A new nomenclature for int-1 and related genes: the Wnt gene family.
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Animals↗
Biomedical subjects
A Brown
Publications and source records attributed to A Brown.
Microtubule dynamics in axons and dendrites.
We have investigated the stability, alpha-tubulin composition, and polarity orientation of microtubules (MTs) in the axons and dendrites of cultured sympathetic neurons. MT stability was evaluated in terms of sensitivity to nocodazole, a potent anti-MT drug. Nocodazole sensitivity was assayed by quantifying the loss of MT polymer as a function of time in 2 micrograms/ml of the drug. MTs in the axon and the dendrite exhibit striking similarities in their drug sensitivity. In both types of neurites, the kinetics of MT loss are biphasic, and are consistent with the existence of two types of MT polymer that depolymerize with half-times of MT polymer that depolymerize with half-times of approximately 3.5 min and approximately 130 min. We define the more rapidly depolymerizing polymer as drug-labile and the more slowly depolymerizing polymer as drug-stable. The proportion of MT polymer that is drug-stable is greater in axons (58%) than in dendrites (25%). On the basis of current understanding of the mechanism of action of nocodazole, we suggest that the drug-labile and drug-stable polymer observed in both axons and dendrites correspond to two distinct types of polymer that differ in their relative rates of turnover in vivo. In a previous study, we established that in the axon, these drug-stable and drug-labile types of MT polymer exist in the form of distinct domains on individual MTs, with the labile domain situated at the plus end of the stable domain (Baas and Black, J Cell Biol 111:495-509, 1990). Because of the great difference in drug sensitivity between the drug-labile and drug-stable MT polymer, we were able to dissect them apart by appropriate treatments with nocodazole. This permitted us to evaluate the drug-labile and drug-stable polymer in terms of polarity orientation and relative content of alpha-tubulin variants generated by posttranslational detyrosination or acetylation. In both the axon and the dendrite, the modified as well as unmodified alpha-tubulins are present in both drug-labile and drug-stable polymer, but at different levels. Specifically, the modified forms of alpha-tubulin are enriched in the drug-stable MT polymer compared to the drug-labile MT polymer. In studies on MT polarity orientation, we demonstrate that in axons, MTs are uniformly plus-end-distal, whereas in dendrites, MTs are non uniform in their polarity orientation, with roughly equal levels of the MTs having each orientation.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Weak-base amines inhibit the anterograde-to-retrograde conversion of axonally transported vesicles in nerve terminals.
Acidotropic weak-base amines were used to investigate the role of acidic compartments in the pathway of aterograde-to-retrograde conversion of axonally transported vesicles in axon terminals. A local concentrated population of nascent axon tips was produced by transecting the rat sciatic nerve in situ to allow local and direct exposure of the axon tips to test solutions. Immersion of the nascent axon tips in solutions containing 10 mM ammonium choloride or 10 mM propylamine caused the axon tips to become distended by an accumulation of elongated membranous tubules and occasional large vacuoles that were both distinct from retrograde organelles. To test whether this accumulation was the result of an impairment of anterograde-to-retrograde conversion, a radioactive pulse-labelling method was used together with a retrograde collection ligature, to quantify the proportion of anterogradely transported proteins that returned from the axon tips by retrograde transport. Exposure of the axon tips to 10 mM ammonium chloride caused the anterogradely transported membrane proteins to accumulate in the axon tips and reduced by about 50% the amount of protein that returned to the retrograde collection ligature. These observations implicate the involvement of acidic membranous compartments in the anterograde-to-retrograde conversion pathway that leads to the formation of retrograde organelles in axon tips. Exposure of nerves to Acridine Orange, which is a vital acidotropic fluorescent dye, confirmed the presence of acidic compartments in the axon tips. Based on these observations, we propose that the membranous tubules that accumulated in the axon tips in the presence of weak-base amines represent a transient intermediate in the pathway of anterograde-to-retrograde conversion of axonally transported vesicles in axon terminals, and that acidic membranous compartments within axon terminals are required for the conversion of these tubules into retrograde organelles.
Acridine Orange↗
The blood pressure and renal responses to SCH 34826, a neutral metalloendopeptidase inhibitor, and C-ANF (4-23) in Doca-salt hypertensive rats.
