A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias

The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that is activated by low cellular energy status and affects a switch away from energy-requiring processes and toward catabolism. While it is primarily regulated by AMP and ATP, high muscle glycogen has also been shown to repress its activation. Mutations in the gamma2 and gamma3 subunit isoforms lead to arrhythmias associated with abnormal glycogen storage in human heart and elevated glycogen in pig muscle, respectively. A putative glycogen binding domain (GBD) has now been identified in the beta subunits. Coexpression of truncated beta subunits lacking the GBD with alpha and gamma subunits yielded complexes that were active and normally regulated. However, coexpression of alpha and gamma with full-length beta caused accumulation of AMPK in large cytoplasmic inclusions that could be counterstained with anti-glycogen or anti-glycogen synthase antibodies. These inclusions were not affected by mutations that increased or abolished the kinase activity and were not observed by using truncated beta subunits lacking the GBD. Our results suggest that the GBD binds glycogen and can lead to abnormal glycogen-containing inclusions when the kinase is overexpressed. These may be related to the abnormal glycogen storage bodies seen in heart disease patients with gamma2 mutations.     

Empirical evidence for key hosts in persistence of a tick-borne disease

An important epidemiological consequence of aggregated host-parasite associations occurs when parasites are vectors of pathogens. Those hosts that attract many vectors will tend to be the focus of transmission. But to what extent, and can we identify characteristics of these key hosts? We investigated these questions with respect to the host-tick relationship of the yellow-necked mouse, Apodemus flavicollis, a critical host in the maintenance of the zoonotic disease, tick-borne encephalitis. Transmission of the virus occurs when ticks feed in a 'co-feeding' aggregation. Thus, the number and frequency of co-feeding groups provides an estimate of the potential rate of virus transmission. We recorded the spatio-temporal variations in co-feeding on a population of rodents in conjunction with recording individual host characteristics. Using Lorenz curves, we revealed conformation of tick-borne encephalitis transmission potential to the 20/80 Rule, where the 20% of hosts most infested with ticks were accountable for 80% of transmission potential. Hosts in the transmission cohort were identified as the sexually mature males of high body mass. Therefore control efforts targeted at this group would substantially reduce transmission potential compared to non-targeted control of the population, which resulted in a linear reduction in transmission potential. Focusing on the 'wrong' functional group would have little impact upon transmission potential until a considerable proportion of the population had been subject to control. However, individuals can change their functional status over time making it difficult to predict the contribution of these individuals to future transmission.     

Selective delta-opioid receptor ligands: potential PET ligands based on naltrindole

Two series of delta-selective ligands related to the prototypic delta-antagonist naltrindole have been prepared and evaluated in opioid binding assays with the aim of developing new PET ligands for the delta-opioid receptor. One compound (5d) had significantly higher selectivity than naltrindole, but with substantially reduced binding affinity. For those compounds retaining similar affinity to naltrindole, those having ethyl and fluoroethyl substituents afforded the highest levels of selectivity. However, none of the compounds combined the high level of affinity and selectivity ideally suited to the development of an imaging agent.     

