Strong population structure in a species manipulated by humans since the Neolithic: the European fallow deer (Dama dama dama).

Species that have been translocated and otherwise manipulated by humans may show patterns of population structure that reflect those interactions. At the same time, natural processes shape populations, including behavioural characteristics like dispersal potential and breeding system. In Europe, a key factor is the geography and history of climate change through the Pleistocene. During glacial maxima throughout that period, species in Europe with temperate distributions were forced south, becoming distributed among the isolated peninsulas represented by Anatolia, Italy and Iberia. Understanding modern patterns of diversity depends on understanding these historical population dynamics. Traditionally, European fallow deer (Dama dama dama) are thought to have been restricted to refugia in Anatolia and possibly Sicily and the Balkans. However, the distribution of this species was also greatly influenced by human-mediated translocations. We focus on fallow deer to better understand the relative influence of these natural and anthropogenic processes. We compared modern fallow deer putative populations across a broad geographic range using microsatellite and mitochondrial DNA loci. The results revealed highly insular populations, depauperate of genetic variation and significantly differentiated from each other. This is consistent with the expectations of drift acting on populations founded by small numbers of individuals, and reflects known founder populations in the north. However, there was also evidence for differentiation among (but not within) physically isolated regions in the south, including Iberia. In those regions we find evidence for a stronger influence from natural processes than may be expected for a species with such strong, known anthropogenic influence.

Ancient and modern DNA track temporal and spatial population dynamics in the European fallow deer since the Eemian interglacial.

Anthropogenic factors have impacted the diversity and evolutionary trajectory of various species. This can be through factors such as pressure on population size or range, habitat fragmentation, or extensive manipulation and translocation. Here we use time-calibrated data to better understand the pattern and processes of evolution in the heavily manipulated European fallow deer (Dama dama). During the Pleistocene, fallow deer had a broad distribution across Europe and were found as far north as Britain during the Eemian interglacial. The last glacial period saw fallow deer retreat to southern refugia and they did not disperse north afterwards. Their recolonisation was mediated by people and, from northern Europe and the British Isles, fallow deer were transported around the world. We use ancient and modern mitochondrial DNA (mtDNA) and mitogenomic data from Eemian Britain to assess the pattern of change in distribution and lineage structure across Europe over time. We find founder effects and mixed lineages in the northern populations, and stability over time for populations in southern Europe. The Eemian sample was most similar to a lineage currently in Italy, suggesting an early establishment of the relevant refuge. We consider the implications for the integration of anthropogenic and natural processes towards a better understanding of the evolution of fallow deer in Europe.

High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

Isolation and characterization of a B lymphocyte mutant with altered signal transduction through its antigen receptor.

A receptor surface Ig (sIg) signaling variant of WEHI-231 was constructed to investigate components and linkages between various signaling events associated with signal transduction through sIg. Unlike the wildtype, crosslinking of sIgM on VS2.12-cl.2 did not result in downregulation of proliferation. Similarly, receptor crosslinking was uncoupled from inositol phospholipid (PI) hydrolysis and upregulation of c-fos expression in the variant. The signaling defect in VS2.12-cl.2 appears to be proximal to phospholipase C activation as direct G protein activation by A1F4- triggers PI hydrolysis and bypassing PI hydrolysis using phorbol diester stimulation of protein kinase C restores the inhibitable phenotype and the ability to upregulate c-fos. Even more interesting, sIg-linked Ca2+ responses by VS2.12-cl.2 are equivalent to these observed in the wildtype WEHI-231. These latter results suggest that contrary to current thought, sIg-generated signals may not be coupled to Ca2+ fluxes entirely via inositol phospholipid hydrolysis. Thus, VS2.12-cl.2 is a new and powerful tool with which to analyze signaling through sIg at the molecular level.

Is it possible to determine use of hospice palliative care services by matching hospice and cancer registry data?

