Copper and manganese influence the uptake of cadmium in marine macroalgae.
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Biomarkers↗
Biomedical subjects
M T Brown
Publications and source records attributed to M T Brown.
A future like ours revisited.
It is claimed by the future like ours anti-abortion argument that since killing adult humans is wrong because it deprives them of a future of value and the fetus has a future of value, killing fetuses is wrong in the same way that killing adult human beings is wrong. In The morality of abortion and the deprivation of futures (this journal, April 2000) I argued that the persuasive power of this argument rests upon an equivocation on the term "future of value". If the expression means "a potential future of value" then the moral claim is implausible because people do not in general have rights to what they need to fulfill their potential; if the expression means "self-represented future of value" then the argument fails because the fetus does not represent its future. Under no interpretation is the argument sound. In Deprivations, futures and the wrongness of killing (this journal, December 2001) Donald Marquis, author of the future like ours argument, responds at length to this objection. In the present essay the focus of the debate shifts to the proper interpretation of the right not to be killed. Donald Marquis argues that this liberty right entails the welfare right to the means necessary to sustain life; I argue that the right not to be killed does not entail unlimited welfare rights. On Marquis's view, the right not to be killed confers upon the fetus the right to whatever it takes to sustain life; on the view I defend, the right not to be killed does not confer upon the fetus or anyone else the right to another person's body. On Marquis's view, abortion is almost never permissible; on my view abortion is almost always permissible.
Abortion, Legal↗
Human adenovirus proteinase: DNA binding and stimulation of proteinase activity by DNA.
The interaction of the human adenovirus proteinase (AVP) with various DNAs was characterized. AVP requires two cofactors for maximal activity, the 11-amino acid residue peptide from the C-terminus of adenovirus precursor protein pVI (pVIc) and the viral DNA. DNA binding was monitored by changes in enzyme activity or by fluorescence anisotropy. The equilibrium dissociation constants for the binding of AVP and AVP-pVIc complexes to 12-mer double-stranded (ds) DNA were 63 and 2.9 nM, respectively. DNA binding was not sequence specific; the stoichiometry of binding was proportional to the length of the DNA. Three molecules of the AVP-pVIc complex bound to 18-mer dsDNA and six molecules to 36-mer dsDNA. When AVP-pVIc complexes bound to 12-mer dsDNA, two sodium ions were displaced from the DNA. A Delta of -4.6 kcal for the nonelectrostatic free energy of binding indicated that a substantial component of the binding free energy results from nonspecific interactions between the AVP-pVIc complex and DNA. The cofactors altered the interaction of the enzyme with the fluorogenic substrate (Leu-Arg-Gly-Gly-NH)2-rhodamine. In the absence of any cofactor, the Km was 94.8 microM and the kcat was 0.002 s(-1). In the presence of adenovirus DNA, the Km decreased 10-fold and the kcat increased 11-fold. In the presence of pVIc, the Km decreased 10-fold and the kcat increased 118-fold. With both cofactors present, the kcat/Km ratio increased 34000-fold, compared to that with AVP alone. Binding to DNA was coincident with stimulation of proteinase activity by DNA. Although other proteinases have been shown to bind to DNA, stimulation of proteinase activity by DNA is unprecedented. A model is presented suggesting that AVP moves along the viral DNA looking for precursor protein cleavage sites much like RNA polymerase moves along DNA looking for a promoter.
Adenoviruses, Human↗
Trace metal concentrations in marine macroalgae from different biotopes in the Aegean Sea.
The commonest species of red, brown, and green macroalgae were sampled from a range of biotopes in the Aegean Sea and analysed for five different trace metals. Significant differences in metal concentrations were found among different seaweed species from the same biotope. The concentrations of metals in the various seaweed species may reflect their morphology, with those having a larger surface area having a greater internal content. Different species of seaweed have different affinities for different heavy metals. This may reflect competition between metals for binding or uptake sites in the seaweed. Comparing metal concentrations in algae among the studied sampling stations clearly indicates that the degree of accumulation depends not only on human activities but also on the geology of the specific area. While seaweed can be used successfully to assess the levels of heavy metals in the marine environment, not all elevated concentrations of heavy metals necessarily reflect increased levels of pollution. Indeed, the high concentrations of certain metals, e.g., Ni, found in our seaweed samples reflected the metaliferrous nature of the rock. It is therefore important to take account of a region's geology before attempting to interpret the data.
