Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: novel and selective histamine H3 receptor antagonists

Novel 4'-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H(3)receptors. Most compounds were highly potent and selective for human and rat H(3) receptors and selected examples such as A-349821 showed functional antagonism of H(3) receptors in vitro and in a mouse dipsogenia model.     

In vivo regulation of Na/Ca exchanger expression by adrenergic effectors

The Na/Ca exchanger encoded by the NCX1 gene plays an important role in calcium homeostasis in cardiac muscle. We previously identified three in vitro signaling pathways that are of major importance in the regulation of Na/Ca exchanger gene expression in neonatal cardiac myocytes, the protein kinase A (PKA) and protein kinase C (PKC) pathways, and intracellular Ca(2+). To determine whether these pathways are important in vivo, we stimulated the PKA and PKC pathways and examined functional expression of the Na/Ca exchanger in adult rat heart. After a 3- and 7-day treatment, norepinephrine (200 microg x kg(-1) x h(-1)), isoproterenol (150 microg x kg(-1) x h(-1)), and phenylephrine (200 microg x kg(-1) x h(-1)) each stimulated a significant increase in NCX1 mRNA levels (35-85%, P < 0.05). Norepinephrine also stimulated a 35% increase in protein abundance (P < 0.05), a 20% decrease in relaxation duration (P < 0.05), and a 25% reduction in the fluorescence decay constant (P < 0.05) after a 7-day treatment. We conclude that a 7-day treatment of alpha- and beta-adrenergic agonists increases the expression of functional Na/Ca exchangers in adult rat heart.     

Molecular and mesoscopic properties of hydrophilic polymer-grafted phospholipids mixed with phosphatidylcholine in aqueous dispersion: interaction of dipalmitoyl N-poly(ethylene glycol)phosphatidylethanolamine with dipalmitoylphosphatidylcholine studied by spectrophotometry and spin-label electron spin resonance

Spin-label electron spin resonance (ESR) spectroscopy, together with optical density measurements, has been used to investigate, at both the molecular and supramolecular levels, the interactions of N-poly(ethylene glycol)-phosphatidylethanolamines (PEG-PE) with phosphatidylcholine (PC) in aqueous dispersions. PEG-PEs are micelle-forming hydrophilic polymer-grafted lipids that are used extensively for steric stabilization of PC liposomes to increase their lifetimes in the blood circulation. All lipids had dipalmitoyl (C16:0) chains, and the polymer polar group of the PEG-PE lipids had a mean molecular mass of either 350 or 2000 Da. PC/PEG-PE mixtures were investigated over the entire range of relative compositions. Spin-label ESR was used quantitatively to investigate bilayer-micelle conversion with increasing PEG-PE content by measurements at temperatures for which the bilayer membrane component of the mixture was in the gel phase. Both saturation transfer ESR and optical density measurements were used to obtain information on the dependence of lipid aggregate size on PEG-PE content. It is found that the stable state of lipid aggregation is strongly dependent not only on PEG-PE content but also on the size of the hydrophilic polar group. These biophysical properties may be used for optimized design of sterically stabilized liposomes.     

Long-term outcome of cleft lip nasal reconstruction in childhood

This study documents the pattern of unilateral cleft lip nasal reconstruction in the practice of one surgeon at a tertiary cleft center, evaluating the long-term appearance outcome of single-operation unilateral cleft lip nasal reconstruction in childhood. A retrospective medical record review was performed for all patients with a diagnosis of unilateral cleft lip and age greater than 15 years. Operative notes were reviewed, recording 15 variables identifying specific rhinoplastic maneuvers. Nasal appearance outcome analysis was performed for all patients who underwent only one nasal surgery before 12 years of age (n = 19). Standard frontal whole face photographic images were presented as opposing pairs in a looseleaf binder to two panels, 1 of 10 lay persons and 1 of 10 plastic surgeons. Each pair consisted of photographs of the same patient at different ages in one of three combinations: preoperative-perioperative, perioperative-longest postoperative, or preoperative-longest postoperative. Participants were asked to compare the appearance of the noses in the two photographs and assign a rating based on a 5-point Likert scale. Statistical analyses were performed on the data collected in the aesthetic analysis. The effect of surgery upon nasal appearance was assessed by comparing the preoperative and perioperative photographs. The effect of growth was assessed by comparing the perioperative and long-term postoperative photographs. The combined effect of surgery and growth was assessed by comparing the preoperative and long-term postoperative photographs. The data were assessed by lay and professional evaluators, together and separately, to determine whether differences existed. The majority of patients did not undergo revisional nasal surgery, whereas those who did usually had one nasal operation. Most revisional nasal surgery was performed in conjunction with other cleft-related secondary surgery. A majority of lay and professional evaluators perceived revisional nasal surgery as improving nasal appearance in the short-term and to a lesser degree in the long-term, as compared with the preoperative state. Evaluations of revisional nasal surgery are generally constant between the short-term and long-term postoperative images. Lay evaluations may be contaminated by a general decline in attractiveness with aging. Patient preference should be a major factor in the decision for nasal revision surgery. Multiple means of assessing nasal appearance outcome need to be used to validate results. Nasal appearance outcomes need to be correlated with outcomes with respect to nasal morphology and function as well as patient and parent satisfaction.     

