Treatment of hypercholesterolaemia in children.
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Child↗
Biomedical subjects
J O'Grady
Publications and source records attributed to J O'Grady.
Modification of platelet function by isosorbide dinitrate in patients with coronary artery disease.
The effect of a four weeks oral treatment with 100 mg isosorbide dinitrate (ISDN) daily on platelet function was evaluated in 40 patients (aged 40-65 years) with proven coronary artery disease. Isosorbide dinitrate decreased platelet reactivity to ADP (p less than 0.001), increased platelet sensitivity to PGI2 (p less than 0.01) while the production of TXB2 from exogenous arachidonic acid substrate and from endogenous substrate were both significantly reduced. Circulating platelet aggregates as measured by the Wu-test were markedly reduced (p less than 0.001) but there was little change in the plasma concentration of the platelet proteins beta-thromboglobulin and platelet factor 4. Overall, platelet activation correlated with smoking, hypertension and a family history of coronary artery disease. The reduced platelet activation seen during treatment with isosorbide dinitrate may contribute to the therapeutic benefit seen with this drug in patients with coronary artery disease.
Adenosine Diphosphate↗
Liver function in acute viral hepatitis as determined by a hepatocyte-specific ligand: 99mTc-galactosyl-neoglycoalbumin.
Twelve patients with recently diagnosed acute viral hepatitis underwent serial 99mTc-galactosyl neoglycoalbumin scanning of the liver (for up to 8 mo). Injection of 99mTc-galactosyl neoglycoalbumin (150 mBq) at a rate of 3.5 mg (50 nmol; 1 ml) revealed that the liver is the exclusive site of tracer uptake. Simulation of 99mTc-galactosyl neoglycoalbumin kinetics allowed quantification of galactosyl neoglycoalbumin binding to human hepatic binding protein. Return of liver function test scores to normal values was associated in two patients with hepatitis A, in four patients with hepatitis B and in two patients with non-A, non-B hepatitis virus infection, with increases in hepatic binding protein concentration (up to three times the initial concentration), binding rate constant and hepatic blood flow. In the other four patients (three patients with hepatitis B and one patient with cytomegalovirus infection) a prolonged course of disease was monitored. In the mean, hepatic binding protein increased from 0.41 +/- 0.11 mumol/L after onset of acute hepatitis (n = 12) to 0.78 +/- 0.21 mumol/L after 6 mo of follow-up (n = 10) (p less than 0.001). During this period, binding rate constant (72.4 +/- 12.6 vs. 82 +/- 11.5 mumol/L/sec; p less than 0.05) and hepatic blood flow (0.027 +/- 0.0051 vs. 0.031 +/- 0.0083 L/sec; p less than 0.05) increased. Hepatic binding protein concentration correlated highly with actual laboratory test results for liver function (r = 0.98; p = 0.0001). We conclude that scintigraphic evaluation of functional liver cell mass using the new receptor-tracer 99mTc-galactosyl neoglycoalbumin could provide an in vivo diagnostic means of quantifying liver function and assessing liver morphology. In addition, our findings suggest that changes in hepatic binding protein-receptor concentration are likely to occur in vivo.
Acute Disease↗
Donated organ as a source of cytomegalovirus in orthotopic liver transplantation.
The importance of the donated organ as a source of CMV was assessed in 120 patients following orthotopic liver transplant and the CMV infections that developed in these patients were graded by severity. Forty-four recipients were CMV antibody negative pre-transplant. Eighteen of these received organs from CMV antibody positive donors and 15 (83%) developed primary CMV infections, 13 (87%) of which were symptomatic. Twenty-six received organs from CMV antibody negative donors and only 2 (8%) became CMV positive post transplant (P less than 0.001). These data suggest that there would be a considerable advantage in matching CMV antibody negative recipients with negative donors. Forty-five percent of secondary infections were asymptomatic compared with 12% of primary infections, and only 11% became disseminated compared with 53% of primary infections. The secondary infections that followed transplantation of an organ from a CMV antibody positive donor were more likely to be symptomatic and were more severe than those in patients who received seronegative livers.
