Increasing diversity in pediatric hematology/oncology.

BACKGROUND: Diversity is necessary for the survival and success of both biological and social systems including societies. There is a lack of diversity, particularly the proportion of women and minorities in leadership positions, within medicine [Leadley. AAMC 2009. Steinecke and Terrell. Acad Med 2010;85:236-245]. In 2009 a group of ASPHO members recognized the need to support the career advancement of women and minority members. This article reports the results of a survey designed to characterize the comparative career pathway experience of women and minority ASPHO members. PROCEDURE: A group of ASPHO members modified a published Faculty Worklife survey [Pribbenow et al. High Educ Policy 2010;23:17-38] for use by Pediatric Hematologist-Oncologists (PHOs). A link to an online version of the survey was sent to all ASPHO members. RESULTS: Of 1,228 ASPHO members polled, 213 responded (17%). Women and minority PHOs reported less satisfaction than their counterparts on 70 of the 90 issues addressed in the survey including the hiring process, access to resources as well as integration and satisfaction with their organizations. Women also expressed greater dissatisfaction with issues of work-life balance, support for family obligations and personal health. CONCLUSIONS: The current literature suggests that there are significant disparities in career opportunities, compensation and satisfaction for women compared to men and minority compared to majority faculty in academic medicine [Nivet. J Vasc Surg 2010;51:53S-58S; Peterson et al. J Gen Intern Med 2004;19:259-265; DesRoches et al. Acad Med 2010;85:631-639; Castillo-Page. AAMC 2008]. Our data, derived from a survey of ASPHO members, suggests that this holds true for PHOs as well.

Blood pressure and heart rate QTL in mice of the B6/D2 lineage: sex differences and environmental influences.

A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F(2) adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F(2) data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F(2) mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.

Advancing institutional efforts to support research mentorship: a conceptual framework and self-assessment tool.

The purpose of this article is to assist institutions in advancing their efforts to support research mentorship. The authors begin by describing how institutions can shape the key domains of research mentorship: (1) the criteria for selecting mentors, (2) incentives for motivating faculty to serve effectively as mentors, (3) factors that facilitate the mentor-mentee relationship, (4) factors that strengthen a mentee's ability to conduct research responsibly, and (5) factors that contribute to the professional development of both mentees and mentors. On the basis of a conceptual analysis of these domains as currently documented in the literature, as well as their collective experience examining mentoring programs at a range of academic medicine institutions and departments, the authors provide a framework that leaders of institutions and/or departments can adapt for use as a tool to document and monitor policies for guiding the mentorship process, the programs/activities through which these policies are implemented, and the structures that are responsible for maintaining policies and implementing programs. The authors provide an example of how one hypothetical institution might use the self-assessment tool to track its policies, programs, and structures across the key domains of research mentorship and, on the basis of this information, identify a range of potential actions to strengthen its research mentoring efforts. The authors conclude with a brief discussion of the limitations of the self-assessment tool, the potential drawbacks and benefits of the overall approach, and proposed next steps for research in this area.

Serum alkaline phosphatase activity is regulated by a chromosomal region containing the alkaline phosphatase 2 gene (Akp2) in C57BL/6J and DBA/2J mice.

Quantitative trait locus (QTL) analyses were conducted to identify chromosomal regions that contribute to variability in serum alkaline phosphatase (AP) enzyme activity in mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains. Serum AP was measured in 400 B6D2 F2 mice at 5 mo and 400 B6D2 F2 mice at 15 mo of age that were genotyped at 96 microsatellite markers, and in 19 BXD recombinant inbred (RI) strains at 5 mo of age. A QTL on the distal end of chromosome 4 was present in all sex- and age-specific analyses with a peak logarithm of odds (LOD) score of 20.36 at 58.51 cM. The Akp2 gene, which encodes the major serum AP isozyme, falls within this QTL region at 70.2 cM where the LOD score reached 13.2 (LOD significance level set at 4.3). Serum AP activity was directly related to the number of D2 alleles of a single nucleotide polymorphism in the 5'-flanking region of the Akp2 gene, although no strain-related differences in hepatic expression of Akp2 RNA were found. A variety of sequence polymorphisms in this chromosomal region could be responsible for the differences in serum AP activity; the Akp2 gene, however, with several known amino acid substitutions between protein sequences of the B6 and D2 strains, is a leading candidate.

