Estrogen therapy and brain muscarinic receptor density in healthy females: a SPET study

Estrogen Therapy (ET) may protect against age-related cognitive decline and neuropsychiatric disorders (e.g. Alzheimer's disease). The biological basis for this putative neuroprotective effect is not fully understood, but may include modulation of cholinergic systems. Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer's disease. However, to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging, and related this to cognitive function. We used Single Photon Emission Tomography (SPET) and (R,R)[(123)I]-I-QNB, a novel ligand with high affinity for m(1)/m(4) muscarinic receptors, to examine the effect of long-term ET and age on brain m(1)/m(4) receptors in healthy females. We included 10 younger premenopausal subjects and 22 postmenopausal women; 11 long-term ET users (all treated following surgical menopause) and 11 ET never-users (surgical menopause, n=2). Also, verbal memory and executive function was assessed in all postmenopausal subjects. Compared to young women, postmenopausal women (ET users and never-users combined) had significantly lower muscarinic receptor density in all brain regions examined. ET users also had higher muscarinic receptor density than ET never-users in all the brain regions, and this reached statistical significance in left striatum and hippocampus, lateral frontal cortex and thalamus. Moreover, in ET users, (R,R)[(123)I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels. We also found evidence for improved executive function in ET users as compared to ET never-users. However, there was no significant relationship between receptor binding and cognitive function within any of the groups. In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding, and this may be related to serum estradiol levels.     

Chemoselective synthesis of erythromycin A ketolides substituted in the C10-methyl group

The substrate for selective substitution in the C10-methyl group in erythromycin A derivatives was 10,11-anhydro-6O-methyl-descladinosylerythromycin. The latter, as an N-oxide, was reacted with NBS in acetic acid to form an allylic acetate. Nucleophilic substitutions and carbylation by Pd-catalysed cross-coupling reactions provided products substituted in the C10-methyl group. Methods for the preparation of 10-methylene derivatives of 11N,12O-cyclocarbamate 3-ketolides are described. The methylene group is part of an alpha,beta-unsaturated carbonyl system involving the 9-keto group. The products from conjugated addition are substituted in the C10-methyl group.     

Medical monitoring during the NASA Artificial Gravity-Bed Rest Pilot Study

The NASA artificial gravity-bed rest pilot study (AGPS) was designed to investigate the efficacy of daily exposure to a +Gz acceleration gradient for counteracting the physiologic decrements induced by prolonged bed rest. Test subjects were continuously monitored by a physician for signs and symptoms of pre-syncope, motion sickness, and arrhythmias while on the centrifuge. In this article, we have summarized the medical monitoring observations that were made during the AGPS and included an assessment of the relative usefulness of the information provided by the various monitoring tools in making a decision to terminate a centrifuge spin.     

Inflammatory obstruction of the olfactory clefts and olfactory loss in humans: a new syndrome?

The first step in the olfactory perception is the activation by odorants of sensory neurones in the olfactory epithelium. In humans, this sensory epithelium is located at 2 narrow passages, the olfactory clefts, at the upper part of the nasal cavities. Little is known about the physiology of these clefts. We examined, in 34 patients, the impact of obstructed clefts upon detection and postlearning identification of 5 odorants. The location and extension of the obstructions were assessed using endoscopy, CT scans, and MRI. The inflammatory obstruction was usually bilateral, extending anteroposteriorly, and confined to the clefts, with no sign of obstruction or any inflammatory disease in the rest of the nasal cavities and sinuses. When tested with 5 odorants, these patients showed greatly impaired olfaction compared with a group of 73 normosmic subjects. The majority of these 34 patients had sensory deficits equivalent to that found in another group of 41 congenital anosmic patients, where inspection with MRI indicated the lack of olfactory bulbs. This study demonstrates that the olfactory clefts, in human, function as an entity that is different from other regions of the nasal cavity and is the target for local inflammatory events that are apparently not responding to corticoid and antibiotic treatments.     

Proteome changes in bovine longissimus thoracis muscle during the early postmortem storage period

Postmortem changes in protein composition up to 24 h in bovine longissimus thoracis muscle were investigated by two-dimensional gel electrophoresis and MALDI-TOF MS/MS. A total of 47 spots were significantly changed the first 24 h postmortem. The 39 identified proteins can be divided into five groups: metabolic enzymes, defense and stress proteins, structural proteins, proteolytic enzymes, and unclassified proteins. The identified metabolic enzymes are all associated with ATP-generating pathways, either the glycolytic pathway or energy metabolism. In addition, several defense and stress proteins were changed in abundance in this study. These findings contribute to a better understanding of the biochemical processes during postmortem storage of meat.     