Antibodies, Viral↗
Isradipine improves platelet function in hypertensives.
The effect of treatment for eight weeks with isradipine 1.25 mg twice daily for 4 weeks and thereafter 2.5 mg twice daily for 4 weeks on ex vivo platelet function was investigated in 10 male hypertensive patients, aged 51 (6.1) y. Systolic and diastolic blood pressure, platelet aggregation in response to ADP, serum thromboxane B2 and beta-thromboglobulin levels were significantly decreased at rest before exercise ergometry, during exercise and at rest after exercise. The platelet count, platelet sensitivity and the plasma levels of 6-oxo-prostaglandin F1 alpha were not affected by isradipine. It is concluded that a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit in the routine treatment of hypertension.
Analysis of Variance↗
Management of acute and fulminant hepatitis A.
Symptomatic viral hepatitis A usually only requires supportive therapy and the majority of cases are managed in the community. The prodromal symptoms of nausea, anorexia and lethargy tend to improve with the onset of clinical jaundice. Fulminant hepatic failure is said to be an uncommon complication, occurring in only 0.14-0.35% of hospitalized cases. However, an increasing incidence has been documented in some northern European countries where up to 20% of cases of fulminant viral hepatitis is due to hepatitis A. This trend parallels the increasingly delayed exposure to hepatitis A and the increased severity of the illness when contracted in later life. The risk of developing fulminant hepatic failure is best monitored using coagulation factor assays, with the prothrombin time and factor V levels being the most favoured. The diagnosis is established with the onset of encephalopathy. Patients progressing to grade 4 encephalopathy have a reasonably good prognosis compared to other aetiologies and survival rates of up to 67% have been obtained with medical management, despite the co-existence of such complications as cerebral oedema, renal and respiratory failure and the metabolic sequelae of acute liver failure. Nevertheless, some patients require emergency liver transplantation and 10 such patients have been reported to date. Transplantation is especially required in older patients (> 40 years) and those who are jaundiced for > 7 days before the onset of encephalopathy. The serum bilirubin and the prothrombin time complement these parameters in the decision making process.
Acute Disease↗
In vivo quantification of cholesterol content in human carotid arteries by quantitative gamma-camera imaging after injection of autologous low density lipoproteins (LDL).
Low density lipoproteins (LDL) were isolated by immunoaffinity chromatography from 18 patients (31-70 years) suffering from primary hypercholesterolemia with angiographically proven atherosclerosis of either one or both carotid arteries. LDL were labeled with 123I (1 mCi/mg LDL) by the iodine monochloride method followed by purification with dialysis and immediately reinjected thereafter. Gamma-camera serial controls over carotid regions allowed visual detection of uptake of the radiocompound uptake in 12 out of the 18 patients. The lipid entry ratio (LER; counts over the vascular region/pixel as compared to the contralateral side after background subtraction) confirmed the visual findings. Whole body images performed until 20 h after reinjection showed 3 different kinetic types of LDL-influx into the vessel wall: decreasing (type I), increasing and then decreasing (type II) and continuously increasing (type III) with time. Four patients underwent endarterectomy within 2-7 weeks after gamma-camera imaging. Histological control revealed an extensive amount of "foam cells" in tissue samples derived during surgery and an absence of endothelial lining in samples belonging to patients with type II kinetics.
Adult↗
The diminished extracellular matrix production induced by isradipine, a calcium channel blocker, is completely abolished by cyclooxygenase inhibition.
Collagen and glycosaminoglycan synthesis are well known to be enhanced during early atherogenesis. In this experimental study the synthesis of collagen was determined using 14C proline incorporation, the glycosaminoglycan production by means of 35S-sulphate incorporation and subsequent quantification by means of autoradiography. Isradipine, a new calcium channel blocker of the dihydropyridine family at a dose of 0.3 mg/kg significantly (p less than 0.01) decreased the incorporation of both the radioactive precursors. This effect was abolished by a concomitant aspirin treatment, while aspirin alone did not exert any significant effect on the precursor incorporation. These data suggest that isradipine, which is known to stimulate PGI2 synthesis, may exert this antiatherosclerotic inhibitory action on extracellular matrix production via the endogenous liberation of PGI2.
