Biomedical subjects
Publications and source records attributed to J Rand.
We have accumulated a significant body of evidence that support the hypothesis that aPL antibody-mediated disruption of annexin A5 crystallization is a mechanism for RSPL in the APS. Further investigation of the functions of the annexins in placental physiology and disease are likely to be productive areas for future research.
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When treating diabetic cats, the primary aim is to control clinical signs without causing clinical hypoglycaemia. Secondary goals are to maximise the chances of attaining diabetic remission and to minimise the risk of complications due to chronic hyperglycaemia. A treatment plan that is convenient for the owner is important for compliance. Underweight or overweight diabetic cats should be fed with the aim of normalising bodyweight. Current evidence suggests that non-obese diabetic cats can be fed ad libitum. The oral hypoglycaemic drug glipizide is well established as a treatment for about a third of diabetic cats, which have residual beta cell function. Preliminary studies on other oral agents such as vanadium salts, metformin, and troglitazone indicate a potential use in some diabetic cats. Insulin treatment remains the treatment of choice for the majority of diabetic cats. Choice of insulin, dose rates and monitoring of treatment are discussed.
OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.
Type-1 diabetes, resulting from immune-mediated destruction of beta cells, appears to be rare in cats. Type-2 diabetes, characterised by inadequate insulin secretion and impaired insulin action, is the most common form of diabetes in cats. Other specific forms of diabetes constitute a substantial minority of cases. The most common is pancreatic destruction from pancreatic adenocarcinoma. Less frequent causes are insulin resistance from other endocrinopathies including acromegaly. Diabetes in cats is characterised by variable loss of insulin secretory capacity and insulin resistance. Glucose toxicity, islet amyloid-deposition, and pancreatitis contribute to further loss of beta cells and failure of insulin secretion. A significant number of cats undergo remission of their diabetes, usually 1-3 months after good glycaemic control is instituted. Obesity, old age, and Burmese breed are recognised risk factors for the development of diabetes in cats.
Tissue factor activity (TFa) is a major activator of the coagulation cascade and may play a role in atheroma-induced thrombosis. Monocyte-macrophages (MO-MF) generate considerable quantities of TFa when stimulated by a variety of inducers. To test the hypothesis that MO could be induced by atheromatous plaque to generate TFa, plaque extracts obtained from patients with obstructive atheromatous disease were used. These extracts were also assayed for constitutive TFa. The constitutive activity was variable from extract to extract but could be very high, up to 250 U TFa. The TFa induced in MO could be also very high, up to 200 U (i.e. 1/5 of the TFa of full strength rabbit brain thromboplastin). These findings point to a major role for MO-MF TFa in the induction or thrombosis by atheromatous plaque.
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The vesicular acetylcholine transporter (VAChT) has been identified and characterized based on the acquisition of high affinity vesamicol binding and proton-dependent, vesamicol-sensitive acetylcholine accumulation by a fibroblast cell line transfected with a clone from a rat pheochromocytoma cDNA library encoding this protein. The distribution of VAChT mRNA coincides with that reported for choline acetyltransferase (ChAT), the enzyme required for acetylcholine biosynthesis, in the peripheral and central cholinergic nervous systems. A human VAChT cDNA was used to localize the VAChT gene to chromosome 10q11.2, which is also the location of the ChAT gene. The entire sequence of the human VAChT cDNA is contained uninterrupted within the first intron of the ChAT gene locus. Transcription of VAChT and ChAT mRNA from the same or contiguous promoters within a single regulatory locus provides a previously undescribed genetic mechanism for coordinate regulation of two proteins whose expression is required to establish a mammalian neuronal phenotype.
