Does thyroid peroxidase provide an antigenic link between thyroid autoimmunity and breast cancer?

Women with breast cancer (BC) and antithyroid peroxidase (TPO) autoantibodies (TPOAb) have a better prognosis than women lacking TPOAb. Sera from women with TPOAb displayed immunoreactivity to BC tissue by immunofluorescence that was not apparent in women without TPOAb. We hypothesize a BC/thyroid shared antigen that provides a target for humoral or cell-mediated immune activity; candidates include the sodium/iodide symporter (expressed in thyroid and BC), cross-reacting epitopes in TPO and lactoperoxidase (LPO) or TPO itself. As the association is with TPOAb, we investigated TPO expression in BC, breast peritumoral tissue (PT), other tissues (tumoral and not) and thyroid as positive control. Transcripts for known and novel TPO isoforms were detected in BC (n = 8) and PT (n = 8) but at approximately 10(4) -fold lower than in thyroid while in non-BC tumors (n = 5) they were at the limit of detection. TPO was expressed also in adipose tissue (n = 17), 10(3) -fold lower than in thyroid. Full length TPO (Mr 105-110 kDa) was detected in Western blots in the majority of examined tissues; preabsorption of the TPO antibody with recombinant TPO (but not LPO) reduced the signal, indicating specificity. The same occurred with some lower molecular weight bands, which could correspond to smaller TPO transcript isoforms, present in all samples. In conclusion, TPO is weakly expressed in BC and other tissues; this could partly explain the high frequency and protective role of TPOAb in BC patients. Further studies will investigate tissue specificity, function and immunogenicity of the novel TPO variants (some BC-specific) identified.

Neighbourhood density and genetic relatedness interact to determine fruit set and abortion rates in a continuous tropical tree population.

Tropical trees may show positive density dependence in fruit set and maturation due to pollen limitation in low-density populations. However, pollen from closely related individuals in the local neighbourhood might reduce fruit set or increase fruit abortion in self-incompatible tree species. We investigated the role of neighbourhood density and genetic relatedness on individual fruit set and abortion in the neotropical tree Jacaranda copaia in a large forest plot in central Panama. Using nested neighbourhood models, we found a strong positive effect of increased conspecific density on fruit set and maturation. However, high neighbourhood genetic relatedness interacted with density to reduce total fruit set and increase the proportion of aborted fruit. Our results imply a fitness advantage for individuals growing in high densities as measured by fruit set, but realized fruit set is lowered by increased neighbourhood relatedness. We hypothesize that the mechanism involved is increased visitation by density-dependent invertebrate pollinators in high-density populations, which increases pollen quantity and carry-over and increases fruit set and maturation, coupled with self-incompatibility at early and late stages due to biparental inbreeding that lowers fruit set and increases fruit abortion. Implications for the reproductive ecology and conservation of tropical tree communities in continuous and fragmented habitats are discussed.

Demographic spatial genetic structure of the Neotropical tree, Jacaranda copaia.

We used genotypes from six microsatellite loci and demographic data from a large mapped forest plot to study changes in spatial genetic structure across demographic stages, from seed rain to seedlings, juveniles, and adult diameter classes in the Neotropical tree, Jacaranda copaia. In pairwise comparisons of genetic differentiation among demographic classes, only seedlings were significantly differentiated from the other diameter classes; F(ST) values ranged from 0.006 to 0.009. Furthermore, only seedlings showed homozygote excess suggesting biparental inbreeding in the large diameter reproductive adults. We found very low levels of relatedness in the first distance class of trees, 1-26 cm diameter (F(ij) = 0.011). However, there was a 5- to 10-fold rise in relatedness in the smallest distance class, from the smallest to the largest tree diameter classes (F(ij) = 0.110 for individuals > 56 cm diameter). A variety of non-mutually exclusive mechanisms have been invoked perviously to explain such a pattern, including natural selection, history, or nonequilibrium population dynamics. The long-term demographic data available for this species allow us to evaluate these mechanisms. Jacaranda is a fast-growing, light-demanding species with low recruitment rates and high mortality rates in the smaller diameter classes. It successfully regenerates only in large light gaps, which occur infrequently and stochastically in space and time. These factors contribute to the nonequilibrium population dynamics and observed low genetic structure in the small size classes. We conclude that the pattern of spatial genetic transitions in Jacaranda is consistent with overlapping related generations and strong but infrequent periods of high recruitment, followed by long periods of population decline.

