The BT-PABA/PAS test in tropical diabetes. A 'screening' test is needed to identify patients with chronic pancreatitis among diabetics in tropical field surveys. We have examined the potential diagnostic yield of the BT-PABA/PAS test of exocrine pancreatic function in this setting. The recoveries of both PABA and PAS in eight healthy controls from Madras, south India, were lower than in controls from Manchester, north west England (mean +/- S.D., 51 +/- 11 vs. 79 +/- 7%, P < 0.001 for PABA; 52 +/- 11% vs. 81 +/- 7%, P < 0.001 for PAS) but the % PABA/PAS excretion index (PEI) was similar (0.96 +/- 0.14 vs. 0.96 +/- 0.06). Using a cut-off value of 0.75 for the PEI in a study group including eight patients with chronic pancreatitis and 26 with primary forms of diabetes, test sensitivity was 75%, specificity 92%, positive predictive value 75%, negative predictive value 92% and efficiency 88%.


Detection of erythrocyte membrane components in hemoglobin-based blood substitutes. Two methods for the detection of membrane components in human stroma-free hemoglobin solutions are described. The first is a phospholipid assay with a detection limit of 0.5-1 nmol phospholipid/ml hemoglobin-solution. For the detection of membrane proteins an immunoassay with a monoclonal antibody against glycophorin alpha was developed (detection limit 0.01% of the original amount). These methods were used to determine the purity of Hb solutions prepared in two different ways. Hb solutions prepared by filtration of red blood cells, gradually swollen in hypotonic buffer, contained 0.25% of the original amount of phospholipid and no detectable glycophorin alpha. For Hb solutions prepared in a similar way from red blood cells lysed in water, the values for phospholipid and glycophorin alpha were 2.5% and 0.06%, respectively. The determination of both glycophorin alpha and phospholipid gives a useful indication of the purity of Hb solutions.


Serum neurone-specific enolase levels in patients with neuroendocrine and carcinoid tumours. We have examined concentrations of neurone-specific enolase (NSE) in sera from 18 patients with various neuroendocrine tumours, 26 patients with carcinoid tumours, 21 patients with non-neuroendocrine tumours and 37 control individuals. No statistically significant difference between the concentrations in patients with neuroendocrine tumours and patients with carcinoid tumours was found. However the NSE concentrations in patients with carcinoid and neuroendocrine tumours, when these two groups were combined, were significantly different from the patients with non-neuroendocrine tumours or the control individuals (P < or = 0.01). 38.5% of the patients with carcinoid tumours had raised NSE concentrations in serum; 55.5% of those with non carcinoid neuroendocrine tumours had raised concentrations. There appeared to be no correlation between the NSE concentrations and the extent of metastases.


Quantitative analysis of extracellular-superoxide dismutase in serum and urine by ELISA with monoclonal antibody. The superoxide anion has been implicated in a wide range of diseases. The major protector against superoxide anion in the extracellular space is extracellular-superoxide dismutase (EC-SOD). EC-SOD is the major SOD isozyme in plasma and forms an equilibrium between the plasma phase and heparan sulfate proteoglycan on the surface of the endothelium. An ELISA method for the measurement of human EC-SOD with monoclonal antibody was established. The proposed method had a high sensitivity (assay range, 0.05-50 ng/ml), good recovery (recovery percentage, 96.9 +/- 5.6%) and reproducibility (within-day assay, C.V. = 8.6-10.2%; between-day assay, C.V. = 6.5-11.7%). EC-SOD levels in sera from healthy persons are clearly divided into two groups: a lower group (Group I, below 120 ng/ml, n = 146) and higher group (Group II, above 400 ng/ml, n = 10). The EC-SOD in Group I were almost normally distributed and the mean level was 55.8 +/- 18.8 ng/ml. The serum EC-SOD level assayed by ELISA correlated well with serum SOD activity. The serum EC-SOD in Group I is heterogeneous with regard to affinity for heparin-Sepharose and could be separated into three approximately equal fractions, whereas the EC-SOD in Group II is mainly one fraction with a high affinity for the column. The apparent molecular weight and carbohydrate structure of serum EC-SOD in Group II are identical to those in Group I. The high EC-SOD level in sera from some individuals may reflect the excessive stimulation of EC-SOD synthesis in vivo or the growth of selected cells in vivo, because EC-SOD is known to be expressed by a few cell types in vivo as a high-heparin-affinity subtype.


Platelet hyperreactivity in hyperlipidaemia with specific reference to platelet lipids and fatty acid composition. Platelet function after thrombin stimulation, the fatty acid composition of individual phospholipids, and levels of lipid components (cholesterol, cholesterol ester, phospholipids and triglycerides) were determined in total membranes of platelets from hyperlipidaemic (HL) and control subjects. Platelet aggregation, thromboxane (TX) B2 production and serotonin release was significantly greater in HL patients than in controls. Levels of platelet cholesterol, total phospholipids, cholesterol ester and triglycerides, were significantly higher in the HL patients. Small differences between the two groups were observed for the phospholipid fatty acid patterns. However, levels of arachidonic acid (AA) were significantly higher in phosphatidylinositol (PI) of HL patients (40.01 +/- 6.59 mol%) as compared to the controls (31.52 +/- 9.91 mol%) (P = 0.002). The higher levels of AA in PI, which is considered a donor pool for eicosanoid synthesis, may be an additional mechanism for the well documented platelet hyperfunction and greater TXB2 production in hyperlipidaemic subjects.


Measurement of ascorbic acid in platelets and its relationship to polymorphonuclear leukocyte levels. A simplified method for measuring ascorbic acid (AA) concentrations in platelets is described. Platelet ascorbate was determined as the difference in concentrations between platelet rich plasma and platelet free plasma. In 20 healthy individuals concentrations of AA in platelets and polymorphonuclear leukocytes were found to be significantly correlated (r = 0.72, P < 0.01). Measurement of platelet ascorbate may provide an estimate of tissue AA status.


Polyclonal immunoglobulin M: location of glycation sites. A four step purification procedure for polyclonal human serum IgM was elaborated, including ultracentrifugation, ammonium sulfate and polyethyleneglycol precipitations and diffusion-exclusion gel chromatography. IgM was glycated in vitro both in the presence of [14C]glucose and with unlabeled glucose. Influence of incubation time up to 10 days and of glucose concentration between 10 and 60 mmol/l were studied. With 10 mmol/l glucose, a molar ratio glucose/IgM of 5.7 was attained in 10 days. Increase of glucose concentration up to 60 mmol/l led to a molar ratio of 16.0. Both basal and in vitro glycation were evaluated by 3H-labeling by gel filtration and Concanavalin A-Sepharose chromatographies. Glycation occurs mainly on the heavy chains (> 85%), particularly on the Fd region.


Characterization of the gliadin-derived peptides which are biologically active in coeliac disease. Reversed-phase HPLC on C18 silica gel at pH 3.5 was used to separate peptides in fraction 9, a mixture of peptides of unknown composition obtained from an enzymic digest of wheat gliadin. This fraction, which has been shown to be toxic to individuals with coeliac disease, yielded a principal peak as well as many minor peaks after HPLC. The significant peaks were subjected to amino acid analysis. The principal peak obtained was purified by rechromatography at pH 6.0 and shown to contain a dodecapeptide of sequence H-Arg-Pro-Gln-Gln-Pro-Tyr-Pro-Gln-Pro-Gln-Pro-Gln-OH. This peptide may have been derived from regions in the A-gliadin molecule corresponding to amino acids numbered 75-86 or from homologous regions in other gliadin molecules. Preliminary results indicate that it is active in two in vitro models of coeliac disease and that it could be the source of one of the undigested peptides (Hexapeptide II, (Glx)3, (Pro)2, Tyr) obtained from coeliac mucosal digestion of fraction 9. Some active serine-containing peptides were also obtained from chromatography at pH 3.5 and attempts are being made to correlate these with the other undigested peptide (Hexapeptide I) of composition (Glx)3, (Pro)2, Ser, obtained after coeliac mucosal digestion of fraction 9.


Copper metabolism--a factor in gestational diabetes? The purpose of the present work was to investigate whether there is an involvement of copper metabolism in the mechanism of gestational diabetes mellitus. No statistically significant differences were found in serum copper and ceruloplasmin concentrations between healthy pregnant women and women with gestational diabetes mellitus. The activity of ceruloplasmin in women with gestational diabetes mellitus was slightly higher and its specific activity significantly raised. The CuZn superoxide dismutase activity was significantly increased (P < 0.05) in women with gestational diabetes mellitus, comparing the two groups by matched pairs according to age. The results indicate that oxidative stress may have a role in gestational diabetes mellitus and that reduced concentrations of copper are not the cause of this stress.


Differences in erythrocyte sodium transport between human plasma and artificial medium: the role and character of sodium efflux and influx stimulating plasma factors. The main objective of this study was to further characterize the plasma factor(s) which stimulate sodium efflux from erythrocytes, which we reported previously. Dialysis of plasma against an artificial medium using membranes with varying molecular mass cut-off points revealed relative molecular mass(es) of the factor(s) of 100-1000 Da. The factor(s) could be absorbed on Dowex at pH 1.5 and Amberlite at pH 11.0, indicating 'Zwitterionic' character. They are hydrophilic and resistant to acid hydrolysis. These characteristics and direct measurements of contents made amino acids likely candidates for the efflux stimulating properties of the factor(s). Indeed, plasma amino acids added to artificial medium could abolish the sodium efflux difference between plasma and the artificial medium. The efflux stimulating effect of amino acids appeared not to be the result of sodium influx stimulation. A coincident finding was that plasma also contains dialyzable sodium influx stimulating factor(s) which are not amino acids.


