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Biomedical subjects

J C Smith

Publications and source records attributed to J C Smith.

At least 19 recordsLinked to original sources
PubMed2007

Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy?

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well-recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS. MATERIALS AND METHODS: Fifteen subjects with AS (mean age 21 years, range 10-35) were studied and compared with age-, sex-, and blood pressure-matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid-femoral and carotid-radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured. RESULTS: Comparing AS subjects vs. controls (mean +/- SD), AIX was elevated in AS subjects (18 +/- 9% vs. 3 +/- 11%, P < 0.0001). No significant changes in brachial PWV (8.1 +/- 1.3 m s(-1) vs. 7.3 +/- 1.1 m s(-1), P = 0.14) or aortic PWV (6.5 +/- 1.1 m s(-1) vs. 6.0 +/- 1.0 m s(-1), P = 0.26) were observed. AS subjects were hyperinsulinaemic and had disturbances in lipid profiles relative to controls. No correlations were observed between vascular, metabolic and echocardiographic parameters. CONCLUSIONS: In AS there are alterations in the shape of the central arterial pressure waveform associated with augmented aortic systolic pressure and indicative of increased wave reflection. Unfavourable central arterial haemodynamics in AS may contribute to the development of cardiomyopathy but other aetiological factors are probably involved.

Adolescent↗
PubMed2006

Intrinsic bursters increase the robustness of rhythm generation in an excitatory network.

The pre-Botzinger complex (pBC) is a vital subcircuit of the respiratory central pattern generator. Although the existence of neurons with pacemaker-like bursting properties in this network is not questioned, their role in network rhythmogenesis is unresolved. Modeling is ideally suited to address this debate because of the ease with which biophysical parameters of individual cells and network architecture can be manipulated. We modeled the parameter variability of experimental data from pBC bursting pacemaker and nonpacemaker neurons using a modified version of our previously developed pBC neuron and network models. To investigate the role of pacemakers in networkwide rhythmogenesis, we simulated networks of these neurons and varied the fraction of the population made up of pacemakers. For each number of pacemaker neurons, we varied the amount of tonic drive to the network and measured the frequency of synchronous networkwide bursting produced. Both excitatory networks with all-to-all coupling and sparsely connected networks were explored for several levels of synaptic coupling strength. Networks containing only nonpacemakers were able to produce networkwide bursting, but with a low probability of bursting and low input and output ranges. Our results indicate that inclusion of pacemakers in an excitatory network increases robustness of the network by more than tripling the input and output ranges compared with networks containing no pacemakers. The largest increase in dynamic range occurs when the number of pacemakers in the network is greater than 20% of the population. Experimental tests of our model predictions are proposed.

Afferent Pathways↗
PubMed2006

Defining synphenotype groups in Xenopus tropicalis by use of antisense morpholino oligonucleotides.

To identify novel genes involved in early development, and as proof-of-principle of a large-scale reverse genetics approach in a vertebrate embryo, we have carried out an antisense morpholino oligonucleotide (MO) screen in Xenopus tropicalis, in the course of which we have targeted 202 genes expressed during gastrula stages. MOs were designed to complement sequence between -80 and +25 bases of the initiating AUG codons of the target mRNAs, and the specificities of many were tested by (i) designing different non-overlapping MOs directed against the same mRNA, (ii) injecting MOs differing in five bases, and (iii) performing "rescue" experiments. About 65% of the MOs caused X. tropicalis embryos to develop abnormally (59% of those targeted against novel genes), and we have divided the genes into "synphenotype groups," members of which cause similar loss-of-function phenotypes and that may function in the same developmental pathways. Analysis of the expression patterns of the 202 genes indicates that members of a synphenotype group are not necessarily members of the same synexpression group. This screen provides new insights into early vertebrate development and paves the way for a more comprehensive MO-based analysis of gene function in X. tropicalis.

Animals↗
PubMed2006

In utero antiepileptic drug exposure: fetal death and malformations.

