Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation

Recent evidence indicates that bone-marrow-derived stromal cells (MSCs) have a histology coherent with endothelial cells that may enable them to contribute to tumor angiogenesis through yet undefined mechanisms. In this work, we investigated the angiogenic properties of murine MSCs involved in extracellular matrix degradation and in neovascularization that could take place in a hypoxic environment such as that encountered in tumor masses. MSCs were cultured in normoxia (95% air and 5% CO(2)) or in hypoxia (1% oxygen, 5% CO(2), and 94% nitrogen). We found that hypoxic culture conditions rapidly induced MSC migration and three-dimensional capillary-like structure formation on Matrigel. In vitro, MSC migration was induced by growth-factor- and cytokine-enriched conditioned media isolated from U-87 glioma cells as well as from MSCs cultured in hypoxic conditions, suggesting both paracrine and autocrine regulatory mechanisms. Although greater vascular endothelial growth factor levels were secreted by MSCs in hypoxic conditions, this growth factor alone could not explain their greater migration. Interestingly, matrix metalloproteinase (MMP)-2 mRNA expression and protein secretion were downregulated, while those of membrane-type (MT)1-MMP were strongly induced by hypoxia. Functional inhibition of MT1-MMP by a blocking antibody strongly suppressed MSC ability to migrate and generate capillary-like structures. Collectively, these data suggest that MSCs may have the capacity to participate in tumor angiogenesis through regulation of their angiogenic properties under an atmosphere of low oxygen that closely approximates the tumor microenvironment.     

Relationship between the ocular and systemic disposition of flurbiprofen: The effect of altered protein dynamics at steady state

The differences in flurbiprofen disposition in the aqueous humor and the plasma were examined after systemic doses. Steady state plasma concentrations of flurbiprofen (20–60 g/mL) were achieved via intravenous infusion to albino rabbits. Flurbiprofen demonstrated linear systemic kinetics throughout the dosing range, with constant body clearance and unbound fraction in plasma. At steady state, aqueous humor drug concentrations depended on the corresponding plasma drug concentration. Two clearance terms—CL_so, the systemic clearance to ocular tissues, and CL_os, the ocular clearance to systemic circulation—were used. After systemic doses, the drug concentration in the aqueous humor was related to that in the plasma as well as to the ratio of these two clearances. Flurbiprofen was extensively bound to plasma proteins and showed limited ocular distribution; its CL_so to CL_so tratio was very small. Thus, the concentration of flurbiprofen in the aqueous humor after systemic doses was lower than that obtained after ophthalmic doses. A plasmapheresis technique was utilized to lower the plasma protein concentrations to 60% of normal levels. As a consequence, flurbiprofen demonstrated reduced aqueous humor protein concentrations, increased unbound fractions in the plasma and the aqueous humor, elevated aqueous humor drug concentrations, and elevated total body clearance. The unbound body clearance stayed unchanged. Our study indicated that a drug should present a significant CL_so/CL_os ratio in order to achieve therapeutic concentrations in the eye via systemic doses. The drug-protein binding kinetics can be different between the plasma and the aqueous humor circulations. Because the ocular compariment is very small compared to the overall systemic distribution of flurbiprofen, it has little effect on the steady state systemic concentrations.     

Autocrine and paracrine growth regulation of human breast cancer

Summary We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGF, TGF, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or byras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.     

Perioperative transfusions associated with colorectal cancer surgery : Clinical judgment versus the hematocrit

We prospectively studied 123 patients with colorectal cancer in order to identify determinants of perioperative blood transfusions and unnecessary transfusions. Transfusions were considered unnecessary if the preoperative hematocrit reading exceeded 36% or the discharge hematocrit level exceeded 33%. Age, sex, admission hematocrit reading, operative procedure, specimen length, duration of surgery, estimated blood loss, tumor size, tumor differentiation, nodal status, Dukes' staging, and attending surgeon were evaluated in relation to perioperative blood transfusion using stepwise logistic regression. Fifty-one (41%) of the 123 patients in the study were transfused and 35 patients (28%) received at least 1 unnecessary unit of blood. Advanced age, low admission hematocrit reading, high estimated operative blood loss, prolonged procedures, and lengthy specimens were significantly related to the administration of blood. Excessive intraoperative transfusions and the practice of administering blood in pairs of units accounted for the unnecessary transfusions. This study indicates that factors that influence clinical judgment and thereby the decision to transfuse a patient are not accurate indicators of when blood should be given. Greater use of pre-transfusion hematocrit testing, especially in the operating room and before transfusing a second unit of blood, will dramatically reduce blood usage in elective colorectal cancer surgery.