C-ANF (4-23) and neutral metalloendopeptidase (NEP) inhibitors have been shown to prevent ANF metabolism and lower blood pressure presumably by the accumulation of ANF in the circulation. In the present study, we examined the interaction between C-ANF (4-23) and SCH 34826, an inhibitor of NEP, and ensuing effects on blood pressure, excretion of urine and sodium, and cGMP in the plasma and urine in conscious DOCA-salt hypertensive rats. C-ANF (100 micrograms/kg, iv bolus plus 10 micrograms/kg/min X 30) or SCH 34826 (90 mg/kg, sc) alone caused significant reductions in blood pressure and increases in plasma and urinary excretion of cGMP, a biochemical marker of endogenous ANF activity, at one hour post-drug. C-ANF (4-23) alone elicited a significant diuresis and natriuresis. SCH 34826 also enhanced sodium excretion and tended to increase urine volume. In comparison, the combination of C-ANF (4-23) and SCH 34826 produced a greater reduction in blood pressure and increases in plasma and urinary excretion of cGMP than either agent alone. The combination also caused significant diuresis and natriuresis. It is suggested that the greater blood pressure and renal responses to a combination of SCH 34826 and C-ANF than either agent alone reflect greater accumulation of endogenous ANF due to concomitant inhibition of both receptor-mediated clearance and NEP.
Animals↗
Resistance of myeloid leukaemia cell lines to ricin A-chain immunotoxins.
Nineteen monoclonal antibodies that recognize antigens on myeloid leukaemia cells were screened upon HL60, KG1, U937 and K562 cells for their ability to form effective ricin A-chain immunotoxins. The screening was performed using an indirect assay in which the cells were treated firstly with the test antibody and then with a Fab' immunotoxin directed against mouse immunoglobulin. Only two antibodies, MEM75 and 120-2A3, both directed against the transferrin receptor (TfR) were predicted to form immunotoxins that would inhibit protein synthesis by the cells by 50% at a concentration (IC50) of 10(-8) M or less. This prediction was subsequently confirmed using several of the antibodies directly conjugated to ricin A-chain. By contrast, the same immunotoxins were highly toxic to non-myeloid cells which shared the target antigens. A comparison was made between the rates of endocytosis and degradation by HL60 cells of an anti-TfR immunotoxin 120-2A3.dgA, that was effective at killing myeloid cells, and a CD33 immunotoxin, p67-7.dgA, that bound to myeloid cells but did not kill them. The difference in potency of the two immunotoxins on HL60 cells was not due to deficient uptake of p67-7.dgA but was probably due to the more rapid intracellular degradation of p67-7.dgA. Fast and effective degradation in lysosomes, if a general finding, could explain the poor susceptibility of myeloid cells to ricin A-chain immunotoxins.
Animals↗
Autoantibodies to glycoprotein antigens mediate subacute demyelinating encephalomyelitis in the Lewis rat.
Serum autoantibodies were induced in Lewis rats by immunization with a mixture of lentil lectin-binding glycoproteins isolated from bovine brain myelin. Intraperitoneal administration of 2-10 million syngeneic myelin basic protein-activated spleen cells to these rats led within 4-5 days to paralysis which, in most cases, persisted for several weeks. The major neuropathological features of the disease were numerous macrophages in both brain and spinal cord and large areas of demyelination, generally with axon preservation, particularly adjacent to the pial surfaces of the cord. This model is easily induced and will be useful for studies of demyelination and remyelination.
Animals↗
Mechlorethamine, vinblastine, procarbazine and prednisolone (MVPP) for advanced Hodgkin's disease.
Between January 1972 and October 1985, 60 patients with advanced Hodgkin's disease were treated with mechlorethamine/vinblastine/procarbazine/prednisolone (MVPP). The complete remission (CR) rate was 50%; the introduction of computed tomography in 1980 reduced the proportion of CR from 62% to 30% (P = 0.017) as a consequence of residual mediastinal abnormality of uncertain significance. With a median follow-up of 9 years, actuarial 5 and 10-year overall survival was 70% and 57%, respectively, with 79% and 65% free from Hodgkin's disease. Only age and pathological subtype influenced survival sufficiently to be of prognostic significance, though the effect of serum albumin, ECOG performance status and B symptoms on Hodgkin's disease mortality may have been clinically important.