Extended Survival and Persistence of Campylobacter spp. in Water and Aquatic Biofilms and Their Detection by Immunofluorescent-Antibody and -rRNA Staining

In water microcosm experiments, the survival times of Campylobacter isolates differed by up to twofold, as determined by culturing; this difference increased to fourfold when particular combinations of temperature and oxygenation were used. The mean survival times were much longer at 4 and 10°C (202 and 176 h, respectively) than at 22 and 37°C (43 and 22 h, respectively). The influence of anaerobiosis on survival time was less dramatic and differed considerably between isolates. In a two-stage water distribution model preparation containing a biofilm consisting of standardized autochthonous water microflora, Campylobacter isolates continued to differ in survival time. However, the survival times of cultures were considerably longer in the presence of the autochthonous water microflora (strains CH1 and 9752 survived 700 and 360 h, respectively, at 4°C) than in the sterile microcosms (strains CH1 and 9752 survived 230 and 157 h, respectively). Although increased temperature and oxygenation were generally detrimental to culturability, the interaction of these two factors influenced the two strains examined differently. When the organisms were grown aerobically at 30°C, the survival of the two strains was reversed; aerobiosis decreased the survival time of strain CH1 by 30%, but unexpectedly improved the persistence time of strain 9752 by more than threefold. Persistence times within biofilms were much longer when they were determined by detection methods not involving culturing. Immunofluorescent-antibody staining demonstrated that the pathogen persisted up to the termination of the experiments after 28 and 42 days of incubation at 30 and 4°C, respectively. The specificity of detection within intact biofilms was reduced because of high background fluorescence. However, preliminary studies with a Campylobacter-specific rRNA probe revealed the same extended persistence of the pathogen within the biofilms.     

Identification of the Vibrio cholerae type 4 prepilin peptidase required for cholera toxin secretion and pilus formation

Cholera toxin secretion is dependent upon the extracellular protein secretion apparatus encoded by the eps gene locus of Vibrio cholerae . Although the eps gene locus encodes several type four prepilin-like proteins, the peptidase responsible for processing these proteins has not been identified. This report describes the identification of a prepilin peptidase from the V. cholerae genomic database by virtue of its homology with the PilD prepilin peptidase of Pseudomonas aeruginosa . Plasmid disruption or deletion of this peptidase gene in either El Tor or classical V. cholerae O1 biotype strains results in a dramatic decrease in cholera toxin secretion. In the case of the El Tor biotype mutants, surface expression of the type 4 pilus responsible for mannose-sensitive haemagglutination is abolished. The cloned V. cholerae peptidase processes either EpsI or MshA preproteins when co-expressed in E. coli . Mutation of the V. cholerae peptidase gene also results in a defect in virulence and decreased levels of OmpU. The V. cholerae peptidase gene sequence shows 80% homology with the Vibrio vulnificus VvpD type 4 prepilin peptidase required for pilus assembly and cytolysin secretion in V. vulnificus . Accordingly, the V. cholerae type 4 prepilin peptidase required for pilus assembly and cholera toxin secretion has been designated VcpD.     

Identifying high-level salt marshes using a palynomorphic fingerprint with potential implications for tracking sea level change

Palynomorph assemblages from South Carolina salt marshes were analyzed from high marsh, low marsh, and salt panne zones. High marsh zones, dominated by Juncus roemerianus, consistently had a distinctive palynomorphic signature, whereas this was not the case for assemblages from low marsh and salt panne zones.The Juncus environment was distinguishable from all others by the following parameters: 1) higher palynomorph diversity (nearly double the taxonomic diversity present in the other types), 2) the presence of a high percentage (over 10% of the palynomorph count) of Fungal Spore Type A, and 3) the presence of Atrotorquata lineata, a fungal species that was found solely in sediments beneath Juncus marshes. Locating the positions of Juncus environments in cores should allow one to trace the rise and fall of sea level over time.