Protection of vascular basement membrane and microcirculation from elastase-induced damage with a fluorinated beta-lactam derivative. N-(2-chloromethylphenyl) 3,3-difluoroazetidin-2-one (AA 231-1), a specific suicide-type inhibitor of elastase which is known to suppress the lysis of chromogenic oligopeptides, elastin and elastic fibers, is effective also in preventing the degradation of the vascular basement membrane. The degradation of porcine glomerular basement membrane by purified human leukocyte elastase (HLE), was reduced in proportion of inhibitor dose (8.3 microM for 50% inhibition). It is noteworthy that there was no reduction of the inhibitory effect when the addition of AA 231-1 was delayed for 1 h after the addition of the enzyme to the substrate. In the guinea pig, reduction of the dermal microhemorrhage due to HLE was related to the dose of inhibitor and to its preincubation time with HLE before intradermal injection. The inflammatory hemorrhage associated with the Arthus skin reaction was moderately depressed by AA 231-1 in situ. A part of the vascular permeability induced by HLE also responded to the inhibitor. In spite of the tissular diffusion and the time-dependence parameters which restrict responsiveness of elastase to AA 231-1 in vivo this biochemical compound should be helpful in the study and possibly the cure of vascular injury related to elastase.


When do we treat hypercholesterolemia?

When do we treat hypercholesterolemia? Although the relationships between elevated total and low-density lipoprotein (LDL) cholesterol and coronary heart disease (CHD) are relatively well established and published treatment guidelines are available, clinicians face a number of complex issues when deciding whom to treat. Specific patient characteristics and potential risk factors, of which less is known, may influence treatment decisions. In this presentation, the current guidelines for treating patients with hypercholesterolemia are reviewed and therapeutic issues that must be considered when selecting patients for treatment are identified.


Therapeutic intervention for hypercholesterolemia. In previous presentations in these proceedings, the important relationships between cholesterol and coronary heart disease (CHD) have been reviewed. Guidelines, for Europe and the United States, for screening and intervention in persons with elevated total or low-density lipoprotein (LDL) cholesterol have been compared. In this presentation, the current approaches for dietary and drug treatment of hypercholesterolemia are discussed.


Cholesterol and cardiovascular disease: how strong is the evidence? The relationship between elevated serum cholesterol and cardiovascular disease, specifically coronary heart disease (CHD), has been and continues to be a source of debate in the medical community. Other issues under debate include criteria for screening for elevated cholesterol, criteria for treatment, and whether intervention to lower elevated cholesterol prior to a cardiac event is cost effective. Most physicians believe this latter statement to be true; however, reports of no decrease in overall mortality rates in those without clinical coronary disease in whom aggressive lowering of cholesterol is achieved may have contributed to the lack of consensus on this most important issue. In this presentation the evidence that links cholesterol and CHD is reviewed and it is demonstrated that lowering elevated cholesterol concentrations can improve quality of life and life expectancy.


Prostaglandins and the cervix.

Prostaglandins and the cervix. The dramatic capabilities of prostaglandins to modify the condition of the uterine cervix have been exploited to the considerable benefit of patients who require therapeutic interventions for labour induction and termination of pregnancy. This will continue to be an important facet of clinical obstetric and gynaecologic practice, although further refinements and improvements in techniques seem certain to continue.


Prostaglandins in the ovary and fallopian tube. More than 20 years following the recognition of a possible role for eicosanoids in ovarian function a physiological role for prostaglandins and/or leukotrienes in human ovulation, corpus luteum function and tubal motility remains to be demonstrated. With respect to ovarian function, the well-characterized preovulatory rise in eicosanoid production in animal species and humans, in conjunction with the large body of experimental evidence employing inhibitors of prostaglandin synthesis and replacement of individual prostaglandins, has provided strong evidence for a role in follicular rupture independent of other LH-mediated ovulatory events. The possible mechanism of prostaglandin-induced follicle rupture may involve stimulation of proteolytic activity via substances such as plasmin and PA; however, this is controversial. A role for prostaglandins in ovarian luteal function is well established in laboratory animals and large ruminant species, where PGF2 alpha derived from the uterus has been demonstrated to be the luteolytic factor. In humans, luteal function may be influenced by local intraovarian eicosanoid production, which has been suggested to involve the paracrine interaction of local ovarian hormones such as oxytocin, noradrenaline, insulin and IGFs, to name but a few. Several lines of evidence have also implicated prostaglandins as an aetiological factor in ovarian pathological states such as seen in the OHSS. However, the bulk of clinical experimental evidence to date has failed to support this contention. Prostaglandin production has likewise been well characterized in the fallopian tube in both humans and animal species. Whereas a role for prostaglandins in tubal transport has been demonstrated with animal species such as the rabbit, several studies have failed to define a similar function in humans. More recently, direct injections of prostaglandin analogues into the fallopian tube and the corpus luteum have been shown to be efficacious as a treatment for ectopic pregnancy. Whether the primary mechanism of action involves effects on tubal musculature or corpus luteum function, or is simply a local vascular effect, remains to be demonstrated. Therefore, although the physiological role for eicosanoids in ovarian and tubal function remains unclear, particularly in the human, an increasing body of recent evidence has suggested an important paracrine function for this class of cellular mediators whose interaction with other more recently characterized local ovarian factors has only begun to be recognized.


The role of prostaglandins in obstetrical disorders. All pregnancy-associated tissues are capable of producing prostaglandins including PGI2 and TXA2. In normal pregnancy there is a dominance of PGI2 over TXA2 which may contribute to the maternal circulatory adaptation to pregnancy. Furthermore, both fetoplacental PGI2 and TXA2 production are important regulators of the fetal blood supply. It has been clearly established that in pre-eclampsia PGI2 production decreases in the fetoplacental tissues and quite probably also in the maternal tissues. The effect of this change may be further exaggerated by the simultaneous stimulation in pre-eclampsia of TXA2 production. The reason for PGI2 deficiency is not known. Other vasoactive agents, such as endothelin, may act in concert with prostaglandins. Relative PGI2 deficiency is likely to exist also in IUGR and lupus anticoagulant syndrome of pregnancy. In the latter, lupus anticoagulant may directly inhibit the synthesis of PGI2. One study suggests PGI2 deficiency also in early pregnancies of women with a history of repeated abortions. Prostaglandin production increases during full-term labour, and similar but smaller changes also occur in preterm labour. A silent bacterial infection may trigger the onset of preterm labour through cytokine-stimulated increase of prostaglandin production. No data were found on prostaglandin production in post-term pregnancies. That oligo-polyhydramnios is possibly prostaglandin mediated is suggested by the control of polyhydramnios by indomethacin treatment. Smoking decreases the production of PGI2 and possibly increases that of TXA2, which may lead to decreased blood flow and IUGR. Which constituent of cigarette smoke exerts this effect is not known. Ethanol consumption causes aberrations in prostaglandin metabolism which cannot be directly connected with fetal alcohol effects.


Therapeutic drug monitoring in saliva. An update. This article re-examines the issue of salivary therapeutic drug monitoring (STDM). The anatomy and physiology of saliva and the salivary glands, as well as the effects of disease and drugs on salivary secretion and composition, are discussed briefly. Drugs for which therapeutic drug monitoring (TDM) has been shown useful are individually considered to determine if salivary drug concentrations (Csal) are reflective of plasma free drug concentrations (C(up)). That is, is the Csal/C(up) ratio time- and concentration-independent, as supported by a review of literature data? The primary determinant which appears to govern the potential utility of STDM for many of the drugs is the pKa of the drug. Drugs which are not ionisable or are un-ionised within the salivary pH range (phenytoin, carbamazepine, theophylline) are candidates for STDM based on current literature data. Digoxin and cyclosporin are potential candidates for STDM; however, further studies are necessary to confirm these preliminary findings. On the basis of current literature data, STDM does not appear to be useful for other drugs therapeutically monitored in serum/plasma.


Optimisation of immunosuppressive therapy using pharmacokinetic principles. Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-à-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.


Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives. Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.(ABSTRACT TRUNCATED AT 400 WORDS)


Time course of trough serum gentamicin concentrations in preterm and term neonates. Trough serum concentrations (Cmin) of gentamicin were followed during up to 96h of treatment in 44 neonates (17 preterm and 27 term), treated with intramuscular gentamicin 2.5 +/- 0.3 mg/kg (mean +/- SD) twice daily, a dosage that was not changed during the follow-up period. Relationships with patients' gestational age, postnatal age, postconceptional age and bodyweight were analysed to identify circumstances in which gentamicin should be monitored. Gentamicin Cmin values after 24h correlated better with neonate's postconceptional age (r = -0.42) or gestational age (r = -0.37) than with postnatal age or bodyweight. Correlations with postconceptional age and gestational age improved after 96h (r = -0.71 and r = -0.67, respectively). From 24 to 96h Cmin increased from 1.5 to 2 mg/L (p < 0.001) in the preterm neonates and from 1.5 to 2.5 mg/L (p < 0.01) in those preterm neonates < or = 32 weeks of gestational age, while differences between neonates < or = 3 days and > 3 days of postnatal age were nonsignificant. The Cmin at 24h was potentially toxic (> 2 mg/L) in 9% of the neonates (12% of preterm and 7% of term neonates). At 96h, the percentage of neonates with toxic Cmin values increased to 25% (65% of all preterm neonates and 100% of preterm neonates < or = 32 weeks of gestational age), whereas in term neonates it decreased to 0%. In conclusion, in preterm neonates < or = 32 weeks of gestational age a dosage of 2.5 mg/kg every 24h should be used, and gentamicin concentrations should be monitored. However, in term neonates > 7 days of postnatal age a dosage of 3.5 mg/kg twice daily should be recommended.


