Abdominal Aortic Aneurysm Genetic Associations: Mostly False? A Systematic Review and Meta-analysis

OBJECTIVE/BACKGROUND: Many associations between abdominal aortic aneurysm (AAA) and genetic polymorphisms have been reported. It is unclear which are genuine and which may be caused by type 1 errors, biases, and flexible study design. The objectives of the study were to identify associations supported by current evidence and to investigate the effect of study design on reporting associations.

METHODS: Data sources were MEDLINE, Embase, and Web of Science. Reports were dual-reviewed for relevance and inclusion against predefined criteria (studies of genetic polymorphisms and AAA risk). Study characteristics and data were extracted using an agreed tool and reports assessed for quality. Heterogeneity was assessed using I(2) and fixed- and random-effects meta-analyses were conducted for variants that were reported at least twice, if any had reported an association. Strength of evidence was assessed using a standard guideline.

RESULTS: Searches identified 467 unique articles, of which 97 were included. Of 97 studies, 63 reported at least one association. Of 92 studies that conducted multiple tests, only 27% corrected their analyses. In total, 263 genes were investigated, and associations were reported in polymorphisms in 87 genes. Associations in CDKN2BAS, SORT1, LRP1, IL6R, MMP3, AGTR1, ACE, and APOA1 were supported by meta-analyses.

CONCLUSION: Uncorrected multiple testing and flexible study design (particularly testing many inheritance models and subgroups, and failure to check for Hardy-Weinberg equilibrium) contributed to apparently false associations being reported. Heterogeneity, possibly due to the case mix, geographical, temporal, and environmental variation between different studies, was evident. Polymorphisms in nine genes had strong or moderate support on the basis of the literature at this time. Suggestions are made for improving AAA genetics study design and conduct.

Prediction of Scattered Dose to the Testes in Abdominopelvic Radiotherapy.

Radical abdominal radiotherapy in men runs the risk of impairing their fertility owing to scattered dose to the testes, outside of the treated volume. In patients for whom this is a concern it is important to be able to predict the dose to the testes before treatment in order to determine whether semen cryopreservation should be undertaken and testicular shielding performed during treatment. Measurements have been made on an anthropomorphic phantom to determine the magnitude of these doses for a four-field treatment consisting of an anterior-posterior parallel pair and a lateral parallel pair. A dataset is presented, which, together with a correction for patients size, allows an estimate of testicular dose to be made given only the photon energy, interfield distances and the distance from the testes to the nearest beam edge. Thermoluminescent dosimetry has been carried out in 17 patients to validate the use of the data tables. The results indicate that testicular doses may be estimated with a standard deviation corresponding to 1%-2% of the tumour dose, which is sufficient for the purpose of determining whether fertility is threatened by a planned treatment.

Ecological impacts of the microsporidian parasite Pleistophora mulleri on its freshwater amphipod host Gammarus duebeni celticus

The microsporidian parasite, Pleistophora mulleri, infects the abdominal muscle of the freshwater amphipod Gammarus duebeni celticus. We recently showed that P. mulleri infection was associated with G. d. celticus hosts being more vulnerable to predation by the invasive amphipod Gammarus pulex. Parasitized G. d. celticus also had a reduced ability to prey upon other co-occurring amphipods. We suggested the parasite may have pervasive influences on host ecology and behaviour. Here, we examine the association between P. mulleri parasitism and parameters influencing individual host fitness, behaviour and interspecific interactions. We also investigate the relationship between parasite prevalence and host population structure in the field. In our G. d. celticus study population, P. mulleri prevalence was strongly seasonal, ranging from 8.5% in summer to 44.9% in winter. The relative abundance of hosts with the heaviest parasite burden increased during summer, which coincided with high host mortality, suggesting that parasitism may regulate host abundance to some degree. Females were more likely to be parasitized than males and parasitized males were paired with smaller females than unparasitized males. Parasitism was associated with reduction in the host's activity level and reduced both its predation on the isopod Asellus aquaticus and aggression towards precopula pairs of the invasive G. pulex. We discuss the pervasive influence of this parasite on the ecology of its host.

