care facilities. HDL but not total cholesterol levels were lower in cigarette smokers and those with chronic illnesses, physical dependence, and poorer performance on physical function tests, and higher among those consuming alcohol. If subjected to the screening guidelines of the National Cholesterol Education Program, a majority of this population, having total cholesterol levels of 5.2 mmol/L (200 mg/dL) or higher, would require further evaluation for possible hyperlipidemia.


Serum levels of cholesterol and ischemic heart disease mortality. The Värmland Study. The objective of the Värmland Study was to examine how serum cholesterol can be used to predict short- and long-term ischemic heart disease (IHD) mortality, especially in women aged 65 or older. This prospective cohort study involved about 20 years of follow-up after a single determination of serum cholesterol and included participants in a health screening undertaken from 1962 to 1965 (48,076 men, 48,732 women). The main outcome measures were mortality from IHD, acute myocardial infarction (MI), and chronic ischemic heart disease (CIHD). An IHD mortality trend was associated with increasing cholesterol levels for people younger than 65 years, and was more pronounced for men than women. For people 65 years or older, there was a weak trend for men, but not even a tendency for women. Regarding acute MI, significant trends were observed for males as well as females, for young as well as old people. A mild CIHD mortality trend was observed for young men. Otherwise no significant trend was seen.


The relationship between cholesterol level and myocardial infarction or mortality risk in patients with coronary artery disease. A report from the Coronary Artery Surgery Study (CASS) registry. Using data from the Coronary Artery Surgery Study (CASS) registry, we evaluated the relationship between cholesterol levels measured at enrollment and the following events: all-cause mortality, cardiac death, fatal myocardial infarction (MI), and nonfatal MI. Only patients with a significant coronary artery disease (at least one lesion with stenosis > or = 50%) were considered for this study. Results presented for mortality are for a period of up to 11.5 years and those for MI are for a maximum of 8 years of follow-up. Analyses were performed for each type of event and for each subgroup: women (n = 1861) and men (n = 10,941) under age 65, and women (n = 426) and men (n = 1144) age 65 or older. After adjusting for important covariates, cholesterol level was not associated with cardiac or all-cause mortality. No relationship between cholesterol level and fatal or nonfatal MI could be demonstrated except for men under age 65. However, in this subgroup the risk of MI was highest for those with low or middle cholesterol levels. The data show that in patients with angiographically determined coronary artery disease, cholesterol level is not a statistically significant risk factor for death or MI over the follow-up period in CASS.


Serum cholesterol and coronary heart disease risk in female and older hypertensives. The experience under usual community care in the Hypertension Detection and Follow-up Program. The coronary heart disease (CHD) risk function associated with baseline serum cholesterol levels among women and older hypertensives was determined for the 5455 participants who were randomized in the Hypertension Detection and Follow-up Program (HDFP), referred to usual care in 14 US communities, and followed for the years 1974 through 1979. The risk of fatal CHD in relation to serum cholesterol for those under age 65 appeared as strong in women as in men in age- and race-adjusted analyses stratified by serum cholesterol levels; however, there was no association of serum cholesterol levels with combined fatal plus nonfatal incident coronary events for these women, adjusting for other major risk factors and covariables. There was no association of serum cholesterol with fatal or combined fatal plus nonfatal CHD events in either adjusted or unadjusted analyses for older hypertensive women. In contrast to the findings for women, serum cholesterol levels were strongly predictive of fatal plus nonfatal CHD in both younger and older hypertensive men, controlling for the effects of other factors such as age, antecedent history of antihypertensive medication, and presence of comorbidity. This study, based on the experience of the usual care group within the HDFP, was observational in nature. Clinical trials of specific regimens of serum cholesterol lowering in hypertensives are required definitively to determine their efficacy and safety for these high-risk patients; however, the experience within the HDFP indicates the desirability of detection and prudent management of hypercholesterolemia in older as well as younger male hypertensives.


