Uterine artery pseudoaneurysm requiring embolization in pregnancy: a case report and review of the literature.

Background: Uterine Artery Pseudoaneurysm is a rare cause of pelvic pain and haemorrhage in pregnancy. It should be considered in the differential diagnosis of pregnant women presenting with abdominal pain and is readily diagnosed by colour Doppler ultrasound. If left untreated, they may bleed into the peritoneum causing severe pain and haemorrhagic shock and may progress to maternal and fetal death. Case presentation: We describe a case of a woman presenting with severe right iliac fossa pain at 26 weeks gestation attributed to a right uterine artery pseudoaneurysm diagnosed on duplex ultrasound which was successfully treated by uterine artery embolization at 28 weeks gestation without complication to the fetus. Conclusion: Uterine artery embolization appears to be a safe and effective method to treat pseudoaneurysm during pregnancy without compromising uteroplacental perfusion

Massive variceal bleeding secondary to splenic vein thrombosis successfully treated with splenic artery embolization: a case report

<p>Abstract</p> <p>Introduction</p> <p>Splenic vein thrombosis results in localized portal hypertension called sinistral portal hypertension, which may also lead to massive upper gastrointestinal bleeding. Symptomatic sinistral portal hypertension is usually best treated by splenectomy, but interventional radiological techniques are safe and effective alternatives in the management of a massive hemorrhage, particularly in cases that have a high surgical risk.</p> <p>Case presentation</p> <p>We describe a 23-year-old Greek man with acute massive gastric variceal bleeding caused by splenic vein thrombosis due to a missing von Leiden factor, which was successfully managed with splenic arterial embolization.</p> <p>Conclusions</p> <p>Interventional radiological techniques are attractive alternatives for patients with a high surgical risk or in cases when the immediate surgical excision of the spleen is technically difficult. Additionally, surgery is not always successful because of the presence of numerous portal collaterals and adhesion. Splenic artery embolization is now emerging as a safe and effective alternative to surgery in the management of massive hemorrhage from gastric varices due to splenic vein thrombosis, which often occurs in patients with hypercoagulability.</p

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

Protocol for a randomised controlled trial of risk screening and early intervention comparing child- and family-focused cognitive-behavioural therapy for PTSD in children following accidental injury

Background: Accidental injury represents the most common type of traumatic event to which a child or adolescent may be exposed, with a significant number of these children going on to experience posttraumatic stress disorder (PTSD). However, very little research has examined potential interventions for the treatment of PTSD in these children. The present trial aims to evaluate and compare child- and family-focused versions of a cognitive-behavioural early intervention for PTSD following accidental injury.Methods/Design: The principal clinical question under investigation is the efficacy of an early, trauma-focused cognitive-behavioural intervention for the treatment of PTSD in children following accidental injury. Specifically, we compare the efficacy of two active treatments (child-focused and family-focused CBT) and a waitlist control (no therapy) to determine which is associated with greater reductions in psychological and health-related outcome measures over time. The primary outcome will be a reduction in trauma symptoms on a diagnostic interview in the active treatments compared to the waitlist control and greater reductions in the family-compared to the child-focused condition. In doing so, this project will also trial a method of stepped screening and assessment to determine those children requiring early intervention for PTSD following accidental injury.Discussion: The present trial will be one of the first controlled trials to examine a trauma-focused CBT, early intervention for children experiencing PTSD following accidental injury (as opposed to other types of traumatic events) and the first within a stepped care approach. In addition, it will provide the first evidence comparing the efficacy of child and family-focused interventions for this target group. Given the significant number of children and adolescents exposed to accidental injury, the successful implementation of this protocol has considerable implications. If efficacious, this early intervention will assist in reducing symptoms of traumatic stress as well as preventing chronic disorder and disability in children experiencing acute PTSD following accidental injury

Buffalo, Bush Meat, and the Zoonotic Threat of Brucellosis in Botswana

Brucellosis is a zoonotic disease of global importance infecting humans, domestic animals, and wildlife. Little is known about the epidemiology and persistence of brucellosis in wildlife in Southern Africa, particularly in Botswana.Archived wildlife samples from Botswana (1995-2000) were screened with the Rose Bengal Test (RBT) and fluorescence polarization assay (FPA) and included the African buffalo (247), bushbuck (1), eland (5), elephant (25), gemsbok (1), giraffe (9), hartebeest (12), impala (171), kudu (27), red lechwe (10), reedbuck (1), rhino (2), springbok (5), steenbok (2), warthog (24), waterbuck (1), wildebeest (33), honey badger (1), lion (43), and zebra (21). Human case data were extracted from government annual health reports (1974-2006).Only buffalo (6%, 95% CI 3.04%-8.96%) and giraffe (11%, 95% CI 0-38.43%) were confirmed seropositive on both tests. Seropositive buffalo were widely distributed across the buffalo range where cattle density was low. Human infections were reported in low numbers with most infections (46%) occurring in children (<14 years old) and no cases were reported among people working in the agricultural sector.Low seroprevalence of brucellosis in Botswana buffalo in a previous study in 1974 and again in this survey suggests an endemic status of the disease in this species. Buffalo, a preferred source of bush meat, is utilized both legally and illegally in Botswana. Household meat processing practices can provide widespread pathogen exposure risk to family members and the community, identifying an important source of zoonotic pathogen transmission potential. Although brucellosis may be controlled in livestock populations, public health officials need to be alert to the possibility of human infections arising from the use of bush meat. This study illustrates the need for a unified approach in infectious disease research that includes consideration of both domestic and wildlife sources of infection in determining public health risks from zoonotic disease invasions