BACKGROUND: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach. OBJECTIVE: To determine if fetal outcomes vary as a function of different in utero AED exposures. METHODS: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69). RESULTS: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect. CONCLUSIONS: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Abnormalities, Drug-Induced↗
PubMed2006

Tes regulates neural crest migration and axial elongation in Xenopus.

Tes is a member of an emerging family of proteins sharing a set of protein motifs referred to as PET-LIM domains. PET-LIM proteins such as Prickle regulate cell behavior during gastrulation in Xenopus and zebrafish, and to ask whether Tes is also involved in controlling cell behavior, we isolated its Xenopus orthologue. Xtes is expressed as a maternal transcript that is maintained at low levels until neurula stages when expression is elevated in the head and axial structures. Depletion of Xtes leads to a foreshortened head and severe defects in axis elongation. The anterior defect is due in part to the inhibition of cranial neural crest migration while the defects in elongation may be due to perturbation of expression of XFGF8, Xdelta-1 and Xcad-3 and thereby to disruption of posterior somitogenesis. Finally, we note that simultaneous depletion of Xtes and Xenopus Prickle results in axial defects that are more severe than those resulting from depletion of Xtes alone, suggesting that the two proteins act together to control axial elongation.

Amino Acid Sequence↗
PubMed2006

Impaired vasoreactivity in bodybuilders using androgenic anabolic steroids.

BACKGROUND: Anabolic androgenic steroids are used by some bodybuilders to enhance performance. While the cardiovascular implications of supraphysiological androgen levels requires further clarification, use is associated with sudden death, left ventricular hypertrophy, thrombo-embolism and cerebro-vascular events. MATERIALS AND METHODS: To further understand the effect of androgenic anabolic steroid abuse on vascular function, this study assessed vascular stiffness (pulse-wave analysis) and cardiovascular risk factors in 28 male, bodybuilding subjects, of whom ten were actively receiving anabolic agents (group A; 26.4 +/- 7.2 years) and eight had undergone a 3-month "wash-out" period (group B; 32.1 +/- 7.1 years). The remaining ten bodybuilding subjects (group C; 24.4 +/- 4.4 years) denied any past use of anabolic steroids or other performance enhancing drugs. Comparisons were made with ten sedentary male controls (group D, 29.3 +/- 4.7 years). RESULTS: Endothelial independent dilatation in response to glycerol trinitrate was significantly impaired in the group currently using anabolic steroids (group A) compared with the other three groups [A (5.63 +/- 3.24%) versus; B (11.10 +/- 4.91%), C (17.88 +/- 9.2%) and D (14.46 +/- 3.9%), P < 0.0005, respectively], whereas no significant differences in endothelial-dependent dilatation were detected between the groups [A (5.0 +/- 3.0%), B (7.4 +/- 3.4%), C (9.6 +/- 4.5%) and D (8.2 +/- 3.3%), P < 0.059, respectively]. CONCLUSIONS: Previous studies described a decline in vascular reactivity occurring in bodybuilding subjects which is independent of anabolic steroid use and may result from smooth muscle hypertrophy with increased vascular stiffness. This study revealed impaired vascular reactivity associated with anabolic agents and that improvement in vascular function may occur following their discontinuation.

Administration, Sublingual↗
PubMed2006

Isoflurane leakage from non-rebreathing rodent anaesthesia circuits: comparison of emissions from conventional and modified ports.