Quantitative trait loci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD) recombinant inbred mice.

BACKGROUND AND AIMS: Genes associated with longevity have been identified using both single gene and genome-wide approaches in a variety of species. The aim of this study was to identify quantitative trait loci (QTLs) that influence longevity in male and female mice from twenty-three C57BL/6J by DBA/2J (BXD) recombinant inbred (RI) strains. METHODS: Approximately 12 animals of each sex for each RI strain were maintained under standard conditions until natural death or moribundity criteria were met. RESULTS: A number of life span-relevant loci previously reported on chromosomes (Chrs) 7, 8, 10 and 11 were confirmed. In addition, 5 previously unreported QTLs for mouse life span on Chrs 1, 2, 6, 11, and X were identified as significant and 3 QTLs on Chrs 5, 8, and 16 were suggestive. CONCLUSIONS: Several QTLs were coincident in males and females although the modest correlation between male and female median lifespans and the identification of sex specific QTLs provide evidence that the genetic architecture underlying longevity in the sexes may differ substantially. The identification of multiple QTLs for longevity will provide valuable resources for both reductionist and integrationist research into mechanisms of life span determination.

Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress.

Loss of motor function in Parkinson's disease is due in part to degeneration of dopamine (DA) neurons. Pharmacological evidence suggests that the mitogen-activated protein kinase signaling pathways involving extracellular signal-regulated kinases (ERKs) play important roles in neuroprotection of DA neurons. However, the relative roles of the several ERK isoforms in the viability of DA neurons have not yet been determined. In the present study, we investigated the contributions of ERK5, as well as ERK1/2, to MN9D cell survival under basal conditions and in response to 6-hydroxydopamine (6-OHDA). We observed that U0126, an inhibitor of ERK activation, decreased basal survival of these cells. To differentiate between ERK1/2 and ERK5, cells were transfected with a dominant negative form of either ERK5 or MEK1, the upstream activator of ERK1/2. Transfection of MN9D cells with either dominant negative construct mimicked U0126, reducing cell survival. Moreover, transfection of the cells in such a way as to increase ERK5 or ERK1/2 activity inhibited 6-OHDA-induced cell death, although this effect was significant only in the case of ERK1/2 activation. These studies suggest that activations of ERK5 and ERK1/2 both promote basal DA cell survival and that ERK1/2 also protects DA cells from oxidative stress. These are the first studies to demonstrate a role for ERK5 in DA neuronal survival and to investigate the relative roles of ERK1/2 and ERK5 in basal DA survival and neuroprotection from oxidative stress.

Duloxetine pharmacology: profile of a dual monoamine modulator.