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Resumen Hemos estudiado en forma prospectiva 123 pacientes con cáncer colorrectal con el objeto de identificar factores determinantes de transfusiones sanguíneas perioperatorias y de transfusiones innecesarias. Se consideró que las transfusiones eran innecesarias si el hematocrito preoperatorio excedía 36% o si el hematocrito de egreso excedía 33%. La edad y sexo, el hematocrito de admisión, el tipo de procedimiento operatorio, la longitud del especimen resecado, la duración de la operación, la magnitud estimada de la pérdida de sangre, el tamaño del tumor, el grado de la diferenciación del tumor, el estado de los ganglios, la clasificación Dukes del tumor y el cirujano, fueron valorados en relación con el volumen de transfusión perioperatoria utilizando el método de regresión logística escalonada. Cincuenta y uno (41%) de los 123 pacientes fueron transfundidos y 35 (28%) recibieron por lo menos una unidad de sangre innecesaria. La edad avanzada, un hematocrito bajo en el momento de la admisión, la escimación de una alta pérdida de sangre, los procedimientos prolongados y los especimenes de gran longitud aparecieron como factores significativamente relacionados con la administracion de sangre. Las transfusiones intraoperatorias excesivas y la práctica de administrar sangre en pares de unidades fueron responsables de las transfusiones innecesarias. Este estudio indica que los factores que influencian el juicio clínico, y por consiguiente la decisión de transfundir a un paciente, no son indicadores precisos de cuando se debe administrar sangre. Una mayor utilización del hematocrito pretransfusión, especialmente dentro de la sala de operaciones y antes de transfundir una segunda unidad de sangre, logrará disminuir en forma dramática el uso de sangre en cirugía electiva para cáncer colorrectal.

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Résumé Les auteurs se sont livrés à une étude prospective de 123 malades atteints de cancer colorectal dans le but d'identifier les facteurs qui ont été à l'origine de transfusions pré-, per-, et postopératoires et de transfusions inutiles. Les transfusions ont été considérées comme inutiles lorsque l'hématocrite préopératoire dépassait 36 pour cent ou qu'il excédait 33 pour cent au moment de la sortie de l'opéré. Pour apprécier la valeur de la transfusion périopératorie ont été pris en compte les divers facteurs suivants : l'âge, le sexe, le taux de l'hématocrite à l'admission, le type de l'intervention, la longueur du spécimen, la durée de l'opération, la quantité de sang perdu, la taille de la tumeur, le degré de différenciation du cancer, l'état des ganglions, le stade évolutif (classification de Dukes), la qualification du chirurgien. Cinquante et un des malades (41%) furent transfusés et 35 parmi eux (28%) reçurent inutilement au moins une unité de sang. L'ae avancé de l'opéré, le taux bas de l'hématocrite à l'admission, la perte importante de sang au cours de l'intervention, la longue durée de l'opération, l'importance de la pièce opératoire réséquée furent en rapport de manière significative avec l'administration de sang. Les transfusions inutiles furent le fait de l'administration excessive de sang au cours de l'opération ou de l'emploi d'unités doubles de sang. Cette étude indique que les facteurs cliniques ne constituent pas des éléments de valeur pour déterminer l'indication de la transfusion de sang. C'est le taux de l'hématocrite avant et au cours de l'intervention qu'il faut prendre en compte. L'observation de cette règle est appelée à réduire considérablement l'emploi du sang au cours de la chirurgie colorectale élective.

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Supported by the Frieda and George Zinberg Foundation and NCI-NIH grant 1 RO1-CA-35558-01.     

Staffing patterns in rural health services for children and adolescents

This paper reviews several current human resources issues in delivering mental health services to children and adolescents, focusing primarily on the lack of systematic data regarding staff involved in these programs. Data from twenty counties in rural western Pennsylvania are then presented demonstrating the personal, educational, employment, and caseload characteristics of this group of staff, as well as their primary job functions and areas of job satisfaction. Professional staff were likely to have terminal master's degrees and to work primarily in outpatient services, whereas bachelor's-level staff were more likely to perform generalist functions, often without adequate supervision and clinical training. Paraprofessional staff were most numerous in community residential settings and performed a variety of functions. The implications of these findings for services development and staff training are discussed.Special thanks are extended to Jacki Herring, who performed the data analysis. An earlier version of this paper was presented at the annual meeting of the American Psychological Association. August 1983.     

Psychosocial Working Conditions Play an Important Role in the Return-to-Work Process After Total Knee and Hip Arthroplasty

Journal of Occupational Rehabilitation - Purpose Both personal and work-related factors affect return to work (RTW) after total knee arthroplasty (TKA) and total hip arthroplasty (THA). Little is...     

Inability to Work Fulltime,Prevalence and Associated Factors Among Applicants for Work Disability Benefit

Journal of Occupational Rehabilitation - Purpose Inability to work fulltime is an important outcome in the assessment of workers applying for a disability benefit. However, limited knowledge is...