Cigarette smoking increases the mean platelet volume in elderly patients with risk factors for atherosclerosis. To study the effects of cigarette smoking and atherosclerosis on platelet size, we measured the mean platelet volume (MPV) and other platelet parameters in 142 elderly smokers and nonsmokers with or without atherosclerotic risk factors. The MPV and the platelet count were highest and their inverse correlation was strongest in the atherosclerotic smokers (r = 0.54, P < 0.05) when compared with the nonsmoking and non-atherosclerotic groups. A 10% decrease of MPV was found in 8 smoking subjects in the atherosclerotic group, who successfully discontinued smoking (P < 0.05). These results suggest that smoking may increase platelet consumption in atherosclerotic vessels and that subsequently megakaryocytes are activated to produce larger platelets, which are more active. Thus, an increase in MPV due to smoking may also contribute to the acceleration of atherosclerosis and should be considered as a risk factor for atherosclerotic disease.


Haematological phenotypes in a family with triplicated alpha-globin gene, beta zero 39 and delta+27 thalassaemia mutations. In this paper we report an unusual Sardinian family, in which the heterozygosity for beta zero 39-thalassaemia and for triple alpha-globin gene complex have been found in two members: the former showing a high HbA2 mild thalassaemia intermedia syndrome, the latter, her daughter, showing a normal HbA2 thalassaemia trait. Molecular analysis revealed the daughter to also be a carrier of a delta+27-thalassaemia point mutation, which in trans to the beta zero 39 defect invariably normalizes the HbA2 levels.


A comparison of differential white cell counting on the Coulter VCS and the Technicon H1 using simple and multiple regression analysis. This study uses the statistical methods of simple and multiple regression to compare the differential white blood count on the Coulter VCS and Technicon H1 analysers. The results demonstrate that both are good at distinguishing lymphocytes, neutrophils and eosinophils. Monocyte differential counts show disappointing correlation, both by simple and multiple regression techniques. Basophils, though less frequently a clinical problem, also correlated poorly in this study.


The effect of hypotonicity on the mean platelet volume of patients with thrombo-embolism. When dipotassium EDTA anticoagulated platelet rich plasma was incubated against a range of hypotonic saline concentrations, platelet volume was seen to change in a particular and reproducible fashion. When platelets taken from patients suffering a thromboembolic episode were tested in the same manner, a different pattern of response was observed the platelets being far less tolerant to osmotic stress. Similar changes occurred in platelets from ante-natal subjects. Platelets from both groups regained their tolerance to hypotonicity following either the thromboembolic incident or parturition respectively.


The use of interferon-gamma-treated U937 cells in chemiluminescence assays to detect red cell, platelet and granulocyte antibodies of potential clinical significance. The chemiluminescent (CL) response of interferon-gamma-treated U937 (IFN-U937) cells to sensitized target cells has been used to detect red cell, platelet and granulocyte antibodies. A clone of U937 cells was selected which expressed Fc receptor I (Fc gamma RI) and which, after incubation with IFN-gamma for 72 h, was capable of generating high levels of lucigenin-enhanced CL. The CL responses of IFN-U937 cells and peripheral blood human monocytes to sensitized red cells, platelets or granulocytes were then compared. Assays using monocytes or IFN-U937 cells were of comparable sensitivity for detection of antibodies against all three types of target cell. In addition, the use of IFN-U937 cells reduced interassay variation and simplified assay performance. The potential clinical usefulness of these CL assays was suggested by the ability of both monocytes and IFN-U937 cells to respond to red cells, platelets or granulocytes sensitized with sera from pregnant women whose babies had either haemolytic disease of the newborn (HDN), alloimmune thrombocytopenia or alloimmune neutropenia respectively. In addition, monocytes and IFN-U937 cells both responded to red cells sensitized with antibodies against a variety of specificities of assumed (although not documented) clinical significance for blood transfusion recipients. In contrast, monocytes and IFN-U937 cells responded only weakly to red cells sensitized with either anti-D in sera from mothers of babies unaffected by HDN, or with antisera containing high titre antibodies with specificities not normally associated with significantly reduced red cell survival.


Respiratory physiology in pregnancy.

Respiratory physiology in pregnancy. In conclusion, it is important to appreciate the anatomic and physiologic adaptations in pregnancy in order to accurately diagnose and treat cardiopulmonary disease states in the gravid woman. Without knowing what constitutes normalcy in pregnancy, inappropriate diagnosis and interventions may occur. Furthermore, this knowledge is fundamental for understanding how disease states affect pregnancy and how pregnancy affects disease.


Dyspnea during pregnancy. Distinguishing cardiac from pulmonary causes. Dyspnea is common during normal pregnancy; however, a variety of significant cardiac and pulmonary disorders present with this as a cardinal symptom. This article describes the cardiopulmonary and clinical findings of pregnancy as well as specific disease indicators in the more common causes of cardiac and pulmonary dyspnea during pregnancy.


Asthma in pregnancy.

Asthma in pregnancy. Most gravidas with asthma can be managed with an inhaled beta-adrenergic agonist (terbutaline or epinephrine) and beclomethasone dipropionate. The administration of prednisone to control exacerbation of asthma is appropriate and should not be withheld if current medications are inadequate. The outcome of pregnancy in gravidas with asthma can approach that of the general population if asthma is controlled effectively. There may be an increased incidence of preterm deliveries or preeclampsia in women with asthma during pregnancy.


Restrictive lung disease in pregnancy.

Restrictive lung disease in pregnancy. Restrictive ventilatory defects characterized by a reduction in lung volumes and an increase in the ratio of forced expiratory volume in 1 second to forced vital capacity occur when lung expansion is limited because of alterations in the lung parenchyma or because of abnormalities in the pleura, chest wall, or neuromuscular apparatus. Few studies have examined pregnant women with carefully defined restrictive lung disorders. The majority of pulmonary diseases have their onset after the childbearing years. When present, most do not alter fertility. Further, these disorders are only a relative contraindication to pregnancy because both the fetus and mother are able to survive without a high risk of increased morbidity or mortality. The clinical course of sarcoidosis is generally not altered by pregnancy. Factors indicative of a poor prognosis in sarcoidosis and pregnancy include parenchymal lesions on chest radiography, advanced roentgenologic staging, advanced maternal age, low inflammatory activity, requirement for drugs other than corticosteroids, and the presence of extrapulmonary sarcoidosis. Pregnancy seldom has a significant effect on the course of the connective tissue diseases. In PSS with significant renal involvement, pregnancy has the potential for poor fetal prognosis and the risk of maternal death due to a lethal progression of renal failure. Worsening of SLE is uncommon in pregnancy, and prophylactic therapy is generally not necessary. Most women with LAM are advised to avoid pregnancy or the use of estrogens because of the concern that it will lead to worsening of their disease. The incidence of kyphoscoliosis in pregnancy is relatively high. Premature birth rates are higher than that in the normal population. The risk of progression of the abnormal curve in a scoliotic patient appears low. However, women with unstable scolioses at the time of pregnancy can demonstrate progression of the curve with the pregnancy. Respiratory complications during pregnancy in patients with kyphoscoliosis have been reported but in general are not serious if appropriately managed. As a rule, patients with severe restrictive lung disease (i.e., vital capacity < 1 L) should be advised to avoid pregnancy or consider therapeutic abortion. If such a patient decides to continue the pregnancy she should be provided with optimal medical management of her underlying disease and should consider delivery by cesarean section.


Fertility and pregnancy in patients with cystic fibrosis. Issues related to fertility and pregnancy, once moot, are now extremely relevant to the care of a growing number of CF patients entering adulthood. With rare exception, men are infertile, due to the almost universal presence of malformations of the reproductive tract causing obstructive azoospermia. Emphasis in the care of these patients should be directed toward confirmation of infertility and counseling to allay anxieties. In contrast, a significant albeit unknown proportion of women are fertile and a steadily increasing number of these women are conceiving. The accumulated clinical experience has demonstrated that pregnancy is well-tolerated by patients with mild disease while associated with increased maternal and fetal complications in those with severe disease. In light of current uncertainties in accurately predicting outcome in all but the most clear-cut cases, the physician must exercise clinical judgment in providing a realistic assessment of the medical risks involved and of the advisability of pregnancy. This assessment should be based on a thorough and objective evaluation of the pulmonary, cardiac, and nutritional status of the patient. Future efforts, assisted by data collected for the national CF patient registry, should be directed toward better defining the long-term impact of pregnancy on the natural history of CF and more precisely defining the pregravid parameters useful in predicting outcome for both mother and child.


Respiration during sleep in pregnancy.

Respiration during sleep in pregnancy. Several changes in maternal physiology may profoundly alter sleep, especially during late pregnancy. Any condition that causes maternal hypoxemia will be worsened during sleep, particularly in the supine position. Although high circulating levels of progesterone increase respiratory drive during sleep, in at least some women this protective mechanism is insufficient to prevent sleep-disordered breathing and hypoxemia. The true incidence of sleep-disordered breathing during pregnancy remains unknown. Although many women report sleep disturbance during pregnancy, those with severe snoring, observed irregular breathing with sleep, or excessive daytime somnolence should be referred for clinical polysomnography. With few data thus far available, nasal CPAP would appear to be the treatment of choice. Given the possible consequences of sleep apnea for fetal outcome, any significant sleep-disordered breathing is probably an indication for treatment.


Deep venous thrombosis and pulmonary embolism in pregnancy. Deep venous thrombosis and pulmonary embolism are relatively frequent occurrences in pregnancy and the postpartum period. The diagnosis of deep venous thrombosis and pulmonary embolism requires accurate objective tests because clinical diagnosis is unreliable. Procedures that expose the fetus to ionizing radiation must sometimes be performed to make an accurate diagnosis; current evidence suggests that the adverse effects to the fetus associated with such procedures are minimal. Heparin is the anticoagulant of choice during pregnancy and is used for both the treatment and prevention of venous thrombosis and pulmonary embolism. Patients with deficiencies of antithrombin III, protein C, or protein S as well as patients with antiphospholipid antibodies are at increased risk for thrombotic complications and require particular vigilance during pregnancy.