Cortactin Phosphorylated by ERK1/2 Localizes to Sites of Dynamic Actin Regulation and Is Required for Carcinoma Lamellipodia Persistence

Tumor cell motility and invasion is governed by dynamic regulation of the cortical actin cytoskeleton. The actin-binding protein cortactin is commonly upregulated in multiple cancer types and is associated with increased cell migration. Cortactin regulates actin nucleation through the actin related protein (Arp)2/3 complex and stabilizes the cortical actin cytoskeleton. Cortactin is regulated by multiple phosphorylation events, including phosphorylation of S405 and S418 by extracellular regulated kinases (ERK)1/2. ERK1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the Arp2/3 regulator neuronal Wiskott-Aldrich syndrome protein (N-WASp), promoting actin polymerization and enhancing tumor cell movement.In this report we have developed phosphorylation-specific antibodies against phosphorylated cortactin S405 and S418 to analyze the subcellular localization of this cortactin form in tumor cells and patient samples by microscopy. We evaluated the interplay between cortactin S405 and S418 phosphorylation with cortactin tyrosine phosphorylation in regulating cortactin conformational forms by Western blotting. Cortactin is simultaneously phosphorylated at S405/418 and Y421 in tumor cells, and through the use of point mutant constructs we determined that serine and tyrosine phosphorylation events lack any co-dependency. Expression of S405/418 phosphorylation-null constructs impaired carcinoma motility and adhesion, and also inhibited lamellipodia persistence monitored by live cell imaging.Cortactin phosphorylated at S405/418 is localized to sites of dynamic actin assembly in tumor cells. Concurrent phosphorylation of cortactin by ERK1/2 and tyrosine kinases enables cells with the ability to regulate actin dynamics through N-WASp and other effector proteins by synchronizing upstream regulatory pathways, confirming cortactin as an important integration point in actin-based signal transduction. Reduced lamellipodia persistence in cells with S405/418A expression identifies an essential motility-based process reliant on ERK1/2 signaling, providing additional understanding as to how this pathway impacts tumor cell migration

Widespread Over-Expression of the X Chromosome in Sterile F1 Hybrid Mice

The X chromosome often plays a central role in hybrid male sterility between species, but it is unclear if this reflects underlying regulatory incompatibilities. Here we combine phenotypic data with genome-wide expression data to directly associate aberrant expression patterns with hybrid male sterility between two species of mice. We used a reciprocal cross in which F1 males are sterile in one direction and fertile in the other direction, allowing us to associate expression differences with sterility rather than with other hybrid phenotypes. We found evidence of extensive over-expression of the X chromosome during spermatogenesis in sterile but not in fertile F1 hybrid males. Over-expression was most pronounced in genes that are normally expressed after meiosis, consistent with an X chromosome-wide disruption of expression during the later stages of spermatogenesis. This pattern was not a simple consequence of faster evolutionary divergence on the X chromosome, because X-linked expression was highly conserved between the two species. Thus, transcriptional regulation of the X chromosome during spermatogenesis appears particularly sensitive to evolutionary divergence between species. Overall, these data provide evidence for an underlying regulatory basis to reproductive isolation in house mice and underscore the importance of transcriptional regulation of the X chromosome to the evolution of hybrid male sterility

Insights into the innate immunity of the Mediterranean mussel Mytilus galloprovincialis

<p>Abstract</p> <p>Background</p> <p>Sessile bivalves of the genus <it>Mytilus </it>are suspension feeders relatively tolerant to a wide range of environmental changes, used as sentinels in ecotoxicological investigations and marketed worldwide as seafood. Mortality events caused by infective agents and parasites apparently occur less in mussels than in other bivalves but the molecular basis of such evidence is unknown. The arrangement of Mytibase, interactive catalogue of 7,112 transcripts of <it>M. galloprovincialis</it>, offered us the opportunity to look for gene sequences relevant to the host defences, in particular the innate immunity related genes.</p> <p>Results</p> <p>We have explored and described the Mytibase sequence clusters and singletons having a putative role in recognition, intracellular signalling, and neutralization of potential pathogens in <it>M. galloprovincialis</it>. Automatically assisted searches of protein signatures and manually cured sequence analysis confirmed the molecular diversity of recognition/effector molecules such as the antimicrobial peptides and many carbohydrate binding proteins. Molecular motifs identifying complement C1q, C-type lectins and fibrinogen-like transcripts emerged as the most abundant in the Mytibase collection whereas, conversely, sequence motifs denoting the regulatory cytokine MIF and cytokine-related transcripts represent singular and unexpected findings. Using a cross-search strategy, 1,820 putatively immune-related sequences were selected to design oligonucleotide probes and define a species-specific Immunochip (DNA microarray). The Immunochip performance was tested with hemolymph RNAs from mussels injected with <it>Vibrio splendidus </it>at 3 and 48 hours post-treatment. A total of 143 and 262 differentially expressed genes exemplify the early and late hemocyte response of the <it>Vibrio</it>-challenged mussels, respectively, with AMP trends confirmed by qPCR and clear modulation of interrelated signalling pathways.</p> <p>Conclusions</p> <p>The Mytibase collection is rich in gene transcripts modulated in response to antigenic stimuli and represents an interesting window for looking at the mussel immunome (transcriptomes mediating the mussel response to non-self or abnormal antigens). On this basis, we have defined a new microarray platform, a mussel Immunochip, as a flexible tool for the experimental validation of immune-candidate sequences, and tested its performance on <it>Vibrio</it>-activated mussel hemocytes. The microarray platform and related expression data can be regarded as a step forward in the study of the adaptive response of the <it>Mytilus </it>species to an evolving microbial world.</p

Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research