Adolescent↗
Laboratory data predicts survival post hospitalization.
From a database of 93,077 in-patient admissions, patients assigned to catastrophic, very severe, moderately severe, and average 30-day mortality risk categories (as defined in Medicare Hospital Mortality Information, 1989 release, from the Health Care Financing Administration (HCFA] were selected for study. These admissions account for 30% of all admissions, but 70% of all deaths up to 1 year post admission. To determine whether laboratory information adds to the predictive power of the information used by HCFA, we compare the performance of 1 year survival predictors (Cox model) that use only diagnostic, demographic, and comorbidity information, with the performance of predictors that also include laboratory information. Using a separate set of patients not used for model definition, we find that laboratory data contain significant prognostic information independent of that already available in non-laboratory data. In HCFA's catastrophic disorders for example, non-laboratory information reduces the average risk of predicting a wrong outcome by 17% relative to considering only catastrophic group membership, and adding laboratory data reduces this risk by a further 21%. These improvements result primarily from considering the outcomes of a small set of routine laboratory tests (maximum BUN, AST, and WBC, and minimum CO2, hematocrit, and sodium).
Centers for Medicare and Medicaid Services, U.S.↗
Headache pain model for assessing and comparing the efficacy of over-the-counter analgesic agents.
To refine the assessment of over-the-counter analgesic agents in the treatment of muscle-contraction headache, we designed a single-dose model with attention to specific methodologic features and two relevant assessments--the percentage of subjects who achieve complete relief and the time until pain is no longer experienced. Subjects were randomly assigned to receive a single dose of 1000 mg acetaminophen, 1000 mg aspirin with 64 mg caffeine, or placebo. Under double-blind conditions, subjects rated headache pain intensity and relief over 4 hours and provided a Comparative Evaluation at the end of the trial. Both active agents were significantly distinguished from placebo on the time-point analyses (p less than 0.05) and summary end point measurements (sum of pain intensity difference [SPID], total of pain relief, percentage of patients with complete relief, percentage of treatment failures, and the Comparative Evaluation), as well as causing a faster elimination of headache (p less than 0.05). The aspirin-caffeine combination was rated higher than acetaminophen on all summary measurements, particularly SPID (p less than 0.05), with significantly more patients obtaining complete relief with aspirin-caffeine (p less than 0.01) than with acetaminophen. We conclude that this headache pain model can be used to demonstrate the efficacy of over-the-counter analgesic agents and to assess their relative efficacy.
Acetaminophen↗
Genetic analysis of a meiotic recombination hotspot on chromosome III of Saccharomyces cerevisiae.
In a previous study, we analyzed meiotic recombination events that occurred in the 22-kb region (LEU2 to CEN3) of chromosome III of Saccharomyces cerevisiae. We found one region with an enhanced level of crossovers (a hotspot) and one region with a depressed level of crossovers. In this study, we show that about one-third of the crossovers that occur between LEU2 and CEN3 are initiated in a 1.3-kb region located approximately 6 kb from the centromere. Both crossovers and gene conversion events are initiated at this site. Events initiated at this position can be resolved as crossovers in regions located either centromere-distally or centromere-proximally from the initiation site.
Base Sequence↗
Effect of primary-stage feline immunodeficiency virus infection on subsequent feline calicivirus vaccination and challenge in cats.
The effect of experimental primary-stage feline immunodeficiency virus (FIV) infection on feline calicivirus (FCV) vaccination and challenge in cats was studied. Clinical signs of acute FCV disease were more widespread in the cats which were infected with FIV than in those which were not. FIV infection also prolonged shedding of FCV, with more of the FIV-infected cats becoming chronic carriers. Although vaccination induced protection against acute FCV disease, this was to a lesser degree in FIV-infected cats. Vaccination by itself also appeared to enhance long-term virus shedding. There was evidence of an impaired anamnestic FCV-neutralizing antibody response in FIV-infected cats following FCV challenge.
Animals↗
Long-term quality of life after kidney transplantation in childhood.