Amniotic fluid embolism.

Amniotic fluid embolism. Amniotic fluid embolism is the most unpredictable and catastrophic complication of pregnancy, accounting for 10% to 20% of maternal deaths. The pulmonary edema commonly seen in this syndrome is probably due primarily to alveolar capillary leakage and may be potentiated by high maternal extracellular volume, low colloid osmotic pressure, and, in some patients, by depressed myocardial function. In patients in whom resuscitation is successful, diuresis leads to rapid resolution of pulmonary edema. Amniotic fluid does not ordinarily enter the maternal circulation, and the identification of large numbers of fetal squames in the postpartum pulmonary microvasculature is probably of clinical significance.


Pleural disease in pregnancy.

Pleural disease in pregnancy. Pleural effusions, pneumomediastinum, and pneumothorax are known complications of pregnancy. Although reported in small series and anecdotal case reports, the serious nature of these complications and the potential for misdiagnosis during the events of labor and delivery warrant a careful review of the available literature. In this article the incidence, clinical manifestations, and, where appropriate, therapeutic options of these disorders are discussed.


Pneumonia complicating pregnancy.

Pneumonia complicating pregnancy. Although pregnancy is infrequently complicated by pneumonia, lung infection by bacteria, viruses, and fungi can pose serious maternal and fetal hazards. Pneumonia may lead to preterm labor and certain infecting agents, most notably the HIV virus, can cross the placenta and lead to neonatal infection. There is some evidence that the incidence of pneumonia in pregnancy may be increasing among certain populations. In addition, infections caused by viruses (varicella and influenza) and fungal agents, ordinarily controlled by cell-mediated immunity, may be more virulent to pregnant women, thereby adding to maternal mortality. Beyond the influence of these pregnancy-induced changes in immunity, there are certain physiologic changes in pregnancy that make it more difficult for the pregnant woman to sustain any type of respiratory infectious insult. Certain types of pneumonias, particularly influenza and aspiration, may be avoided if patients at risk are identified and existing strategies for prevention are applied. When the pregnant women is treated for lung infection, the safety of antimicrobial agents must be considered, and therapy may differ from that used in the nonpregnant patient.


Tuberculosis and pregnancy.

Tuberculosis and pregnancy. After decades of decline, tuberculosis case rates are again increasing in the United States. The increases have been most dramatic among minority young adults of childbearing age. The availability of adequate chemotherapy means that the outcome for both mother and child in pregnancy complicated by tuberculosis should be good. Complete case finding and screening of high-risk adults is essential to bring tuberculosis under control again.


Sepsis in pregnancy.

Sepsis in pregnancy. Sepsis remains an uncommon, but potentially devastating problem in the previously healthy pregnant patient. Although septic sequelae, including organ failure and shock, are unusual, they are likely to lead to morbidity and mortality as high, or higher, than in the general population. At the present time, hemodynamic support, surgery, and antimicrobial therapy aimed at reducing polymicrobial aerobic and anaerobic infection remain the gold standard of therapy. New antimediator and anti-inflammatory therapies offer promise of improved survival in the general and obstetric population with severe sepsis.


Impotence in diabetes: aetiology, implications for treatment and preferred vacuum device. In an assessment of the contributions of autonomic neuropathy and vascular disease to the aetiology of male impotence in diabetes, evidence of autonomic neuropathy was identified in 23/39 (59%) individuals complaining of impotence. Thirteen of 26 men aged < 60 years tested with an intracorporeal injection of papaverine experienced little or no response and seven had tumescence but no rigidity. Radioisotope phallography demonstrated vascular disease in six of these seven, suggesting evidence of a vascular component in 19/26 (73%). Only one patient had non-organic impotence. Overall, evidence of vascular disease alone was demonstrated in 10/26 (38%), vascular disease plus autonomic neuropathy in 9/26 (35%), and autonomic neuropathy alone in 6/26 (23%). Many diabetic men complaining of impotence appear to have a significant vascular component which renders intracorporeal papaverine treatment ineffective. We compared the performance of a vacuum constriction-band (Erecaid) and condom-type (Synergist) device in 10 randomly selected men from this group. The devices, provided in random order for 5 months each, were assessed by questionnaire and interview of both the patient and partner. Two couples defaulted and another could use neither device. Although erectile capacity could be restored in the remainder, subsequent intercourse was only deemed satisfactory to both partners in five couples, who unanimously preferred the constriction-band device. In treatment with vacuum devices the constriction-band type seems to be the device of choice; the condom type should probably be reserved for those unable to use the constriction-band type.


A cross-sectional study of echocardiographic indices, treadmill exercise capacity and microvascular complications in Nigerian patients with hypertension associated with diabetes mellitus. Associations between hypertension and cardiovascular complications of diabetes mellitus in Nigerians, were examined in a cross-sectional study. 20 hypertensive-diabetic patients, 16 hypertensive patients, 10 non-hypertensive diabetic patients and 10 age- and sex-matched healthy controls, underwent M-mode and cross-sectional echocardiography, and Bruce-protocol treadmill exercise performance. Left ventricular (LV) mass indices (+/- SD) were significantly higher in hypertensive patients (164 +/- 12gm-2), diabetic (158 +/- 17gm-2) and hypertensive diabetic patients (125 +/- 129gm-2) compared with normal controls (111 +/- 17gm-2) p < 0.01. However, the LV mass index in the hypertensive-diabetic patients was significantly less than in hypertensive (p < 0.05) or normotensive diabetic patients (p < 0.05). Systolic cardiac contractility measured as fractional fibre shortening, was preserved in the hypertensive patients (24 +/- 4%) compared with the healthy controls (23 +/- 4%), but was depressed in diabetic patients (19 +/- 3%) and to a greater extent in the hypertensive-diabetic patients (15 +/- 4% p < 0.01). Treadmill exercise tolerance time was reduced independently in hypertension (309 +/- 73 seconds) or diabetes (321 +/- 119 seconds), p < 0.05, but was further impaired in hypertensive-diabetic patients (289 +/- 110 seconds) p < 0.01 compared to the healthy controls (490 +/- 156 seconds). The patients with hypertension and diabetes had a greater degree of proteinuria (p < 0.001) and a higher frequency of retinopathy (p < 0.001), in comparison to those with hypertension or diabetes alone.


Risk factors for peripheral vascular disease in hypertensive subjects with type 2 diabetes mellitus. Possible factors predisposing to peripheral vascular disease (PVD) in hypertensive subjects with Type 2 diabetes mellitus were studied. Details of age, sex, duration of diabetes, blood pressure, and smoking habit were recorded in 180 subjects of either White, West Indian Black or Asian ethnic origin. Glycosylated haemoglobin, fasting serum total cholesterol, total high density lipoprotein (HDL), HDL2, low density lipoprotein (LDL-cholesterol), and triglycerides were measured in all subjects. Peripheral vascular disease was defined as an ankle/brachial systolic pressure < 1.0 as measured by the Doppler technique. Multivariate analysis was performed and the following factors were identified as being strongly associated with the presence of PVD with a statistical significance of p < 0.001; LDL-cholesterol, total HDL-cholesterol, age, male sex, diet or oral hypoglycaemic therapy, diastolic blood pressure, and of p < 0.003; systolic blood pressure. When blood pressure was excluded from the analysis the other factors retained their predictive value. We conclude that hypertension and dyslipidaemia are important risk factors for peripheral vascular disease in Type 2 diabetes mellitus.


A double blind study of the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with type 2 diabetes mellitus. Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.


Insulin injection site tissue depths and localization of a simulated insulin bolus using a novel air contrast ultrasonographic technique in insulin treated diabetic subjects. Subcutaneous adipose tissue depth was measured in 50 randomly selected Type 1 diabetic patients by real-time ultrasound at five standard sites commonly used for injection. Tissue depths were often less than the length of the standard insulin syringe needle (12-13 mm) at the arm and thigh injection sites, especially in men. Thus, if the currently recommended perpendicular injection technique were to be employed, there would, in theory, be an appreciable risk of intramuscular insulin deposition. In order to determine the true site of deposition in those at risk (injection site tissue depth of < 12 mm), a novel air-contrast ultrasound imaging technique was developed. A mixture of 0.1 ml of air and 0.2 ml of sterile 0.9% saline was self-injected into an anterior thigh site by 30 subjects using their usual technique. The site of the resultant tissue depot was located by ultrasound. Sixty-three percent of the depots were localized to true subcutaneous tissue and the remaining 37% to between the fascial planes overlying muscle. None of the subjects proved to be injecting into muscle. These results contrast with predictions of the risk of intramuscular injection made from the ultrasound measurement of subcutaneous tissue alone at the anterior and lateral thigh sites of, respectively, 100 and 97% for men and 42 and 37% for women. Although 11 of the 30 subjects claimed to be using a full-depth perpendicular injection technique, on direct observation only four proved to be injecting perpendicularly and none of these to the full depth of the needle.(ABSTRACT TRUNCATED AT 250 WORDS)


A simple method for quantitation of insulin sensitivity and insulin release from an intravenous glucose tolerance test. Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS)


T-cell receptor constant beta chain polymorphisms and susceptibility to type 1 diabetes. Several groups have previously shown that the T-cell receptor (TCR) constant-beta (C beta) chain locus is associated with susceptibility to Type 1 diabetes, although other studies have failed to show this. We have extended these studies by investigating 125 individuals with Type 1 diabetes and failed to confirm the significantly increased frequency of the 10;9.2 kb TCR-C beta/Bgl-II genotype in our patient population. However, further analysis showed that the 10;9.2 kb TCR-C beta genotype was significantly increased in those patients with no microvascular complications after 20 years of diabetes compared to those patients with complications (proteinuria, overt neuropathy, and moderate or severe retinopathy) 69.2% vs 31.7%, respectively, p < 0.005 Pc = 0.025). Similar results were also found in a second group of 74 patients who were analysed in the same way. Hence, the failure of some investigators to confirm the association between TCR-C beta and Type I diabetes may be due to heterogeneity in the patient populations being studied.