Lipid and lipoprotein predictors of coronary heart disease in elderly men in the Honolulu Heart Program. Data from the baseline and follow-up examinations of the Honolulu Heart Program (HHP) cohort of 8006 men of Japanese ancestry were used to examine several questions concerning the predictive role of lipids and lipoproteins for incident CHD. For the question "Do serum cholesterol levels measured in middle age predict incident CHD in elderly men 65 years old or older?" the answer was clearly yes. Multivariate relative risks and attributable risks for early and late onset of CHD were similar and statistically significant. For the question "Do serum cholesterol levels measured in the elderly predict subsequent CHD?" the answer again was clearly yes. Multivariate relative risks for elderly men were similar to those for middle-aged men, and attributable risks were consistently higher for elderly men. For the question "Do other lipid or lipoprotein levels measured in the elderly predict incident CHD better than serum cholesterol level?" the answer was no. Multivariate relative risks for low-density-lipoprotein (LDL) and non-high-density-lipoprotein cholesterol were similar to those for total cholesterol. HDL cholesterol was protective for incident CHD, but the patterns were not significant for the elderly. Serum triglyceride level was not a significant predictor of CHD for the elderly. The conclusion was that no matter at what age serum cholesterol was measured, it predicted subsequent CHD in the elderly men in this cohort.


Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop. The value of serum total cholesterol measurement in predicting coronary heart disease (CHD) is well established in middle-aged men, but has been questioned in middle-aged women and older people of both sexes. To address this, the most recent follow-up data from 25 populations in 22 US and international cohort studies were presented and analyzed at a recent National Heart, Lung, and Blood Institute (NHLBI) workshop. Crude relative and absolute excess risks of fatal CHD were determined for individual studies and pooled across studies to determine pooled risk estimates. Serum total cholesterol and low-density-lipoprotein (LDL) cholesterol levels predicted fatal CHD in middle-aged (< 65 years) and older (> or = 65 years) men and women, though the strength and consistency of these relationships in older women were diminished. High-density-lipoprotein (HDL) cholesterol levels inversely predicted CHD in middle-aged men and women and in older women, but not in older men. Data for minority groups and for overseas populations were similar to those for white people in the United States. Relative risk estimates were generally lower for older than for middle-aged subjects, but absolute excess risk was greater. Older people and middle-aged women with elevated cholesterol levels are clearly at increased risk of coronary disease; whether this risk can be modified by dietary or drug therapy, and at what level intervention is appropriate, must not be determined.


Serum lipids and lipoproteins in advanced age. Intraindividual changes. The Bronx Aging Study is a longitudinal investigation of nondemented, nonterminally ill, community-residing, old old volunteer subjects, designed to assess risk factors for the development of dementia and coronary and cerebrovascular diseases. During the first five annual evaluations, total cholesterol, high-density (HDL) and low-density lipoprotein (LDL), and triglyceride levels were measured. Mean cholesterol values (+/- standard error of the mean) for subjects at baseline were significantly higher for women than for men. Respectively, the values for total cholesterol were 6.1 +/- .1 mm/L (234 +/- 3 mg/dL) and 5.3 +/- .1 mm/L (207 +/- 3 mg/dL); for LDL cholesterol, 4.1 +/- .1 mm/L (158 +/- 2 mg/dL) and 3.7 +/- .1 mm/L (141 +/- 3 mg/dl); and for HDL cholesterol, 1.2 +/- .1 mm/L (47 +/- 1 mg/dL) and 1.0 +/- .1 mm/L (38 +/- 1 mg/dL). Mean triglyceride levels were 1.5 +/- .1 mm/L (135 +/- 5 mg/dL) for women and 1.6 +/- .1 mm/L (138 +/- 5 mg/dL) for men. Further, mean values remained stable over time. However, there was considerable intraindividual change observed in a substantial proportion of subjects between initial and final determinations. Changes of at least 10% from baseline were observed in 41%, 63%, 52%, and 78% of the cohort for cholesterol, HDL, LDL, and triglycerides, respectively. Thus, single measurements appear inadequate for establishing a diagnosis of hyperlipidemia in the elderly.


Lipids and risk of coronary heart disease. The Framingham Study. Total cholesterol level is significantly related to risk of coronary heart disease (CHD), adjusting for other risk factors in women 50 to 79 years old and in men aged 50 to 64 years, at P < .001. Determining the levels of lipoproteins such as low-density-lipoprotein (LDL) cholesterol and high-density-lipoprotein (HDL) cholesterol improves the prediction of risk. Triglycerides are independently related in women at all ages but miss statistical significance in the multivariate studies in men. The total cholesterol-HDL cholesterol ratio is another powerful predictor at all ages in women and is the only lipid predictor independently related to CHD in men 65 to 80 years old. Inspection of the age-specific association of cholesterol with risk in men and women also reveals that the absolute rates of disease worsen with age.


