Toward a theory of discontinuous career transition: investigating career transitions necessitated by traumatic life events.

Career researchers have focused on the mechanisms related to career progression. Although less studied, situations in which traumatic life events necessitate a discontinuous career transition are becoming increasingly prevalent. Employing a multiple case study method, we offer a deeper understanding of such transitions by studying an extreme case: soldiers and Marines disabled by wartime combat. Our study highlights obstacles to future employment that are counterintuitive and stem from the discontinuous and traumatic nature of job loss. Effective management of this type of transitioning appears to stem from efforts positioned to formulate a coherent narrative of the traumatic experience and thus to reconstruct foundational assumptions about the world, humanity, and self. These foundational assumptions form the basis for enacting future-orientated career strategies, such that progress toward establishing a new career path is greatest for those who can orientate themselves away from the past (trauma), away from the present (obstacles to a new career), and toward an envisioned future career positioned to confer meaning and purpose through work.

Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy.

Endometrial cancer--the most common malignancy of the female reproductive tract--arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea--suggested by some prior studies--that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.

Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas.

Mutations in the LKB1 tumor suppressor gene result in the Peutz-Jeghers syndrome, an autosomal dominant condition characterized by hamartomatous polyps of the gastrointestinal tract and a dramatically increased risk of epithelial malignancies at other sites, including the female reproductive tract. Here we show that female mice heterozygous for a null Lkb1 allele spontaneously develop highly invasive endometrial adenocarcinomas. To prove that these lesions were indeed due to Lkb1 inactivation, we introduced an adenoviral Cre vector into the uterine lumen of mice harboring a conditional allele of Lkb1. This endometrial-specific deletion of the Lkb1 gene provoked highly invasive and sometimes metastatic endometrial adenocarcinomas closely resembling those observed in Lkb1 heterozygotes. Tumors were extremely well differentiated and histopathologically distinctive and exhibited alterations in AMP-dependent kinase signaling. Although Lkb1 has been implicated in the establishment of cell polarity, and loss of polarity defines most endometrial cancers, Lkb1-driven endometrial cancers paradoxically exhibit (given their highly invasive phenotype) normal cell polarity and apical differentiation. In human endometrial cancers, Lkb1 expression was inversely correlated with tumor grade and stage, arguing that Lkb1 inactivation or down-regulation also contributes to endometrial cancer progression in women. This study shows that Lkb1 plays an important role in the malignant transformation of endometrium and that Lkb1 loss promotes a highly invasive phenotype.

Genomewide discovery and classification of candidate ovarian fertility genes in the mouse.

Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility.

Imatinib mesylate inhibits antigen-specific memory CD8 T cell responses in vivo.

Imatinib mesylate (IM) is effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia. Because its influence on CD8 T cell responsiveness in vivo is unknown, we investigated the effects of IM by analyzing the response of OT-1 CD8 T cells to Listeria monocytogenes (LM) that express the cognate epitope OVA(257-264) (LM-OVA). In vitro, IM had no effect on Ag-specific expansion, cell division, cell cycle progression, or IFN-gamma expression in naive or memory OT-1 T cells. However, IM induced apoptosis of naive and memory OT-1 T cells at doses of >5 microM. At 15 microM IM, OT-1 T cells did not survive in in vitro cultures. The primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered. In contrast, continuous IM treatment resulted in a diminished memory OT-1 response. The expression of IL-7Ralpha, a receptor required for memory cell survival, was lower (on OT-1 cells) in animals receiving IM. These results indicate that IM treatment affects the ability of the CD8 memory pool to respond to Ag and has the potential to increase susceptibility to infection.

Measurements of hemodialysis catheter blood flow in vivo.