The quality and relevance of peripheral neuropathy data on a diabetic clinical information system. Routinely collected peripheral neuropathy data entered on a diabetic clinical information system since 1979 have been audited for completeness, consistency, accuracy (inter-observer variation), validity by comparison with biothesiometry, and relevance by life table analysis for foot ulceration. Peripheral neuropathy was defined by a neuropathy disability score > or = 4. The data were 98% complete. Forty-nine of 3405 (1.4%) had inconsistent records. Agreement between observers for clinical examination was significant (p < 0.05) for aggregate neuropathy score and its individual components except the knee jerk: Kappa score for observer variation for neuropathy score 0.56 (95% confidence interval 0.36-0.76). There was good agreement between neuropathy defined as aggregate score > or = 4, and as combined vibration perception thresholds for both feet > 60 V: Kappa statistic 0.62 (95% confidence interval 0.44-0.80). The chance of developing a foot problem in 3 years increased from 3% for patients with a score of zero to 45% for people with a score of between 9 and 12. We conclude that the calculation of a clinical neuropathy score is a simple, valid and relevant method for diabetes care both in hospital and the community. When combined with palpation of peripheral pulses most patients at risk of foot ulceration can be identified allowing targeting of preventive chiropody and orthotic resources.


Prescribing and dispensing of insulin: margins for error? To investigate recent anecdotal reports of incorrect insulin dispensing, we compared retail pharmacists' and doctors' understanding of commonly used insulin brands. Eighty pharmacists, 29 general practitioners (GPs), and 31 junior hospital doctors were interviewed and completed a questionnaire concerning the duration of action and formulation of 17 insulins. Views on dispensing of alternative insulins were sought from the pharmacists. Fifteen insulin pairs in two columns, 'insulin prescribed' and 'dispense instead', were presented and pharmacists and doctors asked if substitution was appropriate. Mixtard, Penmix and Actrapid were the best understood insulins, Insulatard, Humulin Zn and Protaphane the worst. Both GPs (p = 0.014) and hospital doctors (p < 0.001) scored better than pharmacists. No pharmacist stated that they would routinely dispense alternative insulin, 27 out of 80 not even in an emergency, though 37 were prepared to do so in such a situation after checking, usually with a doctor or in the relevant literature. Sixteen pharmacists, 24 GPs, and all 31 hospital doctors completed the section on insulin pairs but accuracy at identifying appropriate substitutions was poor. These findings coupled with confusing insulin nomenclature may lead to dangerous dispensing errors.


A survey of lower limb amputation in diabetic patients. A retrospective survey of non-traumatic and non-neoplastic lower limb amputations in Newcastle upon Tyne during 1989-91 was performed. Hospital data were cross-checked with the local limb fitting centre to ensure 100% ascertainment. The diabetic patients were found to be 39% of amputees and 42% of operations (all levels). Incidence of diabetes amputation was 5.7 per 100,000 population per year. Fifteen percent of the diabetic patients had diabetes first diagnosed when they were admitted for amputation. For the known diabetes patients, 46% were under diabetes care by general practitioners only. Forty-seven percent of the patients who were under the care of a hospital service for diabetes had incomplete foot examination and assessment. Mortality rate within 30 days after diabetic amputation was 10% and median life expectancy following amputation was 22 months. It seems likely that assessment and management of the diabetic foot remains suboptimal in Newcastle, and that protocols and audit of care could lead to improvements without additional resources.


Staphylococcal septicaemia complicating intracavernosal autoinjection therapy for impotence in a man with diabetes. Intracavernosal injection of vasoactive drugs is a safe, effective, and commonly used treatment for impotence in diabetic men. In prospective studies infection has rarely occurred. We report a case of life-threatening Staphylococcal septicaemia complicating this treatment in a 61-year-old man with Type 2 diabetes, probably due to a combination of an unsterile technique and drug-induced priapism. Infection is a potential risk in diabetic men using intracavernosal injection therapy and those offered it should be informed of the importance of a scrupulous sterile technique and the need to seek urgent medical help for decompression if an erection persists for more than 4-6 h.


Pre- and postoperative glucose levels for eliciting hypoglycaemic responses in a patient with insulinoma. Counterregulatory hormones and hypoglycaemic symptoms were studied during a gradual decline in plasma glucose in a 66-year-old man before and 9 weeks after removal of an insulin-producing tumour. Before surgery the adrenaline started to respond first at plasma glucose 2.8 mmol l-1. He reported no autonomic symptoms although plasma glucose fell to 2.3 mmol l-1 with a corresponding adrenaline rise to 4.64 nmol l-1. After surgery adrenaline responded at a plasma glucose of 3.7 mmol l-1 and he started to sweat and tremble at a plasma glucose of 3.1 mmol l-1 (corresponding adrenaline 2.63 nmol l-1). The lack of autonomic symptoms preoperatively may indicate adrenaline insensitivity, possibly as a result of repeated hypoglycaemia.


Phrenic neuropathy in association with diabetes. We report the case of a 51-year-old man who presented with breathlessness on exertion and orthopnoea in association with Type 2 diabetes mellitus. Investigation showed bilateral diaphragmatic paralysis due to phrenic neuropathy. There was no evidence of neuropathy or microvascular disease elsewhere. Phrenic neuropathy may be an important, albeit rare, complication of diabetes and diaphragmatic function should be considered in any patient with unexplained breathlessness and orthopnoea.


Diagnosis of typhoid fever by two serologic methods. Enzyme-linked immunosorbent assay of antilipopolysaccharide of Salmonella typhi antibodies and Widal test. Serum samples from 85 patients with proven typhoid fever, 11 patients with p-typhoidal fever, 101 patients with febrile non-typhoidal, and 130 healthy subjects were tested for immunoglobulin G (IgG), IgA, and IgM antilipopolysaccharide (LPS) of Salmonella typhi antibodies by enzyme-linked immunosorbent assay (ELISA) and Widal test. The levels of all three classes of immunoglobulin anti-LPS of S. typhi were higher in typhoid patients than in healthy or febrile nontyphoidal groups; we selected various combinations between the three classes of immunoglobulin to obtain the best combination of sensitivity and specificity. The sum of the absorbance values obtained from the ELISA assay for IgG+IgA+IgM (sigma lgs) was the best choice for diagnostic utility for typhoid fever. We selected a positive test at a decision level of sigma lgs > or = 1.2 with a sensitivity of 94% and a specificity of 92% with a frequency of false negative of 5.9%. The frequency of false positives for healthy controls was 7.7% and, for the febrile nontyphoidal group, it was 7.9%. We also compared receiver (or relative) operating characteristic (ROC) curves for the diagnostic usefulness of the ELISA with that of the Widal test, whose merits and limitations, especially in endemic regions, are discussed. The ELISA assay was much more sensitive and specific than any combination of the Widal test, and hence it could be a useful tool for the serologic diagnosis of typhoidal fever with a single blood sample.


Usefulness of the resting electrocardiogram in the elderly. The ECG is useful in diagnosing acute myocardial infarction and unrecognized Q-wave myocardial infarction in the elderly. Unrecognized myocardial infarction and myocardial infarction associated with clinical symptoms have a similar incidence of new coronary events. Ischemic ST-segment depression on the resting ECG is associated with an increased incidence of new coronary events. The ECG is useful in the diagnosis of LV hypertrophy but is less sensitive and less specific than echocardiography in diagnosing LV hypertrophy. ECG LV hypertrophy is associated with an increased incidence of cardiovascular events in the elderly. However, echocardiographic LV hypertrophy is more sensitive in predicting new coronary events, atherothrombotic brain infarction, and congestive heart failure than is ECG LV hypertrophy. The ECG is also useful in diagnosing conduction defects and arrhythmias in the elderly. In the elderly, left bundle branch block, intraventricular conduction defect, Type II second-degree atrioventricular block, and pacer rhythm are associated with an increased incidence of new cardiac events, whereas right bundle branch block, left anterior fascicular block, and first-degree atrioventricular block are not. In the elderly, atrial fibrillation is associated with an increased incidence of thromboembolic stroke and new cardiac events. Premature atrial complexes and paroxysmal supraventricular tachycardia are not associated with an increased cardiac risk. Complex ventricular arrhythmias on the resting ECG are associated with an increased incidence of cardiac events in elderly patients with heart disease but not in elderly patients without heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of Syngene DNA-DNA probe assays for the identification of the Mycobacterium tuberculosis complex and the Mycobacterium avium complex. Two hundred mycobacterial cultures were used to evaluate two alkaline-phosphatase-labeled DNA probe (SNAP) kits developed by Syngene (San Diego, CA) for identification of Mycobacterium tuberculosis complex and M. avium complex. The M. tuberculosis complex SNAP probe, when compared with standard biochemical identification tests, gave results that were in agreement at 100% sensitivity and 98.7% specificity. Ninety-nine M. avium complex strains that were previously tested by the Gen-Probe M. avium complex probe assays and mycolic acid analysis were included to evaluate the M. avium complex SNAP assay which contained three probes, A (avium), I (intracellulare), and X. Eight strains identified as members of the M. avium complex by biochemical tests did not react with the three SNAP probes. These strains were also negative by the Gen-Probe assays. However, 23 strains identified as M. avium complex by biochemical tests and mycolic acid analysis and negative with the Gen-Probe assays gave positive results with the X probe and negative results with the A and I probes of the SNAP assay.


