Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis.

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Understanding the experience of pain in terminally ill patients.

BACKGROUND: Terminally ill patients commonly experience substantial pain. Unresolved pain has been cited as evidence that end-of-life care is of poor quality. However, the data on which that conclusion is based are limited. We aimed to provide additional data on the experience of pain in such patients. METHODS: We interviewed 988 terminally ill patients from six randomly selected US sites. We asked them who had treated their pain in the previous 4 weeks (primary-care physician, pain specialist, or both), and whether they wanted more pain medication than they were receiving, or why they did not want more. FINDINGS: 496 (50%) terminally ill patients reported moderate or severe pain. 514 (52%) individuals had seen a primary-care physician for treatment of pain in the previous 4 weeks and 198 (20%) saw a pain specialist. Of those who had been treated by their primary-care physician, 287 (29%) wanted more therapy, 613 (62%) wanted their pain therapy to remain the same, and 89 (9%) wanted to reduce or stop their pain therapy. Several reasons for not wanting additional therapy were offered-fear of addiction, dislike of mental or physical side-effects, and not wanting to take more pills or injections. We saw no association between disease and amount of pain between disease and the desire for more treatment. Black patients were more likely to seek additional pain therapy, see a pain specialist, and refuse additional medication because of fear of addiction than other populations. INTERPRETATION: Although half of terminally ill patients experienced moderate to severe pain, only 30% of them wanted additional pain treatment from their primary-care physician. The number of patients experiencing pain remains too high. However, the number is not as large as perceived. Additionally, most are willing to tolerate pain. Furthermore, the experience of pain is constant across major terminal diseases.

Humanities in medical education: revisiting the doctor-patient relationship.

Medical students, overwhelmed by new information, rarely appreciate patients' complaints beyond their biomedical aspects. To encourage students to think more comprehensively about patients, I initiated a biweekly series of seminars in medical humanities at the Duke University School of Medicine. Emphasizing science, without acknowledging the importance of the humanities, undermines the essential attribute of the good physician: the ability to establish a productive dialogue with the patient. Education in the humanities can broaden the student's scientific perspective, and reinforce medicine's critical, interpretive, and interpersonal tasks. The humanities inculcate a tolerance for ambiguity, provide a basis for the reconciliation of competing values, and foster the ability to discern the narrative thread in the setting of illness. The paper highlights the elements of the lecture series and suggests how it helps cultivate a core competency of medical education: learning to engage in the dialogue that grounds the doctor-patient relationship.

Neonatal osteomyelitis examined by bone scintigraphy.

Thirty-three infants less than six weeks of age and suspected of having osteomyelitis were examined by bone scintigraphy. Each of the 25 sites of proved osteomyelitis in 15 individuals demonstrated abnormal radionuclide localization. Ten additional scintigraphically positive but radiographically normal sites were detected. Optimal quality scintigrams of the growth plate complex and osteomyelitis in neonates appeared similar to those in older children. All neonates suspected of having osteomyelitis should be studied with bone scintigraphy following initial radiographs.