The relationship between the blood flow and inflow and outflow pressures was determined in PermCath, dual lumen catheters during regular hemodialyses in vivo in eight patients with average hematocrit of 38%. From the luer lock connector the catheters had an average length of 32 cm to the outflow tip and 30 cm to the inflow tip. The catheters had an internal diameter of 0.2 cm and were straight before implantation. Dialyses were performed on Fresenius 2008 D or E machines with ReadySet blood lines with an 8 mm ID pump segment and a noncollapsible arterial chamber. Pressures and blood flows were measured at pump speeds from 50 to 500 ml/min in increments of 50 ml/min with lines in normal configuration. Blood flow was measured continuously using ultrasound. The correlations between pressures and flows are not linear. The best correlations are according to the Stirling model of exponential growth category equation. Inflow pressure = -9.07-0.4865*(exp(0.0020*blood flow)-1)/0.0020 Outflow pressure = -28.14+0.5002*(exp(0.0015*blood flow)-1/0.0015 Based on these results and Poiseuille's equation a table was developed for the optimal relationship between catheter length and diameter to achieve standardized (average, low and high) blood flows regardless of the lengths of the catheters. The diameter/length relationships are based on theoretical considerations. Because resistances depend on the material and shape of the tubing, the actual measurements of flow/pressure relationships should be done once tubings of different diameters are manufactured, and final catheter design has to be based on these measurements.

Biomechanical evaluation of retrieved massive allografts: preliminary results.

Allograft bone is the primary source of graft material for large skeletal defects. No study has determined the physical characteristics of such grafts after various periods of time in vivo for incorporation and remodeling. The purpose of this pilot study was to obtain allograft tissue and biomechanically evaluate the tissue to assess allograft bone material properties. The mechanical properties of the retrieved allograft tissue were compared to allograft bone prior to transplantation. Histological analysis of the retrieved allograft tissue is currently underway to correlate degree of incorporation, allograft porosity, and microfracture density with allograft material properties. After allograft retrieval, radiographs were used to plan sectioning for histological and biomechanical analyses. Rectangular sections of uniform dimensions (50 x 3 x 3 mm) were mapped and machined from the bulk specimens. The samples were loaded in bending in the medial to lateral direction using a 4-point bending fixture to obtain flexural elastic modulus and breaking strength. Preconditioning was applied to each specimen by cycling through 5 submaximal loading cycles (maximum deflection = 1% specimen length). After preconditioning, the specimens were loaded to failure at a rate of 1 mm/min. Retrieved specimens consisted of 1 tibia, 2 femurs, and 2 humeri ranging from 2 to 13 years in vivo. Two control tibia specimens were also tested. Assuming that material properties of cortical bone are consistent regardless of skeletal site, the preliminary data indicates that allograft modulus and strength decline with time in vivo. Testing and analysis of more specimens continue in order to corroborate these initial results.

A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results.