Organ damage in shock, disseminated intravascular coagulation, and stroke. Disseminated intravascular coagulation (DIC) may cause multiple organ failure. Although DIC may cause capillary occlusion in any and all organs, the lungs, liver, kidneys, gut, heart and brain are particularly affected. Focal brain necrosis can also be caused by DIC. Fibrinolytic therapy will often restore significant blood flow to the capillaries of the lungs. This results in significant increase in lung function because the lung is more resistant to actual necrosis and will resume function once circulation is restored. Administration of fibrinolytic therapy will also prevent liver and kidney failure if started within four hours after trauma. This therapy, when given in low doses intravenously over a twenty-four hour period, has little effect on the coagulation mechanism, and abnormal bleeding, therefore, has not been a concern. It is speculated that if plasminogen activators are effective and safe for treating the intravascular clots of DIC, then perhaps they would be effective in treating other types of intravascular coagulation in the brain, such as various types and degrees of stroke.


The debut of geriatric medicine.

The debut of geriatric medicine. The transition from mystical to scientific medicine for the aging patient is in part due to the observations of Christoph Wilhelm Hufeland. Though centuries old, his observations ring true even for today's comprehensive therapy.


Evaluation of Syva's enzyme immunoassay for the detection of Chlamydia trachomatis in urogenital specimens. A newly developed microwell enzyme immunosorbent assay (EIA) system by Syva Company (Palo Alto, CA) can detect Chlamydia trachomatis in < 3 hr. It uses a polyclonal antibody to chlamydial lipopolysaccharide and end points are determined with a spectrophotometer. Three clinical trial sites (University of California Medical Center, San Francisco, CA; University of Washington, Seattle, WA; and Louisiana State University Medical Center, New Orleans, LA), compared this EIA with tissue culture (TC) for identifying Chlamydia in urogenital specimens. Overall prevalence by TC was 10.4% (136 of 1306). When tests were compared with TC (using vials or microtiter plates and a fluorescent antibody stain), we found an EIA sensitivity of 93.4% (127 of 136) and a specificity of 98.1% (1148 of 1170). This EIA has a performance profile that is, at the very least, comparable with other nonculture methods for diagnosing genital tract infections with C. trachomatis.


Immunosenescence.

Immunosenescence. The aging immune system, while showing little in the way of quantitative changes, demonstrates important functional changes, especially T-cell functions. In addition to increased susceptibility to some infections, there is an increased likelihood of autoantibody production, and the emergence of monoclonal antibodies and other lymphoproliferative disorders. The role of the immune system in degenerative processes, and susceptibility to malignant processes requires further investigation. Biotechnology is producing many new methods of modulating immune function, with ever increasing specificity. Thus the future holds great promise for overcoming the effects of immunosenescence.


Haemophilus test medium interpretive criteria for disk diffusion susceptibility tests with cefdinir, cefetamet, cefmetazole, cefpodoxime, cefdaloxime (RU29246, HR-916 metabolite), and trospectomycin. The disk diffusion zones and the MICs of six newer antimicrobials with significant activity against Haemophilus influenzae were compared using the Haemophilus test medium (HTM) and National Committee for Clinical Laboratory Standards methods. The rank order of potency was cefpodoxime (MIC50, < or = 0.03 micrograms/ml) > cefetamet > cefdinir > cefdaloxime = trospectomycin > cefmetazole (MIC50, 2 micrograms/ml). Susceptible breakpoint interpretive criteria for HTM tests were established that conformed to prior recommendations for each drug when tested against other species. Absolute agreement between methods ranged from 89% to 100% with < or = 1% false-susceptible interpretive errors. The recommended, tentative disk diffusion susceptible interpretive criteria were for 5-micrograms cefdinir disks > or = 20 mm (MIC correlate, < or = 1 micrograms/ml); for 10-micrograms cefetamet disks > or = 18 mm (MIC correlate, < or = 4 micrograms/ml); for 30-micrograms cefetamet disks > or = 21 mm (MIC correlate, < or = 4 micrograms/ml); for 30-micrograms cefmetazole disks > or = 16 mm (MIC correlate, < or = 16 micrograms/ml); for 10-micrograms cefpodoxime disks > or = 21 mm (MIC correlate, < or = 2 micrograms/ml); for 30-micrograms cefdaloxime disks > or = 23 mm (MIC correlate, < or = 2 micrograms/ml) and for 30-micrograms trospectomycin disks > or = 17 mm (MIC correlate, < or = 16 micrograms/ml). beta-Lactamase-negative, ampicillin-resistant (BLNAR) H. influenzae isolates consistently had the highest MICs for each cephalosporin tested.(ABSTRACT TRUNCATED AT 250 WORDS)


An overview of antimicrobial therapy.

An overview of antimicrobial therapy. Dealing with infections is an integral part of clinical practice. The vast number of antimicrobial agents available, with new ones being introduced constantly, behooves practitioners to keep abreast of the properties, antimicrobial activities, clinical uses and possible adverse effects of these agents. This article attempts to present an overview on several classes of antimicrobial agents commonly used in our daily practices, with the hope of steering our colleagues toward rational and judicious usage of these potent medications.


Surgical wound infection by Aspergillus fumigatus in liver transplant recipients. Cutaneous aspergillosis is generally associated with immunosuppression, burns, and major trauma. Most cases are acquired by direct inoculation, although cutaneous involvement does occasionally occur with disseminated disease. Surgical wound infections caused by Aspergillus species are very unusual and to our knowledge have not been described in the setting of organ transplantation. We describe two liver transplant recipients who developed wound aspergillosis during a nosocomial outbreak of Aspergillus infection. Infection developed in the second and fourth postoperative week respectively, and in both cases wound appearance mimicked necrotizing fasciitis. Both patients died despite local debridement and antifungal therapy with amphotericin B. Aspergillus must be added to the list of potential pathogens of surgical wounds, especially in the setting of organ transplantation.


Susceptibility testing interpretive criteria and drug stability for cefdinir, cefetamet, and cefpodoxime against Neisseria gonorrhoeae. Cefdinir, cefetamet, and cefpodoxime, three orally administered cephalosporins, were tested against 100 strains of Neisseria gonorrhoeae having various antimicrobial susceptibility patterns. Triplicate testing of each organism strain was performed for all agar dilution and disk diffusion tests. Cefdinir was the most active compound (MIC90) micrograms/ml) especially against gonococci with chromosomal-mediated resistance to penicillin. The recommended susceptible interpretive criteria were as follows: for the 5-micrograms cefdinir disk, > or = 31 mm (MIC correlate, < or = 0.25 microgram/ml); for the 10-micrograms cefetament disk, > or = 29 mm (MIC correlate, < or = 0.5 microgram/ml; for the 30-micrograms cefetamet disk, > or = 31 mm (MIC correlate, < or = 0.5 microgram/ml); and for the 10-micrograms cefpodoxime disk, > or = 29 mm (MIC correlate, < or = 0.5 microgram/ml). No organisms resistant to these new cephalosporins were detected. Cefdinir, cefetamet, and defpodoxime were stable in GC agar medium for at least 21 days when stored at 2 degrees-5 degrees C.


Isolation of two odorant-binding proteins from mouse nasal tissue. 1. Two soluble proteins, with good affinity to tritiated 2-isobutyl-3-methoxypyrazine, have been purified from mouse nasal mucosa. 2. The first protein is a heterodimer with subunits of apparent M(r) 18 and 19 kDa and isoelectric point of 4.9; the second is a monomer of M(r) 21 kDa and isoelectric point of 4.8. 3. The characteristics of these binding proteins are compared with those of the other known OBPs and urinary proteins and their putative role is discussed.


Organization of non-vertebrate globin genes. The organization of non-vertebrate globin genes exhibits substantially more variability than the three-exon, two-intron structure of the vertebrate globin genes. (1) The structures of genes of the single-domain globin chains of the annelid Lumbricus and the mollusc Anadara, and the globin gene coding for the two-domain chains of the clam Barbatia, are similar to the vertebrate plan. (2) Genes for single-domain chains exist in bacteria and protozoa. Although the globin gene is highly expressed in the bacterium Vitreoscilla, the putative globin gene hmp in E. coli, which codes for a chimeric protein whose N-terminal moiety of 139 residues contains 67 residues identical to the Vitreoscilla globin, may be either unexpressed or expressed at very low levels, despite the presence of normal regulatory sequences. The DNA sequence of the globin gene of the protozoan Paramecium, determined recently by Yamauchi and collaborators, appears to consist of two exons separated by a short intron. (3) Among the lower eukaryotes, the yeasts Saccharomyces and Candida have chimeric proteins consisting of N-terminal globin and C-terminal flavoprotein moieties of about the same size. The structure of the gene for the chimeric protein of Saccharomyces exhibits no introns. According to Riggs, the presence of chimeric proteins in E. coli and other prokaryotes, such as Alcaligenes and Rhizobium, as well as in yeasts, suggests a previously unrecognized evolutionary pathway for hemoglobin, namely that of a multipurpose heme-binding domain attached to a variety of unrelated proteins with diverse functions. (4) The published globin gene sequences of the insect larva Chironomus have an intron-less structure and are present as clusters of multiple copies; the expression of the globin genes is tissue and developmental stage-specific. Furthermore, the expression of many of these genes has not yet been demonstrated despite the presence of apparently normal regulatory sequences in the two flanking regions. Unexpectedly, Bergtrom and collaborators have recently shown that at least three Ctt globin II beta genes contain putative introns. (5) Pohajdak and collaborators have found a seven-exon and six-intron structure for the globin gene of the nematode Pseudoterranova which codes for a two-domain globin chain. Although the second and fourth introns of the N-terminal domain correspond to the two introns found in vertebrate globin genes, the position of the third intron is close to that of the central intron in plant hemoglobins.(ABSTRACT TRUNCATED AT 400 WORDS)


Proteinases and proteinase inhibitors as modulators of animal cell growth. 1. Three distinct lines of evidence indicate that proteinases are involved in the growth of cultured animal cells. 2. Endogenous growth-related proteinases have been identified, and exogenous proteinases can also stimulate cell proliferation, probably by different mechanisms. In some cases, higher concentrations of proteinases are cytotoxic. 3. Proteinase inhibitors, not surprisingly, inhibit cell growth, but can also be mitogenic at sub-inhibitory concentrations. 4. There must, therefore, be at least three major cellular processes in which proteinases or proteinase inhibitors can operate to exert a direct effect on cell proliferation. 5. Details of one action of an exogenous proteinase, typified by thrombin and the thrombin receptor, are becoming clear at the molecular level, but thrombin probably activates at least two intracellular signalling systems, as well as acting as a growth inhibitor in some situations. 6. Much remains to be investigated in other examples.