Discrepancy between self-reported and observed hand hygiene behaviour in healthcare professionals.

Hand hygiene behaviour in 71 healthcare professionals was observed on hospital wards for a total of 132 h, encompassing 1284 hand hygiene opportunities. Questionnaires completed by the participants were used to compare actual behaviours with self-reported behaviours, as well as intentions and attitudes towards hand hygiene. Observed practice showed very poor rates of adherence to guidelines and indicated that staff failed to take account of risk, even with patients colonized with meticillin-resistant Staphylococcus aureus. Observed practice was unrelated to carers' intentions and self-reported behaviour. The results suggest that hand hygiene interventions that target changes in attitudes, intentions or self-reported practice are likely to fail in terms of changing behaviour, and consideration is given to how this could be remedied.

Inferring colonization history from analyses of spatial genetic structure within populations of Pinus strobus and Quercus rubra.

Many factors interact to determine genetic structure within populations including adult density, the mating system, colonization history, natural selection, and the mechanism and spatial patterns of gene dispersal. We examined spatial genetic structure within colonizing populations of Quercus rubra seedlings and Pinus strobus juveniles and adults in an aspen-white pine forest in northern Michigan, USA. A 20-year spatially explicit demographic study of the forest enables us to interpret the results in light of recent colonization of the site for both species. We assayed 217 Q. rubra seedlings and 171 P. strobus individuals at 11 polymorphic loci using nine allozyme systems. Plant genotypes and locations were used in an analysis of spatial genetic structure. Q. rubra and P. strobus showed similar observed levels of heterozygosity, but Q. rubra seedlings have less heterozygosity than expected. Q. rubra seedlings show spatial genetic clumping of individuals on a scale to 25 m and levels of genetic relatedness expected from the clumped dispersion of half-siblings. In contrast, P. strobus has low levels of genetic relatedness at the smallest distance class and positive spatial genetic structure at scales < 10 m within the plot. The low density of adult Q. rubra outside the study plot and limited, spatially clumped rodent dispersal of acorns is likely responsible for the observed pattern of spatial genetic structure and the observed heterozygote deficit (i.e. a Wahlund effect). We attribute weaker patterns observed in P. strobus to the longer dispersal distance of seeds and the historical overlap of seed shadows from adults outside of the plot coupled with the overlap of seed shadows from younger, more recently established reproductive adults. The study demonstrates the utility of long-term demographic data in interpreting mechanisms responsible for generating contemporary patterns of genetic structure within populations.

A genetic evaluation of seed dispersal in the neotropical tree Jacaranda copaia (Bignoniaceae).

Seed dispersal is a critical but poorly understood life-history stage of plants. Here we use a genetic approach to describe seed dispersal patterns accurately in a natural population of the Neotropical tree species Jacaranda copaia (Bignoniaceae). We used microsatellite genotypes from maternally derived tissue on the diaspore to identify which individual of all possible adult trees in the population was the true source of a given seed collected after it dispersed. Wind-dispersed seeds were captured in two different years in a large array of seed traps in an 84-ha mapped area of tropical forest on Barro Colorado Island, Panama. We were particularly interested in the proportion of seeds that traveled long distances and whether there was evidence for direct dispersal into gaps, which are required for successful recruitment of this pioneer tree species. Maximum likelihood procedures were used to fit single- and multiple-component dispersal kernels to the distance data. Mixture models, with separate distributions near and far, best fit the observed dispersal distances, albeit with considerable uncertainty in the tail. We discuss the results in light of different mechanisms responsible for separate distributions near the adult source and in the tail of the curve.

Effects of bilobalide on cerebral amino acid neurotransmission.