Binding Sites↗
"Living off the land": resource efficiency of wetland wastewater treatment.
Bioregenerative life support technologies for space application are advantageous if they can be constructed using locally available materials, and rely on renewable energy resources, lessening the need for launch and resupply of materials. These same characteristics are desirable in the global Earth environment because such technologies are more affordable by developing countries, and are more sustainable long-term since they utilize less non-renewable, imported resources. Subsurface flow wetlands (wastewater gardens(TM)) were developed and evaluated for wastewater recycling along the coast of Yucatan. Emergy evaluations, a measure of the environmental and human economic resource utilization, showed that compared to conventional sewage treatment, wetland wastewater treatment systems use far less imported and purchased materials. Wetland systems are also less energy-dependent, lessening dependence on electrical infrastructure, and require simpler maintenance since the system largely relies on the ecological action of microbes and plants for their efficacy. Detailed emergy evaluations showed that wetland systems use only about 15% the purchased emergy of conventional sewage systems, and that renewable resources contribute 60% of total emergy used (excluding the sewage itself) compared to less than 1% use of renewable resources in the high-tech systems. Applied on a larger scale for development in third world countries, wetland systems would require the electrical energy of conventional sewage treatment (package plants), and save of total capital and operating expenses over a 20-year timeframe. In addition, there are numerous secondary benefits from wetland systems including fiber/fodder/food from the wetland plants, creation of ecosystems of high biodiversity with animal habitat value, and aesthestic/landscape enhancement of the community. Wetland wastewater treatment is an exemplar of ecological engineering in that it creates an interface ecosystem to handle byproducts of the human economy, maximizing performance of the both the natural economy and natural ecosystems. Wetland systems accomplish this with far greater resource economy than other sewage treatment approaches, and thus offer benefits for both space and Earth applications.
Conservation of Natural Resources↗
A new form of antiviral combination therapy predicted to prevent resistance from arising, and a model system to test it.
Combination therapy in the treatment of viral infections in which, for example, three different drugs against three different targets on three independent proteins are administered, has been highly successful clinically. However, it is only a matter of time before a virus will arise resistant to all three drugs, because the mutations leading to drug resistance are independent of each other. But, what if the mutations leading to drug resistance are not independent of each other, but confer some cost to the virus? If the cost is too great, than resistance may not arise. To impose such a cost in the clinical treatment of viral infections, we propose a new form of combination therapy. Here, three different drugs against three different targets on the same virus-coded protein are administered. If the physiological functions of the three different target sites are not independent of each other, then, a mutation at one site may alter the physiological functions at the other sites. We present a model system in which to test the efficacy of this new form of triple combination therapy. Human adenovirus has a virus-coded proteinase that is essential for the synthesis of infectious virus. It contains an active site and two cofactor binding sites; the functions of the active site are dependent upon the cofactors interacting with their binding sites. We describe how to obtain drugs against the three different sites.
Adenoviridae↗
Prevention of viral drug resistance by novel combination therapy.
A new form of antiviral clinical therapy is proposed in which three different drugs are administered against three different targets on the same virus-coded protein. If the physiological functions of the three different target sites are not independent of each other, then a mutation conferring drug resistance at one site may alter the physiological functions at the other sites and further drug resistance may not arise. The adenovirus proteinase, with its two cofactors that act synergistically on enzyme activity, may be a good model system within which to test the efficacy of this form of combination therapy.
Animals↗
The Arf GTPase-activating protein ASAP1 regulates the actin cytoskeleton.