Comparative study of the responses of bovine and mouse intestinal mucosa to iron-dependent lipid peroxidation. 1. The extent of lipid peroxidation in vitro, as indicated by the production of malonaldehyde, was significantly different in homogenates of bovine and mouse intestinal mucosa. 2. Mouse intestinal mucosa was resistant to non-enzymatic lipid peroxidation whereas bovine intestinal mucosa was not. 3. Iron-dependent lipid peroxidation in bovine intestinal mucosa depends on the position the cells occupy along the crypt-villus axis. 4. The addition of methanolic extracts from bovine intestine to mouse liver homogenates produced a considerable increase in non-enzymatic peroxidation whereas those from mouse intestinal mucosa had no effect.


Heat shock protein response in phosphorus-deficient heat-stressed broiler chickens. 1. During acute in vivo heat stress, a normal heat shock protein (HSP) response was not inducible in chickens deficient in inorganic phosphorus (P(i)-deficient). 2. Small quantities of HSP 70 and HSP 90 were induced, but little or no HSP 23 was induced in P(i)-deficient chickens compared to P(i)-adequate chickens. 3. Increased susceptibility of P(i)-deficient chickens to acute heat stress was attributed to their inability to produce an adequate HSP response.


Inverse relation in the de novo arginase synthesis and nitric oxide production in murine and rat peritoneal macrophages in long-term cultures in vitro. 1. The de novo synthesis of arginase was much higher in murine than in rat peritoneal macrophages. This process was inhibited irreversibly by protein synthesis inhibitors and reversibly by glycolysis blockers. 2. Rat macrophages produce more nitric oxide (NO) than murine cells. NO production was inhibited by the inhibitors of protein synthesis or glycolysis. 3. The loading of macrophages by exogenous arginine for 24 hr in vitro resulted in the increase of arginase and nitrite in macrophages to different extents. 4. No great differences in lysozyme production was observed. 5. The proportion of arginine taken up and incorporated is contrasted in murine and rat macrophages.


Effects of ATP level on glutathione regeneration in rabbit and guinea-pig erythrocytes. 1. Effects of ATP level on GSH regeneration were studied in the rabbit and guinea-pig erythrocytes. 2. There was a species difference in the efficacy of adenine, inosine and glucose as substrates for ATP recovery in the erythrocytes. 3. Erythrocytes GSH regeneration rate was found to be dependent on the cellular level of ATP in both the species.


Effects of phenol compounds, glutathione analogues and a diuretic drug on glutathione S-transferase, glutathione reductase and glutathione peroxidase from canine erythrocytes. 1. Phenol compounds (ellagic acid, quercetin and purpurogallin), glutathione analogues (S-hexylglutathione and S-octylglutathione) and a diuretic drug (ethacrynic acid) were compared for their inhibitory effects on glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) in the canine erythrocytes. 2. All these compounds inhibited GST activity; quercetin was found to be the most potent inhibitor. 3. Ellagic acid, purpurogallin, quercetin and ethacrynic acid inhibited GR activity; S-hexylglutathione and S-octylglutathione had no effect on GR and GSH-Px activities. 4. Quercetin and purpurogallin inhibited GST non-competitively toward glutathione, whereas ellagic acid showed a competitive inhibition. Ellagic acid and purpurogallin inhibited GR non-competitively toward oxidized glutathione.


Heparin-binding properties of lactoferrin and lysozyme. 1. Binding of biotin-heparin to immobilized lactoferrin and lysozyme was optimum at pH 6.0, 100 mM NaCl. Complex interactions between NaCl and CaCl2 concentrations were observed for heparin binding to both proteins. 2. The metal ions Cu2+, Zn2+, Fe2+ and Fe3+ inhibited heparin binding, with half-maximal inhibition of binding to lactoferrin occurring between 600 microM and 1 mM and for lysozyme between 500 and 800 microM. 3. Binding of biotin-heparin to both proteins was inhibited to varying degrees by heparin, heparan sulfate, chondroitin sulfate A, dextran sulfate and DNA.


Glutathione reductases from a variety of sources are inhibited by physiological levels of glutathione. 1. Glutathione reductase from human platelets, bovine intestinal mucosa, yeast and E. coli were inhibited in vitro by physiological levels of reduced glutathione with IC50s of 6.61 mM, 2.92 mM, 2.40 mM and 12.11 mM, respectively. 2. A steady-state kinetic examination revealed that glutathione inhibited the NADPH oxidation (at constant [glutathione-disulphide]) catalysed by the eucaryotic enzymes uncompetitively, whereas the E. coli enzyme appeared unaffected by glutathione concentrations of up to 10 mM. 3. With respect to glutathione inhibition of glutathione-disulphide reduction (at constant [NADPH]), the human enzyme was inhibited uncompetitively; the bovine and yeast enzymes displayed apparent mixed hyperbolic inhibition; the E. coli enzyme was inhibited competitively.


Studies on the blood of fallow deer (Dama dama) and red deer (Cervus elaphus): haematology, red cell enzymes, metabolic intermediates and glycolytic rates. 1. Blood samples were obtained from fallow deer (Dama dama) and red deer (Cervus elaphus). Basic haematology, red cell enzymes, and metabolic intermediates and the glycolytic rate of the red cells incubated with different substrates were measured. 2. The major findings were (i) the activity of glucose phosphate isomerase was notably high in the red blood cells of the red deer; (ii) red deer cells also utilized adenosine more efficiently than those of fallow deer and (iii) red cells of both species utilized galactose more efficiently than other species of ruminants.


Effect of energy metabolism on 13C/12C-ratios in milk fat and lactose of cows. 1. The ratios of stable carbon isotopes 13C/12C in milk constituents of Holstein dairy cattle were investigated by mass spectrometry. 2. Under physiological feeding conditions the natural abundance of 13C in lactose was greater than in milk fat. 3. Reduction of energy intake diminished the abundance of 13C in lactose resulting in values similar to those of fat. 4. It is suggested that by comparing the 13C/12C ratios in milk fat and lactose the metabolic energy state of cows may be rated.


High-affinity calcium-stimulated, magnesium-dependent adenosine triphosphatase in Trypanosoma cruzi. 1. A high-affinity (Ca2+ + Mg2+)-ATPase and a low-affinity Mg(2+)-ATPase were identified in the 105,000 g fraction from epimastigote forms of Trypanosoma cruzi, the agent of Chagas' disease (Tulahuen strain). 2. Activities were conserved after enzyme solubilization with deoxycholate. 3. The Ca(2+)-stimulated ATPase activity was (a) lower than that of the Mg(2+)-ATPase; (b) inhibited by p-chloromercurobenzoate and orthovanadate and (c) insensitive to oligomycin. 4. Optimal stimulation by Ca2+ was observed at pH 6.5-6.8 in the presence of 1 mM MgCl2 and 0.1 M KCl. 5. The Mg(2+)-ATPase was insensitive to p-chloromercurobenzoate and orthovanadate and did not require KCl for activity. 6. Kinetic analysis of the (Ca2+ + Mg2+)-ATPase yielded a half-maximal stimulating concentration of 1.1 microM for Ca2+ and a Km of 66 microM for ATP. 7. The (Ca2+ + Mg2+)-ATPase clearly differed from the Ca(2+)- or Mg(2+)-ATPases previously characterized in the same strain of T. cruzi (Frasch et al., 1978; Comp. Biochem. Physiol. 60B, 271-275).


Bitis arietans nerve growth factor is a disulphide-linked homodimer. 1. Nerve growth factor from Bitis arietans venom was isolated in high yield and purified to homogeneity using a rapid two-step procedure involving gel exclusion chromatography and reversed-phase HPLC. 2. On polyacrylamide gel electrophoresis in SDS, the NGF migrates as a 25 kDa homodimer and is thus atypical of other Viperid NGFs. 3. Evidence suggests that, unlike mammalian beta NGFs, the subunits of the Bitis arietans homodimer are covalently linked by a disulphide bond(s). 4. Partial sequence analysis shows that only 6 out of the first 21 amino acids are identical with those of cobra NGF including cys-14 and val-21 which are known to be important for NGF activity.


Histidine dipeptide levels in ageing and hypertensive rat skeletal and cardiac muscles. 1. In rat skeletal muscles (longissimus dorsi and quadriceps femoris), carnosine and anserine levels decreased 35-50% during senescence, and were 35-45% lower in hypertensive rats compared to normotensive levels. 2. In rat left ventricular cardiac muscle, although no free carnosine and anserine were detected, the total level of histidine dipeptides declined 22% during senescence and in hypertensive animals decreased 35% compared to normotensive levels. 3. The significance of these changes in relation to the possible antioxidant roles of histidine dipeptides in muscle is discussed.


