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Biomedical subjects

A Smith

Publications and source records attributed to A Smith.

At least 577 records · Page 32Linked to original sources
PubMed1996

Effects of sodium intake on albumin excretion in patients with diabetic nephropathy treated with long-acting calcium antagonists.

OBJECTIVE: To determine whether sodium intake alters albumin excretion in patients with nephropathy from non-insulin-dependent diabetes mellitus who were treated with two different long-acting calcium antagonists. DESIGN: Prospective, crossover, open-label trial. SETTING: Rush-Presbyterian-St. Luke's Medical Center. PATIENTS: 9 men and 6 women (mean age +/- SD, 56 +/- 8 years) with non-insulin-dependent diabetes mellitus, hypertension, renal insufficiency, and macroalbuminuria. INTERVENTION: Diltiazem (mean dose, 392 +/- 27 mg/d) or nifedipine (mean dose, 83 +/- 9 mg/d) was used to decrease blood pressure to less than 140/90 mm Hg. All patients also received furosemide concomitantly for blood pressure control. RESULTS: Blood pressure reduction with once-daily diltiazem decreased urine albumin excretion (2967 +/- 784 mg/d at baseline compared with 1294 +/- 679 mg/d after diltiazem therapy; P < 0.05) at 4 weeks while patients received a diet consisting of 50 mEq of sodium per day. Albumin excretion did not decrease when sodium intake was increased to 250 mEq/d, and blood pressure was reduced to levels similar to those seen with the low-sodium diet. Similar blood pressure reduction with once-daily nifedipine did not significantly alter albumin excretion regardless of sodium intake. CONCLUSION: Sodium intake affects the albumin-decreasing effects of certain calcium antagonists. Recent studies suggest that antihypertensive medications that reduce albumin excretion and arterial pressure correlate with reduced renal mortality compared with medications that do not have albumin-decreasing effects. Thus, a low-sodium diet should be prescribed to maximize the albumin-decreasing effects of certain calcium antagonists.

Aged↗
PubMed1996

Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach.

The target site of the antifungal compound LY214352 [8-chloro-4-(2-chloro-4-fluorophenoxy) quinoline] has been identified through a dual biochemical and molecular-genetics approach. In the molecular-genetics approach, a cosmid library was prepared from an Aspergillus nidulans mutant that was resistant to LY214352 because of a dominant mutation in a single gene. A single cosmid (6A6-6) that could transform an LY214352-sensitive strain of A. nidulans to LY214352-resistance was isolated from the library by sib-selection. Restriction fragments from cosmid 6A6-6 containing the functional resistance gene were identified by transformation, and sequenced. The LY214352-resistance gene coded for a protein of 520 amino acids that had a 34% identity and a 57% similarity in a 333 amino-acid overlap to E. coli dihydroorotate dehydrogenase (DHO-DH). The results of a series of biochemical mechanism-of-action studies initiated simultaneously with molecular-genetic experiments also suggested that DHO-DH was the target of LY214352. Assays measuring the inhibition of DHO-DH activity by LY214352 in a wild-type strain (I50=40 ng/ml) and a highly resistant mutant (I50>100 microgram/ml) conclusively demonstrated that DHO-DH is the target site of LY214352 in A. nidulans. Several mutations in the DHO-DH (pyrE) gene that resulted in resistance to LY214352 were identified.

Antifungal Agents↗
PubMed1996

Tooth wear--dental erosion.

This article aims to address the issues arising out of the increasing concern by general dental practitioners of erosion-related tooth wear. The prevalence, common presentation, differential diagnosis, likely aetiology, prevention and management of suspected cases of this form of tooth wear are considered.

Adolescent↗
PubMed1996

Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma.