Arf family GTP-binding proteins are best characterized as regulators of membrane traffic, but recent studies indicate an additional role in cytoskeletal organization. An Arf GTPase-activating protein of the centaurin beta family, ASAP1 (also known as centaurin beta4), binds Arf and two other known regulators of the actin cytoskeleton, the tyrosine kinase Src and phosphatidylinositol 4,5-bisphosphate. In this paper, we show that ASAP1 localizes to focal adhesions and cycles with focal adhesion proteins when cells are stimulated to move. Overexpression of ASAP1 altered the morphology of focal adhesions and blocked both cell spreading and formation of dorsal ruffles induced by platelet-derived growth factor (PDGF). On the other hand, ASAP1, with a mutation that disrupted GTPase-activating protein activity, had a reduced effect on cell spreading and increased the number of cells forming dorsal ruffles in response to PDGF. These data support a role for an Arf GTPase-activating protein, ASAP1, as a regulator of cytoskeletal remodeling and raise the possibility that the Arf pathway is a target for PDGF signaling.
3T3 Cells↗
Evaluating environmental contamination in Ria Formosa (Portugal) using stress indexes of Spartina maritima.
Species of Spartina are potentially useful for biomonitoring coastal systems because they are abundant in the intertidal and have a wide geographic distribution in temperate zones. In this study, three indexes of physiological stress, thiolic protein concentration, adenylic energy charge (AEC) index [AEC = ATP + 0.5ADP/(ATP + ADP + AMP)] and photosynthetic efficiency (Fv/Fm), are measured in Spartina maritima plants collected at four sites and compared with metal concentrations in the sediments and Spartina tissues. Two sites were close to urban centers and two were located further away, in less contaminated areas. Concentrations of copper, cadmium, lead and zinc were determined by atomic absorption spectrophotometry, thiolic proteins were determined by polarography and adenilic nucleotides were determined by high performance liquid chromatography. Photosynthetic efficiencies were measured with a fluorometer. The sediments of sites closer to urban centers had higher concentrations of metals than the sites located further away. Metal concentration within plants did not follow this spatial pattern, probably due to spatial differences in metal bioavailability, uptake rates, internal transport and excretion processes. Concentrations of all metals studied were higher in underground plant structures than aerial, except cadmium whose levels were not significantly different. On the other hand, the stress indexes followed the spatial pattern of metals in the sediment. Thiolic protein concentrations were higher in plants from polluted sites, and were three to four times higher in aerial than in underground plant structures. Leaf AEC ratios and photosynthetic efficiencies were lower in plants from polluted sites indicating that they were growing under stressful conditions. We conclude that the use of these indexes in S. maritima represent a useful tool to monitor contamination in Ria Formosa lagoon as they provide an integrated measure of the toxicological burden of contamination.
Environmental Monitoring↗
The morality of abortion and the deprivation of futures.
In an influential essay entitled Why abortion is wrong, Donald Marquis argues that killing actual persons is wrong because it unjustly deprives victims of their future; that the fetus has a future similar in morally relevant respects to the future lost by competent adult homicide victims, and that, as consequence, abortion is justifiable only in the same circumstances in which killing competent adult human beings is justifiable. The metaphysical claim implicit in the first premise, that actual persons have a future of value, is ambiguous. The Future Like Ours argument (FLO) would be valid if "future of value" were used consistently to mean either "potential future of value" or "self-represented future of value", and FLO would be sound if one or the other interpretation supported both the moral claim and the metaphysical claim, but if, as I argue, any interpretation which makes the argument valid renders it unsound, then FLO must be rejected. Its apparent strength derives from equivocation on the concept of "a future of value".
Aborted Fetus↗
Assessment of donor-site functional morbidity from radial forearm fasciocutaneous free flap harvest.