Left visuo-spatial neglect: a meaningless entity? Six patients with unilateral right hemisphere damage are reported. Each patient performed two tasks that are traditionally regarded as diagnostic for left (peripersonal) visuospatial neglect: target cancellation and horizontal line bisection. Two patients were unimpaired on both tasks, and two were impaired on both. The two remaining patients showed a classic (and reliable) double-dissociation between the tasks. One of the patients who scored within normal limits on both cancellation and bisection showed left sided omissions on representational drawing. We argue that these results question the validity of any unitary concept of unilateral visuo-spatial neglect in peripersonal space.


Preservation of priming for interactive context in amnesics. The performance of a group of 12 amnesics of mixed aetiology was compared with that of two groups of normal subjects on a priming task in which subjects' spontaneous definitions of homonyms were biased in accordance with the sense of interactive context words which had earlier been shown with the homonyms. The amnesics showed significant and normal levels of interactive context priming even when the amount of attention paid to the interactive context words was minimized during training. Reducing the amount of attention paid to the context words during training did, however, decrease the amount of priming, shown by both groups of subjects, to the same degree. It also decreased recognition of trained homonym-context word pairs to a similar extent in amnesics and normal people. In an additional condition of the study, it was shown that normal subjects were aware of the meaningful relationship between homonyms and context words even when the amount of attention they paid to context words was minimized during training. Priming seemed to be stochastically independent of recognition and was also unrelated to signs of frontal lobe damage, intelligence or explicit memory. All three groups of subjects showed similar and significant levels of priming regardless of whether or not only definitions that made no direct reference to the context words were scored. It was concluded that amnesics have preserved priming for interactive context words that are encoded with low levels of attention even though there is evidence that they have a disproportionate recognition deficit for this kind of information under these conditions. The theoretical implications of the results are discussed.


"Cognitive activity" monitored by non-invasive measurement of cerebral blood flow velocity and its application to the investigation of cerebral dominance. We have developed a method of non-invasively detecting language lateralisation by measuring the increase in middle cerebral artery blood flow velocity occurring during a word association task, using transcranial Doppler ultrasonography. All exclusively right handed subjects (N = 12) showed a relative increase in left sided flow velocity during the task; mean rise was 4.04% on the left, and -0.03% on the right (p < 0.002). Left handed subjects (N = 6) showed a mixed pattern with three showing much greater increases (> 5%) in left, compared with right, hemisphere flow velocity, and three showing only small differences between left and right sides, possibly reflecting bilateral language representation. This technique offers potential not only in studying patterns of cerebral dominance, but also in studying cognitive responses to other stimuli.


Five tests of hand skill.

Five tests of hand skill. Four group tests of hand skill, square marking (SQUARES), dotting between targets (DOTS), line drawing between targets (LINES) and punching holes through targets (HOLES), were given to samples of undergraduates and schoolchildren, most of whom were also tested individually on a peg moving task (PEGS). Findings for PEGS were shown to be comparable to those of previous samples. Each new task was compared with PEGS for a standard measure of hand skill asymmetry (R-L%) using 4 criteria of comparison. For 3 criteria there was good agreement: correlations were statistically significant, hand preference subgroups were similar for rank order and the extent of asymmetry was more strongly associated with left hand scores than with right hand scores. This last finding was true for all of 12 comparisons for differing tests and samples, indicating that the finding is unlikely to be an artefact of score transformations as suggested by Bishop (1990a, 1990b). The fourth criterion of comparison, the distribution of R-L% scores, differed between the tasks. All of the new tasks found larger differences between the hands than PEGS. Whereas the shape of the distribution was unimodal for PEGS, as in previous studies, the distributions for DOTS and HOLES were clearly bimodal. Possible reasons for the larger between hand differences for some tasks are considered. It is suggested that the main difference between PEGS (and also to a lesser extent LINES) in comparison with DOTS and HOLES lies in the demand characteristics of the testing situation. Tasks which merely invite subjects to mark as many targets as possible in a unit of time may underestimate the skill of the nonpreferred hand.


Visual agnosia: a case of reduced attentional "spotlight"? A case study is presented of a patient with presenile dementia, for whom the dominant clinical feature from onset was a visual agnosia. The characteristics of the patient's visual agnosia were investigated in light of her apparent use of a "feature-by-feature" strategy to identify objects. Results from various tasks showed that the patient was unable to use global shape information or other grossly defined property cues characteristic of a "wide angle" attentional processing stage (Treisman, 1988) in object recognition. The patient appeared instead to rely on 'parts' or identifying features of the objects for object recognition. The patient showed significant improvement when the size of the drawing was reduced in size, thus suggesting that the disorder may be functionally localized to a reduction of the patient's attentional "spotlight".


Hemispheric interactions: the bilateral advantage and task difficulty. Twenty-five normal subjects made "same-different" responses to dot patterns presented in the LVF, RVF or bilaterally. Task difficulty was manipulated in each condition by varying the number of dots in the two patterns presented from two to four to six. The pairs of patterns always had the same number of dots on a given trial. Response latency and accuracy worsened as the number of dots increased for all three presentation conditions and for both "same" and "different" judgements. Overall, responding was faster and the number of errors lower on Bilateral presentations. For response latencies to identical patterns of dots, the size of the bilateral advantage increased relative to RVF responding as task difficulty increased but did not change significantly relative to LVF responding. When the two patterns were not identical the size of the advantage did not change as task difficulty increased. "Same" judgements were faster but less accurate than "different" judgements. A model of hemispheric interactions is proposed to account for the findings.


Discrepant oral and written spelling after left hemisphere tumour. Repetition, reading, confrontation naming, and oral and written spelling were studied in a 57 year-old man with a left hemisphere tumour. These tasks were repeated over a period of two weeks when the patient was being treated for brain oedema prior and subsequent to neurosurgical intervention. In the context of intact repetition and good reading, the most striking finding was a significant qualitative and quantitative discrepancy between oral and written spelling, with the latter task more severely affected. The pattern on oral spelling was that of lexical (or surface) agraphia. On written output, however, orthographic errors predominated. The relatively greater impairment of written spelling was not secondary to a motoric or visuo-spatial deficit. The observed patterns are not easily accommodated by current models of writing.


A multidimensional model of cellular effects on the spread of electrotonic currents and on propagating action potentials. This study was designed to develop a two-dimensional cellular model of uniform anisotropic muscle and to determine how irregularities of shape and variations in size of cardiomyocytes influence the passive (electrotonic) spread of currents at a microscopic level. A secondary purpose was to determine how the passive transfer of impressed currents across the gap junctions is related to the charge flow across the gap junctions during active propagation of depolarization. The decrease in electrotonic Vm with distance at a large size scale was described by a single exponential in both the longitudinal and transverse directions, as occurs in a continuous anisotropic medium. At a microscopic level, however, the falloff of Vm with distance was directionally different. Longitudinally, Vm decreased primarily along the length of cells, with small step-like decreases at the intercalated disks. Transversely, Vm was more nearly isopotential throughout each cell, and most of the decay in Vm occurred as large step-like decreases across the borders of the cells. Different gap junctions were used for charge flow for longitudinal versus transverse electrotonus. Remarkably similar results were obtained for propagating action potentials, i.e., different gap junctions were used for longitudinal versus transverse conduction. A major implication of the results is that it may be possible to gain information about the different longitudinal and transverse effects of the nonhomogeneous distribution of the cellular connections by improved measurements of propagation at a microscopic level.


Cardiac propagation simulation.

Cardiac propagation simulation. We have completed a range of membrane-based simulations of action potential propagation in two- and three-dimensional models of ventricular myocardium. The two-dimensional simulations included a bidomain representation of the myocardium which explicitly characterized the component volume conductors in the intracellular, interstitial, and extracellular spaces. With these simulations, we studied the contribution of the extracellular volume conductor to transmural myocardial propagation during depolarization. We also used two-dimensional bidomain simulations to study the effect of the interstitial volume conductor in the setting of planar myocardial depolarization with nominal and extreme tissue conductivities. Our three-dimensional simulations included a monodomain representation of the myocardium which characterized the three component volume conductors as a single lumped conductor. With these simulations, we examined the effects of the intramural rotation of the fiber axes on the timing and pattern of activation. To achieve practical solution times, we extended numerical techniques from previous reports and developed a range of new techniques applicable to this class of problems. Simulations of the depolarization wavefront used the nonlinear Ebihara and Johnson membrane equations for the fast sodium current as the membrane model. Simulations of the full action potential cycle combined the Ebihara and Johnson fast sodium current with the Beeler and Reuter membrane equations. Our results demonstrated that the individual volume conductors and the rotation of fiber axes have unique and identifiable consequences on the electrical activation in models of ventricular myocardium.


Models of the spreading of excitation in myocardial tissue. We consider a macroscopic model of the excitation process in the anisotropic myocardium involving the transmembrane, extracellular, and extracardiac potentials v, ue, and u0. The model is described by a reaction-diffusion (R-D) system, and the component v exhibits a front-like behavior reflecting the features of the excitation process. In numerical simulations, the presence of a moving excitation layer imposes severe constraints on the time and space steps to achieve stability and accuracy; consequently, application of the model is very costly in terms of computer time. An approximate model has been derived from the R-D system by means of a singular perturbation technique, and it is described by an eikonal equation, nonlinear and elliptic, in the activation time psi (x). Larger space steps are possible with this equation. From psi (x), we can derive, for a given instant t, the transmembrane potential v and subsequently, by solving an elliptic problem, we can compute the corresponding extracellular and extracardiac potentials ue and u0. The results of the R-D and the eikonal models applied to a portion of the ventricular wall are in excellent agreement; moreover, the eikonal model requires only a small fraction of the computer time needed by the R-D system. Therefore, for large-scale simulations of the excitation process, only the eikonal model has been used, and we investigate its ability to cope with complex situations such as front-front collisions and related potential patterns.