The influence of polymorphism in the glutathione S-transferase, GSTM3 gene on susceptibility to cutaneous basal cell carcinoma (BCC) has been investigated. We have reported previously two GSTM3 alleles, GSTM3*A and GSTM3*B, distinguished by a recognition motif for the YY1 transcription factor in GSTM3*B. In this study, immunohistochemistry was used to identify GSTM3 expression in the epidermis of skin samples from 11 controls and 9 patients with BCC. A PCR method was used to identify GSTM3*A and GSTM3*B and thereby the GSTM3 AA, GSTM3 AB, and GSTM3 BB genotypes in 300 controls and 286 Caucasians with 1-35 primary BCCs. Genotypes at GSTM1, GSTT1, and the cytochrome P450 CYP1A1 and CYP2D6 loci were also determined. Frequencies of GSTM3, GSTM1, GSTT1, CYP2D6, and CYP1A1 genotypes in the cases and controls were not different. Dividing the BCC cases into groups of 92 patients with 1 lesion and 194 patients with 2-35 lesions showed that the frequencies of GSTM3 BB (2.6%) and GSTM1 A/B (1.3%) in the group with 2-35 tumors were almost significantly lower than in the group with 1 lesion (7.6%, exact P = 0.0601, chi 2(1) = 3.390; 6.5%, exact P = 0.055, chi 2(1) = 4.946, respectively). Within the cases with 2-35 tumors, a Poisson regression model was used to identify genotypes, characteristics such as skin type, and interactions between genotypes and characteristics associated with increasing numbers of tumors. This showed, after correction for male gender and age, that GSTM3 AA was not associated with risk of increased numbers of tumors, although in combination with skin type 1, GSTM1 null, and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio, 1.470 respectively). The data suggest that, like other allelic GST, GSTM3 influences cancer risk. As GSTM3 AA was associated with increased tumor numbers, it appears that YY1 acts as an activator of the recognition motif in GSTM3*B.

Aged↗
PubMed1996

Preparation of a trivalent antigen-binding construct using polyoxime chemistry: improved biodistribution and potential for therapeutic application.

In an attempt to improve the pharmacokinetic behavior of an antitumor radioimmunoconjugate, we have prepared a trivalent antigen-binding construct formed from three Fab' fragments derived from the parent murine monoclonal antibody (MAb) 35 directed against the carcinoembryonic antigen. The construct was generated by a novel approach using polyoxime chemistry. This approach leads to a homogeneous construct, as judged by SDS-PAGE and by mass spectrometry, which was found to retain full immunoreactivity. A comparison of the monovalent, divalent, and trivalent F(ab')n materials in vitro revealed the expected trend of increasing association constant with increasing valency. The in vivo biodistribution of the 125I-labeled trivalent construct was studied in xenograft-bearing nude mice. Absolute tumor accumulation seen with the trivalent construct (10.8% injected dose/g) was lower than that seen with the intact MAb35 (15.2% injected dose/g). This finding and the more rapid loss of activity from tumor are presumably the consequence of the quicker blood clearance of the trivalent material. However, the construct showed tumor:blood ratios up to 10-fold higher than those seen for the parent antibody, and ratios of tumor:normal tissue accumulation were generally greatly improved. These improvements were achieved despite only modest reduction in maximum tumor accumulation when compared to the parent MAb35, and this augurs well for an improved potential for this novel construct as an agent for radioimmunotherapy and radioimmunoscintigraphy.

Animals↗
PubMed1996

Hemopexin in the human retina: protection of the retina against heme-mediated toxicity.

The existence of the blood-retinal barrier means that proteins that protect the retina from damage by reactive oxygen species must either be made locally or specifically transported across the barrier cells; however, such transepithelial transport does not seem to occur. Among the circulatory proteins that protect against iron-catalyzed production of free radicals are apo-transferrin, which binds ferric iron and has previously been shown to be made by cells of the neural retina (Davis and Hunt, 1993, J. Cell Physiol., 156:280-285), and the extracellular antioxidant, apo-hemopexin, which binds free heme (iron-protoporphyrin IX). Since hemorrhage and heme release can be important contributing factors in retinal disease, evidence of a hemopexin-based retinal protection system was sought. The human retina has been shown to contain apo-hemopexin which is probably synthesized locally since its mRNA can be detected in retinal tissue dissected from human donor eyes. It is likely that the retina contains a mechanism for the degradation of hemopexin-bound heme since the blood-retinal barrier also precludes the exit of heme-hemopexin from the retina. Retinal pigment epithelial cells have been found to bind and internalize heme-hemopexin in a temperature-dependent, saturable, and specific manner, analogous to the receptor-mediated endocytic system of hepatoma cells. Moreover, the binding of heme-hemopexin to the cells stimulates the expression of heme oxygenase-1, metallothionein-1, and ferritin.

Apoproteins↗
PubMed1996

Heme-mediated reactive oxygen species toxicity to retinal pigment epithelial cells is reduced by hemopexin.