OBJECTIVE: To quantitate the functional morbidity to the hand and wrist following harvest of a radial forearm fasciocutaneous free flap. DESIGN: Prospective case-control study, with each patient providing his or her internal control, comparing preoperative and postoperative operated to nonoperated forearms. SETTING: Tertiary care hospital in large metropolitan area. PATIENTS: A consecutive sample of 11 patients who underwent a radial forearm free flap reconstruction of the head and neck from April 1997 to May 1998. MAIN OUTCOME MEASURES: Range of motion of the wrist (flexion and extension, ulnar and radial deviation), grip and pinch strength, and sharp and dull sensation in the distribution of the radial, ulnar, and median nerves. RESULTS: Statistically significant differences (P<.05) were measured in wrist flexion, pinch strength, and sharp sensation in the anatomical snuffbox of the operated forearm. No subjective complaints of loss of function were reported by any patient. CONCLUSIONS: Donor-site functional morbidity associated with harvest of the radial forearm fasciocutaneous free flap is measurable. The statistical differences found do not translate into subjective patient complaints of everyday functional morbidity.
Adult↗
Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans.
BACKGROUND: Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme. Reboxetine, a selective norepinephrine reuptake inhibitor, is metabolized by cytochrome P450 3A4. The potential interaction of reboxetine with this representative from the azole derivative class was examined. METHODS: Eleven healthy volunteers received (1) 4 mg reboxetine orally on the second day of a 5-day regimen of 200 mg ketoconazole once daily and (2) 4 mg reboxetine orally in a crossover design. Plasma concentrations of reboxetine enantiomers [R,R(-)-reboxetine and the more active S,S(+)-reboxetine] were measured by high-performance liquid chromatography-tandem mass spectrometry. Effects of ketoconazole on enantiomer pharmacokinetics were assessed by ANOVA. RESULTS: Ketoconazole increased R,R(-)-reboxetine and S,S(+)-reboxetine mean area under the plasma concentration-time curves (AUC) by 58% and 43%, respectively (P < .02). Oral clearance of both enantiomers was consequently decreased 34% and 24%, respectively, by ketoconazole (P < .005). Ketoconazole did not significantly affect maximal plasma concentrations (P > .1). Mean terminal half-life after administration of ketoconazole (21.5 hours and 18.9 hours) was significantly longer than after reboxetine alone (14.8 hours and 14.4 hours; P < or = .005). The AUC ratio for R,R(-)-reboxetine to S,S(+)-reboxetine was reduced by ketoconazole administration (2.76 after ketoconazole versus 2.39; P < .003). CONCLUSION: Ketoconazole decreases clearance of both reboxetine enantiomers. Although the adverse effect profile for reboxetine was not altered by ketoconazole, the results of this study suggest that caution should be used and that a reduction in reboxetine dose should be considered when the two are coadministered.
Adult↗
Nutritional differences in patients with proximal femoral fractures.
BACKGROUND: The reason why elderly human hips tend to break in one of two anatomical regions is uncertain. Nutritional factors may affect the site of fracture. OBJECTIVE: To assess possible nutritional differences in patients with proximal femoral fractures. DESIGN: Prospective observational cohort study. SETTING: University teaching hospital. SUBJECTS: 119 consecutive patients over the age of 65 with a hip fracture admitted to the trauma wards in a single centre. METHODS: One researcher measured triceps, biceps and supra-iliac skinfold thickness, and mid upper arm circumference on admission and on the fifth post-operative day. Body mass index was calculated for each patient, and used to classify patients as severely, moderately or mildly malnourished, normal, overweight or obese. Logistic regression was used to determine the influence of various factors on fracture site. RESULTS: According to their body mass index, 31% of patients were classified as malnourished and 11% as severely malnourished. Patients with intracapsular fractures were significantly more malnourished than patients with trochanteric fractures (P < 0.008). Nutritional status was not related to post-operative complications. Ability to weigh a patient on the fifth post-operative day was the single most important prognostic indicator for complications. CONCLUSIONS: Patients with intracapsular fractures are more malnourished. Those with trochanteric fractures tend to be overweight.
Aged↗
Acute leukemia following treatment of malignant glioma.