OBJECTIVES: In a prospective clinical study, we tested the hypothesis that sparing the parotid glands may result in significant objective and subjective improvement of xerostomia in patients with head-and-neck cancers. The functional outcome 6 months after the completion of radiation therapy is presented. METHODS AND MATERIALS: From February 1997 to February 1999, 41 patients with head-and-neck cancers were enrolled in a prospective salivary function study. Inverse-planning intensity-modulated radiation therapy (IMRT) was used to treat 27 patients, and forward-planning three-dimensional radiation therapy in 14. To avoid potential bias in data interpretation, only patients whose submandibular glands received greater than 50 Gy were eligible. Attempts were made to spare the superficial lobe of the parotid glands to avoid underdosing tumor targets in the parapharyngeal space; however, the entire parotid volume was used to compute dose-volume histograms (DVHs) for this analysis. DVHs were computed for each gland separately. Parotid function was assessed objectively by measuring stimulated and unstimulated saliva flow before and 6 months after the completion of radiation therapy. Measurements were converted to flow rate (mL/min) and normalized relative to that before treatment. The corresponding quality-of-life (QOL) outcome was assessed by five questions regarding the patient's oral discomfort and eating/speaking problems. RESULTS: We observed a correlation between parotid mean dose and the fractional reduction of stimulated saliva output at 6 months after the completion of radiation therapy. We further examined whether the functional outcome could be modeled as a function of dose. Two models were found to describe the dose-response data well. The first model assumed that each parotid gland is comprised of multiple independent parallel functional subunits (corresponding to computed tomography voxels) and that each gland contributes equally to overall flow, and that saliva output decreases exponentially as a quadratic function of irradiation dose to each voxel. The second approach uses the equivalent uniform dose (EUD) metrics, which assumes loss of salivary function with increase in EUD for each parotid gland independently. The analysis suggested that the mean dose to each parotid gland is a reasonable indicator for the functional outcome of each gland. The corresponding exponential coefficient was 0.0428/Gy (95% confidence interval: 0.01, 0.09). The QOL questions on eating/speaking function were significantly correlated with stimulated and unstimulated saliva flow at 6 months. In a multivariate analysis, a toxicity score derived from the model based on radiation dose to the parotid gland was found to be the sole significant predictive factor for xerostomia. Neither radiation technique (IMRT vs. non-IMRT) nor chemotherapy (yes or no) independently influenced the functional outcome of the salivary glands. CONCLUSION: Sparing of the parotid glands translates into objective and subjective improvement of both xerostomia and QOL scores in patients with head-and-neck cancers receiving radiation therapy. Modeling results suggest an exponential relationship between saliva flow reduction and mean parotid dose for each gland. We found that the stimulated saliva flow at 6 months after treatment is reduced exponentially, for each gland independently, at a rate of approximately 4% per Gy of mean parotid dose.

All currently used measurements of recirculation in blood access by chemical methods are flawed due to intradialytic disequilibrium or recirculation at low flow.

Blood flows and recirculations with standard and reversed direction of lines were measured by chemical (urea and creatinine) and ultrasound dilution (saline) methods in 47 chronic hemodialysis patients. Thirty-seven patients had 47 dual-lumen, central vein (CV) catheters: 32 were PermCath (Quinton Instruments Company, Seattle, WA), 6 were Access Cath (MEDCOMP, Harleysville, PA), 3 were Soft Cell PC (Vas Cath, Mississauga, Ontario, Canada) and 6 were SNIJ (experimental catheters). Three of these last catheters had the tip staggered 7 mm, and three had flush tips; PermCath, Access Cath, and Soft Cell PC catheters have the tips staggered 23 to 25 mm. Forty-six catheters were implanted into the superior vena cava/right atrium, and one catheter was implanted through the left saphenous vein into the left iliac vein. The catheters were studied 1 to 31 months after implantation (median, 3.0 months). Ten patients with arteriovenous (AV) graft access were also studied. The stop-flow method was used in catheter dialysis, and the slow-flow method was used to calculate recirculations in AV access dialysis with samples for systemic blood concentrations taken from arterial line both before and after samples from the arterial and venous lines. At 500 mL/min pump speed, actual blood flow was 436+/-18 mL/min (mean+/-SD; range, 407 to 464 mL/min) with standard direction of catheter lines. At 500 mL/min pump speed, the arterial chamber pressure was -330+/-48 mm Hg (mean+/-SD; range, -380 to -225 mm Hg, and the venous chamber pressure was 259+/-48 mm Hg (mean+/-SD; range, 140 to 310 mm Hg). Arterial chamber pressure was less negative, and venous chamber pressure was less positive with SNIJ catheters, which had larger internal diameter (2.1 mm) compared with the other catheters (2.0 mm). Recirculation varied with the catheter design and the location of the catheter tip. In the catheters with tip staggered more than 20 mm and with standard line connection at pump speeds of 50 mL/min and 500 mL/min, recirculations were approximately 1 % and 5%, respectively, when measured by the chemical method. In the same catheters with reversed lines, the recirculations were approximately 5% and 27%, respectively. Inflow failure catheters with reversed lines had similar recirculation values to those of well-functioning catheters with reversed lines. In catheters with tips staggered 7 mm, and with standard connection of lines, recirculations were approximately 3% and 8%, respectively, at pump speeds of 50 and 500 mL/min. With reversed lines, at the same pump speeds, the values were 7% and 12%, respectively. In flush-tip catheters, the recirculation was higher at a 50 mL/min pump speed (approximately 17%) than at a pump speed of 500 mL/min (approximately 13%). The ultrasound dilution method usually gave lower values than the chemical methods, most likely because of overestimation of recirculation by chemical methods. At least triplicate measurements are needed because single measurements by the ultrasound dilution method are associated with substantial variation. We conclude that both currently used methods (stop flow and slow flow) of taking systemic samples for measurements of recirculation by chemical methods are flawed because of disequilibrium and recirculation at low flow.