Serum cholesterol and mortality from coronary heart disease in young, middle-aged, and older men and women from three Chicago epidemiologic studies. The association of total serum cholesterol with mortality from coronary heart disease was examined in 1210 white men aged 42 to 60 in 1959 to 1963 and 1008 white men aged 45 to 64 in 1959 to 1969, followed up to 25 years from the Chicago Peoples Gas Company Study; in 1903 white men aged 41 to 57 in 1959, followed up to 24 years from the Chicago Western Electric Company Study; and in 17,880 white men aged 25 to 74 and 8327 white women aged 40 to 74 in 1967 to 1973, followed up to 18 years from the Chicago Heart Association Detection Project in Industry. In these studies total cholesterol level was related positively to coronary mortality in young men and in middle-aged and older men and women. Relative risks of mortality were generally higher in young and middle-aged persons compared to older persons, whereas absolute excess risks were generally greater in older than in younger persons.


A dose-response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure. We performed a quantitative assessment of the risk of lung cancer from exposure to cadmium based on a retrospective cohort mortality study of cadmium-exposed workers. The study population consisted of white male workers who were employed for at least 6 months at a cadmium smelter between January 1, 1940, and December 31, 1969, and who were first employed at the facility on or after January 1, 1926. The study findings were analyzed using a modified life-table analysis to estimate standardized mortality ratios (SMRs), and various functional forms (i.e., exponential, power, additive relative rate, and linear) of Poisson and Cox proportional hazards models to examine the dose-response relationship. Estimates of working lifetime risk (45 years) were developed using an approach that corrects for competing causes of death. An excess in mortality from lung cancer was observed for the entire cohort (SMR = 149, 95% confidence interval (CI) = 95, 222). Mortality from lung cancer was greatest among non-Hispanic workers (SMR = 211, 95% CI = 131, 323), among workers in the highest cadmium exposure group (SMR = 272, 95% CI = 123, 513), and among workers with 20 or more years since the first exposure (SMR = 161, 95% CI = 100, 248). A statistically significant dose-response relationship was evident in nearly all of the regression models evaluated. Based on our analyses, the lifetime excess lung cancer risk at the current Occupational Safety and Health Administration standard for cadmium fumes of 100 micrograms/m3 is approximately 50 to 111 lung cancer deaths per 1000 workers exposed to cadmium for 45 years.


Is weight loss a modifier of the cholesterol-heart disease relationship in older persons? Data from the NHANES I Epidemiologic Follow-up Study. The relationship between cholesterol and 14-year incidence of coronary heart disease was compared for men and women of two age groups, 25 to 64 years and 65 to 74 years. While cholesterol levels of 6.2 mmol/L or higher were associated with a risk of coronary heart disease in the younger group, this was not true for either men or women aged 65 to 74. Further analyses for older persons showed that weight loss modified the cholesterol-heart disease relationship. Those with stable weight showed a positive relationship between cholesterol and coronary heart disease, similar to the younger age group (relative risk [RR] = 1.8 [95% confidence interval: 1.1, 2.9] for men; RR = 1.6 [.7, 3.4] for women). Among those with a weight loss of 10% or more, the relationship of cholesterol to heart disease was inverse (RR = .8 [.5, 1.2] for men; RR = .6 [.3, 1.0] for women). These data suggest that the relationship of cholesterol to coronary disease in healthier older persons may be similar to that in younger persons, and that health status should be considered in analyses of cholesterol risk in old age.


