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Biomedical subjects

Andrew M Smith

Publications and source records attributed to Andrew M Smith.

16 recordsLinked to original sources
PubMed2026

Weight Loss without Food Intake Suppression through Size-Dependent Retention of Anti-Inflammatory Nanomedicines.

Obesity is a risk factor for high-mortality health conditions, including cardiovascular diseases and type 2 diabetes, which makes the advancement of efficacious and safe weight loss therapies a high priority in pharmacology. The causal link between obesity and its comorbid conditions is believed to be a chronic state of inflammation originating within adipose tissue, with macrophages playing central roles, an axis that is not targeted directly by current therapies. Here, we use nanocarriers to deliver an anti-inflammatory glucocorticoid receptor agonist to adipose tissue macrophages and report the impact of size on therapeutic effect. Three dextran nanocarriers between 4-30 nm in hydrodynamic diameter released molecular drug cargo at equivalent rates and exhibited similar biological potency in vitro. In vivo in a mouse model of obesity, body weight and body fat were reduced in a size-dependent manner after 2-4 weeks of treatment. Unlike current clinical pharmacotherapies for weight loss, these body composition changes were not associated with changes in food intake. Greater retention of larger dextran nanocarriers in visceral adipose tissue appears to elicit a local change to promote browning by increasing mitochondrial abundance and lipid droplet fragmentation. Further development of this platform may result in a safe and potent modulator of adipose tissue in the state of obesity without direct action on nutrient intake to address malnutrition and lean body mass deficiencies observed with current weight loss pharmacotherapies.

Animals↗
PubMed2006

Investigation of mechanisms underlying the T-cell response to the hapten 2,4-dinitrochlorobenzene.

T-cell mediated contact sensitization by small molecular weight xenobiotics results in significant morbidity and absences from work. To be recognized by T-cells, xenobiotics must act as haptens, becoming protein-bound. At present, the requirement for processing and presentation of xenobiotics, the nature of the T-cell responses to them and the mechanisms that confer individual susceptibility in humans are unclear. We have investigated the T-cell response to the hapten 2,4-dinitrochlorobenzene (DNCB) which can sensitize all immunocompetent people. Fourteen healthy adults were sensitized with DNCB; 11 demonstrated positive T-cell responses to the chemical in vitro. Responding cells were of both CD4+ and CD8+ subsets, of Th1 and Tc1 phenotypes, producing high levels of IFN-gamma and low levels of IL-10. DNCB-specific T-cell clones were raised from 2 subjects, which in the presence of fixed and unfixed autologous Epstein-Barr virus transformed B cells as antigen-presenting-cells (APC), demonstrated that the chemical requires metabolic processing by the APC in order to initiate the T-cell response. Intracellular-reduced glutathione is consumed in detoxication of DNCB, leaving residual non-detoxified DNCB free to bind to proteins. The results suggest that DNCB forms multiple haptens with intracellular and extracellular proteins leading to Th1 and Tc1 responses in individuals exposed to this compound.

Adult↗
PubMed2006

Direct observation of oligomeric species formed in the early stages of amyloid fibril formation using electrospray ionisation mass spectrometry.

Numerous debilitating human disorders result from protein misfolding and amyloid formation. Despite the grave nature of these maladies, our understanding of the structural mechanism of fibril assembly is limited. Of paramount importance is the need to identify and characterize oligomeric species formed early during fibril assembly, so that the nature of the initiating assembly mechanism can be revealed and species that may be toxic to cells identified. However, the transient nature of early oligomeric species, combined with their heterogeneity and instability, has precluded detailed analysis to date. Here, we have used electrospray ionisation mass spectrometry (ESI-MS), complemented by analytical ultracentrifugation (AUC) and measurements of thioflavin-T fluorescence, to monitor the early stages of assembly of amyloid-like fibrils formed from human beta-2-microglobulin (beta2m) in vitro. We show that worm-like fibrils that form with nucleation-independent kinetics assemble by a mechanism consistent with monomer addition, with species ranging from monomer to > or = 13-mer being identified directly and uniquely as transient assembly intermediates. By contrast, only monomers, dimers, trimers and tetramers are observed during nucleated growth, which leads to the formation of long straight fibrils. The results highlight the unique power of non-covalent ESI-MS to identify protein assembly intermediates in complex heterogeneous systems and demonstrate its great potential to identify and characterise individual species formed early during amyloid assembly.

