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.

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.

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.

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.

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.

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.

The use of benzodiazepines in palliative care.

BACKGROUND: Benzodiazepines are widely used in palliative care, but few studies have attempted to study their use. AIM: To determine the frequency and nature of benzodiazepine prescribing in a palliative care setting. METHOD: The notes of a consecutive series of 100 patients who had died or been discharged from the hospice were studied. Demographic, illness and prescription data were noted. The indication for the administration of benzodiazepines, their effectiveness and any adverse effects were recorded. RESULTS: Notes were found on 93 patients. Some 54 (58%) were prescribed benzodiazepines either by the hospice or their General Practitioner. Younger patients and those on opioids or antipsychotics were more likely to be prescribed benzodiazepines. Most administration of benzodiazepines occurred within the last three weeks of life in response to symptoms of anxiety or less specific distress. CONCLUSIONS: A relatively high proportion of patients was prescribed benzodiazepines. The role of benzodiazepines at different stages of palliative care merits further study.

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.

Analgesia for patients with advanced disease: 2.

The first article in this series explored epidemiology and patterns of pain in advanced disease, non-pharmacological treatments, and the use of opioids to manage pain. This second article examines the use of non-opioid drugs and anaesthetic interventions for pain relief in advanced disease. It also discusses an approach to managing analgesia in dying patients and finally looks at future developments.

Analgesia for patients with advanced disease: I.

This series of two articles explores the challenge of managing pain in patients with advanced malignant and non-malignant disease. Pain is a common symptom in advanced disease. Despite guidance from organisations such as the World Health Organisation, cancer pain is often inadequately managed. Managing pain in non-malignant conditions, such as end stage cardiac failure, presents an even greater challenge to healthcare professionals. This first article discusses epidemiology, definitions, pathophysiology, assessment, non-pharmacological approaches, the analgesic "ladder", and opioids. The second article will examine the use of non-opioids, anaesthetic techniques, and analgesia in dying patients as well as discussing future directions.

Opioid use in last week of life and implications for end-of-life decision-making.

This study was prompted by public and professional concern that the use of opioids for symptom control might shorten life. We retrospectively analysed the pattern of opioid use in the last week of life in 238 consecutive patients who died in a palliative care unit. Median doses of opioid were low (26.4 mg) in the last 24 h of life and patients who received opioid increases at the end of life did not show shorter survival than those who received no increases. The doctrine of double effect therefore need not be invoked to provide symptom control at the end of life.

Detection of Cryptosporidium oocysts in water: techniques for generating precise recovery data.

When determining the recovery efficiency of a procedure for the detection of Cryptosporidium or the removal efficiency of a treatment process, it is necessary to accurately enumerate a 'seed dose'. Conventional techniques for this are highly variable and consequently, can result in misleading data. In this study, a flow cytometric method was developed for the production of suspensions of Cryptosporidium oocysts in which the number of organisms could be precisely determined. A Becton Dickinson FACScalibur flow cytometer was employed to produce oocyst suspensions containing 100 oocysts. Analysis of these suspensions resulted in a mean dose of 99.5 oocysts (S.D. = 1.1, %cv = 1.1). These results indicate that the use of such suspensions to seed test systems generates far more accurate data than is presently possible using conventional techniques. In addition, the use of immunomagnetic separation (IMS) for the isolation of oocysts from three different water matrices, after seeding with oocysts counted using flow cytometry, was investigated. The recovery efficiency of the IMS procedure was found to be high, with the percentage recovery of oocysts ranging from 82.3 to 86.3%, and the use of precise numbers of oocysts allowed accurate recovery efficiency data to be generated. A laser scanning instrument (ChemScan RDI) was employed for the rapid detection and enumeration of oocysts after capture using membrane filtration. This technique was found to be faster and easier to perform than conventional epifluorescence microscopy. These findings demonstrate that the ChemScan RDI system may be used as alternative procedure for the routine examination of IMS supernatant fluids for the presence of Cryptosporidium.

A method for the measurement of three-dimensional geometry of casts used for the manufacture of ankle foot orthoses.

OBJECTIVE: To develop a method to measure the geometry of casts for the manufacture of ankle foot orthosis. DESIGN: A measurement study in which the feasibility of the technique, and its reliability were studied, using statistics based upon the analysis of variance. BACKGROUND: Studies have shown that the effectiveness of ankle foot orthoses is influenced by small changes in geometry and, particularly, by the amount of dorsiflexion. This study is concerned with a technique to identify the variations between nominally identical casts. METHODS: A measuring technique was used to determine the coordinates of grids drawn on the surface of the casts. Repeatability studies involved the measurement of six casts of the same leg produced by one orthotist. The influence of rectification, in which the technician makes modification prior to moulding, was also studied. RESULTS: The measurement technique was reliable, and there were no significant differences in grid dimensions among the casts. There were significant differences in dorsiflexion (up to 11 degrees) which were not influenced by rectification. CONCLUSIONS: This technique has been shown to be suitable to study the geometry of casts for the manufacture of ankle foot orthoses, and has demonstrated that relatively large variations may occur between nominally identical casts. There is a need to apply this procedure to study the influence of orthotic technique on geometry and function. RELEVANCE: AFO's are prescribed for patients with neurological disabilities. Since it is known that a correctly manufactured orthosis can achieve significant improvements in gait, it is necessary to quantify manufacturing accuracy.

The relationship between opioid use and laxative use in terminally ill cancer patients.

The frequency of the use of laxatives, and the relationship between doses of laxatives and of opioid analgesia, were determined by a prospective study of 498 hospice inpatients with advanced cancer. Laxatives were required by 87% of patients taking oral strong opioids, 74% of those on weak opioids and 64% of those not receiving opioid analgesia. The form of the relationship appears to be hyperbolic, as suggested by the presentation of the results arranged by opioid quartile and by the improved correlation obtained by subjecting the opioid data to a logarithmic transformation. It is concluded that opioids account for about a quarter of the constipation found in terminally ill cancer patients in a hospice. However, the dose of laxative required is likely to be significantly higher if an opioid is being taken than if not. The form of the relationship between laxative and strong opioid doses is what might be expected from the mediation of opioid-induced constipation by opioid receptors.

[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 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.