RESUMEN

The number of primary care physicians in the United States is inadequate to meet current or projected needs. This is likely exacerbated by continuing increases in the cost of medical education and student debt. The Geisinger Commonwealth School of Medicine is part of an integrated care delivery system in which primary care is central to managing health, improving access, and advancing value-based care. The need for primary care providers and psychiatrists is difficult to meet despite generous recruiting incentives. To address this, the Abigail Geisinger Scholars Program (AGSP) represents a novel curricular approach linked with the provision of full tuition and fees and a living stipend to students who commit to work at Geisinger in primary care or psychiatry following residency. The support is provided as a forgivable loan. The program features preferential clinical placements, curricular enhancements, and celebration of the dedicated cohort. Fair and nonpunitive provisions allow students to opt-out. The AGSP supports 45 students in each class of 115. Outcomes monitored include withdrawals from the AGSP; academic performance of participants and their satisfaction with the program; the number who choose to repay the loan rather than fulfill the service obligation; the percentage who remain at Geisinger and in primary care following the period of obligation; and other measures. This model offers an attractive opportunity for students to experience a curriculum enhanced in primary care while receiving generous financing for their medical education. It bolsters the primary care physician workforce and aligns care delivery with new financing models.

RESUMEN

We evaluate the no-boundary path integral exactly in a Bianchi type IX minisuperspace with two scale factors. In this model the no-boundary proposal can be implemented by requiring one scale factor to be zero initially together with a judiciously chosen regularity condition on the momentum conjugate to the second scale factor. Taking into account the nonlinear backreaction of the perturbations we recover the predictions of the original semiclassical no-boundary proposal. In particular we find that large perturbations are strongly damped, consistent with vacuum state wave functions.

RESUMEN

BACKGROUND: As most children with acute lymphoblastic leukaemia (ALL) achieve long-term survival, minimising late effects of treatment is a priority. Acute lymphoblastic leukaemia survivors treated historically with protocols including cranial irradiation demonstrate increased weight gain. METHODS: We retrospectively studied all 134 patients treated on the MRC/UKALL97 protocol (without cranial irradiation as standard therapy) at a single centre, with 77 inclusions. Height-, weight- and body mass index (BMI) standard-deviation scores (SDS) were recorded at diagnosis and annually until 3 years out (YO) from end of treatment (EoT); changes across time were explored using a univariate model (significance P ≤ 0.001 to account for multiple comparisons). RESULTS: Whole-group height SDS was lower from 1 year into treatment until 2 YO, whereas weight- and BMI-SDS remained higher until 3 YO. In females, height-SDS was lower until EoT, but higher weight- and BMI-SDS persisted until 3 YO. In males, height-SDS was lower at EoT and at 2 YO; differences in BMI-SDS had resolved by 2 YO. By WHO criteria, more patients were overweight or obese at 3 YO than at diagnosis (P=0.01). CONCLUSION: Survivors of childhood ALL, particularly females, exhibit adverse changes in height-, weight- and BMI-SDS, which arise during treatment and persist into follow-up. Patients should be supported with appropriate dietary and lifestyle advice during ALL treatment and follow-up, which may minimise these changes and reduce associated long-term morbidity.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estatura , Índice de Masa Corporal , Peso Corporal , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Sobrevivientes , Adolescente , Niño , Preescolar , Irradiación Craneana , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Obesidad/etiología , Factores Sexuales

RESUMEN

Renal artery stenting is a widely performed procedure for atherosclerotic renal artery stenosis. It is very important to identify patients that will benefit from this procedure as this may involve potential risk and complications. Our study is a retrospective analysis aimed at evaluation of mid-pole renal cortical thickness at the time of stenting and correlating with renal function and blood pressure after the procedure. A total of 48 procedures were done on 31 patients evaluated in this study. The change in SBP was greater for the abnormal group compared to the normal group (-1.49 mmHg vs. -0.98 mmHg, P = 0.7813). The change in DBP was greater for the abnormal group compared to the normal group (-0.68 mmHg vs. 0.04 mmHg, P = 0.3809). The change in odds of having a GFR in higher categories was greater for the abnormal group compared to the normal group (OR =1.23 vs. 1.05, P = 0.3085). Our study did not show a significant association of renal cortical thickness and outcomes of BP and GFR following stenting of atherosclerotic renal artery stenosis. However, we did find a greater improvement in BP and GFR in patients with abnormal cortical thickness compared to those with normal cortical thickness.