Alzheimer Disease↗
PubMed2006

The interactive effect of alcohol and nicotine on NGF-treated pheochromocytoma cells.

Previous studies have reported that alcohol exposure reduces the number of neuronal-like pheochromocytoma (PC12) cells in culture. In this study, the interactive effect of coexposure of alcohol and nicotine on PC12 cell numbers was examined in comparison with the effect derived from alcohol or nicotine exposure individually. Moreover, the role of apoptosis in mediating changes in PC12 cell numbers was also investigated. It was hypothesized that alcohol would result in cell loss, and the presence of nicotine would attenuate the damaging effects of alcohol. PC12 cells were exposed to alcohol (100 mM), nicotine (10 microM), or both alcohol and nicotine for 24, 48, 72, or 96 h. Caspase-3 activity and DNA fragmentation, markers for apoptotic cell death, were measured to determine the role of apoptosis in mediating decreases in PC12 cell numbers. The findings indicated that both alcohol and nicotine exposure significantly decreased PC12 cell numbers when compared with the control treatment. Furthermore, the coexposure of these two drugs caused a significantly greater decrease in cell numbers when compared with cells exposed to either alcohol or nicotine alone. This additive effect was related to the duration of exposure with a marked reduction in cell numbers following 96 h of coexposure to alcohol and nicotine. Neither alcohol nor nicotine exposure appeared to alter caspase-3 activity or DNA fragmentation levels, suggesting that the reduction in PC12 cell numbers following alcohol and/or nicotine exposure may possibly be due to factors other than apoptosis, such as interference with proliferation rates.

Animals↗
PubMed2006

Effects of nicotine exposure during prenatal or perinatal period on cell numbers in adult rat hippocampus and cerebellum: a stereology study.

Smoking during pregnancy poses a potential risk to unborn children. The present study examined the long-term effects of early nicotine exposure on the number of pyramidal and granule cells in the hippocampus, and Purkinje cells in the cerebellar vermis. The loss of neurons is the most severe form of brain injury with significant functional implications. In this study, rats were exposed to nicotine during either the prenatal (PRE) period or both the prenatal and early postnatal (PERI) period. It was hypothesized that nicotine treatment would result in long-term decreases in neuronal numbers, and that PERI treatment would be more detrimental to these cell populations than the PRE treatment. The results showed that neither PRE nor PERI nicotine exposure reduces the numbers of pyramidal, granule or Purkinje cells. Neither the regions where these cells reside, nor the cell densities were affected by nicotine. Although no significant cell loss was observed, the current nicotine exposure regimens may lead to alterations in cellular functions or cytoarchitectures. The present results in conjunction with previous reports showing significant cell loss from nicotine exposure during the brain growth spurt suggest that "patch-like" nicotine exposure during prenatal period may alter the sensitivity or the responsiveness of the developing brain to the injurious effects of nicotine during the most vulnerable stage of brain development - the brain growth spurt. Furthermore, the current stereology cell counting results are not in agreement with some reports in the literature, and this discrepancy may simply be a function of different cell counting techniques used.

Animals↗
PubMed2006

Behavioral and molecular effects of dopamine D1 receptor stimulation during naloxone-precipitated morphine withdrawal.

Morphine dependence is characterized by somatic and motivational signs of withdrawal that likely contribute to the maintenance of addictive behavior. The nucleus accumbens (NAc) receives extensive dopaminergic input and is an important substrate for mediating these aversive states. In the NAc, the function of the transcription factor cAMP response element binding protein (CREB) and AMPA glutamate receptor subunit, type 1 (GluR1) can be regulated by dopamine (DA) D1 receptor-mediated phosphorylation (P-CREB, P-GluR1). However, the roles of D1 receptors, CREB, and GluR1 in morphine dependence are not well understood. Here, we show that somatic signs of naloxone-precipitated withdrawal were associated with increased P-CREB, but not P-GluR1, in the NAc of morphine-dependent rats. The D1 receptor agonist chloro-APB hydrobromide (SKF 82958) was rewarding in morphine-dependent rats and blocked naloxone-induced place aversions and somatic signs of withdrawal. Surprisingly, SKF 82958 increased P-GluR1, but not P-CREB, in the NAc, and naloxone reduced SKF 82958-mediated P-GluR1 induction specifically in morphine-dependent rats. Together, these results confirm that aversive treatments can increase CREB function in the NAc. Furthermore, they suggest a dependence-associated shift in the molecular mechanisms that regulate the consequences of D1 receptor stimulation, favoring activation of GluR1 rather than CREB. These data raise the possibility that the rewarding effects of SKF 82958 in morphine-dependent rats involve increased P-GluR1 in the NAc, although the involvement of other brain regions cannot be ruled out. Regardless, these findings suggest for the first time that D1 agonists might be useful for the treatment of withdrawal symptoms that contribute to the maintenance of opiate addiction in humans.