Population-based studies investigating access to palliative care often use death in a hospice as a proxy for service use. We linked data from a large South London hospice to Thames Cancer Registry (TCR) data to determine whether patients who received hospice services differed from those who did not. We matched hospice data for 2474 cancer patients dying between 2000 and 2006, while resident within a restricted catchment area, to TCR data for residents in this area. During matching 14.2% (n = 352) of hospice patients were excluded due to differing key dates or addresses. In addition, 5.6% (n= 175) of residents initially defined as not receiving hospice services were recorded as dying in a hospice in the TCR dataset. The problems of overlapping catchment areas and of defining patients receiving services meant we could not adequately determine use of hospice services. This method might be applied more successfully to non-urban hospices, primary care trusts or larger regions.

The management of constipation in palliative care: clinical practice recommendations.

Constipation is one of the most common problems in patients receiving palliative care and can cause extreme suffering and discomfort. The aims of this study are to raise awareness of constipation in palliative care, provide clear, practical guidance on management and encourage further research in the area. A pan-European working group of physicians and nurses with significant experience in the management of constipation in palliative care met to evaluate the published evidence and produce these clinical practice recommendations. Four potentially relevant publications were identified, highlighting a lack of clear, practical guidance on the assessment, diagnosis and management of constipation in palliative care patients. Given the limited data available, our recommendations are based on expert clinical opinion, relevant research findings from other settings and best practice from the countries represented. Palliative care patients are at a high risk of constipation, and while general principles of prevention should be followed, pharmacological treatment is often necessary. The combination of a softener and stimulant laxative is generally recommended, and the choice of laxatives should be made on an individual basis. The current evidence base is poor and further research is required on many aspects of the assessment, diagnosis and management of constipation in palliative care.

Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.

BACKGROUND AND METHODS: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. RESULTS: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male-male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male-male and 74 male-female/female-female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male-female/female-female ASP (MLS = 2.62 v 0.00, for non-male and male-male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at approximately 112 cM, and maternal MLS = 1.83 at approximately 135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at approximately 30 cM; paternal MLS = 0.02). CONCLUSION: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.

Signalling through sIgA on a novel murine B lymphoma.

A novel murine B lymphoma expressing membrane-associated IgA was isolated and used to compare mechanisms of signal transduction by sIgM and sIgA. Like other isotypes so far studied, crosslinking of sIgA by anti-immunoglobulin antibodies stimulates hydrolysis of inositol phospholipids and causes elevation of intracellular free calcium. Furthermore, signals generated through sIgA are coupled to elevation of c-fos proto-oncogene expression. Coupling appears to be through the protein kinase C rather than through the Ca2+ component of sIg signalling as phorbol diester, but the Ca2+ ionophore cannot mediate this effect. Thus these results, coupled with those from earlier studies, show that early signal transduction through surface immunoglobulin appears to be similar regardless of the particular isotype involved in binding ligand.

Magnetic labeling and cell sorting.

Magnetic labeling by a magnetite-antibody conjugate has been combined with magnetic filtration (high gradient magnetic separation) to effect a rapid and efficient separation of a selected cell population from a suspension of single cells. Samples of more than 10(8) cells could be fractionated in about 5 min with complete recovery. The system has been applied to a model system using red blood cells (sheep or chicken) and commercial antibodies against species-determined cell surface antigens. Enrichments of labeled cells by factors of up to 37-fold were observed. The approach was relatively insensitive to details in the experimental protocol and to the number of unlabeled cells which were in the sample. Thus, the method was easy to use and can readily be scaled up to handle large samples containing 10(8) labeled cells in a total of 10(11) or more. It should be useful as a pre-enrichment scheme for suspensions in which cells of interest are rare and, consequently, very inefficiently sorted by fluorescence-activated instruments.

Acne. A review of optimum treatment.