Asunto(s)

Angioplastia/métodos , Presión Sanguínea/fisiología , Tasa de Filtración Glomerular/fisiología , Corteza Renal/patología , Obstrucción de la Arteria Renal/cirugía , Stents , Anciano , Biopsia , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Corteza Renal/diagnóstico por imagen , Masculino , Obstrucción de la Arteria Renal/diagnóstico , Obstrucción de la Arteria Renal/fisiopatología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ultrasonografía

RESUMEN

There is no uniform data regarding prophylactic cholecystectomy in patients undergoing renal transplantation with gallbladder disease. Data analyses suggest that posttransplant patients on cyclosporine have a higher incidence of gallbladder calcifications compared with nonimmunosuppressed patients. Laparoscopic cholecystectomy is a relatively safe procedure in modern-day surgery. Taking these facts into consideration, we attempted to compare risks and complications associated with gallbladder disease and eventual cholecystectomy in pretransplant versus posttransplant patients. Between June 1999 and December 2005, 210 renal transplants were performed at our institution. One hundred four patients who had transplants before April 2003 were not screened for gallbladder disease and nine of these patients developed gallbladder disease. These patients form our control group. One hundred six patients who had transplants after April 2003 had pretransplant screening for gallbladder disease and 11 patients were identified with gallbladder disease. These patients form our study group. Nine patients who developed gallbladder disease after renal transplant underwent laparoscopic cholecystectomy with three resulting morbidities (33%), two graft losses (22%), and one mortality (11%). There was one mortality (11%) in this group. One patient in the study group died of acute gallstone pancreatitis. Of the 11 patients who were found to have gallbladder disease on screening, nine patients underwent laparoscopic cholecystectomy with one morbidity and no mortality or graft loss. Given the relative rarity of the critical events in this study (morbidity, mortality, and graft loss), the definitive statistical value of prescreening for gallbladder disease cannot be established. However, our results are suggestive of clinical value and thus we tentatively recommend ultrasound screening for gallbladder disease for all pretransplant patients and laparoscopic cholecystectomy for those identified to have gallbladder disease.

Asunto(s)

Enfermedades de la Vesícula Biliar/diagnóstico por imagen , Enfermedades de la Vesícula Biliar/epidemiología , Trasplante de Riñón , Colecistectomía Laparoscópica , Estudios de Cohortes , Enfermedades de la Vesícula Biliar/cirugía , Humanos , Incidencia , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/cirugía , Trasplante de Riñón/efectos adversos , Evaluación de Resultado en la Atención de Salud , Estudios Retrospectivos , Medición de Riesgo , Ultrasonografía

RESUMEN

Transplantation of kidneys with pre-existing glomerulonephritis (GN) has rarely been reported. Little is known of the subsequent evolution of donor pathology in the recipient. We report a transplant using a donor with systemic lupus erythematosus (SLE) and a history of remote acute renal failure but normal renal function at death. Although the screening harvest biopsy was unremarkable, time zero post-implantation renal biopsy showed evidence of lupus nephritis (LN). Sequential protocol biopsies demonstrated gradual resolution of the donor pathology, and renal function was stable despite severe cardiac disease in the recipient. Studies examining the role of functional and biopsy data on outcomes in expanded criteria renal transplantation are reviewed, and the limits of guidance from use of this data are discussed. Pre-existing mild GN may not be an absolute donor exclusion for candidates willing to accept expanded criteria donors. Use of expanded pool kidneys should be guided by functional, biopsy and demographic information, as no single factor alone predicts outcome.

Asunto(s)

Fallo Renal Crónico/cirugía , Trasplante de Riñón , Lupus Eritematoso Sistémico , Nefritis Lúpica , Donantes de Tejidos , Obtención de Tejidos y Órganos/métodos , Lesión Renal Aguda , Estudios de Seguimiento , Humanos , Trasplante de Riñón/efectos adversos , Nefritis Lúpica/etiología , Masculino , Registros Médicos , Persona de Mediana Edad

Asunto(s)

Bacteriemia/prevención & control , Catéteres de Permanencia/microbiología , Infecciones por Bacterias Grampositivas/epidemiología , Infecciones por Bacterias Grampositivas/prevención & control , Mupirocina/uso terapéutico , Antibacterianos/uso terapéutico , Bacteriemia/epidemiología , Soluciones para Hemodiálisis/uso terapéutico , Humanos , Diálisis Renal/métodos , Diálisis Renal/tendencias