Catalysis of the formation of reactive oxygen species (RO2S) by low molecular weight complexes of iron has been implicated in several pathological conditions in the retina since photoreceptors and retinal pigment epithelial cells are likely to be especially sensitive to RO2S. Since protective proteins cannot cross the blood-retinal barrier, it is likely that the retina performs its own protective functions by synthesizing proteins that bind iron and nonprotein iron complexes, the major catalysts of RO2S generation. Investigations were carried out to determine whether pigment epithelial cells are themselves sensitive to iron-generated RO2S and whether apo-transferrin and apo-hemopexin, known to be made locally in the retina, can perform a protective function. In 51Cr release assays, the toxicity of exogenous RO2S including hydrogen peroxide or superoxide (generated by xanthine oxidase/hypoxanthine) to human retinal pigment epithelial cells was inhibited by the iron chelators, desferrioxamine and apo-transferrin. Free but not protein-bound ferric iron and heme exacerbated the toxic effect. The toxic effect of heme was abolished by the heme-scavenging, extracellular antioxidant, apo-hemopexin, and also by exogenous bovine serum albumin. In addition, heme toxicity was inhibited by a 3 h preincubation of cells with either heme, apo-hemopexin, or heme-hemopexin 24 h prior to the toxicity assay. It is concluded, first, that toxic effects of iron and heme can be prevented by apo-transferrin or apo-hemopexin and, second, that exposure of RPE cells to free heme or hemopexin sets in motion a series of biochemical events resulting in protection against oxidative stress. It is probable that these include heme oxygenase induction.

Antioxidants↗
PubMed1996

Induction of CCK mRNA levels in the limbic-hypothalamic circuit: time course and site-specific effects of estrogen.

Estrogenic regulation of cholecystokinin (CCK) and its receptors is correlated with the initiation and termination of lordosis behavior. To understand the effect of circulating estrogen concentration on the temporal aspects of CCK mRNA expression in the posterodorsal medial amygdaloid nucleus (MeApd) and the central part of the medial preoptic nucleus (MPNc) of the limbic-hypothalamic circuit, ovariectomized female rats were treated with a 10 mm Silastic capsule filled with estradiol, a bolus injection of 50 micrograms estradiol benzoate or 2 micrograms estradiol benzoate every 4 days for five "cycles." In situ hybridization was used to compare the relative changes of CCK mRNA levels at 0 h to levels measured at 6, 12, 24, 48, 72, or 96 h after estrogen administration. In the MPNc and the MeApd, the 10-mm capsule significantly increased and maintained CCK mRNA levels from 6 to 96 h. The range of the increase was 3.0-5.1-fold in the MPNc and 2.8-5.0 in the MeApd. The 50-micrograms injections significantly increased and maintained CCK mRNA levels in the MPNc from 12 to 96 h (range of the increase 2.4-4.1-fold) and in the MeApd from 24 to 96 h (range of the increase 2.2-2.8-fold). The repeated administration of 2 micrograms estrogen induced a significant increase of message levels in the MPNc at 12 and 24 h that were 4.2- and 4.7-fold, respectively. In the MeApd this estrogen treatment did not significantly increase CCK mRNA. These studies demonstrate that small doses (2 micrograms) of estrogen that mimic the pattern and circulating levels of estrogen dramatically stimulate CCK mRNA levels in the limbic-hypothalamic circuit. To further study this steroid stimulation, ovariectomized female rats were implanted with estradiol-filled cannulae into the bed nucleus of the stria terminalis or MeA. Estrogen elevated CCK mRNA levels locally in each nucleus. Implants in the bed nucleus also elevated CCK mRNA levels in the MeApd indicating that physiologic estrogen stimulation of CCK in the MeApd is the result of both local and distal transsynaptic elevation of CCK mRNA levels. The sitespecific induction of CCK mRNA levels within the limbic-hypothalamic nuclei provides another important facet of estrogenic modulation of CCK induction.

Animals↗
PubMed1996

Effects of dihydropyridine calcium antagonists on albuminuria in patients with diabetes.

