Ferromagnetic exchange coupling in the linear,chloride-bridged cluster (cyclam)CoII[(μ-Cl)UIV(Me2Pz)4]2

The trinuclear cluster (cyclam)Co[(μ-Cl)U(Me₂Pz)₄]₂ (cyclam = 1,4,8,11-tetraazacyclotetradecane, Me₂Pz^? = 3,5-dimethylpyrazolate) is synthesized through cleavage of the homoleptic dimer [U(Me₂Pz)₄]₂ by (cyclam)CoCl₂. A single crystal X-ray diffraction analysis reveals a linear chloride-bridged structure analogous to that previously reported for (cyclam)M[(μ-Cl)U(Me₂Pz)₄]₂ (M = Ni, Cu, Zn). The magnetic exchange coupling of the CoU₂ cluster was probed by analyzing the temperature dependence of its magnetic susceptibility. Comparison of χ_MT versus T between the CoU₂ species and the diamagnetic ZnU₂ cluster demonstrates the presence of ferromagnetic coupling between the Co^II and U^IV centers. We present methods for estimating upper and lower bounds for the exchange interaction energy in such systems and find that for CoU₂, the exchange constant, J, lies in the range 15–48 cm^?1. Application of these methods to the previously reported NiU₂ cluster suggests somewhat weaker ferromagnetic exchange, with J lying in the range 2.8–19 cm^?1. AC magnetic susceptibility experiments were not indicative of single-molecule magnet behavior for the CoU₂ cluster, although qualitative interpretation of the low-temperature magnetization data suggests the presence of significant zero-field splitting in the ground state.     

Field site selection: getting it right first time around

The selection of suitable field sites for integrated control of Anopheles mosquitoes using the sterile insect technique (SIT) requires consideration of the full gamut of factors facing most proposed control strategies, but four criteria identify an ideal site: 1) a single malaria vector, 2) an unstructured, relatively low density target population, 3) isolation of the target population and 4) actual or potential malaria incidence. Such a site can exist in a diverse range of situations or can be created. Two contrasting SIT field sites are examined here: the desert-flanked Dongola Reach of the Nile River in Northern State, Sudan, where malaria is endemic, and the island of La Reunion, where autochthonous malaria is rare but risk is persistent. The single malaria-transmitting vector at both sites is Anopheles arabiensis. In Sudan, the target area is a narrow 500 km corridor stretching from the rocky terrain at the Fourth Cataract - just above the new Merowe Dam, to the northernmost edge of the species range, close to Egypt. Vector distribution and temporal changes in density depend on the Nile level, ambient temperature and human activities. On La Reunion, the An. arabiensis population is coastal, limited and divided into three areas by altitude and exposure to the trade winds on the east coast. Mosquito vectors for other diseases are an issue at both sites, but of primary importance on La Reunion due to the recent chikungunya epidemic. The similarities and differences between these two sites in terms of suitability are discussed in the context of area-wide integrated vector management incorporating the SIT.     

Current concepts in RET-related genetics, signaling and therapeutics

The receptor tyrosine kinase RET is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation and survival during embryogenesis. Germline and somatic mutations in RET that produce constitutively activated receptors cause the cancer syndrome multiple endocrine neoplasia type 2 and several endocrine and neural-crest-derived tumors, whereas mutations resulting in nonfunctional RET or lower expression of RET are found in individuals affected with Hirschsprung disease. This review focuses on the genetics and molecular mechanisms underlying the different inherited human neural-crest-related disorders in which RET dysfunction has a crucial role and discusses RET as a potential therapeutic target.     

2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity

The discovery and structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.     

Avian olfactory receptor gene repertoires: evidence for a well-developed sense of smell in birds?

Among vertebrates, the sense of smell is mediated by olfactory receptors (ORs) expressed in sensory neurons within the olfactory epithelium. Comparative genomic studies suggest that the olfactory acuity of mammalian species correlates positively with both the total number and the proportion of functional OR genes encoded in their genomes. In contrast to mammals, avian olfaction is poorly understood, with birds widely regarded as relying primarily on visual and auditory inputs. Here, we show that in nine bird species from seven orders (blue tit, Cyanistes caeruleus; black coucal, Centropus grillii; brown kiwi, Apteryx australis; canary, Serinus canaria; galah, Eolophus roseicapillus; red jungle fowl, Gallus gallus; kakapo, Strigops habroptilus; mallard, Anas platyrhynchos; snow petrel, Pagodroma nivea), the majority of amplified OR sequences are predicted to be from potentially functional genes. This finding is somewhat surprising as one previous report suggested that the majority of OR genes in an avian (red jungle fowl) genomic sequence are non-functional pseudogenes. We also show that it is not the estimated proportion of potentially functional OR genes, but rather the estimated total number of OR genes that correlates positively with relative olfactory bulb size, an anatomical correlate of olfactory capability. We further demonstrate that all the nine bird genomes examined encode OR genes belonging to a large gene clade, termed gamma-c, the expansion of which appears to be a shared characteristic of class Aves. In summary, our findings suggest that olfaction in birds may be a more important sense than generally believed.     

