摘要:

Adenotin is a low affinity adenosine binding protein that has amino terminal homology with mammalian and avian stress proteins. Human placental adenotin was solubilized and reconstituted into phospholipid vesicles with an overall yield of 30%. The properties of adenotin in vesicles were similar to the native membranes as follows: association has a Kobsof 0.61 ± 0.03 minute−1; equilibrium is reached in approximately 15 minutes; and the first order dissociation constant is 5.0 ± 0.3 minute−1. Displacement analysis reveals an agonist potency order and Ki values as follows: N-ethylcarboxamidoadenosine, 0.35 μM; 2-chloroadenosine, 1.5 μM; R-phenylisopropyladenosine, greater than 1000 μM. The addition of 100 μM 5'-guanylylimidodiphosphate did not decrease binding of 5'-N-ethylcarboxamidoadenosine (NECA) at 37° C or 4° C but did decrease the IC50for PC12 and JAR cell membrane agonist binding from 9.9 to 3.3 μM and increase the binding to 150–211% of the control value at 37° C. The latter studies at 37° C showed high variability. Using binding sites reconstituted into vesicles and gel filtration chromatography and agonist related guanine nucleotide release, the authors investigated whether these changes were related to an interaction between adenotin and a guanine nucleotide regulatory protein. No evidence for such an interaction was found. These data suggest that adenotin retains its binding properties when reconstituted into phospholipid vesicles. The function of this low affinity adenosine binding site remains to be discovered. However, the reconstitution of adenotin into phospholipid vesicles provides a method to study its function.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The treatment of hyperthermia produced by passive warming was studied in anesthetized rats weighing 250–300 grams. In the first set of seven experiments, the authors found that venous blood oxygen fell as core temperature rose. Intraperitoneal injection of 20 ml of the oxygen carrying fluorocarbon (perfluorotributylamine, FC-43) emulsion in three of the animals shifted the curve to the right improving venous oxygen content (p < 0.1). In the second series of experiments, a catheter was placed in the carotid artery. This catheter was attached to a pressure transducer for continuous recording of blood pressure and heart rate. Periodic blood samples were removed for measurement of blood gases, pH, and lactate. Four of the animals received 20 ml of isotonic saline, three received 20 ml of FC-43 emulsion both given intraperitoneally, and four served as controls. In the control group, there was an increase in systolic blood pressure and heart rate which peaked at a colon temperature of 42° C, followed by cardiovascular collapse and death around 43° C. Arterial PO2(corrected for temperature) remained relatively constant up to 42° C, and then fell. The arterial PCO2rose sharply when the core temperature exceeded 43° C. Arterial lactate content began to increase at 42° C and above 43° C was 2.5 fold elevated. Isotonic saline provided circulatory support but did not change the hypoxia or mixed acidosis from CO2and lactate above 43° C. FC-43 emulsion decreased hypoxia and improved circulatory performance but was associated with a mild respiratory alkalosis as arterial PCO2fell. The authors conclude that tissue hypoxia is an important component of heat stress because of a decrease in blood oxygen content at a given pressure of oxygen and increase in metabolic rate as the temperature increases. This finally results in circulatory collapse. Intraperitoneal administration of an emulsion of fluorocarbon containing oxygen and salt solution equal to 8% of body weight during elevated body temperature improved the circulatory and respiratory response to heat stress in these rats.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The authors examined the effects of the alpha2-adrenergic agonist guanabenz and other alpha-adrenergic ligands on aldosterone secretion and cyclic nucleotide content in isolated rat adrenal glomerulosa cells. Guanabenz inhibited aldosterone secretion stimulated by potassium, angiotensin II (AII), and adrenocorticotropic hormone (ACTH), exhibiting IC50values of 35 μM, 43 μM, and 58 μM for stimulation by 10 mM K+, 1 nM AII, and 10 pM ACTH, respectively. Guanabenz did not affect the cGMP content of purified adrenal glomerulosa cells but inhibited ACTH stimulation of cAMP accumulation. Guanabenz inhibition of ACTH-induced cAMP may represent a mechanism for inhibition of aldosterone secretion, however, guanabenz also inhibited