Cholesterol, coronary heart disease, and total mortality in middle-aged and elderly men and women in Tecumseh. Relationships between serum cholesterol and coronary heart disease (CHD) were investigated in Tecumseh men and women who were 45 to 92 years old and initially free of CHD. Recruitment continued through three cycles of examinations over a period of 10 years, beginning in 1959. Follow-up for mortality ended in 1986 to 1987. Age-adjusted relative risks for CHD death for cholesterol levels of 5.2 to 6.2 mmol/L and greater than 6.2 mmol/L, compared with levels less than 5.2 mmol/L for men aged 45 to 64 years, were 1.2 and 1.7; for older men they were 1.0 and 1.8. Comparable relative risks for CHD death by cholesterol level were .7 and 1.4 for 45- to 64-year-old women and .8 and .7 for older women. Coefficients for cholesterol were significant for fatal CHD in men under and those 65 years and older when age, systolic blood pressure, body mass index, cigarette smoking status, and glucose intolerance were controlled in proportional hazards models. Cholesterol was a significant predictor of fatal CHD plus nonfatal myocardial infarction in middle-aged, but not elderly women. Relative risks for total mortality were lowest for middle-aged men and women with cholesterol levels of 5.2 to 6.2 mmol/L and the difference was significant in men.


A community-based epidemiologic study of health sequelae of exposure to hydrofluoric acid. An accident at an oil refinery in Texas City, Texas, released around 40,000 lb of hydrogen fluoride, exposing the community to the highly toxic and corrosive substance. A population-based epidemiologic study was conducted to evaluate the impact of the accident on the health of the community. Exposure assessment was done using a multipronged approach through a door-to-door survey of 10,811 individuals. A symptom survey resulting in 1994 completed interviews was conducted with a stratified random sample selected from the exposure study database. The sampling was balanced with respect to age, gender, and predisposition across the three ordinal exposure categories. The results show a strong dose relationship (P < 10(-4)) between the exposure and symptoms reported following the accident and 2 years later, most notably breathing and eye symptoms. However, substantial improvement in health was reported over the 2-year period regardless of the level of exposure. Problems of recall bias and behavioral sensitization are considered and it is recognized that the study may have overestimated the effect. It is also recognized that the study may not have completely unraveled the relative importance of exposure and host response in health outcome, since the two were probably conflated in the exposure measure. Nevertheless, the independence of predisposition and reported level of exposure, the magnitude of effect and its consistency, the unmistakable dose response, the large sample size, and the mutual corroboration of various findings make it difficult to dismiss the interpretation that the hydrofluoric acid exposure indeed caused health problems in the community that continued for at least 2 years after the accident.


Diet and risk of basal cell carcinoma of the skin in a prospective cohort of women. We conducted a prospective study of diet in relation to the incidence of basal cell carcinoma of the skin in a cohort of 73,366 women who were 34 to 59 years old in 1980 and without previous skin or other cancer. During 4 years of follow-up, 771 incident cases of basal cell carcinoma were diagnosed. When adjusted for other risk factors, women in the highest quintile of energy intake were at higher risk of basal cell carcinoma compared with those in the lowest quintile (relative risk, 1.28; 95% confidence interval, 1.02 to 1.60). No significant associations were observed between risk of basal cell carcinoma and energy-adjusted intake of dietary fat, carotenoids with vitamin A activity, and retinol, vitamin C, vitamin D, and vitamin E, either with or without supplements. Use of specific vitamin A, C, D, or E supplements, or multivitamins, did not materially alter risk. Although the period of follow-up was relatively short, these data are most consistent with no major role for these nutrients in the etiology of basal cell carcinoma.


Demographics of the prevalence, incidence, and management of coronary heart disease in the elderly and in women. Cardiovascular disease constitutes an expanding problem in the elderly because of the increasing size of the aged population. Atherosclerosis, hypertension, and diabetes are responsible for the predonderance of cardiovascular disease, which causes 70% of all deaths beyond age 75. Coronary heart disease (CHD) is the most common and most lethal cardiovascular event in both sexes, exacting a large toll in disability and deteriorated quality of life in old age. Unrecognized myocardial infarctions are especially common and are as serious as symptomatic infarctions. beyond age 65, women are as vulnerable to cardiovascular death as men. The predisposing modifiable risk factors for coronary disease, stroke, peripheral arterial disease, and cardiac failure are similar in young and old and in men and women. These include hypertension, dyslipidemia, impaired glucose tolerance, physical indolence, and cigarette smoking. An attenuated risk ratio for some risk factors is offset by a greater incidence of cardiovascular events in advanced age so that the attributable risk and the potential benefit of treatment rise with age. Because the major risk factors predict CHD as efficiently in the elderly as in the young, and the decline in cardiovascular mortality has included the elderly, preventive efforts in the elderly may have substantial potential benefit. At advanced age, total cholesterol levels are considerably higher in women than in men. Some 10 million elderly, two-thirds of whom are women, may require investigation and treatment for elevated lipid levels, as determined by National Heart, Lung, and Blood Institute (NHLBI) guidelines. Because of the preponderance of women in the elderly population, trials of the efficacy of correcting risk factors in general, and lipids in particular, should include women.