Single-stage, autologous breast restoration

The skin-sparing mastectomy, when performed with immediate reconstruction, is a major advance in breast reconstruction. Traditionally, reconstruction of the nipple-areola complex is performed as a subsequent procedure. In this study, 17 patients (mean age, 43 years; range, 35 to 53 years) underwent one-stage breast and nipple-areola reconstruction over a 21-month period. In all cases of breast reconstruction, a buried transverse rectus abdominis musculocutaneous (TRAM) flap was used, and all patients had a simultaneous nipple-areola complex reconstruction performed. Nine patients had a Wise keyhole pattern used and contralateral reduction performed. Four patients retained all their breast skin, and a TRAM skin island was used in another four. It has recently been shown that patients with early-stage breast cancer and peripherally sited tumors have a very low risk of nipple-areola involvement. In 10 patients with early disease and peripheral tumors, the areola was retained (as a thin full-thickness graft), but more recently, in three patients with early-stage disease, the entire nipple-areola complex was used as a thin full-thickness graft. The thin full-thickness skin graft is removed from the breast in an apple-coring fashion, so that most of the ducts are retained as part of the mastectomy specimen. (There was histological confirmation of absence of tumor in the nipples of these patients.)One-stage autologous reconstruction should be considered for all patients undergoing immediate breast reconstruction. In patients with early-stage disease and peripheral tumors, the nipple-areola complex may be retained through the use of a thin full-thickness graft that is applied to a deepithelialized CV flap on the TRAM flap. This allows the best method of nipple-areola complex reconstruction: by retaining the original breast envelope, the color match and texture in the reconstruction are ideal. Patient satisfaction in this study was high. Necrosis of the mastectomy flaps impaired the cosmetic results in some patients. A large multicenter study is required to confirm the effectiveness of this procedure.     

Short-scar breast reduction: why all the fuss?

The breast can be considered conceptually as a cone. This article compares and contrasts short-scar breast reduction techniques with inverted T techniques using the cone model. Four issues are examined-the base of the breast, breast projection, the inframammary fold, and the pedicle. The short-scar techniques focus on reshaping the breast parenchyma, and skin redraping occurs secondarily. Application of this model suggests that these techniques have the advantage of better projection and greater longevity. These techniques seldom give a square shape and are better at dealing with upper pole deficiency. However, the ability of the skin to redrape is the limiting factor; hence, results are less predictable with large-volume breast reductions. The emphasis of this article is on increasing the understanding of the mechanics of breast reduction. It is this factor that will enable appropriate selection of a particular technique.     

Diversity and development of circadian rhythms in the European rabbit

Three main concerns underlie this review: 1) The need to draw together the widely dispersed information available on the circadian biology of the rabbit. Although the rabbit is a classic laboratory mammal, this extensive body of information is often overlooked by chronobiologists, and despite several advantages of this species. In terms of its general biology the rabbit is the best studied laboratory mammal in the wild, it demonstrates a wide variety of robust circadian functions, and being a lagomorph, it provides a useful comparison with more commonly studied rodent species. 2) The need to more fully exploit a developmental approach to understanding circadian function, and the particular suitability of the rabbit for this. Female rabbits only visit their altricial young for a few minutes once every 24 h to nurse, and survival of the young depends on the tight circadian-controlled synchronization in behavior and physiology of the two parties. Patterns of circadian rhythmicity in neonatal pups associated with nursing do not form a smooth continuum into weaning and adult life, and may reflect the action of separate mechanisms operating in their own right. 3) Using information from the first two points, to emphasize the diversity and complexity of circadian rhythms underlying behavioral and physiological functions in adult and developing mammals. Information accruing on circadian functions in the rabbit makes it increasingly difficult to account for these in terms of one or two regulatory mechanisms or "oscillators." Thus, it is argued that in addition to the reductionist, molecular approaches currently dominating much of chronobiology, the study of circadian systems as emergent characteristics of whole organisms operating in complex environments merits special attention.     

The Handlebars gene is required with Phantastica for dorsoventral asymmetry of organs and for stem cell activity in Antirrhinum

In angiosperms, individual lateral organs and whole flowers may develop asymmetrically along their dorsoventral axes. Dorsoventral asymmetry of Antirrhinum leaves requires activity of the Phantastica gene and other factors acting redundantly with it. We describe the effects of a mutation in the Handlebars gene, identified as an enhancer of the phantastica mutant phenotype. Genetic analysis suggests that Handlebars functions redundantly with Phantastica to promote dorsal fate in lateral organs and to maintain activity of stem cells within shoot apical meristems. Handlebars appears dispensable in vegetative development but is needed for asymmetry of petals along the dorsoventral axis of the flower as a whole. This suggests that common mechanisms may control dorsoventral asymmetry in lateral organ primordia and in floral meristems.