aldosterone secretion stimulated by the cAMP analog dibutyryl cAMP. The effect of guanabenz on the early and late pathways of steroidogenesis was tested in the isolated rat glomerulosa cells using 25-OH cholesterol and steroid precursors to aldosterone. Guanabenz inhibited the steroidogenic response to 25-OH cholesterol stimulation of aldosterone secretion but induced a much smaller inhibition of the steroidogenic response to exogenous pregnenolone, progesterone, and 11-deoxycorticosterone. These results suggested that guanabenz inhibited aldosterone secretion primarily through inhibition of the early component of the steroidogenic pathway prior to pregnenolone formation. The effects of guanabenz were not mimicked by other alpha-adrenergic ligands suggesting that these effects of guanabenz were not mediated through activation of alpha-adrenergic receptors.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The application of recombinant DNA methodology to clinical medicine offers the clinician a new generation of more potent and specific therapies. Recombinant methods offer great promise in the treatment of coronary artery thrombosis. This review focuses on the characterization of 1) molecules that activate plasminogen locally (in the vicinity of a thrombus) rather than systemically, and 2) molecules that offer new approaches to the inhibition of platelet activation and thrombin activity. We first describe the methods used to uncover these molecules and their characterization at the molecular level. The ways in which this knowledge can lead to the development of agents tailored to clinical needs are then explored.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Hemochromatosis was recognized as an iron-storage disease for 50 years before it was proposed to treat it by removing hemoglobin. Davis and Arrowsmith are credited with the first report that demonstrated its value. Larger series have provided statistically valid evidence of improved quality of life and increased longevity. The earlier the disease is discovered, the less risk of morbidity and mortality. Screening tests (serum iron, total iron-binding capacity, serum ferritin) are recommended for all blood relatives of index cases of this hereditary disease and for all clinics where complications of hemochromatosis may be treated: liver disorder however mild, diabetes mellitus, heart disease, arthropathies, sterility, impotence, premature menopause, and abnormal pigmentation of the skin.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Iron is essential for life, but iron overload is toxic and potentially fatal. The liver is a major site of iron storage and is particularly susceptible to injury from iron overload, especially when (as in primary hemochromatosis) the iron accumulates in hepatocytes. Iron can be taken up by the liver in several forms and by several pathways including: (1) receptor-mediated endocytosis of diferric or monoferric transferrin or ferritin, (2) reduction and carrier-facilitated internalization of iron from transferrin without internalization of the protein moiety of transferrin, (3) electrogenic uptake of low molecular weight, non-protein bound forms of iron, and (4) uptake of heme from heme-albumin, heme-hemopexin, or hemoglobin-haptoglobin complexes. Normally, pathway 2 is probably the major one for uptake of iron by hepatocytes. Iron is stored in the liver in the cores of ferritin shells and as hemosiderin, an insoluble product derived from iron-rich ferritin. Iron in hepatocytes stimulates translation of ferritin mRNA and represses transcription of DNA for transferrin and transferrin receptors. The major pathologic effects of chronic hepatic iron overload are: (1) fibrosis and cirrhosis, (2) porphyria cutanea tarda, and (3) hepatocellular carcinoma. Although precise pathogenetic mechanisms remain unknown, iron probably produces these and other toxic effects by increasing oxidative stress and lysosomal lability. Vigorous efforts at diagnosis and treatment of iron overload are essential since the pathologic effects of iron are totally preventable by early vigorous iron removal and prevention of iron re-accumulation.