Development and evaluation of a vaginal ring device for sustained delivery of HIV microbicides to non-human primate

Background There is considerable interest in developing coitally indepen- dent, sustained release formulations for long-term administration of HIV microbicides. Vaginal ring devices are at the forefront of this formulation strategy. Methods Non-medicated silicone elastomer vaginal rings were prepared having a range of appropriate dimensions for testing vaginal ?t in pig- tailed and Chinese rhesus macaques. Cervicovaginal proin?ammatory markers were evaluated. Compression testing was performed to compare the relative ?exibility of various macaque and commercial human rings. Results All rings remained in place during the study period and no tissue irritation or signi?cant induction of cervicovaginal proin?ammatory mark- ers or signs of physical discomfort were observed during the 8-week study period. Conclusions Qualitative evaluation suggests that the 25 · 5-mm ring pro- vided optimal ?t in both macaque species. Based on the results presented here, low-consistency silicone elastomers do not cause irritation in maca-

A phase I study of the p-glycoprotein antagonist Tarquidar in combination with Vinorelbine.

P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. EXPERIMENTAL DESIGN: Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. RESULTS: Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. CONCLUSIONS: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patch-type system loaded with 5-aminolevulinic acid

Background: The work in this study appraised photodynamic treatment (PDT) as a treatment method for vulval intraepithelial neoplasia (VIN) using a novel bioadhesive patch to deliver aminolevulinic acid. An analysis of changes in expression of apoptotic and cell cycle proteins (p53, p21, Mdm2, Blc-2, Bax, Ki-67) in response to PDT was evaluated. Methods: PDT was performed using non-laser light, either as a one or two-cycle treatment, with clinical and pathological assessment following after 6 weeks. Twenty-three patients with 25 VIN lesions underwent 49 cycles of PDT Patches were designed to conform to uneven vulval skin and contained 38 mg cm(-2) aminolevulinic acid. Assessment was carried out at 6 weeks post-treatment. Patient-based treatment assessment, along with clinical and pathological changes, were monitored. Immunohistochemical staining was used to elucidate a possible biomolecular basis for induced cellular changes. Results: Most patients (52%) reported a symptomatic response, with normal pathology restored in 38% of lesions. The patch was easy to apply and remove, causing minimal discomfort. Fluorescence inspection confirmed protoporphyrin accumulation. Pain during implementation of PDT was problematic, necessitating some form of local analgesia. Changes in expression of cell cycle and apoptotic-related proteins suggested involvement of apoptotic pathways. Down regulation of p21 and inverse changes in Bcl-2 and Bax were key findings. Conclusion: Treatment of VIN lesions using a novel bioadhesive patch induced changes in cell cycle and apoptotic proteins in response to PDT with possible utilisation of apoptotic pathways. The efficacy of PDT in treating VIN could be improved by a better understanding of these apoptotic mechanisms, the influence of factors, such as HPV status, and of the need for effective pain management.

Cranioplasty: why throw the bone flap out?

Patients who undergo decompressive craniectomy for intracranial hypertension often require interval cranioplasty. Many cranioplasty agents are currently in use. The authors suggest that storage of the patient's own bone flap in the subcutaneous tissue of the abdominal wall, is a safe, efficacious and cost-effective alternative to use of synthetic cranioplasty materials.