We report two patients with acute myeloid leukemia (AML) following therapy for malignant glioma; one was a young women treated heavily with alkylating agents for glioblastoma and the other a young man treated with high doses of procarbazine, lomustine, and vincristine (PCV) for anaplastic astrocytoma. We found 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients. Including our two, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after radiotherapy alone. Based upon analogy with other cancers, the cumulative dose of chemotherapy, especially alkylating agents, is the major risk factor for development of secondary AML. Agents implicated include carmustine (BCNU), lomustine (CCNU), and procarbazine. Conventional radiotherapy appears not to confer additional risk. Progressive macrocytosis, early dose reductions for thrombocytopenia, and refractory anemia may provide early diagnostic clues. Current glioma therapy is leukemogenic but the number of patients who survive the interval required to induce AML is small; nevertheless, the identification of chemosensitive types of glioma, and subgroups of patients who derive the most benefit from chemotherapy, may result in increasing numbers of patients at risk of long term complications. If regimens such as PCV continue to prove valuable in neurooncology the risk of leukemia will require integration into the clinical decision process. A search for more effective therapy with minimal mutagenicity remains critical.
Acute Disease↗
"Will the real plastic surgeon please stand up?".
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Cosmetic Techniques↗
ASAP1, a phospholipid-dependent arf GTPase-activating protein that associates with and is phosphorylated by Src.
Membrane trafficking is regulated in part by small GTP-binding proteins of the ADP-ribosylation factor (Arf) family. Arf function depends on the controlled exchange and hydrolysis of GTP. We have purified and cloned two variants of a 130-kDa phosphatidylinositol 4, 5-biphosphate (PIP2)-dependent Arf1 GTPase-activating protein (GAP), which we call ASAP1a and ASAP1b. Both contain a pleckstrin homology (PH) domain, a zinc finger similar to that found in another Arf GAP, three ankyrin (ANK) repeats, a proline-rich region with alternative splicing and SH3 binding motifs, eight repeats of the sequence E/DLPPKP, and an SH3 domain. Together, the PH, zinc finger, and ANK repeat regions possess PIP2-dependent GAP activity on Arf1 and Arf5, less activity on Arf6, and no detectable activity on Arl2 in vitro. The cDNA for ASAP1 was independently identified in a screen for proteins that interact with the SH3 domain of the tyrosine kinase Src. ASAP1 associates in vitro with the SH3 domains of Src family members and with the Crk adapter protein. ASAP1 coprecipitates with Src from cell lysates and is phosphorylated on tyrosine residues in cells expressing activated Src. Both coimmunoprecipitation and tyrosine phosphorylation depend on the same proline-rich class II Src SH3 binding site required for in vitro association. By directly interacting with both Arfs and tyrosine kinases involved in regulating cell growth and cytoskeletal organization, ASAP1 could coordinate membrane remodeling events with these processes.
ADP-Ribosylation Factor 1↗
Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.
PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS: In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS: We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.
Adolescent↗
Locally increased uptake of fluorine-18-fluorodeoxyglucose after intracavitary administration of iodine-131-labeled antibody for primary brain tumors.
UNLABELLED: After the intracavitary administration of 131I-labeled monoclonal antibody for treatment of primary brain tumors after surgical resection, a persistent rim of 18F-fluorodeoxyglucose (FDG) accumulation surrounding the cavity can be observed on PET. This rim, although it accumulates more FDG than adjacent normal brain tissue, is not necessarily associated with tumor. In our study, we examine the characteristics of the rim that indicate persistent tumor and tumor progression. METHODS: Sequential PET studies obtained after treatment in 10 patients were reviewed and the results correlated with dosimetry and post-treatment histologic diagnoses. RESULTS: The rim of FDG accumulation was seen on the first post-treatment scan obtained 1-3 mo after therapy and persisted unchanged over the 2-26 mo follow-up period. Pathologically, the nonmalignant rim was associated with marked increase of macrophage infiltrates. Nodularity of the rim was associated with tumor. CONCLUSION: Our study demonstrates that a rim of FDG accumulation is seen after intracavitary administration of 131I-labeled monoclonal antibody therapy independent of the presence of malignant disease. Malignant recurrence is suggested by the development of new nodularity in the rim of FDG accumulation.
Adolescent↗