Animals↗
PubMed2006

Engineering luminescent quantum dots for in vivo molecular and cellular imaging.

Semiconductor quantum dots are luminescent nanoparticles that are under intensive development for use as a new class of optical imaging contrast agents. Their novel properties such as optical tunability, improved photostability, and multicolor light emission have opened new opportunities for imaging living cells and in vivo animal models at unprecedented sensitivity and spatial resolution. Combined with biomolecular engineering strategies for tailoring the particle surfaces at the molecular level, bio-conjugated quantum dot probes are well suited for imaging single-molecule dynamics in living cells, for monitoring protein-protein interactions within specific intracellular locations, and for detecting diseased sites and organs in deep tissue. In this article, we describe the engineering principles for preparing high-quality quantum dots and for conjugating the dots to biomolecular ligands. We also discuss recent advances in using quantum dots for in vivo molecular and cellular imaging.

Animals↗
PubMed2006

Multicolor quantum dots for molecular diagnostics of cancer.

In the pursuit of sensitive and quantitative methods to detect and diagnose cancer, nanotechnology has been identified as a field of great promise. Semiconductor quantum dots are nanoparticles with intense, stable fluorescence, and could enable the detection of tens to hundreds of cancer biomarkers in blood assays, on cancer tissue biopsies, or as contrast agents for medical imaging. With the emergence of gene and protein profiling and microarray technology, high-throughput screening of biomarkers has generated databases of genomic and expression data for certain cancer types, and has identified new cancer-specific markers. Quantum dots have the potential to expand this in vitro analysis, and extend it to cellular, tissue and whole-body multiplexed cancer biomarker imaging.

Animals↗
PubMed2005

Neonatal alcohol exposure increases malondialdehyde (MDA) and glutathione (GSH) levels in the developing cerebellum.

It has been suggested that developmental alcohol-induced brain damage is mediated through increases in oxidative stress. In this study, the concentrations of malondialdehyde (MDA) and reduced glutathione (GSH) were measured to indicate alcohol-mediated oxidative stress. In addition, the ability of two known antioxidants, melatonin (MEL) and lazaroid U-83836E (U), to attenuate alcohol-induced oxidative stress was investigated. Sprague-Dawley rat pups were randomly assigned to six artificially-reared groups, ALC (alcohol), MEL, MEL/ALC, U, U/ALC, and GC (gastrostomy control), and one normal suckle control (to control for artificial-rearing effects on the dependent variables). The daily dosages for ALC, MEL, and U were 6 g/kg, 20 mg/kg, and 20 mg/kg, respectively. Alcohol was administered in 2 consecutive feedings, and antioxidant (MEL or U) was administered for a total of 4 consecutive feedings (2 feedings prior to and 2 feedings concurrently with alcohol). The animals received treatment from postnatal days (PD) 4 through 9. Cerebellar, hippocampal, and cortical samples were collected on PD 9 and analyzed for MDA and GSH content. The results indicated that MDA concentrations in the cerebellum were significantly elevated in animals receiving alcohol; however, MDA levels in the hippocampus and cortex were not affected by alcohol treatment. Additionally, GSH levels in the cerebellum were significantly elevated in groups receiving alcohol, regardless of antioxidant treatment. Neither antioxidant was able to protect against alcohol-induced alterations of MDA or GSH. These findings suggest that alcohol might increase GSH levels indirectly as a compensatory mechanism designed to protect the brain from oxidative-stress-mediated insult.

Analysis of Variance↗
PubMed2004

Chemical analysis and cellular imaging with quantum dots.

Quantum dots are tiny light-emitting particles on the nanometer scale. They are emerging as a new class of biological labels with properties and applications that are not available with traditional organic dyes and fluorescent proteins. Their novel properties such as improved brightness, resistance against photobleaching, and multicolor light emission, have opened new possibilities for ultrasensitive chemical analysis and cellular imaging. In this Research Highlight article , we discuss the unique optical properties of semiconductor quantum dots, surface chemistry and bioconjugation, current applications in bioanalytical chemistry and cell biology, and future research directions.