Blood recirculation in intravenous catheters for hemodialysis.

Long-term i.v. catheters for hemodialysis have the outflow tip extending approximately 2 to 3 cm beyond the inflow tip to prevent blood recirculation during dialysis; however, the lumens are frequently reversed because of inflow failure (i.e., inadequate flow when the inflow lumen is used for blood inflow into the dialyzer). Blood recirculation with reversed lumens (outflow lumen used for blood inflow) in inflow failure catheters and with standard and reversed lumens in well-functioning catheters was measured. Recirculation was measured at a blood flow of 300 mL/min. Systemic blood samples were taken after blood flow was slowed to 50 mL/min. Blood recirculation was calculated as a percentage of the difference between systemic and inflow lumen solute concentrations divided by the difference between systemic and outflow lumen solute concentrations. For each catheter, the recirculation values were calculated separately for urea and creatinine. Average recirculation as measured by both solutes was also calculated. Blood recirculations with standard lumens of well-functioning catheters, reversed lumens of well-functioning catheters, and reversed lumens of inflow failure catheters were 2.09 +/- 1.95, 13.58 +/- 9.87, and 7.10 +/- 5.12 (mean +/- SD), respectively. Whereas recirculation with standard lumens of well-functioning catheters is negligible, reversal of lumens causes considerable recirculation. Recirculation in inflow failure catheters with reversed lumens is significantly less than that with reversed lumens of well-functioning catheters. It was proposed that a blood clot attached at and/or immediately distal to the inflow lumen may disperse outflowing blood and diminish recirculation in inflow failure catheters.(ABSTRACT TRUNCATED AT 250 WORDS)

Prescribing dialysate bicarbonate concentrations for hemodialysis patients.

A rearranged equation of Sargent and Gotch (1) was used to determine dialysate bicarbonate concentrations for hemodialysis patients. Parameters in this equation include an estimate of the acid generated by each patient between treatments, an estimate for the dialyzer dialysance for bicarbonate, ultrafiltration rate, blood flow rate and a targeted mid-dialysis plasma bicarbonate concentration of 25 mEq/L. Nine patients were studied over a 35 week period to verify this method of determining each patient's dialysate bicarbonate concentration. Prescribed dialysate bicarbonate concentrations for the nine patients varied from 29 to 38 mEq/L with five patients having a prescribed value of 35 mEq/L. After a baseline period of five weeks, five patients switched from a 37 mEq/L acetate dialysate to their prescribed dialysate bicarbonate concentration. Four patients who had already been on bicarbonate dialysis at a concentration of 35 mEq/L were dialyzed with their prescribed dialysate bicarbonate concentrations. Patients were then followed for a study period of 30 weeks. The prescribed dialysate bicarbonate concentration resulted in more normal acid/base chemistries for both groups of patients. The results also demonstrate that chronic hemodialysis patients require individualization of dialysate bicarbonate concentrations.

Development of the eye-antenna imaginal disc and morphogenesis of the adult head in Drosophila melanogaster.

