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Biomedical subjects

M C Smith

Publications and source records attributed to M C Smith.

At least 19 recordsLinked to original sources

Minimum speed limit for ocean ridge magmatism from 210Pb-226Ra-230Th disequilibria.

Although 70 per cent of global crustal magmatism occurs at mid-ocean ridges-where the heat budget controls crustal structure, hydrothermal activity and a vibrant biosphere-the tempo of magmatic inputs in these regions remains poorly understood. Such timescales can be assessed, however, with natural radioactive-decay-chain nuclides, because chemical disruption to secular equilibrium systems initiates parent-daughter disequilibria, which re-equilibrate by the shorter half-life in a pair. Here we use 210Pb-226Ra-230Th radioactive disequilibria and other geochemical attributes in oceanic basalts less than 20 years old to infer that melts of the Earth's mantle can be transported, accumulated and erupted in a few decades. This implies that magmatic conditions can fluctuate rapidly at ridge volcanoes. 210Pb deficits of up to 15 per cent relative to 226Ra occur in normal mid-ocean ridge basalts, with the largest deficits in the most magnesium-rich lavas. The 22-year half-life of 210Pb requires very recent fractionation of these two uranium-series nuclides. Relationships between 210Pb-deficits, (226Ra/230Th) activity ratios and compatible trace-element ratios preclude crustal-magma differentiation or daughter-isotope degassing as the main causes for the signal. A mantle-melting model can simulate observed disequilibria but preservation requires a subsequent mechanism to transport melt rapidly. The likelihood of magmatic disequilibria occurring before melt enters shallow crustal magma bodies also limits differentiation and heat replenishment timescales to decades at the localities studied.

Journal Article↗

Episodic temporal generalization: a developmental study.

Groups of 5-year-olds, 10-year-olds, and adults completed either an episodic temporal generalization task, in which no stimuli were repeated, or a repeated standard temporal generalization task, in which there was a fixed standard that was repeated on every trial. Significant developmental improvements were found on both tasks. In both tasks, gradients of performance over two different stimulus ranges superimposed well when plotted on the same relative scale. Performance was similar for the adults and 10-year-olds across tasks, but the 5-year-olds performed better on the repeated standard task. These findings suggest that perceptual processes are a source of scalar variability in timing, and that there are developmental changes in levels of such variability.

Adult↗

Application of monoclonal antibodies in functional and comparative investigations of heavy-chain immunoglobulins in new world camelids.

Of the three immunoglobulin G (IgG) isotypes described to occur in camelids, IgG2 and IgG3 are distinct in that they do not incorporate light chains. These heavy-chain antibodies (HCAbs) constitute approximately 50% of the IgG in llama serum and as much as 75% of the IgG in camel serum. We have produced isotype-specific mouse monoclonal antibodies (MAbs) in order to investigate the roles of HCAbs in camelid immunity. Seventeen stable hybridomas were cloned, and three MAbs that were specific for epitopes on the gamma chains of llama IgG1, IgG2, or IgG3 were characterized in detail. Affinity chromatography revealed that each MAb bound its isotype in solution in llama serum. The antibodies bound to the corresponding alpaca IgGs, to guanaco IgG1 and IgG2, and to camel IgG1. Interestingly, anti-IgG2 MAbs bound three heavy-chain species in llama serum, confirming the presence of three IgG2 subisotypes. Two IgG2 subisotypes were detected in alpaca and guanaco sera. The MAbs detected llama serum IgGs when they were bound to antigen in enzyme-linked immunosorbent assays and were used to discern among isotypes induced during infection with a parasitic nematode. Diseased animals, infected with Parelaphostrongylus tenuis, did not produce antigen-specific HCAbs; rather, they produced the conventional isotype, IgG1, exclusively. Our data document the utility of these MAbs in functional and physiologic investigations of the immune systems of New World camelids.

Animals↗

Sex and the pregnant kidney: does renal allograft gender influence gestational renal adaptation in renal transplant recipients?

