Enteric campylobacter: purging its secrets?

Campylobacterial infections are the most common cause of bacterial enterocolitis in humans. Among children, especially in developing countries, Campylobacter infections can cause severe life-threatening diarrheal disease. Although usually associated with a benign outcome in the developed world, the burden of illness posed by Campylobacter infections is enormous, and serious neurologic sequelae also can occur. For a variety of reasons our understanding of the molecular and cellular pathogenesis of Campylobacter infection has lagged far behind that of other enteric pathogens. However, recent completion of the genome sequence of Campylobacter jejuni promises to open up the Campylobacter research field with the prospect of developing novel therapeutic and preventive strategies.     

Comparison of MRI and CT for detection of acute intracerebral hemorrhage

Context  Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. Objective  To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. Design, Setting, and Patients  A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. Main Outcome Measures  Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. Results  The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT—each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. Conclusion  MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.      

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues. Novel nicotinic antagonist

A series of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues (5a-k) showed high affinity for alpha4beta2 binding with no affinity at alpha7 nAChRs. The most potent compound was 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (5g) which possessed a Ki value of 0.009 nM. Surprisingly, none of the compounds showed agonist effects in pain tests and body temperature changes in mice even when tested at 10-15 mg/kg with the exception of 5b, which showed only very weak agonist effects. In contrast, all the compounds were potent functional antagonists of nicotine-induced antinociception. Interestingly, the 3'-substituted phenyl analogues 5b-k were 10-870-fold more effective as antagonists in the tail-flick test versus the hot-plate procedure. They failed to antagonize nicotine-induced hypothermia. The 4-chlorophenyl analogue (5e) (AD50 = 0.0003 in the tail-flick test) was the most potent and selective analogue. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. These compounds also deserve consideration as potential pharmacotherapies for treatment of smoking cessation.     

Signaling pathways involved in the development of cannabinoid tolerance

Considerable plasticity exists in the endogenous cannabinoid system, as evidenced by the high degree of tolerance that develops following repetitive exposure to exogenously administered cannabinoid receptor agonists. This tolerance development is accompanied by cannabinoid CB(1) receptor downregulation and attenuation of G-protein activation. The biological processes responsible for CB(1) receptor downregulation remain to be fully understood. However, recent evidence suggests that several protein kinases participate in the development of cannabinoid tolerance. These observations implicate a role for protein kinases in cannabinoid signaling pathways. It remains to be established whether these protein kinases are directly involved in CB(1) receptor regulation or whether they contribute to tolerance by modulating additional signaling pathways.     

A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach

Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site.     

Chemistry and biology of curacin A

Many natural and synthetic compounds bind to tubulin, an ubiquitous globular protein that provides the building blocks for the cellular microtubule network that controls chromosome segregation during mitosis, vesicle movements, intracellular transport of organelles, ciliar and flagellar movement, and maintenance of cell shape. Since the isolation of the antimitotic marine natural product curacin A in 1994, synthetic work on this colchicine-site binding agent has been intense, but only recently have synthetic derivatives been identified that match its potency for tubulin polymerization inhibition and its high level of growth inhibition in cancer cell lines. In addition to several total synthesis efforts, combinatorial libraries were constructed using solution phase and fluorous scavenging approaches. Low water-solubility and lack of chemical stability represent strong detriments for the clinical development of curacin A, but synthetic analogs with improved bioavailability might ultimately probe the paradigm for anticancer efficacy of colchicine-site tubulin binding agents.     

Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors

Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated the effects of hydrobupropion enantiomers on monoamine transporters and nicotinic acetylcholine receptor (nAChR) subtypes. Racemic bupropion and hydroxybupropion inhibit [(3)H]norepinephrine (NE) uptake with similar potency (IC(50) values of 1.9 and 1.7 microM, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC(50) = 520 nM) rather than (2S,3R)-hydroxybupropion (IC(50) > 10,000 nM). Similar results were found with [(3)H]dopamine (DA) uptake. The effects of bupropion and enantiomers of hydroxybupropion on human nAChR subtypes indicate that the (2S,3S) isomer is more potent than the (2S,3R) isomer or racemic bupropion as an antagonist of alpha(4)beta(2) (functional IC(50) = 3.3 microM). In addition, (2S,3S)-hyroxybupropion and bupropion were considerably more potent than (2R, -3R)-hydroxybupropion in a mouse depression model (forced swimming test) and in antagonism of acute nicotine effects in mice. Together, our results suggest that clinical and behavioral effects of bupropion arise from actions at nAChR as well as DA and NE transporters. Furthermore, our data suggest that the (2S,3S)-hydroxybupropion isomer may be a better drug candidate for smoking cessation than bupropion because of its higher potency at the relevant targets.     

The Relationship between Lutein and Zeaxanthin Status and Body Fat

The objective of this project was to investigate the relationships between total and regional distribution of body fat and tissue lutein (L) and zeaxanthin (Z) status. Healthy men and women (N = 100; average age: 22.5 year, average BMI: 23.4 kg/m²) were evaluated. Total body and regional fat mass were assessed by dual-energy X-ray absorptiometry (Hologic Delphi A). Serum LZ was measured using reverse phase high-performance liquid chromatography, and retinal LZ (referred to as macular pigment optical density; MPOD) was measured using heterochromatic flicker photometry. Body fat percentage (total and regional) was inversely related to MPOD (p < 0.01) but no significant relationship was found for serum LZ. Higher body fat percentage, even within relatively healthy limits, is associated with lower tissue LZ status. The results indicate that adiposity may affect the nutritional state of the retina. Such links may be one of the reasons that obesity promotes age-related degenerative conditions of the retina.