Bilobalide is one of many active constituents found in EGb 761 (definition see editorial), which is extracted from Ginkgo biloba leaves. Whilst there is good, sound evidence that bilobalide exhibits neuroprotective actions in a variety of model systems, there is currently no consensus on its mechanism of action. This present communication summarises the results we have obtained with this compound on excitatory amino acid neurotransmission in the central nervous system using both neurochemical and electrophysiological techniques. Bilobalide was shown to reduce glutamate and aspartate release elicited by both high potassium-containing artificial cerebrospinal fluid (aCSF) or veratridine from mouse cortical slices. In addition, bilobalide had a very potent effect (IC (50) 2.7 microM) on glutamate release elicited by hypoxia/hypoglycaemia-induced release from rat cortical slices. Electrophysiologically, bilobalide also decreased the frequency of gamma-aminobutyric acid (GABA) uptake inhibitor-induced depolarisations in mouse cortical slices, an effect probably mediated by a decrease in glutamate release. No definitive conclusions can be reached concerning the mechanism of action of bilobalide, but an ability to decrease excitotoxic amino acid release, particularly glutamate, would suggest that this is a probable mechanism to account for its neuroprotective properties.

Effects of bilobalide on amino acid release and electrophysiology of cortical slices.

This study investigated the effects of bilobalide, a constituent of Ginkgo biloba, on potassium and veratridine-induced release of glutamate and aspartate from mouse cortical slices. We also studied its effects on spontaneous and N-methyl-D-aspartate (NMDA)-induced depolarizations elicited in magnesium-free artificial cerebrospinal fluid (aCSF) as well as its effect on NO-711 (a gamma-aminobutyric acid (GABA) uptake inhibitor)-induced depolarizations. Bilobalide, 100 microM significantly reduced both glutamate and aspartate release elicited by potassium or veratridine. Bilobalide (5-100 microM) also significantly reduced the frequency of NO-711 induced depolarizations, however, it had no effect on spontaneous or on NMDA-induced depolarizations at 5-200 microM. These results suggest that the neuroactive properties of bilobalide may be mediated by a reduction in excitatory amino acid neurotransmitter release.

The anticonvulsant effects of the enantiomers of losigamone.

1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the effects of the S(+)- and R(-)- enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 microM) significantly reduced both potassium- and veratridine-elicited release of glutamate and aspartate from cortical slices. R(-)-losigamone had no effect on release at concentrations up to 400 microM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free artificial cerebrospinal fluid. S(+)-losigamone significantly reduced these depolarizations at 50-200 microM whilst R(-)-losigamone had a significant effect at 200-800 microM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg-1, i.p.) significantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg-1. There was no protection at 20 mg kg-1 with R(-)-losigamone. 5 These results, from both in vitro and in vivo experiments, confirm that the pharmacological activity profiles of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(-)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more effective clinically than losigamone or its R(-)-enantiomer.

Computerized tomographic densitometry of the solitary pulmonary nodule using a nodule phantom.

The successful application of computerized tomographic density analysis for evaluating the solitary pulmonary nodule has previously been described and the technique has since been simplified by using a calcium-equivalent nodule reference phantom. Because published experience with this technique remains limited, the current research reports the Cleveland Clinic experience with the CIRS model III pulmonary nodule reference phantom. Without knowledge of the final diagnosis, the nodule phantom was used as the standard for categorizing 31 nodules in 29 patients as either benign or indeterminate. Secure diagnoses were obtained in all cases. Eleven nodules were called benign and ten proved so, whereas 20 nodules were classified as indeterminate. One lesion, an adenocarcinoma, was falsely called benign using this technique. The excellent density discrimination achieved with CT makes this a superior tool for analysis of the solitary pulmonary nodule, and the nodule reference phantom has greatly simplified the technique of CT densitometry. As demonstrated by this and prior studies, calcification is not a unique feature of the benign lesion and successful clinical application of this technique requires cautious interpretation of results.

Differential down-regulation of delta opioid binding sites during physical dependence on methionine enkephalin in the rat.

Post-synaptic receptor modulation is thought to be one important mechanism involved in the adaptation of a neuronal system during chronic exposure to a drug. However, initial studies of opioid receptor regulation following chronic in vivo administration of narcotic agonists, such as morphine, reported no down-regulation in the number of opioid receptors in the brain. Subsequent studies, employing in vitro preparations, have reported evidence of opioid receptor down-regulation under specific conditions. It remains to be determined whether the in vitro phenomena of opioid receptor plasticity is relevant to the intact mammalian central nervous system. The data in this report shows that chronic in vivo administration the opioid peptide methionine enkephalin, results in a significant, regionally specific down-regulation of delta opioid receptors in rat brain: 30% decrease in receptor density in the striatum; no change in hypothalamus.