The present study was designated to assess the effects of two different dyhydropyridine calcium antagonists (DHPCAs) on proteinuria in patients with noninsulin-dependent diabetes mellitus (NIDDM). The hypothesis that similar levels of blood pressure reduction with two different DHPCAs produce similar degrees of proteinuria reduction was tested. In a prospective randomized study, 14 patients with NIDDM, hypertension, proteinuria, and renal insufficiency were given either isradipine (n = 7) or nifedipine XL (n = 7) for 6 months. After a 2-week washout period, patients were crossed over to the other drug and observed for an additional 6 months. Drugs were titrated to lower arterial pressure to < 140/90 mmHg. Patients also instructed to follow a low-sodium diet at the initial visit. Blood pressure and 24-hour urine values for creatinine clearance, albuminuria, proteinuria, and sodium were assessed monthly. At the end of the initial and crossover treatment periods, there were no significant reductions in the level of albuminuria from baseline with either drug. Sodium excretion was < 110 mEq/L with each drug tested. The results of this study support the concept that DHPCAs do not reduce proteinuria in patients with type II diabetes. This failure to reduce albuminuria and proteinuria occurred despite adequate blood pressure reduction and an effort at dietary sodium restriction.

Adult↗
PubMed1996

Motor unit recruitment strategy changes with skill acquisition.

The modifications of motor unit recruitment strategy due to skill acquisition was determined in the elbow flexor-extensor muscles of normal human subjects. The median frequency of the power density spectra of the electromyograms recorded from the biceps and triceps muscles during a 3-s linear increase in flexion force in the range of 0-100% maximal voluntary contraction (MVC) was calculated for each subject, every 2 weeks over a total 6-week period during which subjects practiced linear flexion force increase three times a week. Electromyograms were recorded with two pairs of electrodes of different size and electrode spacing. It was shown that skill acquisition due to the 360 practice trials over the 6-week period caused an increase in the initial motor unit recruitment phase of the agonist's force generation cycle from about 0-65% MVC to about 0-85% MVC. The increase in the recruitment range was gradual and statistically significant for the measurements made every 2 weeks. The recruitment range of the antagonist triceps demonstrated a minor, but statistically insignificant, decrease over the same training period. There was a minor, but statistically insignificant, advantage of using small electrodes and inter-electrode spacing. It was concluded that skill acquisition, due to repeated functional use of a muscle in the same contraction mode, results in a slower, prolonged recruitment of motor units in the initial segment of the force generation cycle, thereby allowing a more precise and accurate control of the increments of force increase. Such conclusions reinforce the concept advocating the plasticity of motor unit control according to the functional demands imposed on the muscle. The results have significant implications in the design of various athletic, occupational and rehabilitation training modalities for optimal performance of various movement functions.

Adult↗
PubMed1996

Heme binding by a bacterial repressor protein, the gene product of the ferric uptake regulation (fur) gene of Escherichia coli.

The fur gene product, Fur, of Escherichia coli is a repressor when it binds Fe(II). Since heme and iron metabolism are closely linked and Fur is rich in histidine, a ligand for heme, the binding of heme to Fur was investigated. The oxidized Fur-heme complex is stable and low spin with a Soret maximum at 404 nm and no 620-nm band. CO coordinates with the reduced heme-Fur complex, causing a shift from 412 nm to 410 nm, and stabilizes it, increasing the half-life from 5 to 15 min. Circular dichroism (CD) spectra in the Soret region show heme bound in an asymmetric environment in Fur, both in the oxidized and reduced-CO forms. Quenching of tyrosine fluorescence by heme revealed rapid, tight binding (Kd < 1 microM) with an unusual stoichiometry of 1 heme:1 Fur dimer. Fur binds Mn(II), a model ligand for the endogenous Fe(II), much more weakly (Kd > 80 microM). Far-ultraviolet CD spectroscopy showed that the alpha-helix content of apo-Fur decreases slightly with heme binding, but increases with Mn(II) binding. Competition experiments indicated that heme interacts with Fur dimers at the same site as Mn(II) and can displace the metal. In contrast to Mn(II), Zn(II) did not quench the tyrosine fluoroescence of Fur, affected the CD spectrum less than Mn(II), but did bind in a manner which prevented heme from binding. In sum, Fur not only binds heme and Zn(II) with sufficient affinity to be biologically relevant, but the interactions that occur between these ligands and their effects on Mn(II) binding need to be taken into account when addressing the biological function of Fur.

Bacterial Proteins↗
PubMed1996

Investigation of the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance.