Transplantation is the treatment of choice for children with end-stage renal disease. However, the long-term quality of life and socioprofessional outcome for those with successful transplants have not previously been reported. We studied these factors in patients transplanted when less than 18 years old who currently have greater than or equal to 10 years of graft function. A total of 57 questionnaires were sent out; 57 (100%) responded [24 female and 33 male patients; average (+/- SD) age at tx = 10 +/- 5 years (0.9-17.7); average f/u = 15.6 +/- 3 years (10-26); current age = 26 +/- 5 years (12-38); 26 had greater than 1 transplant]. Of the 57 respondents, 9 are less than 18 (all are in school); 48 are greater than or equal to 18 (7 in school, 37 employed, 4 unemployed); 12 are married, 1 engaged, and 2 divorced; and 9 have children. While in school, 43 (75%) had participated in sports, 37 (65%) in other extracurricular activities; 7 (12%) were A and 33 (58%) B students; 15 (26%) received awards or scholarships. For those working, the range of occupations is broad (average work week = 41 +/- 5 hr). Health-related absence from work has been nonexistent for 93%. Health is rated as good to excellent by 91% and fair by 9%. The future is regarded as hopeful or promising by 80%. Similarly, 89% are satisfied with life in general; 95% said health never or seldom interferes with family life; 95% feel health and drug side effects are of no or minor concern in sexual relationships. Only 3% feel health is a problem in maintaining a sexual relationship (41% are not sexually active). Only 4% stated that health often interferes with social life; 98% meet with friends on a regular basis; 76% are satisfied with personal relationships and 8% dissatisfied; 91% are satisfied with their ability to perform at work or school and 5% dissatisfied. Of note, 32% are dissatisfied with body appearance. Major concerns are short stature and brittle bones. Major suggestions include education/support groups to deal with teasing at school and peer problems. We conclude that transplanted children with long-term graft function have a favorable social and professional outcome. Overall, quality of life seems excellent.
Adolescent↗
Necator americanus secretory acetylcholinesterase and its purification from excretory-secretory products by affinity chromatography.
Acetylcholinesterase (AChE) secretion by adult N. americanus was enhanced in vitro by incorporating insoluble collagen rafts into culture dishes. Enzyme produced in this way had preferential substrate specificity for acetylthiocholine iodide (ATC), and its activity was inhibited by eserine (1.1 x 10(-8) M). Ancylostoma ceylanicum, another hookworm species, failed to produce comparable amounts of AChE in culture. AChE was efficiently purified from culture medium by affinity chromatography on edrophonium sepharose; 81% of the AChE activity was retained by the affinity matrix, although this fraction contained only 4.3% of the protein loaded. Antisera raised against purified AChE in rabbits immunohistochemically stained the oesophageal glands of the parasite, and reacted with molecules of 32, 60, 80, 140 and 220 kDa in reduced adult ES products on Western blotting, although differential activity was observed against worm homogenates and earlier developmental stages. On IEF, purified AChE resolved predominantly with a pl of 3.55; proteins with a similar pl were recognized by rabbit anti-AChE. IgG preparations of this antiserum inhibited AChE activity in ES products, and inhibited AChE secretion by adult worms in culture. The availability of this immunological probe will allow definitive experiments to be conducted on the role of this enigmatic enzyme in the host-parasite relationship.
Acetylcholinesterase↗
Alterations in elastin of the optic nerve head in human and experimental glaucoma.
The optic nerve heads from normal and glaucomatous eyes of humans and monkeys were examined by light and electron microscopy for the presence and distribution of elastin. Elastin densely lined the insertion of the lamina cribrosa into the sclera and was prominent in the laminar beams. The long axis of elastin paralleled that of the collagen fibrils and corresponded to the directions of expected forces on the tissue. In glaucomatous eyes elastin molecules were curled instead of straight and seemed disconnected from the other elements of the connective tissue matrix. Laminar beams stretch and reorganise their substructure during glaucomatous atrophy, probably leading to changed compliance. Differences in elastin function may have a part in susceptibility to glaucomatous injury.
Aged↗
Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport.