Hypercholesterolemia predicts early death from coronary heart disease in elderly men but not women. The Rancho Bernardo Study. In a 3-year follow-up study of 761 elderly men and 983 elderly women, total plasma cholesterol levels predicted fatal coronary heart disease (CHD) in men but not women. Low-density lipoprotein level was no better a predictor of fatal CHD than total cholesterol in either sex. Women had higher levels of high-density lipoprotein than men, which explains most of their usual higher total cholesterol levels. These data suggest that cholesterol screening of elderly women would have little value without a lipoprotein evaluation.


Pregnancy estrogens in relation to coffee and alcohol intake. Total estrogen (TE), estradiol (E2), estriol (E3), and human placental lactogen (hPL) levels were determined by radioimmunoassay in the blood of 141 pregnant women during their 26th and 31st weeks of pregnancy and the results were studied in relation to coffee and alcohol intake. After controlling for maternal age, maternal weight at the corresponding week of pregnancy, parity, and tobacco smoking, as well as for mutual confounding effects, coffee intake, ascertained at the 26th week, was found to be negatively related to pregnancy E2 levels (P = 0.04 during the 26th week, and P = .16 during the 31st week), whereas alcohol intake, also ascertained at the 26th week, was found to be positively related to pregnancy TE levels (P = .04 during the 26th week, and P = .18 during the 31st week). The negative relation between coffee consumption on the one hand and E2 (and possibly TE) levels on the other may be responsible for the inverse association between maternal coffee intake and birth weight; the latter association has been repeatedly confirmed in the literature, although it was neither strong nor statistically significant in the present study. The relations of maternal coffee and alcohol consumption with pregnancy estrogen levels, if confirmed, could be utilized in studies exploring the role of prenatal exposure to these hormones in the etiology of gonadal germ-cell tumors and possibly other diseases.


Cholesterol as a risk factor for coronary heart disease in elderly men. The Baltimore Longitudinal Study of Aging. In order to explore the relationship of cholesterol to coronary heart disease (CHD), defined as angina pectoris, myocardial infarction, and sudden coronary death, in older men, a group of 1052 men, participants in the Baltimore Longitudinal Study on Aging, were examined. Subjects were stratified into three age groups, 28 to 64, 65 to 74, and 75 to 97 years old. In all three age groups, cholesterol was a significant risk factor for CHD. In the oldest age group (n = 250), the relationship between cholesterol and risk was linear (P = .003) as opposed to younger age groups where the relationship was exponential. This study extends the age range in which hypercholesterolemia has been shown to be associated with CHD to include the 75- to 97-year range.


One less for the road. International trends in alcohol consumption and vehicular fatalities. We used data for the years 1965 to 1987 from 19 countries to study the relationship between per capita alcohol consumption and vehicular fatalities. Cross-sectional data for the most recent years show a strong relationship between per capita alcohol consumption and vehicular deaths (r = .83, P < .001). When we examined time trends, we noted an increase in per capita alcohol consumption and vehicular deaths for the years 1965 to 1973, a dissociation of the two variables in response to the oil crisis during the 1970s, and a recent gratifying reduction in both variables for the period 1980 to 1987. On average, for the years 1980 to 1987, a 1% reduction in per capital alcohol consumption was associated with a 1% reduction in vehicular deaths (95% confidence interval, .9 to 1.1). For many countries alcohol consumption has already peaked and these findings provide quantitative support for the beneficial effects of continued efforts to control overall per capita consumption of alcohol.