Chronic exposure to low levels of fluorocarbon-based waste anaesthetic gas (WAG) has been linked to a multitude of human health problems. We have shown that isoflurane exhaust from passive gas-scavenging canisters is often quite high when using conventional rodent anaesthesia protocols and equipment. Another likely source of WAG build-up in rodent procedure rooms is leakage at the interface between the breathing circuit and the animal's face. We evaluated this possibility using three non-rebreathing circuits: traditional Bain, modified Bain, and Mapleson (type E). For the Mapleson E circuit, a conical rodent facemask was attached and used in one of two configurations: normal aperture, or aperture modified with a latex diaphragm (cut from an unpowdered surgical glove) to reduce the orifice diameter and tighten the seal. Adult female Sprague-Dawley rats were anaesthetized with isoflurane (5% for induction, 2% or 3.5% for maintenance) in oxygen (2 L/min for induction, 1 L/min for maintenance). Isoflurane leakage was assessed by real-time spectrophotometry. In 94% of the trials, three configurations - traditional Bain, modified Bain, and Mapleson E with unmodified mask - permitted isoflurane leakage approaching or exceeding 100 ppm at the face/port interface. In contrast, the Mapleson circuit with diaphragm-modified mask emitted significantly (P<or=0.0003) less isoflurane (peak of 9.5+/-1.7 ppm [mean+/-standard error]). These data indicate that (1) WAG leakage from standard rodent non-rebreathing circuits is substantial, and that (2) a simple, rapid, and economical modification to a conventional rodent facemask can significantly reduce WAG exposure to workers performing many rodent anaesthesia procedures in one session.

Air Pollutants, Occupational↗
PubMed2005

Dynamics of immobilized and native Escherichia coli dihydrofolate reductase by quasielastic neutron scattering.

The internal dynamics of native and immobilized Escherichia coli dihydrofolate reductase (DHFR) have been examined using incoherent quasielastic neutron scattering. These results reveal no difference between the high frequency vibration mean-square displacement of the native and the immobilized E. coli DHFR. However, length-scale-dependent, picosecond dynamical changes are found. On longer length scales, the dynamics are comparable for both DHFR samples. On shorter length scales, the dynamics is dominated by local jump motions over potential barriers. The residence time for the protons to stay in a potential well is tau = 7.95 +/- 1.02 ps for the native DHFR and tau = 20.36 +/- 1.80 ps for the immobilized DHFR. The average height of the potential barrier to the local motions is increased in the immobilized DHFR, and may increase the activation energy for the activity reaction, decreasing the rate as observed experimentally. These results suggest that the local motions on the picosecond timescale may act as a lubricant for those associated with DHFR activity occurring on a slower millisecond timescale. Experiments indicate a significantly slower catalytic reaction rate for the immobilized E. coli DHFR. However, the immobilization of the DHFR is on the exterior of the enzyme and essentially distal to the active site, thus this phenomenon has broad implications for the action of drugs distal to the active site.

Binding Sites↗
PubMed2005

Mechanistic studies on percutaneous penetration enhancement by N-(4-halobenzoyl)-S,S-dimethyliminosulfuranes.

Halogen-substituted iminosulfuranes are transdermal penetration enhancers (TPEs) in permeation studies using hairless mouse or human cadaver skin. The interaction of N--(4--R-benzoyl)-S,S-dimethyliminosulfuranes 1--4, where R=H, Cl, Br, and I, with l-alpha-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) has been studied using differential scanning calorimetry, isothermal titration calorimetry, nuclear Overhauser effect spectroscopy (NOESY), and NMR spectroscopy, and by calculation of the iminosulfurane polarizabilities in order to elucidate the molecular basis of the TPE activity. The active compounds reduce the melting temperature of the gel-to-liquid-crystal phase transition and induce multiple components in the transition excess heat capacity profile. The partitioning of the bromo derivative 3, the most active compound, into DMPC is unique in that 3 may be trapped in the bilayer, affording an enhanced residence time and a reason for its high TPE activity. The entropy decrease associated with the transfer of 3 to the bilayer is much lower than that for the other compounds, indicating that 3 occupies or induces sites that afford it considerable local motional freedom. Correlations between the iminosulfurane TPE activities, the partition coefficients, and NOESY crosspeak volume were observed. Molecular polarizabilities are not consistent with a TPE mode of action involving interaction of these agents with protein side chains.

Animals↗
PubMed2005

Microarray-based identification of VegT targets in Xenopus.