Animals↗
PubMed2003

Perioperative complications of the Scarf osteotomy.

We reporting the perioperative complications during our early experience using the Scarf osteotomy to correct hallux valgus. A case note review was carried out for the first 100 Scarf osteotomy procedures completed by the senior author. There were six patients (6%) with perioperative complications. Four of these were intraoperative complications including a split first metatarsal in three cases, a shearing of the K-wire in one case and there were two cases of postoperative stress fracture. These complications should be considered by those beginning to master the Scarf osteotomy procedure and by surgeons teaching surgical trainees.

Adult↗
PubMed2002

Chronic continuous nicotine exposure during periadolescence does not increase ethanol intake during adulthood in rats.

BACKGROUND: Nicotine has been considered as the gateway drug, because many teenagers experience cigarette smoking before seeking out other drugs. By using an animal model system, we assessed the effects of chronic continuous nicotine exposure during periadolescence on ethanol intake during young adulthood. METHODS: Periadolescent Sprague-Dawley rats (35 days old) were used at the beginning of this study. These animals received subcutaneous implantation of nicotine pellets (15 or 25 mg in 21-day time-release pellets) or placebo pellets (0 mg of nicotine) on postnatal day 35. Beginning on postnatal day 53, the animals received various concentrations of ethanol solution during their active period (5:00 PM to 9:00 AM) starting with 2% (v/v, 4 days), then 5% (5 days), 8% (6 days), and 10% (6 days). Between 9:00 AM and 5:00 PM of the same day, the ethanol solution was replaced by regular tap water. The amounts of ethanol solution and regular water were measured daily. RESULTS: The analyses showed that ethanol intake (grams per kilogram of body weight) in the nicotine 15 and 25 mg groups did not differ from that in the nicotine 0 mg group, and no sex difference was found in ethanol intake. However, ethanol intake was increased as a function of the treatment days. CONCLUSIONS: The results showed that chronic continuous nicotine exposure during adolescence did not increase ethanol intake in rats during young adulthood.

Age Factors↗
PubMed2002

Biochemical differences between trail mucus and adhesive mucus from marsh periwinkle snails.

The composition of the adhesive form of marsh periwinkle mucus was compared to the trail mucus used during locomotion. The trail mucus consists primarily of large, carbohydrate-rich molecules with some relatively small proteins. In contrast, the adhesive mucus has 2.7 times as much protein with no significant difference in carbohydrate concentration. The resulting gel has roughly equal amounts of protein and carbohydrate. This substantial increase in protein content is due to the additional presence of two proteins with molecular weights of 41 and 36 kD. These two proteins are absent from the trail mucus. Both proteins are glycosylated, have similar amino acid compositions, and have isoelectric points of 4.75. This change in composition corresponds to an order of magnitude increase in tenacity with little clear change in overall concentration. The difference between adhesive and non-adhesive mucus suggests that relatively small proteins are important for controlling the mechanics of periwinkle mucus.

Amino Acids↗
PubMedDate not supplied

Novel bile duct repair for bleeding biliary anastomotic varices: case report and literature review.

An unusual case of variceal bleeding at the site of a biliary enteric anastomosis is presented. This entity can occur when a high-to-low pressure gradient forms in a variceal field. In this case the anastomotic site was the location of the pressure gradient from the high-pressure small bowel varices to the low-pressure biliary tract. This was successfully treated by disconnection of the anastomosis. The resulting biliary defect was patched with small intestinal submucosa, which functioned successfully as a scaffold for biliary epithelial ingrowth.

Adult↗
PubMedDate not supplied

Quantum dot nanocrystals for in vivo molecular and cellular imaging.

Semiconductor quantum dots (QD) are nanometer-sized crystals with unique photochemical and photophysical properties that are not available from either isolated molecules or bulk solids. In comparison with organic dyes and fluorescent proteins, QD are emerging as a new class of fluorescent labels with improved brightness, resistance against photobleaching and multicolor fluorescence emission. These properties could improve the sensitivity of biological detection and imaging by at least 10- to 100-fold. Further development in high-quality near-infrared-emitting QD should allow ultrasensitive and multicolor imaging of molecular targets in deep tissue and living animals. Here, we discuss recent developments in QD synthesis and bioconjugation, applications in molecular and cellular imaging as well as promising directions for future research.

Animals↗