The antiphospholipid antibody syndrome (APS) is characteristically associated with thrombosis. Heparan sulfate (HS) is a physiologic endothelial cell surface modulator of normal anticoagulation, containing a specific oligosaccharide sequence that binds antithrombin III with high affinity and also is present in heparin, a related glycosaminoglycan. We hypothesized that a subset of antiphospholipid antibodies with high affinity for heparan sulfate/heparin epitopes may inhibit the function of HS, promoting a procoagulant state. Purified IgG from all seven patients with APS studied were reactive with heparin by enzyme-linked immunosorbent assay, whereas none of five controls had antiheparin reactivity. IgG antiheparin antibodies were purified from two APS patients by affinity chromatography on heparin-Sepharose. Specificity studies showed that low-affinity electrostatic interactions clearly did not account for the observed reactivity with heparin, and that APS IgG antiheparin antibodies were specifically reactive with a disaccharide present in the heparin pentasaccharide that binds antithrombin III. Furthermore, APS IgG antiheparin antibodies inhibited heparin-accelerated formation of antithrombin III-thrombin complexes. We conclude that antiheparan sulfate/heparin antibodies may be a cause of autoimmune vascular thrombosis in the antiphospholipid antibody syndrome.
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Patients with acute leukemia undergoing remission induction chemotherapy occasionally develop venous thrombosis despite severe thrombocytopenia and in the absence of disseminated intravascular coagulation. This observation prompted us to study the levels of the naturally occurring anticoagulant proteins C and S prospectively in patients undergoing remission induction chemotherapy for acute leukemia. Plasma samples from 50 adult patients with acute leukemia (34 AML, 16 ALL) were analyzed for protein C antigen, functional protein C, immunologic total and free protein S as well as levels of C4b binding protein (C4bBP). Plasma levels of immunologic protein C were significantly lower in patients with active acute myelocytic leukemia (mean = 77.9) than in controls (mean = 123.6) or patients in remission (mean = 132). Functional protein C levels were also significantly lower in AML patients with active disease (mean = 58.5) than controls (mean = 95.5) or patients in remission (mean = 98.5). Patients with acute lymphocytic leukemia (ALL) had normal levels of immunologic and functional protein C. Although total protein S levels were normal in all patients studied, levels of free protein S were significantly decreased in patients with active AML (mean = 29.3) compared with patients in remission (mean = 42.0) or controls (mean = 42.4). In contrast, patients with ALL, both with active disease and in remission had normal free protein S levels. This decrease in free protein S seen in active AML was not associated with liver disease, white cell count or an increase in C4bBP. These findings provide a possible explanation for the occasional occurrence of venous thrombosis in patients with acute myelocytic leukemia.
While artificial brains are in the realm of science fiction, artificial neural networks (ANNs) are scientific facts. An artificial neural network is a computational structure modeled somewhat on the neural structure of the brain; both have many highly interconnected processing elements. These biologically inspired processing elements are taught by feeding examples until the results are acceptable. In the past 5 years, neural networks have become successful in providing meaningful second opinions in clinical diagnosis. In our research, a prototype artificial neural network was trained on numeral ultrasound data of 52 actual cases and then correctly identified renal cell carcinoma from renal cysts and other conditions without diagnostic errors. Our nonlinear artificial neural network was trained on software using the standard backpropagation paradigm on a 80386 microcomputer. Our ANN learned from ultrasound data in 52 cases (17 malignant, 30 cysts, and 5 other) at a Memphis hospital. The trained prototype performed without error on 47 cases which were not in the data used for training. This prototype must be validated by extending this study to more cases.
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A portion of the hepatocellular uptake of nonesterified long-chain fatty acids is mediated by a specific 40-kDa plasma membrane fatty acid binding protein, which has also been isolated from the gut. To investigate whether a similar transport process exists in other tissues with high transmembrane fatty acid fluxes, initial rates (Vo) of [3H]oleate uptake into isolated rat adipocytes were studied as a function of the concentration of unbound [3H]oleate in the medium. Vo reached a maximum as the concentration of unbound oleate was increased (Km = 0.30 +/- 0.03 microM; Vmax = 2470 +/- 90 pmol/min per 5 X 10(4) adipocytes) and was significantly inhibited both by phloretin and by prior incubation of the cells with Pronase. A rabbit antibody to the rat liver plasma membrane fatty acid binding protein inhibited adipocyte fatty acid uptake by up to 63% in dose-dependent fashion. Inhibition was noncompetitive; at an immunoglobulin concentration of 250 micrograms/ml Vmax was reduced from 2480 +/- 160 to 1870 +/- 80 pmol/min per 5 X 10(4) adipocytes, with no change in Km. A basic (pI approximately equal to 9.1) 40-kDa adipocyte plasma membrane fatty acid binding protein, isolated from crude adipocyte plasma membrane fractions, reacted strongly in both agar gel diffusion and electrophoretic blots with the antibody raised against the corresponding hepatic plasma membrane protein. These data indicate that the uptake of oleate by rat adipocytes is mediated by a 40-kDa plasma membrane fatty acid binding protein closely related to that in liver and gut.