Serum cholesterol--risk factor for coronary disease mortality in younger and older blacks and whites. The Charleston Heart Study, 1960-1988. Serum total cholesterol (> or = 6.7 mmol/L) measured in 1960 in the Charleston Heart Study cohort was found to be a risk for mortality from coronary heart disease during the period of 1960 to 1988 in white men (relative risk [RR] 1.5; 95% confidence interval [CI]: 1.1, 2.2), white women (RR 1.7; 95% CI: 1.1, 2.7), and black women (RR 1.6; 95% CI: .9, 2.9) after age, systolic blood pressure, smoking status, education level, obesity, and diabetes were considered. For black men, the relative risk was .96 (95% CI, .39, 2.39). Only among white women was the relative risk (RR 2.4; 95% CI, 1.2, 4.5) increased among those in the older ages (55 to 74) in 1960. The evidence for cholesterol as a risk factor for coronary disease mortality in black men is inconclusive and requires further study.


Patterns of exposure and severity of measles infection. Copenhagen 1915-1925. Using data on children hospitalized with measles in Copenhagen from 1915 to 1925, I found that secondary cases (infected at home) exposed to two or more index cases had a higher case fatality rate than did children exposed to a single index case (relative risk (RR) = 1.90; 95% confidence interval (CI): 1.12 to 3.22). Compared with surviving cases, fatal secondary cases had a shorter interval between their own rashes and rash in the index case (P < .02), suggesting a shorter period of incubation for severe cases. Secondary cases infected by a severe case of measles had higher mortality (RR = 3.87; 95% CI: 1.65 to 9.08) than did secondary cases infected by an index case without pneumonia. These observations suggest that differences in patterns of exposure, possibly due to the dose of infection, may be important for understanding variation in measles mortality.


Differential effect of risk factors on early and late wound infections in patients undergoing herniorrhaphies. In a prospective follow-up of 2846 patients who underwent hernia repair in 22 general surgery departments in Israel, factors affecting early or late infections were explored. Risk factors included inherent patient characteristics such as old age, ethnic group, and type of hernia prior to the surgery. Patient management factors included duration of the operation, use of urinary catheters, and use of drains. Of the 12 variables studied, only three had a constant effect during the entire 30-day follow-up. The other factors affected the occurrence of either early or late infections, but not both. For example, patients undergoing long operations, or from ethnic minorities, had a high rate of early infection, while those with special wound treatment (such as evacuation of hematomas) had high rates of late infection. It is postulated that factors present at the time of the operative incision tend to "cause" early infections, while factors that accumulate over time, or develop after leaving the operating theater, tend to affect late infections.


Do coronary heart disease risk factors measured in the elderly have the same predictive roles as in the middle aged. Comparisons of relative and attributable risks. Risk factors for the 12-year incidence of definite coronary heart disease (CHD) among 3440 men who were middle-aged (51 to 59 years old) and 1419 men who were elderly (65 to 74 years old) at baseline examination were examined for differences in predictive values in terms of both relative risk and attributable (excess) risk of the highest versus the lowest quartile or appropriate categories. In multivariate models using Cox life-table regression procedures, serum cholesterol level, cigarette smoking, systolic blood pressure, and history of treatment for diabetes were significant predictors of incident CHD for both age groups. Alcohol consumption when modeled as drinker versus nondrinker showed a protective effect in both younger and older men. There was no dose relationship, however, among elderly drinkers. While the relative risks for the variables studied were similar between the two age groups, the excess risk was typically between 1.5 to 2.0 times higher for the older than the middle-aged men. In contrast, the detrimental effect of adiposity as measured by body mass index appeared to decline after age 65 for both measures of risk. This may partly be attributed to diminished adiposity overall in the older age group. The implications of these results are that serum cholesterol level, smoking, hypertension, diabetes, and possibly alcohol consumption continue to be important predictors for CHD when measured after age 65, and that the public health impact of these risk factors, in terms of excess risk, may be more important in the elderly.