Resolution of a taxonomic conundrum: an ultrastructural and molecular description of the life cycle of Pleistophora mulleri (Pfeiffer 1895; Georgevitch 1929)

The classification of a microsporidian parasite observed in the abdominal muscles of amphipod hosts has been repeatedly revised but still remains inconclusive. This parasite has variable spore numbers within a sporophorous vesicle and has been assigned to the genera Glugea, Pleistophora, Stempellia, and Thelohania. We used electron microscopy and molecular evidence to resolve the previous taxonomic confusion and confirm its identification as Pleistophora mulleri. The life cycle of P. mulleri is described from the freshwater amphipod host Gammarus duebeni celticus. Infection appeared as white tubular masses within the abdominal muscle of the host. Light and transmission electron microscope examination revealed the presence of an active microsporidian infection that was diffuse within the muscle block with no evidence of xenoma formation. Paucinucleate merogonial plasmodia were surrounded by an amorphous coat immediately external to the plasmalemma. The amorphous coat developed into a merontogenetic sporophorous vesicle that was present throughout sporulation. Sporogony was polysporous resulting in uninucleate spores, with a bipartite polaroplast, an anisofilar polar filament and a large posterior vacuole. SSU rDNA analysis supported the ultrastructural evidence clearly placing this parasite within the genus Pleistophora. This paper indicates that Pleistophora species are not restricted to vertebrate hosts.

Foraging ecology, fluctuating food availability and energetics of wintering brent geese

Changing energy requirements and dramatic shifts in food availability are major factors driving behaviour and distribution of herbivores. We investigate this in wintering East Canadian High Arctic light-bellied brent geese Branta bernicla hrota in Northern Ireland. They followed a sequential pattern of habitat use, feeding on intertidal Zostera spp. in autumn and early winter before moving to predominantly saltmarsh and farmland in late winter and early spring. Night-time feeding occurred throughout and made a considerable contribution to the birds' daily energy budget, at times accounting for > 50% of energy intake. Nocturnal feeding, however, is limited to the intertidal, possibly because of predation risk on terrestrial habitat, and increases with moonlight. The amount of Zostera spp., declined dramatically after the arrival of birds, predominantly, but not entirely, due to consumption by the birds. Birds gained fat reserves in the first 2 months but then this was dramatically lost as their major food source collapsed and their daily energy intake declined. Single birds consistently fared worse than paired birds and pairs with juveniles fared better than those without suggesting a benefit of having a family to compete for food. Many birds leave the Lough at this time of reduced Zostera spp. for other sea inlets in Ireland but some remain. Body condition of the latter gradually improved in early spring and reflected a heavy reliance on terrestrial habitats, particularly farmland, to meet the birds' daily energy requirements. However, even in the period immediately before migration to the breeding ground, the birds did not regain the amount of abdominal fatness observed in November. The dramatic changes in available food and requirements of the birds drive the major changes seen in foraging behaviour as the birds evade starvation in the wintering period.

Can physical activity modulate pancreatic cancer risk?:a systematic review and meta-analysis

Numerous epidemiological studies have examined the association between physical activity and pancreatic cancer; however, findings from individual cohorts have largely not corroborated a protective effect. Among other plausible mechanisms, physical activity may reduce abdominal fat depots inducing metabolic improvements in glucose tolerance and insulin sensitivity, thereby potentially attenuating pancreatic cancer risk. We performed a systematic review to examine associations between physical activity and pancreatic cancer. Six electronic databases were searched from their inception through July 2009, including MEDLINE and EMBASE, seeking observational studies examining any physical activity measure with pancreatic cancer incidence/mortality as an outcome. A random effects model was used to pool individual effect estimates evaluating highest vs. lowest categories of activity. Twenty-eight studies were included. Pooled estimates indicated a reduction in pancreatic cancer risk with higher levels of total (five prospective studies, RR: 0.72, 95% CI: 0.52-0.99) and occupational activity (four prospective studies, RR: 0.75, 95% CI: 0.59-0.96). Nonsignificant inverse associations were seen between risks and recreational and transport physical activity. When examining exercise intensity, moderate activity appeared more protective (RR: 0.79, 95% CI: 0.52-1.20) than vigorous activity (RR: 0.97, 95% CI: 0.85-1.11), but results were not statistically significant and the former activity variable incorporated marked heterogeneity. Despite indications of an inverse relationship with higher levels of work and total activity, there was little evidence of such associations with recreational and other activity exposures.