BACKGROUND: Animal work indicates that ovarian hormones are important in initiating and maintaining enhanced renal function in pregnant rats and that a renal response resembling pregnancy can be provoked in male rats exposed to pregnancy hormones. Women becoming pregnant following renal transplantation provide an opportunity to compare the functional response of male and female allografts to the gestational endocrine environment. METHODS: This retrospective observational study included 20 renal allograft recipients (age 29.7 +/- 2.4 yrs) (mean +/- SE) who had 22 pregnancies beyond 24 weeks (gestation at delivery 35.5 +/- 0.6 weeks). Donor characteristics, transplant details, renal follow-up data, and information about pregnancy and allograft function were obtained from hospital notes. RESULTS: Thirteen women received male allografts (donor age 30.0 +/- 3.9 years) (mean +/- SEM) and 7 women, female allografts (donor age 45.1 +/- 6.0 years) (P = .04). There were no significant differences between the two groups in maternal recipient age, transplant to pregnancy interval, antenatal complications, pregnancy outcome, or postnatal graft function. Compared to prepregnancy values serum creatinine (SCr) decrements and augmented 24-hour creatinine clearance (CrCl) were observed over the first trimester in both male and female allografts: Delta CrCl from 106.8 +/- 13.2 mL/min to 114.4 +/- 11.4 mL/min (35.6% increase) and 71.8 +/- 7.4 to 89.5 +/- 11.3 mL/min (24.7% increase), respectively, and Delta SCr from 90.1 +/- 5.4 micromol/L to 73.6 +/- 6.6 micromol/L (17.8% decrease) and 99.8 +/- 9.7 micromol/L to 78.0 +/- 5.7 micromol/L (13.5% decrease), respectively. Differences between the two groups did not reach statistical significance. CONCLUSIONS: Donor gender and/or age do not appear to influence the gestational renal response in kidney transplant recipients.

Adult↗

Refinement of the nickel site structure in Desulfovibrio gigas hydrogenase using range-extended EXAFS spectroscopy.

We have reexamined the Ni EXAFS of oxidized, inactive (as-isolated) and H(2) reduced Desulfovibrio gigas hydrogenase. Better spatial resolution was achieved by analyzing the data over a 50% wider k-range than was previously available. A lower k(min) was obtained using the FEFF code for phase shifts and amplitudes. A higher k(max) was obtained by removing an interfering Cu signal from the raw spectra using multiple energy fluorescence detection. The larger k-range allowed us to better resolve the Ni-S bond lengths and to define more accurately the Ni-O and Ni-Fe bond lengths. We find that as-isolated, hydrogenase has two Ni-S bonds at approximately 2.2 A, but also 1-2 Ni-S bonds in the 2.35+/-0.05 A range. A Ni-O interaction is evident at 1.91 A. The as-isolated Ni-Fe distance cannot be unambiguously determined. Upon H(2) reduction, two short Ni-S bonds persist at approximately 2.2 A, but the remaining Ni-S bonds lengthen to 2.47+/-0.05 A. Good simulations are obtained with a Ni-Fe distance at 2.52 A, in agreement with crystal structures of the reduced enzyme. Although not evident in the crystal structures, an improvement in the fit is obtained by inclusion of one Ni-O interaction at 2.03 A. Implications of these distances for the spin-state of H(2) reduced H(2)ase are discussed.

Absorption↗

Using rotifer population demographic parameters to assess impacts of the degradation products from trinitrotoluene phytoremediation.

The objective of this study was to evaluate the chronic lethal and sublethal aquatic toxicity effects associated with the phytoremediation of water contaminated with 2,4,6-trinitrotoluene (TNT) by the wetland plant species Myriophyllum aquaticum (parrot feather). Rotifers (Brachionus calyciflorus) feeding on an algal species (Nannochloropsis spp.) were used as the aquatic test organisms. Continuous flow laboratory microcosms were used to quantify effects on rotifer populations from TNT and the primary degradation product aminodinitrotoluene (ADNT) during and after phytoremediation. Rotifer demographic parameters from life tables, including survivorship, fecundity, reproductive values, net reproductive rate, generation time, intrinsic growth rate, and life expectancy, were used as measures of treatment effects. High-performance liquid chromatography analyses were performed to determine nitroaromatic concentrations. Results from this study have revealed significant differences in rotifer demographic parameters between microcosms with elevated initial TNT concentrations. Significant differences in demographic parameters also existed between the microcosms that did and did not receive phytoremediation treatment and the control microcosms. Study results have indicated that TNT phytoremediation via artificial wetlands not only may clean up hazardous waste at munitions sites but also may encourage the growth of aquatic populations such as rotifers.

Algorithms↗

Predictors of 90-day outcome in patients stabilized after acute coronary syndromes.

AIMS: We investigated predictors of 90-day risk among patients surviving the early period after an acute coronary syndrome (ACS). METHODS AND RESULTS: The study population included 15 904 stabilized ST-segment elevation or non-ST-segment elevation ACS patients randomized in SYMPHONY and 2nd SYMPHONY. We developed risk models for death, death or myocardial infarction (MI), and death, MI, or severe recurrent ischaemia (SRI) using Cox proportional-hazards techniques. Demographic, history, and pre-randomization clinical and medication variables were tested. Validation techniques included development of individual trial models, backward elimination and bootstrapping. Of 118 variables, 17 independently predicted mortality. The strongest associations included greater age (chi(2)=31.1), higher randomization heart rate (chi(2)=27.4), and heart failure (HF) variables (HF between qualifying event and randomization, chi(2)=21.8; history of HF, chi(2)=12.2). Higher creatinine clearance (chi(2)=17.7) and percutaneous coronary intervention between qualifying event and randomization (chi(2)=11.1) most strongly predicted lower risk. Similar characteristics entered the double and triple composite models, but HF variables and age less strongly predicted these end-points. CONCLUSIONS: In patients stabilized after ACS, those at highest risk over the next 90 days can be identified. Typical clinical markers are better at identifying risk of death than non-fatal MI or SRI. Novel risk markers are needed for these outcomes.