Animals↗
Postprandial hyperlipemia does not inhibit platelet aggregation.
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Adult↗
Prostaglandin I2 and the nitric oxide donor molsidomine have synergistic effects on thromboresistance in man.
1. In vitro synergistic effects of nitric oxide and prostaglandin I2 (PGI2) have been shown. Consequently we examined any potentiating effect of the nitric oxide donor molsidomine on the reduction in thrombogenicity produced by PGI2 in patients with peripheral vascular disease. 2. Thirty-six patients all with peripheral and also coronary artery disease were randomly allocated to receive PGI2 5 ng kg-1 min-1 for 6 h daily, 5 days a week for 5 weeks, alone (12 patients), with molsidomine 12 mg daily (12 patients) or molsidomine 12 mg daily alone (12 patients). 3. The effect of each treatment regimen was measured in terms of femoral artery platelet uptake and platelet survival after autologous 111Indium-oxine labelling. Molsidomine alone had no effect on platelet uptake or survival but in combination with PGI2 it significantly potentiated the decreased platelet uptake and prolonged platelet survival observed with PGI2 alone.
Aged↗
Demonstration of Leishmania specific cell mediated and humoral immunity in asymptomatic dogs.
An ELISA and a lymphocyte proliferation assay were used for the detection of anti-Leishmania antibodies and parasite specific cellular immunity respectively in a preliminary study of canine leishmaniasis in Oporto, Portugal. A high rate of infection was found considering the comparatively small group sampled. Of 34 dogs examined two had anti-leishmanial antibodies but their lymphocytes did not proliferate in the presence of Leishmania infantum. Conversely two dogs demonstrated antigen specific lymphocyte proliferation in the absence of any detectable anti-parasite antibodies. To our knowledge this is the first time that cellular immunity and presumably resistance of dogs to leishmanial infection has been demonstrated. These results suggest that there may be a spectrum of canine leishmaniasis similar to that observed in the human disease.
Animals↗
Aspirin abolishes the decreased low-density lipoprotein (LDL) entry into the rabbit arterial wall induced by the calcium channel blocker isradipine.
After deendothelialization and experimentally induced hypercholesterolemia in rabbits, an increased LDL entry into the vascular wall can be monitored using radiolabelled LDL. In male rabbits aged 6 months the abdominal aortic endothelium was removed by a Fogarty catheter. The animals fed a 1% cholesterol supplemented diet were treated either with isradipine (0.3 mg/kg/daily) (n = 36) alone or in combination with aspirin (5 mg/kg/daily) (n = 36) for four weeks. Thirty-six animals served as controls. 1, 3, 6, 12, 24 and 48 hours prior to sacrificing, 10 microCi 125I-LDL was administered intravenously to six rabbits in each group. The LDL entry was quantified in the abdominal aorta according to morphologically assessed type of surface lining. Aortic cholesterol content was assessed by Sudan-III staining and quantitative determination. Endothelialized segments exhibited a significantly (p less than 0.05 - p less than 0.001) lower LDL uptake as compared to re- or deendothelialized segments. The LDL entry was significantly lower with isradipine treatment than in controls. In parallel the cholesterol content decreased and the Sudan-III-positive areas were smaller in size. This beneficial effect as well as that on aortic lipid content was abolished by a pretreatment with aspirin. While in the isradipine-treated animals PGI2 synthesis was significantly (p less than 0.01) enhanced, it was almost completely blocked by aspirin. These findings indicate that the benefit of reduced LDL entry caused by isradipine may be mediated by an increased endogenous PGI2 synthesis.
Animals↗
Failure of simple biochemical indexes to reliably differentiate fulminant Wilson's disease from other causes of fulminant liver failure.
Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (< 0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (chi 2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Reversible dyslipoproteinemia in patients with malaria is associated with a shortened prostaglandin I2 half-life in plasma.