Dysregulation within central monoaminergic systems is believed to underlie the pathology of depression. Drugs that selectively inhibit the reuptake of central monoamines have been used clinically to alleviate symptoms of depressive illnesses. Duloxetine, a novel compound currently under investigation for the treatment of depression, binds selectively with high affinity to both norepinephrine (NE) and serotonin (5-HT) transporters and lacks affinity for monoamine receptors within the central nervous system. It has been suggested that dual inhibition of monoamine reuptake processes may offer advantages over other antidepressants currently in use. In preclinical studies, duloxetine mimics many physiologic effects of antidepressants. Consistent with other antidepressants, duloxetine, by acute administration, elevates extracellular monoamine levels, while by chronic administration it does not alter basal monoamine levels. Like the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic application, duloxetine inhibits neuronal cell firing. However, in comparison with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor. Furthermore, in behavioral experiments, duloxetine attenuates immobility in forced swim tests in animal models of depression to a greater extent than several other commonly used antidepressants. In a six-week open label uncontrolled study, duloxetine was evaluated in patients with a history of depression. Duloxetine was effective in treating depression as determined by marked reduction in Hamilton Depression Rating scores. Adverse effects reported during duloxetine treatment were minor and similar to those of other antidepressants. In an eight-week multicenter, double-blind, placebo-controlled study in patients with a major depressive disorder, duloxetine was effective as an antidepressant, particularly in patients with greater symptom severity. Only limited data are available regarding the pharmacokinetic profile of duloxetine in humans, although a half-life of 10 to 15 h has been reported. Studies conducted in healthy human subjects confirm the preclinical profile of duloxetine as an inhibitor of 5-HT and NE reuptake. Taken together, existing data suggest that duloxetine is a novel and effective antidepressant.

Functional mu opioid receptors are reduced in the spinal cord dorsal horn of diabetic rats.

BACKGROUND: The mechanisms of decreased spinal analgesic potency of morphine in neuropathic pain are not fully known. Agonist-stimulated [35S]GTPgammaS receptor autoradiography has been used to measure receptor activation of G proteins in vitro. Using this technique, we determined changes in the functional mu opioid receptors in the spinal dorsal horn in diabetic rats. METHODS: Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The lumbar spinal cord was obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO, 10 microm)-stimulated [35S]GTPgammaS binding was performed in both tissue sections and isolated membranes. RESULTS: The DAMGO-stimulated [35S]GTPgammaS binding in the spinal dorsal horn was significantly reduced (approximately 37%) in diabetic rats compared with normal rats. However, [35S]GTPgammaS bindings in the spinal dorsal horn stimulated by other G protein-coupled receptor agonists, including [D-Pen2,D-Pen5]-enkephalin, R(-)N6-(2-phenylisopropyl)-adenosine, and WIN-55212, were not significantly altered in diabetic rats. The basal [35S]GTPgammaS binding in the spinal dorsal horn was slightly (approximately 13%) but significantly increased in diabetic rats. Western blot analysis revealed no significant difference in the expression of the alpha subunits of G(i) and G(o) proteins in the dorsal spinal cord between normal and diabetic rats. CONCLUSIONS: These data suggest that the functional mu opioid receptors in the spinal cord dorsal horn of diabetic rats are reduced. The impaired functional mu opioid receptors in the spinal cord may constitute one of the mechanisms underlying the reduced spinal analgesic effect of mu opioids in diabetic neuropathic pain.

Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter.

Recent studies suggest that the mesoaccumbens dopamine system undergoes neurochemical alterations as a result of restricted feeding conditions with access to sugars. This effect appears to be similar to the neuroadaptation resulting from drugs of abuse and may underlay some pathological feeding behaviors. To further investigate the cellular mechanisms of these alterations, the present study used quantitative autoradiography and in situ hybridization to assess dopamine membrane transporter (DAT) protein density and mRNA expression in restricted-fed and free-fed adult male rats. The restricted feeding regimen consisted of daily limited access to either a normally preferred sucrose solution (0.3 M) or a less preferred chow in a scheduled (i.e., contingent) fashion for 7 days. Restricted-fed rats with the contingent sucrose access lost less body weight, ate more total food, and drank more fluid than free-fed, contingent food, or noncontingent controls. In addition, these animals had selectively higher DAT binding in the nucleus accumbens and ventral tegmental area. This increase in protein binding also was accompanied by an increase in DAT mRNA levels in the ventral tegmental area. In contrast to the restricted-fed groups, no differential effect in DAT regulation was observed across free-fed groups. The observed alteration in behavior and DAT regulation suggest that neuroadaptation in the mesoaccumbens dopamine system develops in response to repeated feeding on palatable foods under dietary constraints. This supports the notion that similar cellular changes may be involved in restrictive eating disorders and bingeing.