The Xenopus T box family member VegT is expressed maternally in the vegetal hemisphere of the embryo. Mis-expression of VegT in prospective ectodermal tissue causes ectopic activation of mesodermal and endodermal markers, and ablation of VegT transcripts prevents proper formation of the mesendoderm, with the entire embryo developing as epidermis. These observations define VegT as a key initiator of mesendodermal development in the Xenopus embryo, and in an effort to understand how it exerts its effects we have used microarray analysis to compare gene expression in control animal caps with that in ectodermal tissue expressing an activated form of VegT. This procedure allowed the identification of 99 potential VegT targets, and we went on to study the expression patterns of these genes and then to ask, for those that are expressed in mesoderm or endoderm, which are direct targets of VegT. The putative regulatory regions of the resulting 14 genes were examined for T domain binding sites, and we also asked whether their expression is down-regulated in embryos in which VegT RNA is ablated. Finally, the functions of these genes were assayed by both over-expression and by use of antisense morpholino oligonucleotides. Our results provide new insights into the function of VegT during early Xenopus development.

Animals↗
PubMed2005

Three laboratory assessments of a new triple-head toothbrush and the Oral-B 40 toothbrush.

OBJECTIVE: The objective of this series of laboratory studies was to assess a new triple-head toothbrush, the DR BEST FreiKopf, compared to the Oral-B 40 toothbrush, for interproximal access efficacy (IAE), gingival margin cleaning (GMC), and subgingival access (SA) as measures of toothbrush efficacy. METHODOLOGY: In each procedure, six toothbrushes of each product were tested four times for a total of twenty-four tests on each toothbrush design. In the IAE assay, the tooth brushing technique involved independent evaluations of each toothbrush in a vertical or horizontal brushing motion, tooth shapes simulating anterior and posterior teeth, and a brushing weight of 250 g. The brushing apparatus was set to brush 15 seconds at two strokes per second with a 50 mm stroke. In the GMC assay, the tooth brushing technique involved independent evaluations of each toothbrush in a horizontal brushing motion, tooth shapes simulating posterior teeth, and a brushing weight of 500 g. Simulated gingivae were prepared from self-curing dental acrylic. The brushing apparatus was set to brush for 60 seconds at two strokes per second with a 15 mm stroke. In the SA evaluations, the tooth shapes simulating posterior teeth were used, as well as a brushing weight of 500 g for 60 seconds at two strokes per second with a 15 mm stroke. All readings were measured with 3x magnification by one investigator. RESULTS: The mean IAE value on anterior and posterior tooth shapes, with vertical and horizontal brushing, and overall, was significantly (p < 0.001) higher for the triple-head toothbrush than for the Oral-B 40 toothbrush. In the GMC assay, the triple-head toothbrush had a significantly (p < 0.001) superior mean value compared to the Oral-B 40 product tested. In the SA study, the triple-head toothbrush was significantly (p < 0.001) superior compared to the Oral-B 40 toothbrush product tested. CONCLUSIONS: The triple-head toothbrush has demonstrated superiority to a traditional flat-head toothbrush for access into interproximal areas, and for removing deposits from the gingival margin, as well as below the gumline, in these laboratory assays.

Analysis of Variance↗
PubMed2004

A Xenopus tribbles orthologue is required for the progression of mitosis and for development of the nervous system.

The product of the Drosophila gene tribbles inhibits cell division in the ventral furrow of the embryo and thereby allows the normal prosecution of gastrulation. Cell division is also absent in involuting dorsal mesoderm during gastrulation in Xenopus, and to ask whether the two species employ similar mechanisms to coordinate morphogenesis and the cell cycle, we isolated a putative Xenopus homologue of tribbles which we call Xtrb2. Extensive cDNA cloning identified long and short forms of Xtrb2, termed Xtrb2-L and Xtrb2-S, respectively. Xtrb2 is expressed maternally and in mesoderm and ectoderm at blastula and gastrula stages. Later, it is expressed in dorsal neural tube, eyes, and cephalic neural crest. Time-lapse imaging of GFP-tagged Xtrb2-L suggests that during cell division, it is associated with mitotic spindles. Knockdown of Xtrb2 by antisense morpholino oligonucleotides (MOs) disrupted synchronous cell divisions during blastula stages, apparently as a result of delayed progression through mitosis and cytokinesis. At later stages, tissues expressing the highest levels of Xtrb2 were most markedly affected by morpholino knockdown, with perturbation of neural crest and eye development.