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Apolipoprotein A-I↗
Platelet lipoxygenase defect (Wien-Penzing defect) in two patients with myocardial infarction.
In 2 male patients (35 and 38 years) presenting with myocardial infarction an abnormal conversion of exogenous 14C-arachidonic acid by the patients' platelets, incubated in vitro, was observed. Neither patient's platelets showed evidence of a lipoxygenase pathway. Platelet thromboxane formation from exogenous and endogenous substrate was high, while the platelet aggregation responses were normal. A myeloproliferative syndrome was excluded by bone marrow puncture. Similar defects have only been described so far in patients with myeloproliferative syndrome. This defect may be causative for the onset of clinical thrombotic events. It is speculative whether in vivo therapy with r-IFN alpha 1c might be able to eradicate the pathological platelet clone.
Adult↗
A serological investigation of human herpesvirus 6 infections in liver transplant recipients and the detection of cross-reacting antibodies to cytomegalovirus.
Sera from 50 orthotopic liver transplant recipients were examined for antibodies to human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), and the findings correlated with the clinical condition of the patients. Both primary and secondary HHV-6 infections were detected serologically following liver transplantation. Interpretation of serological assays is complicated by CMV and HHV-6 antibody cross reactions which were common. Sera from 5 patients became HHV-6 antibody negative following absorption with CMV infected cells. Thirty patients were initially seronegative for HHV-6 antibodies, 12 remained so following transplantation, 5 developed cross reacting antibodies, and 13 seroconverted. The seroconversions occurred at 4 to 8 weeks post-transplant in the same time period as CMV antibody rises. HHV-6 IgM was detected in only 4 of the 13. Of the 7 patients who had serological evidence of active HHV-6 infections but no evidence of CMV infection, 4 (56%) had fever, 1 (14%) hepatitis, 1 (14%) lung dysfunction, and 3 (42%) neurological disorders. In the 12 patients who remained HHV-6 antibody negative, there were fewer fevers and neurological disorders.
Antibodies, Viral↗
Immunohistological analysis of the immunoreactivity of normal lymphoid cells and lymphomas with the monoclonal antibody OPD4.
OPD4 is a recently described monoclonal antibody that recognizes a fixation-resistant 200 kD antigen restricted to a subset of T cells. Immunolabelling with OPD4 in paraffin sections of normal lymphoid tissues and cases of malignant lymphoma was compared with that of other antibodies in common use, including the T-cell restricted antibodies MT1 and UCHL1 and the B-cell restricted antibodies MB1, F8-11-13, and L26. OPD4 showed similar immunoreactivity to UCHL1 in normal tissues. OPD4 did not stain Reed-Sternberg cells in Hodgkin's disease. In non-Hodgkin's lymphomas, OPD4, like UCHL1, reacted with only 2/22 B-cell lymphomas. OPD4 was, however, less useful as a marker of T-cell lymphomas, staining only 11/32 cases, while UCHL1 stained 22/32 cases. We conclude that OPD4 is not a useful antibody for the routine diagnosis of T-cell lymphoma.
Adult↗
Low density lipoprotein labelling characterizes experimentally induced atherosclerotic lesions in rabbits in vivo as to presence of foam cells and endothelial coverage.
The entry of autologous iodine-125 low density lipoprotein (125I-LDL) into the aortic wall in rabbits was measured. After abdominal endothelium abrasion with a Fogarthy catheter the animals were fed a 1% cholesterol-supplemented diet for 4 weeks. The animals were killed 1-48 h after administration of 25 muCi 125I-LDL. Local entry of radiolabelled LDL was estimated and correlated to endothelial surface lining and foam cell content, both controlled morphologically. Endothelialized segments showed the lowest entry of 125I-LDL, the maximum uptake was reached at around 8 h. In de-endothelialized segments the entry was higher and the peak later (12 h), while in re-endothelialized segments a continuous increase in 125I-LDL entry up to 48 h was measured. Number and extent of foam cells correlated with the entry of LDL. The data indicate the usefulness of LDL radiolabelling for qualitative in vivo information on surface lining and foam cell content.
Animals↗