This study examined the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance. Twenty-six subjects (12 males, 14 females, mean age 23 years 10 months, age range 18-39 years) were tested once a week for a period of a month. Fifteen subjects were suffering from a common cold on the first week and the other 11 subjects were matched healthy controls. Subjects attended for an initial 3-h testing period that consisted of a set of practice trials and two test sessions involving mood rating and performance of a battery of tests measuring psychomotor functions, attention, and memory. Sessions 3, 4, and 5 took place 1, 2, and 3 weeks later, respectively. In addition to measuring mood and mental performance, symptom severity was rated on a subjective checklist. The results showed that subjects with a cold reported an increase in negative mood and that this was only significant in the first week. Impairments of psychomotor function (simple reaction time and tracking) were also observed at this time. Performance of sustained and selective attention tasks was also impaired in subjects with colds but this effect was only significant in the second week. Other functions such as working and semantic memory were unimpaired in subjects with colds at any point in the experiment. Overall, the present results confirm many of the earlier results obtained in studies of experimentally induced upper respiratory tract illnesses. Indeed, these results are both of great practical importance and theoretical interest and further studies must now elucidate the mechanisms underlying these effects.

Adolescent↗
PubMed1996

Multiplex PCR assay for the routine detection of Listeria in food.

The development and validation of a multiplex PCR assay for the detection of Listeria that can be employed in routine investigation of food samples are described. The assay, which employs a short culture enrichment step followed by isolation of bacterial cells and detection by multiplex PCR reaction, is highly sensitive and specific for the detection of Listeria monocytogenes and all other Listeria species. Over 350 food samples were tested in parallel by standard cultural procedures and the PCR assay, with no false-positive or false-negative results obtained with the PCR assay. Compared to the standard cultural methods the PCR assay is highly sensitive, cost effective and extremely rapid with results obtained within 48 h from sample receipt.

Food Microbiology↗
PubMed1996

Complementary tissue-specific expression of LIF and LIF-receptor mRNAs in early mouse embryogenesis.

The maintenance of pluripotential embryonic stem (ES) cells is dependent on the cytokine LIF. This report documents the mRNA expression profiles of LIF and the two components of the LIF-receptor complex, LIF-R and gp130, during early mouse embryogenesis. These mRNAs were undetectable in 1- or 2-cell embryos, but all were present by the blastocyst stage. LIF transcripts were localised in the differentiated trophectoderm, and were absent from the pluripotential inner cell mass. In contrast, LIF-R mRNA was found in the inner cell mass but not in the trophectoderm. This complementary pattern of expression is suggestive of a paracrine coupling between stem cells and differentiated progeny at the earliest stage of mammalian development. After implantation, transcripts for all components were down-regulated in the embryo. High levels of LIF-R and gp130 mRNAs were observed in the deciduum, however. These dynamic, tissue-specific expression patterns are consistent with regulatory roles for LIF or related cytokines, both in the maintenance of pluripotency in the mouse embryo, and in development of the foeto-maternal interface.

Animals↗
PubMed1996

Identification of a developmentally regulated protein tyrosine phosphatase in embryonic stem cells that is a marker of pluripotential epiblast and early mesoderm.

A sensitive RT-PCR display technique was used to examine the expression of protein tyrosine phosphatases (PTPs) during the differentiation of mouse embryonic stem (ES) cells. The majority of PTPs are expressed constitutively but one is present only in undifferentiated ES cells. This PTP was cloned and named ES cell phosphatase (ESP). ESP mRNA is detectable in oocytes and throughout early mouse embryo development. At early egg cylinder stages, transcripts are localised in the pluripotential epiblast. As gastrulation commences, however, epiblast expression is lost. Transcripts are present transiently in newly formed embryonic mesoderm. These data suggest that this transmembrane signaling molecule is associated with developmental lability in early embryogenesis.

Amino Acid Sequence↗
PubMed1996

Corneoscleral laceration caused by air-bag trauma.

PURPOSE: To report a case of a corneoscleral laceration sustained as a direct result of inflation of a driver-side air bag. METHODS: A patient who sustained a severe ocular injury in a low-speed motor vehicle accident underwent clinical and radiologic examination and subsequent treatment. RESULTS: The left eye underwent primary repair of a complex corneoscleral laceration. Two weeks postoperatively, visual acuity in the left eye remained at bare hand motion. CONCLUSION: Although air-bag-related eye trauma may be relatively infrequent, the severity of the injuries incurred warrant research efforts to explore new air-bag designs that minimize the risk of ocular injury.

Accidents, Traffic↗