Aged↗

1H-Pyrrole-2-carbothioamide.

The reaction of ethoxycarbonylpyrrole-2-thiocarboxamide with sodium hydroxide affords the known title compound, C(5)H(6)N(2)S, whose structure shows a three-dimensional hydrogen-bonded lattice.

Crystallography, X-Ray↗

Hypertension in hemodialysis patients.

Hypertension is very common and often poorly controlled in patients undergoing chronic hemodialysis. While high blood pressure has been documented to adversely impact several intermediate outcomes of cardiovascular disease, whether hypertension is an independent risk factor for mortality in this population is not clear. Expansion of extracellular fluid volume is the major pathophysiologic mechanism for the development of hypertension in these patients; however, alterations in other humoral mechanisms also play a significant role. Optimization of volume status is, therefore, the cornerstone of therapy with additional use of antihypertensive medications as needed. Good quality prospective studies are urgently needed to define the measurement techniques and blood pressure goals, and to develop therapeutic strategies for more effective management of hypertension in this high-risk population.

Blood Pressure↗

Attention constraints of semantic activation during visual word recognition.

The reduction of semantic priming following letter search of the prime suggests that semantic activation can be blocked if attention is allocated to the letter level during word processing. Is this true even for the very fast-acting component of semantic activation? To test this, the authors explored semantic priming of lexical decision at stimulus onset asynchronies (SOAs) of either 200 or 1,000 ms. Following semantic prime processing, priming occurred at both SOAs. In contrast, no priming occurred at the long SOA following letter-level processing. Of greatest interest, at the short SOA there was priming following the less demanding consonant/vowel task but not following the more attention-demanding letter search task. Hence, semantic activation can occur even when attention is directed to the letter level, provided there are sufficient resources to support this activation. The authors conclude that the default setting during word recognition is for fast-acting activation of the semantic system.

Adult↗

Glycosylation of a Streptomyces coelicolor A3(2) cell envelope protein is required for infection by bacteriophage phi C31.

Mutants of Streptomyces coelicolor A3(2) J1929 (Delta pglY) were isolated that were resistant to the Streptomyces temperate phage phi C31. These strains could be transfected with phi C31 DNA, but could not act as infective centres after exposure to phage. Thus, it was concluded that infection was blocked at the adsorption/DNA injection step. The mutants fell into three classes. Class I mutants were complemented by a gene, SCE87.05, isolated from the cosmid library of S. coelicolor A3(2). The product of SCE87.05 had good overall homology to a Mycobacterium tuberculosis hypothetical protein and regions with similarity to dolichol phosphate-D-mannose:protein O-D-mannosyltransferases. Concanavalin A (ConA) inhibited phi C31 infection of S. coelicolor J1929, and this could be partially reversed by the addition of the sugar, alpha-D-methyl-pyranoside. Moreover, glycosylated proteins from J1929, but not from the class I mutant DT1017, were detected using ConA as a probe in Western blots. Class I and II mutants were sensitive to phi C31hc, a previously isolated phage exhibiting an extended host range phenotype, conferred by h. A phage with the same phenotype, phi DT4002, was isolated independently, and a missense mutation was found in a putative tail gene. It is proposed that the phi C31 receptor is a cell wall glycoprotein, and that the phi C31h mutation compensates for the lack of glycosylation of the receptor.

Amino Acid Sequence↗

'See and treat' at colposcopy--achieving the standard.

The National Health Service Cervical Screening Programme has issued quality standards for the colposcopy service nationally. One standard is that for women who undergo treatment at their first colposcopy clinic visit, 90% should have proven cervical intra-epithelial neoplasia (CIN) on histology. We have assessed data from a teaching hospital colposcopy clinic over a 9-year period to assess the criteria that should be satisfied in order to achieve this target. We propose that only those women with severe dyskaryosis on the referral smear and a colposcopic appearance of CIN 2 or 3, or those in whom the colposcopic appearance suggests CIN 3 with any grade of dyskaryosis undergo treatment at their first visit.

Journal Article↗

Identification of Streptococcus pneumoniae revisited.