Niemann-Pick Type C (NPC) disease is a cholesterol lipidosis resulting from defective postlysosomal cholesterol transport. In normal cells this segment of cholesterol trafficking is inhibited by treatment with either U18666A or imipramine. Other compounds are also capable of blocking postlysosomal cholesterol transport: stearylamine, RV-538, and sphinganine inhibit low-density lipoprotein-induced esterification of cholesterol and cause unesterified cholesterol to accumulate in perinuclear vesicles. These vesicles can be stained with filipin to give a staining pattern indistinguishable from that seen in NPC fibroblasts. Because all of these compounds are hydrophobic amines, we conclude that most, if not all, hydrophobic amines block the postlysosomal transport of cholesterol. These results also raise the possibility that an endogenous amine, e.g., sphinganine, may inhibit cholesterol transport in NPC.
Amines↗
Extrarenal production of calcitriol in normal and uremic humans.
We have previously reported low serum levels of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and increased 1,25-(OH)2D3 production after the administration of 25-hydryoxyvitamin D (25OHD) to anephric humans. Since normal alveolar macrophages are known to synthesize 1,25-(OH)2D3 when stimulated with gamma-interferon or lipopolysaccharide, we determined whether macrophages derived from peripheral blood monocytes could be an extrarenal source of 1,25-(OH)2D3. Our results demonstrated that macrophages from normal individuals synthesize 1,25-(OH)2D3. The apparent Km for 25OHD3 was 6.6 +/- 0.5 nM and the maximum velocity was 47.4 +/- 13.7 fmol 1,25-(OH)2D3/h.microgram DNA. The activity of this enzyme was reduced 37.2 +/- 3.1% by physiological concentrations (96 pmol/L) of 1,25-(OH)2D3 in the incubation medium. Normal macrophages further hydroxylated 1,25-(OH)2D3 to more polar metabolites, and this catabolic activity was significantly enhanced by physiological concentrations of 1,25-(OH)2D3. In chronic renal failure, peripheral macrophages exhibited an enhanced 1 alpha-hydroxylase activity (8.2 +/- 0.8 vs. 4.2 +/- 0.5 fmol 1,25-(OH)2D3/microgram DNA.h in controls) and a decreased capacity to degrade 1,25-(OH)2D3. Exogenous 1,25-(OH)2D3, in physiological concentrations, reduced 1,25-(OH)2D3 synthesis to a degree (23.6 +/- 8.5%) comparable to that observed in normal cells. 1,25-(OH)2D3 production by macrophages did not correlate with the severity of hyperparathyroidism. Moreover, human PTH-(1-34) in supraphysiological concentrations (20,000 and 100,000 ng/L) did not stimulate the 1 alpha-hydroxylase activity of macrophages from either normal or uremic subjects. These results demonstrate that 1) normal peripheral macrophages metabolize 25OHD3 and 1,25-(OH)2D3; 2) macrophages in uremia display higher rates of 1,25-(OH)2D3 synthesis and lower rates of catabolism than normal macrophages; and 3) 1,25-(OH)2D3 deficiency, but not hyperparathyroidism, may play a role in the stimulation of 1,25-(OH)2D3 production by macrophages in chronic renal failure.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
Tropistic responses of Avena seedlings in simulated hypogravity.
Results from investigation of the gravitropic responses of the Avena coleoptile under simulated weightlessness are presented. The tests were conducted using the flight hardware, identified by NASA as the Gravitational Plant Physiology Facility (GPPF), designed to support the Spacelab experiment, GTHRES. Weightlessness or so-called microgravity-conditions were simulated by the use of a so-called somersault clinostat. The plants were gravitropically stimulated with different g-forces and stimulation durations on a centrifuge. Timelapse video pictures of the plants were taken during the last hour prior to the stimulation and in a period of 3 hours after. The gravitropic responses of the plants were analyzed with the aid of an image analyzing system. Dose-response curves for stimulation forces 0.2, 0.4, 0.6, 0.8, and 1.0 g with different stimulation times ranging from 2 to 250 min were achieved. The results show that the reciprocity between force and stimulation time may be valid for small stimulation doses (lower than 5 g min), but not for larger doses. Furthermore, the threshold values (i.e. the smallest stimulation the plants are able to detect) found by extrapolation of the dose response curves, are less than 30 g s. The results are discussed with respect to an accepted space experiment, GTHRES, where the corresponding experiments will be carried out in the same apparatus under true microgravity conditions.
Avena↗
Chairing a meeting.
How many meetings have you been to which seem to go on and on? How many meetings have you attended with little idea of what will be discussed and so have been unable to prepare effectively?
Communication↗