Acne vulgaris is a disease of the pilosebaceous unit of the skin. It may have profound psychological sequelae. The lesions are due to abnormally adherent keratinocytes causing plugging of the follicular duct followed by accumulation of sebum and keratinous debris. This results in the formation of the primary lesion of acne, the comedo. Inflammation of comedones produces papules, pustules and nodules, which often prompt patients to seek treatment. Various effective treatments include topical anti-inflammatory, antibiotic and peeling agents, oral antibiotics, topical and oral retinoids, and hormonal agonists and antagonists. Useful combination regimens are discussed, and treatment approaches suggested. Mild cases of comedonal acne may respond to a topical retinoid or benzoyl peroxide, while inflammatory lesions benefit from topical antibiotics. More severe inflammatory acne is treated with systemic antibiotics. Recalcitrant cases often require oral isotretinoin or hormonal manipulation.

C syndrome with apparently normal development.

C syndrome is an autosomal recessive craniosynostosis syndrome with characteristic cranial, facial, palate, and joint abnormalities. All but 2 of the reported patients have had severe mental retardation. We report on an 8-month-old girl with C syndrome and apparently normal development except for tasks hindered by her lower body abnormalities. We also offer a possible explanation for the palatal configuration.

A volunteer model for the comparison of laxatives in opioid-related constipation.

Loperamide was used to provide a source of opioid-induced constipation in healthy volunteers. Each volunteer took a sequence of three dose levels of loperamide. One of three laxatives was used to counterbalance the effect of loperamide and restore bowel function to what the individual considered normal at each stage before the dose of loperamide was increased. Lactulose, senna, and codanthrusate were selected as examples of a softening, a stimulant, and a combination laxative, respectively. Outcome measures were the doses of laxative used, stool form and frequency, ease of defecation, a rating scale of subjective bowel function, and the occurrence of adverse effects. Each laxative was taken by ten volunteers, and all proved capable of maintaining normal bowel function. A combination of stimulant and softening laxatives was most likely to maintain normal bowel function at the lowest dose and least adverse effects. The mean final dose of lactulose was excessive for use in ill patients. Senna was associated with significantly more adverse effects than the other laxatives, mainly abdominal pain (P < 0.001). This model of constipation may provide a standardized means of assaying the clinical effectiveness of oral laxatives.

[The hospice approach to pain and problems in home palliative care]. / O hospicijskom pristupu boli i problemima kucne palijativne skrbi.

Author points to principles upon which not only the control of pain but also of all other symptoms depends: an appreciation of symptoms as a psychosomatic phenomenon, an accurate diagnosis of the cause of the symptom and in reference to pain application of the World Health Organisation's Analgesic Ladder for Cancer Pain. He takes these principles for granted and elaborates on the use of drugs and to lesser extent, other techniques which are used in hospice practise. Morphine is metabolised into M6G i M3G, the first being significantly more potent an analgesic as morphine. Its late and prolonged presence is probably basic for continuous morphine application instead of "as required" way. Author is giving very precise recommendations for per os and parenteral dose titration, discussing the side-effects and data about the related drugs, the analgesia in neuropathic pain and the special techniques like radiation, nerve blocks and epidural analgesia. Speaking about the palliative home care problems the author explains the most important factors enabling a family to continue their care at home. The author keeps discussing the poor appetite, vomiting, dysphagia, constipation. Respiratory problems are elaborated with more details especially those in "death rattle", with the optimal drug option recommendation, and many technical details.

A microfabricated graphitic carbon column for high performance liquid chromatography.

We report the first development of a novel, planar, microfluidic, graphitic carbon separations column utilizing an array of graphitic micropillars of diamond cross-section as the chromatographic stationary phase. 795 nm femtosecond laser ablation was employed to subtractively machine fluidic architectures and a micropillared array in a planar, graphitic substrate as a monolithic structure. A sample injector was integrated on-chip, together with fluid-flow distribution architectures to minimize band-broadening and ensure sample equi-distribution across the micro-pillared column width. The separations chip was interfaced directly to the ESI probe of a Thermofisher Surveyor mass spectrometer, enabling the detection of test-mixture analytes following their differential retention on the micro-pillared graphitic column, thus demonstrating the exciting potential of this novel separations format. Importantly, unlike porous, graphitic microspheres, the temperature and pressure resilience of the microfluidic device potentially enables use in subcritical H(2)O chromatography.