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The authors compared the amount of hepatic parenchymal cell stainable iron in 159 hemochromatosis homozygotes. They were separated into four groups. Group 1: 59 symptomatic hemochromatosis probands with hemochromatosis (mean age 49 years) who were identified because of symptoms and signs of iron overload. Group 2: 38 asymptomatic probands with hemochromatosis (mean age 29 years) identified during population screening studies or during routine health maintenance evaluation. Group 3: 47 homozygous relatives (mean age 43 years) of Group 1 probands. Group 4: 15 homozygous relatives (mean age 30 years) of Group 2 probands. The symptomatic probands (Group 1) were 20 years older and had much more stainable hepatic iron (p < 0.0001) than the asymptomatic probands (Group 2). The homozygous relatives (Group 3) of the symptomatic probands also were older and had much more stainable hepatic iron than the homozygous relatives (Group 4) of asymptomatic probands (p < 0.0002). The results of this study suggest that population screening studies can result in early identification of individuals with hemochromatosis before massive hepatic iron overload occurs and before symptoms of iron overload develop.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Hereditary hemochromatosis (HH), an iron overload disease caused by unregulated intestinal iron absorption, is a recessive HLA-linked disease. HH is the most common inherited metabolic disorder with one of every 400 to 500 individuals having both genes and being likely to develop the disease. Thus, although the product of the hemochromatosis gene is unknown, its mode of inheritance allows HLA-genotyping of the proband and his/her siblings to be highly predictive of the genetic propensity to develop the clinical features of HH. In view of the known immunoregulatory properties of iron and its binding proteins, it is important to determine if the high levels of storage iron in HH influence the immunosurveillance network in HH patients and whether that has any clinical relevance. We have defined certain alterations of the effector cells of the cellular arm of the immune system and have studied a patient with HH who had specific immune alterations, including delayed cutaneous-type hypersensitivity anergy, and was diagnosed with poorly differentiated adenocarcinoma of the stomach four years after his HH diagnosis. Those findings are consistent with the interpretation that in certain clinical situations of elevated body iron stores, the immunoregulatory balance or environment may be tipped in favor of growth and development of cancer cells.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A 35-year-old woman presented with liver failure, hepatic iron overload, and secondary amenorrhea due to hypogonadotropic hypogonadism. She had chronic inflammatory hepatitis which was considered to be due to post-transfusional viral hepatitis. Her hepatic iron overload was considered to be due to hemochromatosis. Her premature menopause was thought to be due to the severity of her liver disease, but her iron overload also could have contributed to gonadotrophin deficiency. She underwent liver transplantation and 5 months later, she experienced return of menstrual function. The distinction between hepatitis as a cause of iron loading, hemochromatosis as a cause of hepatic inflammation, the small influence of alcohol on increased iron stores, and other features of her history, physical examination, and laboratory evaluation are discussed.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The objective of this investigation was to evaluate certain quantitative and functional characteristics of the effector cells of the cellular arm of the immune system in hereditary hemochromatosis (HH) with respect to treatment status. Two observations were consistent with the postulate that the elevated levels of storage iron has in vivo immunoregulatory properties: (1) the absolute number of CD8-positive T cells were significantly elevated in untreated HH patients (n = 7) and reduced in treated patients (n = 7), as compared with controls; and (2) the proliferative response of peripheral blood mononuclear cells from untreated HH patients to mitogens was suboptimal but the response of peripheral blood mononuclear cells (PBM) from treated HH patients was normal. Furthermore, immunoglobulin secretion by PBM from treated HH patients as compared to controls was altered. Finally, one T effector cell abnormality was unrelated to treatment status in that a subset of mature, non-activated T lymphocytes aberrantly formed thermostable erythrocyte-rosettes (TER), a lymphoid surface marker usually expressed on thymocytes or activated T cells. Taken together these data define certain immune alterations that are consistent with the interpretation that cellular immunity may be influenced by the high level of storage iron in HH patients.

ISSN:0002-9629    

出版商:OVID    

年代:1991

数据来源: OVID