Serum cholesterol and 20-year mortality in black and white men and women aged 65 and older in the Evans County Heart Study. Serum cholesterol and 20-year mortality rates were studied in 396 Evans County black and white men and women who were 65 years and older and free of prevalent coronary heart disease (CHD) at baseline examination in 1960 to 1962. Previous reports on Evans County men and women younger than 65 found cholesterol levels to be significantly associated with all-cause and CHD mortality in white men, with CHD mortality in black men, and with cardiovascular disease mortality in white women. The independent role of total serum cholesterol as a predictor of CHD and all-cause mortality in the 65-and-older age group was evaluated using Cox proportional hazards models. Among white men, serum cholesterol level was positively associated with CHD mortality (relative risk of 1.54, P < 0.05 for an increment of 40 mg/dL [1.03 mmol/L], or one standard deviation in cholesterol). A significant J-shaped relationship of cholesterol with all-cause mortality was found among white men. Among black women, cholesterol was negatively associated with all-cause mortality. Neither all-cause nor CHD mortality was related to serum cholesterol among black men or white women. Although based on small numbers, the results of this study suggest that in Evans County, total serum cholesterol is an independent predictor of mortality in white men aged 65 and over, while these results should not be generalized to other race-gender groups in this cohort.


Change in glycemia in a four-year interval in younger-onset insulin-dependent diabetes. Hyperglycemia is an important risk factor for the development of retinopathy and nephropathy in people with diabetes mellitus. There are few population-based data on changes in glycemia over time. The purpose of this study was to examine changes in glycemia, as measured by glycosylated hemoglobin in 1980 to 1982 and in 1984 to 1986, in a large population-based study of people who were diagnosed to have diabetes before the age of 30 years and who used insulin (n = 697). Glycosylated hemoglobin was measured by a microcolumn technique at both examinations. There was a significant (P < .001) fall in the mean glycosylated hemoglobin from 10.8 to 10.1% over the 4-year interval of the study. In contrast, there was no change in the glycosylated hemoglobin (6.2%) in a similarly aged nondiabetic comparison group over the same period. The decrease in mean glycosylated hemoglobin over the 4-year period in the diabetic group was associated with several characteristics of diabetes management. These include changes in the insulin regimen (going from intermediate- or long-acting insulin only to combinations with short-acting insulin), an increase in the number of doses of insulin per day, and a higher frequency of self-monitoring of blood glucose level. It was also associated with an increased number of reported insulin reactions. These data suggest that recent changes in treatment and management of diabetes may be related to a significant decrease in glycemia.


Baseline characteristics of participants in phase I of the Trials of Hypertension Prevention. Phase I of the Trials of Hypertension Prevention was designed to test the effectiveness and safety of three life-style (weight loss, sodium restriction, and stress management) and four nutrition supplement (calcium, magnesium, potassium, and fish oil) interventions in reducing diastolic blood pressure (DBP) in persons with a high-normal blood pressure. A total of 2182 persons with a DBP between 80 and 89 mm Hg met the eligibility criteria for participation in phase I and were randomized to one of the active intervention or control treatment groups. Most were white (82%), male (70%), married (76%), nonsmoking (88%), college graduate (53%), full-time employees (91%). The average blood pressure prior to entry into the trial was 124.9 mm Hg systolic and 83.8 mm Hg diastolic. A variety of baseline observations, including sociodemographic characteristics, personal and family medical history, health habits, diet, and biologic measurements, were documented before randomization and compared among the seven active intervention and control groups. As might be expected in a randomized trial of this sample size, the distribution of measured baseline characteristics was virtually identical in the treated and control groups. Based on this finding and the knowledge that randomization procedures were implemented without deviation from the phase I protocol, it is probable that unknown potential confounders were also equally distributed at entry into the study. Given the achievement of high rates of follow-up, subsequent differences in blood pressure are unlikely to have been due to baseline differences between the active treatment and control groups, and can probably be attributed to effects of the active interventions.


Estimating familial aggregation while adjusting for covariates. Application to pulmonary function data from black and white sibships. Although crude correlations are useful in family studies, some adjustment for effects of risk factors that vary both within and among families if often needed. A linear model for estimating sibship correlations while simultaneously considering height, age, race, sex, ascertainment, and smoking status was used on pulmonary function data on 1-second forced expiratory volume (FEV1) and the natural logarithm of the ratio of FEV1 to forced vital capacity (lnFEV%) from 402 adults in 152 white sibships and 172 adults in 59 black sibships. Crude correlations of .271 +/- .048 (FEV1) and .342 +/- .047 (lnFEV%) decreased significantly to .206 +/- .048 and .231 +/- .048, respectively, after adjustment. For black and white sibs, adjusted intraclass correlations, although not statistically different, were .153 +/- .089 and .225 +/- .055 (FEV1), respectively, and were .103 +/- .088 and .275 +/- .054 (lnFEV%), respectively, suggesting that pulmonary function may aggregate more strongly among whites. This analysis illustrates how risk factor adjustment can be readily incorporated into familial correlation studies.


