Pharmacokinetics of human leptin in mice and rhesus monkeys.

ObjectiveThe pharmacokinetic characteristics of human leptin were examined in rhesus monkeys and in C57BL/6J mice fed a normal chow or a high-fat diet.DesignFor the monkey study, in nine rhesus monkeys (body weight 12.4 +/- 2.4 kg; mean +/- s.d.), recombinant met-human leptin was injected intravenously or subcutaneously (1 mg/kg). For the mouse study, after 6 months of feeding C57BL/6J mice a high-fat diet (body weight 32.9 +/- 3.6 g; n = 8) or a control diet (24.5 +/- 1.2 g; n = 6), recombinant met-human leptin was administered intraperitoneally (10 microg/g). Blood samples were collected for leptin measurement at specific time points after leptin administration.MeasurementsPlasma leptin concentrations were determined by radioimmunoassay and pharmacokinetic analysis was performed.ResultsDisposition of human leptin in rhesus monkeys was biphasic following intravenous administration, with a terminal phase half-life of 96.4 +/- 16.5 min and clearance of 1.8 +/- 0.2 ml/min/kg. Subcutaneously administered leptin was absorbed slowly, perhaps by a zero-order process as leptin levels appeared to plateau and remained elevated throughout the 8 h sampling period. In C57BL/6J mice, the absorption and elimination of human leptin were both first-order following intraperitoneal administration. Pharmacokinetic parameters did not differ between normal-weight mice fed a chow diet and obese mice fed a high-fat diet. The elimination half-life was 47.0 +/- 26.4 min in mice fed a high-fat diet and 49.5 +/- 12.0 min in mice fed a control diet.ConclusionThe kinetics of leptin in rhesus monkeys were biphasic and clearance was similar to values previously reported in humans. The estimated half-life was 96.4 min in rhesus monkeys and 49.5 min in normal weight mice. The was no difference in leptin kinetics between high-fat fed and control mice, suggesting that the increased baseline leptin levels in the obese mice are due to increased leptin production and secretion

The liminality of trajectory shifts in institutional entrepreneurship

In this paper, we develop a process model of trajectory shifts in institutional entrepreneurship. We focus on the liminal periods experienced by institutional entrepreneurs when they, unlike the rest of the organization, recognize limits in the present and seek to shift a familiar past into an unfamiliar and uncertain future. Such periods involve a situation where the new possible future, not yet fully formed, exists side-by-side with established innovation trajectories. Trajectory shifts are moments of truth for institutional entrepreneurs, but little is known about the underlying mechanisms of how entrepreneurs reflectively deal with liminality to conceive and bring forth new innovation trajectories. Our in-depth case study research at CarCorp traces three such mechanisms (reflective dissension, imaginative projection, and eliminatory exploration) and builds the basis for understanding the liminality of trajectory shifts. The paper offers theoretical implications for the institutional entrepreneurship literature

The inevitable youthfulness of known high-redshift radio galaxies

Radio galaxies can be seen out to very high redshifts, where in principle they can serve as probes of the early evolution of the Universe. Here we show that for any model of radio-galaxy evolution in which the luminosity decreases with time after an initial rapid increase (that is, essentially all reasonable models), all observable high-redshift radio-galaxies must be seen when the lobes are less than 10^7 years old. This means that high-redshift radio galaxies can be used as a high-time-resolution probe of evolution in the early Universe. Moreover, this result helps to explain many observed trends of radio-galaxy properties with redshift [(i) the `alignment effect' of optical emission along radio-jet axes, (ii) the increased distortion in radio structure, (iii) the decrease in physical sizes, (iv) the increase in radio depolarisation, and (v) the increase in dust emission] without needing to invoke explanations based on cosmology or strong evolution of the surrounding intergalactic medium with cosmic time, thereby avoiding conflict with current theories of structure formation.Comment: To appear in Nature. 4 pages, 2 colour figures available on request. Also available at http://www-astro.physics.ox.ac.uk/~km

Personal health promotion at US medical schools: a quantitative study and qualitative description of deans' and students' perceptions

BACKGROUND: Prior literature has shown that physicians with healthy personal habits are more likely to encourage patients to adopt similar habits. However, despite the possibility that promoting medical student health might therefore efficiently improve patient outcomes, no one has studied whether such promotion happens in medical school. We therefore wished to describe both typical and outstanding personal health promotion environments experienced by students in U.S. medical schools. METHODS: We collected information through four different modalities: a literature review, written surveys of medical school deans and students, student and dean focus groups, and site visits at and interviews with medical schools with reportedly outstanding student health promotion programs. RESULTS: We found strong correlations between deans' and students' perceptions of their schools' health promotion environments, including consistent support of the idea of schools' encouraging healthy student behaviors, with less consistent follow-through by schools on this concept. Though students seemed to have thought little about the relationships between their own personal and clinical health promotion practices, deans felt strongly that faculty members should model healthy behaviors. CONCLUSIONS: Deans' support of the relationship between physicians' personal and clinical health practices, and concern about their institutions' acting on this relationship augurs well for the role of student health promotion in the future of medical education. Deans seem to understand their students' health environment, and believe it could and should be improved; if this is acted on, it could create important positive changes in medical education and in disease prevention

Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia

In the present study, we analysed the expression and localization of p21Waf1/Cip1 in normal and malignant haematopoietic cells. We demonstrate that in normal monocytic cells, protein kinase C (PKC)-induced p21 gene activation, which is nuclear factor-κB (NF-κB) independent, results in predominantly cytoplasmic localized p21 protein. In acute monocytic leukaemia (M4, M5), monocytic blasts (N=12) show constitutive cytoplasmic p21 expression in 75% of the cases, while in myeloid leukaemic blasts (N=10), low nuclear and cytoplasmic localization of p21 could be detected, which is also PKC dependent. Constitutive p21 expression in monocytic leukaemia might have important antiapoptotic functions. This is supported by the finding that in U937 cells overexpressing p21, VP16-induced apoptosis is significantly reduced (20.0±0.9 vs 55.8±3.8%, P<0.01, N=5), reflected by a reduced phosphorylation of p38 and JNK. Similarly, AML blasts with high cytoplasmic p21 were less sensitive to VP16-induced apoptosis as compared to AML cases with low or undetectable p21 expression (42.25 vs 12.3%, P<0.01). Moreover, complex formation between p21 and ASK1 could be demonstrated in AML cells, by means of coimmunoprecipitation. In summary, these results indicate that p21 has an antiapoptotic role in monocytic leukaemia, and that p21 expression is regulated in a PKC-dependent and NF-κB independent manner.

Self-rated health of primary care house officers and its relationship to psychological and spiritual well-being

<p/> <p>Background</p> <p>The stress associated with residency training may place house officers at risk for poorer health. We sought to determine the level of self-reported health among resident physicians and to ascertain factors that are associated with their reported health.</p> <p>Methods</p> <p>A questionnaire was administered to house officers in 4 residency programs at a large Midwestern medical center. Self-rated health was determined by using a health rating scale (ranging from 0 = death to 100 = perfect health) and a Likert scale (ranging from "poor" health to "excellent" health). Independent variables included demographics, residency program type, post-graduate year level, current rotation, depressive symptoms, religious affiliation, religiosity, religious coping, and spirituality.</p> <p>Results</p> <p>We collected data from 227 subjects (92% response rate). The overall mean (SD) health rating score was 87 (10; range, 40–100), with only 4 (2%) subjects reporting a score of 100; on the Likert scale, only 88 (39%) reported excellent health. Lower health rating scores were significantly associated (P < 0.05) with internal medicine residency program, post-graduate year level, depressive symptoms, and poorer spiritual well-being. In multivariable analyses, lower health rating scores were associated with internal medicine residency program, depressive symptoms, and poorer spiritual well-being.</p> <p>Conclusion</p> <p>Residents' self-rated health was poorer than might be expected in a cohort of relatively young physicians and was related to program type, depressive symptoms, and spiritual well-being. Future studies should examine whether treating depressive symptoms and attending to spiritual needs can improve the overall health and well-being of primary care house officers.</p

Facial expressions depicting compassionate and critical emotions: the development and validation of a new emotional face stimulus set

Attachment with altruistic others requires the ability to appropriately process affiliative and kind facial cues. Yet there is no stimulus set available to investigate such processes. Here, we developed a stimulus set depicting compassionate and critical facial expressions, and validated its effectiveness using well-established visual-probe methodology. In Study 1, 62 participants rated photographs of actors displaying compassionate/kind and critical faces on strength of emotion type. This produced a new stimulus set based on N = 31 actors, whose facial expressions were reliably distinguished as compassionate, critical and neutral. In Study 2, 70 participants completed a visual-probe task measuring attentional orientation to critical and compassionate/kind faces. This revealed that participants lower in self-criticism demonstrated enhanced attention to compassionate/kind faces whereas those higher in self-criticism showed no bias. To sum, the new stimulus set produced interpretable findings using visual-probe methodology and is the first to include higher order, complex positive affect displays

Organisational participation and women - an attitude problem?

Employee participation is a dynamic and contested area of organisational behaviour, attracting continuing academic, practitioner and policy interest and debate. This chapter focuses on organisational participation and women

Testing in the incremental design and development of complex products

Testing is an important aspect of design and development which consumes significant time and resource in many companies. However, it has received less research attention than many other activities in product development, and especially, very few publications report empirical studies of engineering testing. Such studies are needed to establish the importance of testing and inform the development of pragmatic support methods. This paper combines insights from literature study with findings from three empirical studies of testing. The case studies concern incrementally developed complex products in the automotive domain. A description of testing practice as observed in these studies is provided, confirming that testing activities are used for multiple purposes depending on the context, and are intertwined with design from start to finish of the development process, not done after it as many models depict. Descriptive process models are developed to indicate some of the key insights, and opportunities for further research are suggested

Dual Use of Veterans Health Administration and Indian Health Service: Healthcare Provider and Patient Perspectives

Many American Indian and Alaska Native veterans are eligible for healthcare from Veterans Health Administration (VHA) and from Indian Health Service (IHS). These organizations executed a Memorandum of Understanding in 2003 to share resources, but little was known about how they collaborated to deliver healthcare. To describe dual use from the stakeholders’ perspectives, including incentives that encourage cross-use, which organization’s primary care is “primary,” and the potential problems and opportunities for care coordination across VHA and IHS. VHA healthcare staff, IHS healthcare staff and American Indian and Alaska Native veterans. Focus groups were conducted using a semi-structured guide. A software-assisted text analysis was performed using grounded theory to develop analytic categories. Dual use was driven by variation in institutional resources, leading patients to actively manage health-seeking behaviors and IHS providers to make ad hoc recommendations for veterans to seek care at VHA. IHS was the “primary” primary care for dual users. There was little coordination between VHA and IHS resulting in delays and treatment conflicts, but all stakeholder groups welcomed future collaboration. Fostering closer alignment between VHA and IHS would reduce care fragmentation and improve accountability for patient care