Development of a longitudinal integrated clerkship at an academic medical center

In 2005, medical educators at the University of California, San Francisco (UCSF), began developing the Parnassus Integrated Student Clinical Experiences (PISCES) program, a year-long longitudinal integrated clerkship at its academic medical center. The principles guiding this new clerkship were continuity with faculty preceptors, patients, and peers; a developmentally progressive curriculum with an emphasis on interdisciplinary teaching; and exposure to undiagnosed illness in acute and chronic care settings. Innovative elements included quarterly student evaluation sessions with all preceptors together, peer-to-peer evaluation, and oversight advising with an assigned faculty member. PISCES launched with eight medical students for the 2007/2008 academic year and expanded to 15 students for 2008/2009. Compared to UCSF's traditional core clerkships, evaluations from PISCES indicated significantly higher student satisfaction with faculty teaching, formal didactics, direct observation of clinical skills, and feedback. Student performance on discipline-specific examinations and United States Medical Licensing Examination step 2 CK was equivalent to and on standardized patient examinations was slightly superior to that of traditional peers. Participants' career interests ranged from primary care to surgical subspecialties. These results demonstrate that a longitudinal integrated clerkship can be implemented successfully at a tertiary care academic medical center

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

High-throughput miRNA profiling of human melanoma blood samples

<p>Abstract</p> <p>Background</p> <p>MicroRNA (miRNA) signatures are not only found in cancer tissue but also in blood of cancer patients. Specifically, miRNA detection in blood offers the prospect of a non-invasive analysis tool.</p> <p>Methods</p> <p>Using a microarray based approach we screened almost 900 human miRNAs to detect miRNAs that are deregulated in their expression in blood cells of melanoma patients. We analyzed 55 blood samples, including 20 samples of healthy individuals, 24 samples of melanoma patients as test set, and 11 samples of melanoma patients as independent validation set.</p> <p>Results</p> <p>A hypothesis test based approch detected 51 differentially regulated miRNAs, including 21 miRNAs that were downregulated in blood cells of melanoma patients and 30 miRNAs that were upregulated in blood cells of melanoma patients as compared to blood cells of healthy controls. The tets set and the independent validation set of the melanoma samples showed a high correlation of fold changes (0.81). Applying hierarchical clustering and principal component analysis we found that blood samples of melanoma patients and healthy individuals can be well differentiated from each other based on miRNA expression analysis. Using a subset of 16 significant deregulated miRNAs, we were able to reach a classification accuracy of 97.4%, a specificity of 95% and a sensitivity of 98.9% by supervised analysis. MiRNA microarray data were validated by qRT-PCR.</p> <p>Conclusions</p> <p>Our study provides strong evidence for miRNA expression signatures of blood cells as useful biomarkers for melanoma.</p

A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice

The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist—an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo

Role of Homer Proteins in the Maintenance of Sleep-Wake States

Sleep is an evolutionarily conserved process that is linked to diurnal cycles and normal daytime wakefulness. Healthy sleep and wakefulness are integral to a healthy lifestyle; this occurs when an organism is able to maintain long bouts of both sleep and wake. Homer proteins, which function as adaptors for group 1 metabotropic glutamate receptors, have been implicated in genetic studies of sleep in both Drosophila and mouse. Drosophila express a single Homer gene product that is upregulated during sleep. By contrast, vertebrates express Homer as both constitutive and immediate early gene (H1a) forms, and H1a is up-regulated during wakefulness. Genetic deletion of Homer in Drosophila results in fragmented sleep and in failure to sustain long bouts of sleep, even under increased sleep drive. However, deletion of Homer1a in mouse results in failure to sustain long bouts of wakefulness. Further evidence for the role of Homer1a in the maintenance of wake comes from the CREB alpha delta mutant mouse, which displays a reduced wake phenotype similar to the Homer1a knockout and fails to up-regulate Homer1a upon sleep loss. Homer1a is a gene whose expression is induced by CREB. Sustained behaviors of the sleep/wake cycle are created by molecular pathways that are distinct from those for arousal or short bouts, and implicate an evolutionarily-conserved role for Homer in sustaining these behaviors