Clinical medicine meets modern epidemiology--and both profit. The clinical epidemiology movement can be understood best through the work of people who have chosen to call themselves clinical epidemiologists. It has strong ties to both clinical medicine and epidemiology but is distinct from them; it bridges the two disciplines and helps each recognize and use the strengths of the other. Epidemiology has given clinicians strong methods for answering clinical questions, a population perspective on the care of individual patients, and the scientific basis for preventive health care. Clinicians have brought to epidemiology in-depth understanding of the biology of disease, direct experience with epidemiologic variables, and a strong interest in how the results of research will be used. The success of clinical epidemiology are apparent through research, courses, textbooks, and contributions to clinical and public policy. Clinical medicine and epidemiology began together, then drifted apart. Both have suffered from the schism and both can now profit from becoming reacquainted.


Thrombosis and cardiovascular disease.

Thrombosis and cardiovascular disease. It was only quite recently that the thrombotic component in myocardial infarction and sudden coronary death was generally acknowledged. When attention was eventually paid to it, interest initially centered primarily on platelet function. There is, of course, no doubt about the central role of platelet adhesion and aggregation in thrombogenesis, but still no generally accepted measure of platelet function has been shown to be associated with the later onset of ischemic heart disease (IHD). Epidemiologically, the assessment of coagulability has been more rewarding. Several prospective studies have now shown a strong relationship between the plasma fibrinogen level and the incidence of IHD and stroke. Epidemiologic and laboratory studies have also implicated factor VII and extrinsic pathway activity in the onset of IHD. Other components of the hemostatic system that are probably involved include factor VIII activity and the fibrinolytic system. It is increasingly clear that lipoproteins exert a major influence on coagulability as well as their better known role in atherogenesis. Any further polarization of hypotheses for IHD as being purely atherogenic or purely thrombogenic is therefore counterproductive. At the same time, antithrombotic measures for primary prevention need to be evaluated as thoroughly as lipid-lowering regimens. If thrombosis is seen as the final arterial event in virtually all major episodes of IHD, the indications for antithrombotic agents in primary prevention may be wider than those for lipid-lowering regimens. It is therefore necessary to establish as quickly as possible not only the preventive effectiveness of antithrombotic measures, including low-dose aspirin and low-intensity oral anticoagulation, but also the relative effectiveness and safety of antithrombotic and lipid-modifying regimens.


Potential analytes for the diagnosis of thrombosis. An overview. The coagulation response is a complex interaction involving the vascular surface, blood platelets, and the plasma coagulation factors. These reactions are integrated to give rise to a locally efficient generation of both platelet aggregates and the enzymatic process associated with fibrin formation. Following mechanical, chemical, or biological "damage" to the vascular endothelial surface, coagulation is initiated by a composite of cellular adhesive reactions certainly involving the platelet and potentially also involving other inflammatory cells. The blood coagulation mechanism can be presented as a collection of zymogen-to-enzyme transformations, with each proteases participating with a cofactor protein on a "surface" that gives rise to the competent blood clotting complex. These complexes catalyze the generation of additional enzymes required for succeeding reaction complexes. It is likely that the coagulation reaction system is continuously "on," producing products at some low "idling" rate, with the products of the various reactions being neutralized by the collection of protease inhibitors and cofactor-neutralizing reactions that regulate the blood clotting process. These latter systems include, as principal components, the antithrombin III-heparin anticoagulant and the activated protein C pathway that disables cofactor proteins. Small changes in the concentrations of modulators can cause large effects in response to relatively small inputs. The coagulation process may be regarded as being at an incipient stage, separated from visually observable coagulation by a narrow threshold, which, once crossed, gives rise to the generation of fibrin and other products associated with alpha-thrombin generation.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetic factors determining thrombosis and fibrinolysis. Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)