Chemotherapy-induced pica and anorexia are reduced by common hepatic branch vagotomy in the rat

Anticancer agents, such as cisplatin, induce vomiting, nausea, and anorexia. Cisplatin primarily acts on vagal afferents to produce emesis, but little is known about how this drug generates nausea and anorexia. Electrophysiology indicates that cisplatin activates vagal afferents of the common hepatic branch (CHB). Rats lack an emetic response but do ingest kaolin clay (a pica response) when made sick by toxins, and this behavior can be inhibited by antiemetic drugs. It has been postulated that pica may serve as a proxy for emesis in the rat. The goal of this study was to assess the effect of CHB or ventral gastric (Gas) or celiac (Cel) branch vagotomies on pica and anorexia produced by cisplatin in the rat. The effects of apomorphine, a dopamine receptor agonist, which induces emesis via a central mechanism, were also assessed. Cisplatin-induced pica was suppressed by CHB vagotomy (a 61% reduction) but not by Gas and Cel vagotomy. Suppression of daily food intake and body weight following cisplatin treatment was also blunted by CHB ablation but not by Gas or Cel vagotomy. No vagotomy condition exhibited altered apomorphine-induced pica. The results indicate that the CHB, which innervates primarily the duodenum, plays an important role in cisplatin-induced malaise. These data suggest that pica has sensory pathways similar to emetic systems, since a vagotomy condition inhibited cisplatin-induced pica but had no effect on apomorphine-induced pica. This investigation contributes to the delineation of the physiology of pica and neural systems involved in malaise in the nonvomiting rat.     

Sperm binding properties and secretory activity of the bovine oviduct immediately before and after ovulation

The possibility that differences in hormonal regimes between the two oviducts in the cow around ovulation affects secretory activity of the oviduct epithelial cells and/or sperm-oviduct binding was studied. Oviducts were collected immediately after slaughter at 6 hr before to 5 hr after timed ovulation of 14 normally cyclic cows that had been inseminated (n = 6) or not (n = 8) and material obtained from the same cows was processed in three ways. First, in vivo, after artificial insemination of the cows, low numbers of sperm cells (approx. 15 per oviduct) were found within the entire oviducts as observed by scanning electron microscopy (SEM). Almost all sperm were located in the isthmus and then only on ciliated cells and showed without exception fully matured, intact morphology. Secretory activity of noninseminated oviduct epithelia was induced after ovulation which was most predominant in the pockets of the ipsi-lateral ampulla compared to the contra-lateral ampulla (P < 0.01). Second, ex vivo, explants dissected from oviducts of the noniseminated cows were incubated with sperm. In all cases, the sperm bound to the explants in a similar pattern as observed in vivo and this binding was strictly fucose-dependent. The main difference with in vivo experiments was the high numbers of sperm bound at any site of the oviduct ( approximately 3,000 cells per mm(2)) indicating the high sperm binding capacity of the oviduct epithelia. Ovulation induced a striking drop in sperm binding capacity in the oviducts and was most pronounced in the isthmus ( approximately 1,300 cells per mm(2); P < 0.001) and to a lesser extent in the ampulla ( approximately 2,000 cells per mm(2), P < 0.01). Third, in vitro, pieces of tissue dissected from oviducts of the noninseminated cows were cultured to mono-layers. Culturing epithelial cells resulted in loss of their normal morphological appearance. In all cases, the sperm binding capacity in monolayers was very low (<50 cells per mm(2)) when compared to corresponding explants (P < 0.0001). Sperm binding to monolayers originating from the isthmus (<25 cells per mm(2)) was lower than in those from the ampulla (40-50 cells per mm(2); P < 0.01) and remained similar after ovulation. In all three approaches, no significant differences were found in sperm-oviduct binding characteristics and sperm-distribution in the ipsi- versus contra-lateral oviducts. This indicates, that systemic endocrine changes around ovulation rather than specific oviduct changes at the ipsi-lateral oviduct induce secretion in oviduct epithelial cells, and thus induce sperm release.     

Prolonged conservative care versus early surgery in patients with sciatica from lumbar disc herniation: cost utility analysis alongside a randomised controlled trial

Objective To determine whether the faster recovery after early surgery for sciatica compared with prolonged conservative care is attained at reasonable costs.Design Cost utility analysis alongside a randomised controlled trial.Setting Nine Dutch hospitals.Participants 283 patients with sciatica for 6-12 weeks, caused by lumbar disc herniation.Interventions Six months of prolonged conservative care compared with early surgery.Main outcome measures Quality adjusted life years (QALYs) at one year and societal costs, estimated from patient reported utilities (UK and US EuroQol, SF-6D, and visual analogue scale) and diaries on costs (healthcare, patient’s costs, and productivity).Results Compared with prolonged conservative care, early surgery provided faster recovery, with a gain in QALYs according to the UK EuroQol of 0.044 (95% confidence interval 0.005 to 0.083), the US EuroQol of 0.032 (0.005 to 0.059), the SF-6D of 0.024 (0.003 to 0.046), and the visual analogue scale of 0.032 (−0.003 to 0.066). From the healthcare perspective, early surgery resulted in higher costs (difference €1819 (£1449; $2832), 95% confidence interval €842 to €2790), with a cost utility ratio per QALY of €41 000 (€14 000 to €430 000). From the societal perspective, savings on productivity costs led to a negligible total difference in cost (€−12, €−4029 to €4006).Conclusions Faster recovery from sciatica makes early surgery likely to be cost effective compared with prolonged conservative care. The estimated difference in healthcare costs was acceptable and was compensated for by the difference in absenteeism from work. For a willingness to pay of €40 000 or more per QALY, early surgery need not be withheld for economic reasons.Trial registration Current Controlled Trials ISRCTN 26872154.