Amino Acid Sequence↗
PubMed2004

Many ways to make a gradient.

A recent publication describes a novel mechanism by which a morphogen gradient might be established. These results concern a gradient of FGF8 expression along the longitudinal axis of the chick embryo with a high level of transcripts at the tail, fading off in an anterior direction. Assaying for intron transcripts, it is shown that fgf8 is transcribed only in the tail cells and that the gradient of fgf8 transcripts is produced by growth and mRNA degradation. This possible mechanism of gradient formation can operate only when growth is involved, as is the case in many examples including the longitudinal axis formation of vertebrates, but is not in some other systems.

Animals↗
PubMed2004

Identification and characterisation of the posteriorly-expressed Xenopus neurotrophin receptor homolog genes fullback and fullback-like.

We have identified fullback and fullback-like, two Xenopus laevis neurotrophin receptor homolog (NRH1) genes. The sequences of Fullback and Fullback-like are very similar to that of the neurotrophin receptor p75NTR, in both their extracellular and their intracellular domains. As their names imply, fullback and fullback-like are expressed in essentially identical patterns in the posterior of the embryo from the early gastrula stage onward. At tailbud and tadpole stages transcripts are also present in dorsal somites and the head, in addition to the growing tailbud. This expression pattern differs from that of p75NTR, suggesting that fullback and fullback-like have different functions from p75NTR during early development.

Amino Acid Sequence↗
PubMed2004

Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex.

Connective-tissue growth factor (CTGF) is a member of the CCN family of secreted proteins. CCN family members contain four characteristic domains and exhibit multiple activities: they associate with the extracellular matrix, they can mediate cell adhesion, cell migration and chemotaxis, and they can modulate the activities of peptide growth factors. Many of the effects of CTGF are thought to be mediated by binding to integrins, whereas others may be because of its recently identified ability to interact with BMP4 and TGF beta. We demonstrate, using Xenopus embryos, that CTGF also regulates signalling through the Wnt pathway, in accord with its ability to bind to the Wnt co-receptor LDL receptor-related protein 6 (LRP6). This interaction is likely to occur through the C-terminal (CT) domain of CTGF, which is distinct from the BMP- and TGF beta-interacting domain. Our results define new activities of CTGF and add to the variety of routes through which cells regulate growth factor activity in development, disease and tissue homeostasis.

Amino Acid Sequence↗
PubMed2004

Bilateral adrenal enlargement and non-suppressible hypercortisolism as a presenting feature of gastric cancer.

In patients with cancer, adrenal enlargement due to either metastatic disease or diffuse non-metastatic hyperplasia is increasingly recognized with modern imaging techniques. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by non-suppressible hypercortisolism, has also been described in neoplasia in the absence of ectopic adrenocorticotrophic hormone (ACTH) production. In the majority of cases of malignancy-associated hypercortisolism, it might be expected that the presence of malignant disease would be clinically apparent, thus rendering a detailed endocrinological evaluation of the HPA axis unnecessary. However, in the present case we describe a patient with occult malignancy presenting with bilateral adrenocortical enlargement and non-suppressible hypercortisolism that was not due to the ectopic ACTH syndrome. There were no clinical Cushingoid features other than hypertension and new-onset diabetes mellitus. Detailed diagnostic investigations for the possibility of Cushing's syndrome were performed before the underlying diagnosis of gastric adenocarcinoma eventually became apparent. Characteristics and potential mechanisms of non-suppressible hypercortisolism in cancer are discussed. We believe that this scenario will occur with greater frequency in the future, given the increasing early use of sophisticated high-resolution imaging for the evaluation of suspected intra-abdominal pathology.

Adenocarcinoma↗