The sensitivities and specificities of several different diagnostic assays for Streptococcus pneumoniae were assessed using 99 clinical isolates of S. pneumoniae and 101 viridans streptococci and were as follows: Pneumoslide, 99 and 87%, respectively; Directigen, 100 and 85%, respectively; Phadebact, 100 and 98%, respectively; deoxycholate drop test, 99 and 98%, respectively; deoxycholate tube test, 100 and 99%, respectively; optochin, 99 and 98%, respectively; and Gram Positive Identification Card, 90 and 96%, respectively. Identification of clinical isolates of S. pneumoniae should be confirmed using one or more diagnostic assays with well-documented high (e.g., > or =95%) sensitivities and specificities.

Bacterial Typing Techniques↗

Modulating semantic feedback in visual word recognition.

According to the interactive activation framework proposed by McClelland and Rumelhart (1981), activation spreads both forward and backward between some levels of representation during visual word recognition. An important boundary condition, however, is that the spread of activation from lower to higher levels can be prevented (e.g., explicit letter processing during prime processing eliminates the well-documented semantic priming effect). Can the spread of activation from higher to lower levels also be prevented? This question was addressed with a choice task procedure in which subjects read a prime word and then responded to a target, performing either lexical decision or letter search depending on the color of the target. A semantic context effect was observed in lexical decision, providing evidence of semantic-level activation. In contrast, there was no semantic context effect in the letter search task, despite evidence of lexical involvement: Words were searched faster than nonwords. Further evidence of lexical involvement in the letter search task appeared in Experiment 2 in the form of greater identity priming for words than for nonwords. The results of these experiments are consistent with the conclusion that feedback from the semantic level to the lexical level can be blocked. Hence, between-level activation blocks can be instantiated in both bottom-up and top-down directions.

Adult↗

Interdialytic weight gain, compliance with dialysis regimen, and age are independent predictors of blood pressure in hemodialysis patients.

Hypertension is a common problem in patients undergoing chronic hemodialysis. The purpose of this study is to identify the clinical and demographic factors independently associated with blood pressure in this population. Data collected for the Dialysis Morbidity and Mortality Study Wave 1 by the US Renal Data System were analyzed. The mean predialysis blood pressure for this cohort of 5,369 patients was 149/79 mm Hg. Sixty-three percent of the patients were hypertensive; 27%, 25%, and 11% had stages 1, 2, and 3 hypertension, respectively. Young age, black race, male sex, diabetes as cause of end-stage renal disease, erythropoietin therapy, and smoking were associated with higher blood pressure in the univariate analysis. Patients skipping or shortening one or more dialysis treatments had higher blood pressure. The presence of congestive heart failure and coronary heart disease was associated with lower blood pressure. On multivariate analysis, high interdialytic weight gain, noncompliance with dialysis regimen, and younger age were independent predictors of higher blood pressure. In summary, hypertension is common and poorly controlled in patients undergoing chronic hemodialysis. Greater interdialytic weight gain and noncompliance with dialysis regimen are independently associated with higher blood pressure, and advancing age is associated with lower blood pressure levels in this population. Therapeutic regimens emphasizing reduction of interdialytic weight gain and improved compliance with the dialysis regimen need to be evaluated for improving the management of hypertension. The effect of age and other comorbid conditions, particularly cardiovascular disease, must be considered while studying the relationship between blood pressure and mortality in patients undergoing chronic hemodialysis.

Age Factors↗

Control of directionality in the site-specific recombination system of the Streptomyces phage phiC31.

The genome of the Streptomyces temperate phage phiC31 integrates into the host chromosome via a recombinase belonging to a novel group of phage integrases related to the resolvase/invertase enzymes. Previously, it was demonstrated that, in an in vitro recombination assay, phiC31 integrase catalyses integration (attP/attB recombination) but not excision (attL/attR). The mechanism responsible for this recombination site selectivity was therefore investigated. Purified integrase was shown to bind with similar apparent binding affinities to between 46 bp and 54 bp of DNA at each of the attachment sites, attP, attB, attL and attR. Assays using recombination sites of 50 bp and 51 bp for attP and attB, respectively, showed that these fragments were functional in attP/attB recombination and maintained strict site selectivity, i.e. no recombination between non-permissive sites, such as attP/attP, attB/attL, etc., was observed. Using bandshifts and supershift assays in which permissive and non-permissive combinations of att sites were used in the presence of integrase, only the attP/attB combination could generate supershifts. Recombination products were isolated from the supershifted complexes. It was concluded that these supershifted complexes contained the recombination synapse and that site specificity, and therefore directionality, is determined at the level of stable synapse formation.

Attachment Sites, Microbiological↗

OctreoTher: ongoing early clinical development of a somatostatin-receptor-targeted radionuclide antineoplastic therapy.

OctreoTher ((90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide, a.k.a. (90)Y-SMT 487) consists of a somatostatin peptide analogue (Tyr(3)-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle x 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.

Animals↗