Why should physicians read? Understanding clinical judgement and its relation to literary experience

Is literary experience of any practical relevance to the clinician? This is the over-all question addressed by this investigation, which starts by tracing the historical roots of scientific medicine. These are found to be intimately linked to a form of rationality associated with the scientific revolution of the 17th century and with “modernity”. Medical practice, however, is dependent also on another form of rationality associated with what Stephen Toulmin calls “the epistemology of the biographical”. The very core of clinical medicine is shown to be the clinical encounter, an interpretive meeting where the illness experience is at the centre of attention. The physician can reach the goals of medicine only by developing clinical judgement. Clinical judgement is subjected to close analysis and is assumed to be intimately connected to the form of knowledge Aristotle called phronesis. In order to explore how literature – drama, novels, poetry – may be related to clinical judgement, a view of literature is presented that emphasizes literature as an invitation to the reader, to be met responsibly and responsively. Literature carries a potential for a widened experience, for a more nuanced perception of reality – and this potential is suggested to be ethically relevant to the practice of medicine. The “narrative rationality” of a literary text constitutes a complement to the rationality pervading scientific medicine. The final step in my analysis is a closer exploration of the potential of the literary text to contribute to the growth of clinical judgement, in relation to the challenges of everyday clinical work. Some of the conditions that may facilitate such growth are outlined, but it is also shown that full empirical evidence for the beneficial effects of reading on the clinician reader is beyond reach

Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis

Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here, we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while the loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility

An in vivo cis-Regulatory Screen at the Type 2 Diabetes Associated TCF7L2 Locus Identifies Multiple Tissue-Specific Enhancers

Genome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC) enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP) rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition

Tissue-specific alternative splicing of TCF7L2

Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been identified as the strongest genetic risk factors for type 2 diabetes (T2D). However, the mechanisms by which these non-coding variants increase risk for T2D are not well-established. We used 13 expression assays to survey mRNA expression of multiple TCF7L2 splicing forms in up to 380 samples from eight types of human tissue (pancreas, pancreatic islets, colon, liver, monocytes, skeletal muscle, subcutaneous adipose tissue and lymphoblastoid cell lines) and observed a tissue-specific pattern of alternative splicing. We tested whether the expression of TCF7L2 splicing forms was associated with single nucleotide polymorphisms (SNPs), rs7903146 and rs12255372, located within introns 3 and 4 of the gene and most strongly associated with T2D. Expression of two splicing forms was lower in pancreatic islets with increasing counts of T2D-associated alleles of the SNPs: a ubiquitous splicing form (P = 0.018 for rs7903146 and P = 0.020 for rs12255372) and a splicing form found in pancreatic islets, pancreas and colon but not in other tissues tested here (P = 0.009 for rs12255372 and P = 0.053 for rs7903146). Expression of this form in glucose-stimulated pancreatic islets correlated with expression of proinsulin (r2 = 0.84–0.90, P < 0.00063). In summary, we identified a tissue-specific pattern of alternative splicing of TCF7L2. After adjustment for multiple tests, no association between expression of TCF7L2 in eight types of human tissue samples and T2D-associated genetic variants remained significant. Alternative splicing of TCF7L2 in pancreatic islets warrants future studies. GenBank Accession Numbers: FJ010164–FJ010174

Understanding clinical judgement and its relation to literary experience

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