Microgeographical, inter-individual, and intra-individual variation in the flower characters of Iberian pear Pyrus bourgaeana (Rosaceae)

Flower characteristics have been traditionally considered relatively constant within species. However, there are an increasing number of examples of variation in flower characteristics. In this study, we examined the variation in attracting and rewarding flower characters at several ecological levels in a metapopulation of Pyrus bourgaeana in the Doñana area (SW Spain). We answered the following questions: what are the variances of morphological and nectar characters of flowers? How important are intra-individual and inter-individual variance in flower characters? Are there microgeographical differences in flower characters? And if so, are they consistent between years? In 2008 and 2009, we sampled flowers of 72 trees from five localities. For six flower morphological and two nectar characteristics, we calculated coefficients of variation (CV). The partitioning of total variation among-localities, among-individuals, and within-individuals was estimated. To analyze differences among localities and their consistency between years, we conducted generalized linear mixed models. The CVs of nectar characters were always higher than those of morphological characters. As expected, inter-individual variation was the main source of variation of flower morphology, but nectar characters had significant variation at both intra- and inter-individual levels. For most floral traits, there were no differences among localities. Our study documents that variation is a scale-dependent phenomenon and that it is essential to consider intra- and inter-individual variance when investigating the causes and consequences of variation. It also shows that single year studies of floral characters should be viewed with caution

National review of maternity services 2008: women influencing change

<p>Abstract</p> <p>Background</p> <p>In 2009 the Australian government announced a major program of reform with the move to primary maternity care. The reform agenda represents a dramatic change to maternity care provision in a society that has embraced technology across all aspects of life including childbirth.</p> <p>Methods</p> <p>A critical discourse analysis of selected submissions in the consultation process to the national review of maternity services 2008 was undertaken to identify the contributions of individual women, consumer groups and organisations representing the interests of women.</p> <p>Results</p> <p>Findings from this critical discourse analysis revealed extensive similarities between the discourses identified in the submissions with the direction of the 2009 proposed primary maternity care reform agenda. The rise of consumer influence in maternity care policy reflects a changing of the guard as doctors' traditional authority is questioned by strong consumer organisations and informed consumers.</p> <p>Conclusions</p> <p>Unified consumer influence advocating a move away from obstetric -led maternity care for all pregnant women appears to be synergistic with the ethos of corporate governance and a neoliberal approach to maternity service policy. The silent voice of one consumer group (women happy with their obstetric-led care) in the consultation process has inadvertently contributed to a consensus of opinion in support of the reforms in the absence of the counter viewpoint.</p

Clinical application of genetic testing for posterior uveal melanoma

Uveal melanoma is the most common primary intraocular tumor in adults, and it has a strong potential to metastasize. Traditionally, clinicopathological features of these tumors were used to provide a limited prediction of the metastatic risk. However, early genetic studies using karyotype analysis, fluorescence in situ hybridization, and comparative genetic hybridization of posterior uveal melanoma samples identified multiple chromosomal abnormalities associated with a higher risk of fatal metastasis. This correlation between specific genetic abnormalities in uveal melanoma and a patient’s risk for development of metastasis has recently been widely studied, and the development of new prognostic tests has allowed clinicians to predict this metastatic risk with increased accuracy. Such novel tests include gene expression profiling, which analyzes the RNA expression patterns of tumor cells, and multiplex ligation-dependent probe amplification, which detects deletions or and amplifications of DNA in tumor cells. This review discusses the current status of prognostic testing techniques available to clinicians and patients for posterior uveal melanomas

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

<p>Abstract</p> <p>Background</p> <p>Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.</p> <p>Methods</p> <p>We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).</p> <p>Results</p> <p>Our analysis revealed a genomic deletion containing the oxytocin receptor gene, <it>OXTR </it>(MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate <it>OXTR </it>expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that <it>OXTR </it>mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.</p> <p>Conclusion</p> <p>Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of <it>OXTR </it>in the development of the disorder.</p> <p>See the related commentary by Gurrieri and Neri: <url>http://www.biomedcentral.com/1741-7015/7/63</url></p