We have studied the organization and development of the eye-antenna imaginal disc of Drosophila melanogaster. We examined the pattern of gynandromorph mosaicism and determined the "sturt distances" between 42 different structures of the head, antenna, and maxillary palpus. A morphogenetic map based on these sturt distances resembles more closely in size and shape that of a single thoracic segment than that of two or more adjacent segments, suggesting that the eye-antenna disc is derived from a single embryonic body segment. We examined the morphology of the eye-antenna discs in situ in late third-instar larvae in serial cross sections. The two discs are connected medially by a thin cellular membrane that probably serves to join the two discs during evagination and morphogenesis of the adult head. A fate map of the imaginal disc was established by cutting the mature disc into fragments and transplanting the fragments into host larvae for metamorphosis. The peripodial layer of the eye-antenna disc is thickened in several regions, and our data suggest that these thickened areas represent primordia of adult head structures. A comparison of the location of precursors in the imaginal disc with those of the differentiated structures of the adult head revealed the nature of the morphogenetic movements that must occur during evagination and differentiation.

Comparative effects of acetate and bicarbonate hemodialysis on left ventricular function.

To assess the comparative effects of hemodialysis with acetate versus bicarbonate base on left ventricular systolic function, we performed M-mode echocardiography on 36 patients prior to and immediately following 4-hr maintenance hemodialysis. Patients were initially dialyzed against either sodium acetate or sodium bicarbonate and 1 week later were dialyzed against the alternate base. The mean velocity of circumferential fiber shortening (mean Vcf, circumferences/s) was used to assess left ventricular systolic function. In patients with normal pre-dialysis mean Vcf hemodialysis with acetate produced no significant change in mean Vcf, whereas hemodialysis with bicarbonate produced a significant increase in mean Vcf. In patients with low pre-dialysis mean Vcf hemodialysis with either base produced a significant increase in mean Vcf. Mean Vcf values obtained after hemodialysis with bicarbonate were significantly higher than those obtained after hemodialysis with acetate, both in patients with normal and low pre-hemodialysis mean Vcf. We conclude that hemodialysis with bicarbonate produces a comparatively greater improvement in left ventricular systolic function than hemodialysis with acetate.

The maternal and zygotic roles of the gene Polycomb in embryonic determination in Drosophila melanogaster.

The mutation Polycomb (Pc) is known to cause a variety of intersegmental transformations in homozygous and heterozygous individuals of Drosophila melanogaster; Pc+ is thought to act as a negative regulator of genes of the bithorax complex. The function of this gene in the maternal germ line has been assessed by examining the variation in expression of these homoeotic phenotypes in individuals derived from a maternal germ line with a single or no dose of the Pc+ allele. Mosaic individuals with a homozygous or heterozygous Pc germ line were produced by transplantation of pole cells, the embryonic precursors of the germ line. By employing an X-linked dominant female-sterile mutation, the identification of mosaic females and the study of progeny derived from the exogenous germ line were greatly simplified; the advantages of this system for the transplantation of pole cells for such analyses are described. In general, all thoracic and abdominal segments of homozygous Pc embryos differentiate characteristics of the eighth, most posterior, abdominal segment. The extent and uniformity of this transformation as well as other manifestations of the homozygous Pc genotype are described and shown to be correlated with the maternal germ line genotype; homozygous Pc embryos derived from a homozygous Pc maternal germ line show greater expression of these phenotypes than do genetically identical embryos derived from a heterozygous Pc maternal germ line. The expression of some homoeotic phenotypes typical of heterozygous Pc adults shows only a slight correlation with the maternal genotype, while no homoeotic transformations are clearly evident in heterozygous larvae of either origin. Thus, the maternal effect of Pc is rescuable. The results suggest that the Pc+ gene is active in the maternal germ line but that the absence of the maternally derived Pc+ product can be largely compensated by the introduction of a wild-type allele upon fertilization; this rescue indicates that the maternal activity of Pc+ plays no major role in the normal process of embryonic segmental determination. The normal fertility of males and females with a homozygous Pc germ line and of their progeny suggests that Pc+ plays no role in the determination or development of the germ line in either the maternal or zygotic genome.