Are mismatches the norm? Timing of flowering,fruiting, dispersal and germination and their fitness effects in Frangula alnus (Rhamnaceae)

The close morphological and temporal links between phases of plant growth and reproduction call for integrated studies incorporating several reproductive phases from flowering to recruitment, and associated plant‐animal interactions. Phenological strategies, as well as plastic phenological response to climate change, incorporate complex interactions between developmental constraints, pollination and seed dispersal. Relationships between reproductive phenology and components of fitness were studied for two years in the north‐temperate, self‐incompatible, insect‐pollinated, and bird‐dispersed shrub Frangula alnus (Rhamnaceae). Fruit set, dispersal, germination and juvenile survival, as well as seed mass and juvenile size were measured in relation to flowering, fruiting and germination time. The results suggest that effects of flowering and fruiting time prevailed in subsequent phases, to some extent as far as to the juvenile phase, but effects of timing were complex and had partly opposing effects on different fitness components. Early flowers had higher fruit‐set and experiments indicated that synchronous peak flowering increased fruit‐set, but later flowers had higher seed mass. Peak fruiting was not associated with peak dispersal. Late fruits derived from late flowers promoted dispersal. Juvenile recruitment was enhanced by increasing seed size. We conclude that the phenology of flowering and fruiting in F. alnus comprises several features, each with different and sometimes counteracting effects on fitness components. From a general perspective, this result implies that we should not expect to find finely tuned matches in timing specifically between flowering and pollinators, and fruiting and seed dispersing birds.     

The historical biogeography of Apsilochorema (Trichoptera,Hydrobiosidae) revised,following molecular studies

The genus Apsilochorema Ulmer, 1907 is unique in the family Hydrobiosidae Ulmer, being widely distributed in the Palaearctic, Oriental and Australian Regions. All other 49 genera in the family, except the New World Atopsyche Banks, 1905, are confined to a single biogeographical Region. This unique distribution has independently stimulated researchers to formulate competing hypotheses about the biogeographical history of the genus. Molecular sequence data from mitochondrial cytochrome oxidase I (COI) and nuclear cadherin (CAD) genes of Apsilochorema species from the Oriental and Australian areas were analysed phylogenetically. The results retain a monophyletic Apsilochorema, which forms the sistergroup to the other genera in the subfamily Apsilochorematinae. The results from the biogeographical analyses dispute the earlier assumptions of an Oriental or northern Gondwana origin for the genus, revealing unambiguously an initial Australian radiation of the ancestral Apsilochorema with a subsequent dispersal into the Oriental Region. All but one of the Apsilochorema species occurring on the Pacific islands had an Oriental ancestor. The exception is the sistergroup to the New Caledonian species, which is found in both Australia and Oriental Regions. The molecular dating analysis, using a relaxed clock model, indicates that the genus Apsilochorema is about 36.4 MY old and that it dispersed from Australia into the Oriental Region about 28.3 Ma. It also gives an estimate of the approximate ages of the dispersals into New Caledonia to about 15.3 Ma; to the Solomon Islands at about 16.2 Ma; to the Fiji Islands at about 16.1 Ma; and to the Vanuatu Islands at about 5.4 Ma.     

Dissecting the conserved NPxxY motif of the M3 muscarinic acetylcholine receptor: critical role of Asp-7.49 for receptor signaling and multiprotein complex formation

Acetylcholine challenge produces M(3) muscarinic acetylcholine receptor activation and accessory/scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved M(3) muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation. Interestingly, while a N7.49D receptor mutant showed normal ligand binding properties a N7.49A mutant had reduced antagonist binding and increased affinity for carbachol. Also, besides this last mutant was able to physically couple to Gα(q/11) after carbachol challenge it was neither capable to activate phospholipase C nor phospholipase D. On the other hand, we demonstrated that the Asn-7.49 is important for the interaction between M(3)R and ARF1 and also for the formation of the ARF/Rho/β γ signaling complex, a complex that might determine the rapid activation and desensitization of PLD. Overall, these results indicate that the NPxxY motif of the M(3) muscarinic acetylcholine receptor acts as key conformational switch for receptor signaling and multiprotein complex formation.     

Early changes in bone mineral density measured by digital X-ray radiogrammetry predict up to 20 years radiological outcome in rheumatoid arthritis

Introduction  

Changes in bone mineral density (BMD) in the hand as evaluated by digital X-ray radiogrammetry (DXR) of the second to fourth metacarpal bones has been suggested to predict future joint damage in patients with rheumatoid arthritis (RA). This study's objective was to investigate whether DXR-BMD loss early in the course of the disease predicts the development of joint damage in RA patients followed for up to 20 years.