Lung microvascular injury induced in sheep by intravenous infusion of Escherichia coli endotoxin, oleic acid, or air emboli caused the appearance in lung lymph of high levels of a protease with trypsin-like activity. The enzyme was isolated as an apparently homogeneous protein from pooled samples of active lung lymph, after an almost 9000-fold purification by affinity chromatography on columns of Reactive Blue 2-agarose, aprotinin-agarose, and p-aminobenzamidine-agarose, and chromatography on a column of Sephadex G-100. A molecular weight of about 70,000 to 75,000 was determined from mobility in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The pH optimum was between 7.3 and 7.6. The isolated enzyme was quite labile, rapidly losing activity at both 37 and 25 degrees C. Addition of albumin to enzyme solutions protected against inactivation. Inhibition by diisopropylfluorophosphate and phenylmethanesulfonyl fluoride indicated that the enzyme belongs to the class of serine proteases. The enzyme cleaved peptide bonds on the carboxyl side of arginine residues and showed a relatively high affinity toward peptides containing several basic amino acid residues. Bonds involving the carboxyl group of lysine were cleaved at a much slower rate. The enzyme showed no plasminogen activator activity and its substrate specificity was quite different from that of several proteases of the clotting cascade. Its appearance in lymph was not influenced by lymph clotting and the isolated enzyme was not capable of correcting the clotting defect of plasmas deficient in factors XII, XI, IX, VII, and X.
Native (nonanticoagulated) and heparinized blood from both normal swine and swine with von Willebrand's disease was exposed to de-endothelialized thoracic aorta from normal pigs under controlled flow conditions. We have shown that these normal de-endothelialized vessel segments do not contain von Willebrand factor (vWF) in the subendothelial surface; thus, the vascular model that we are using here is representative of the conditions in severe von Willebrand's disease. The blood was recirculated for selected periods of time through an extracorporeal circuit (carotid-jugular shunt), containing a tubular perfusion chamber that held the vessel segment. Flow rates and chamber diameters were selected such that the wall shear rates at the vascular segment were 212 to 3380 sec-1. Platelets were labeled with indium 111 and their total deposition determined by a gamma counter; selected areas were also observed by electron microscopy. When native blood was perfused, the deposition of platelets depended on platelet-plasma vWF only at high wall shear rates (1690 sec-1 or greater) typical of the microcirculation, but not at the lower shear rates (212 and 424 sec-1), more characteristic of the larger arteries and veins. In contrast, when heparinized blood was perfused, platelet deposition on the vascular segments depended on the presence of vWF over the entire range of shear conditions studied. These findings demonstrate in an extracorporeal perfusion system that the defect in platelet-vessel wall interaction in swine with von Willebrand's disease is influenced by both the local flow conditions and the level of activation of the coagulation system. In the presence of an intact coagulation system a synergistic interaction between procoagulant moieties and vWF was observed at high shear rates.
The effect of labeling media on the kinetics of[111In]platelets was evaluated by performing a paired crossover study in eight normal human subjects using tropolone and oxine methods. Platelets were labeled in autologous plasma with [111In]tropolone (In-tr) and in ACD-saline with [111In]oxine (In-ox) and reinjected. Starting at 1 hr, ten blood samples were obtained over an 8-day period. The in vivo platelet recovery was higher at 1 hr and throughout the 8 days of study with In-tr and the gamma camera images showed less uptake in liver and spleen than with In-ox. When platelet life-span (PLS) was estimated using all ten samples, only linear regression showed that the platelet life-span was longer with In-tr (10.7 +/- 1.5) than with In-ox (9.5 +/- 0.8). When the PLS was estimated excluding the 1-hr sample point, the life-span of platelets was significantly longer with In-tr than with In-ox based on three out of four models of curve fitting. These results demonstrate that platelets labeled with In-tr in plasma are preserved better in circulation and have equal or longer life-span than platelets labeled with In-ox in ACD-saline.