RESUMEN

Because coronary artery disease is the leading cause of death in patients with end-stage renal disease, we prospectively studied the prognostic value of dobutamine stress echocardiography (DSE) compared to coronary angiography (CA) as an evaluative tool. Thirty-three patients at high risk for coronary artery disease were selected from a cohort of 133 renal transplant candidates and underwent both DSE and CA. In this study, the value of DSE was found to exist in its strong negative predictive value (92%). A negative DSE coupled with a negative clinical cardiac evaluation was found to practicably exclude the necessity for CA. DSE can thus serve as a non-invasive, low cost screening test.

Asunto(s)

Agonistas Adrenérgicos beta , Angiografía Coronaria , Enfermedad Coronaria/epidemiología , Dobutamina , Ecocardiografía , Trasplante de Riñón , Complicaciones Posoperatorias , Ecocardiografía/efectos de los fármacos , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo

RESUMEN

We consider a number of proposals for the entropy of sets of classical coarse-grained histories based on the procedures of Jaynes, and we prove a series of inequalities relating these measures. We then examine these as a function of the coarse-graining for various classical systems, and show explicitly that the entropy is minimized by the finest-grained description of a set of histories. We propose an extension of the second law of thermodynamics to the entropy of histories. We briefly discuss the implications for decoherent or consistent history formulations of quantum mechanics.

RESUMEN

The presence of a cation-sensing mechanism in osteoblasts is suggested by the ability of specific cations to stimulate osteoblastic proliferation in culture and to induce de novo bone formation in some experimental models. Our study examines whether extracellular cations stimulate osteoblasts through the recently identified G protein-coupled calcium receptor (CaR). We found that CaR agonists, calcium (Ca2+), gadolinium (Gd3+), aluminum (Al3+), and neomycin, stimulated DNA synthesis in murine-derived MC3T3-E1 preosteoblasts, whereas magnesium (Mg2+), nickel (Ni2+), cadmium (Cd2+), and zinc (Zn2+) had no effect. With the exception of Mg2+, the cation specificities and apparent affinities were similar to that reported for CaR. CaR agonists also stimulated DNA synthesis in C3HT10(1/2) fibroblasts, but not in mesangial PVG, CHO, hepatic HTC, COS-7 cells, or malignant transformed ROS17/2.8 and UMR-106 osteoblasts. In addition, similar to other growth factors, CaR agonists activated transcription of a serum response element luciferase reporter construct (SRE-Luc) stably transfected into MC3T3-E1 osteoblasts, but had no effect on SRE-Luc transfected into CHO and COS-7 cells. We were unable to detect CaR expression by Northern analysis using a mouse CaR-specific probe or to amplify CaR mRNA by reverse transcribed polymerase chain reaction in MC3T3-E1 osteoblasts. These findings suggest that an extra-cellular cation-sensing mechanism is present in murine-derived osteoblasts that is functionally similar to but molecularly distinct from CaR.

Asunto(s)

Proteínas de Unión al Calcio/fisiología , Cationes/análisis , ADN/biosíntesis , Proteínas de Unión al GTP/fisiología , Osteoblastos/metabolismo , Receptores de Superficie Celular/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , División Celular/fisiología , Línea Celular , Clonación Molecular , Ratones , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Transcripción Genética

RESUMEN

Extracellular cations have paradoxical trophic and toxic effects on osteoblast function. In an effort to explain these divergent actions, we investigated in MC3T3-E1 osteoblasts if polyvalent cations differentially modulate the agonist-stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic function. We found that a panel of cations, including gadolinium, aluminum, calcium, and neomycin, inhibited prostaglandin E1 (PGE)-stimulated cAMP accumulation but paradoxically potentiated parathyroid hormone (PTH)-stimulated cAMP production. In contrast, these cations had no effect on forskolin- or cholera toxin-induced increases in cAMP, suggesting actions proximal to adenylate cyclase and possible modulation of receptor interactions with G proteins. Phorbol 12-myristate 13-acetated (PMA) mimicked the effects of cations on PGE1- and PTH-stimulated cAMP accumulation in MC3T3-E1 cells, respectively, diminishing and augmenting the responses. Moreover, down-regulation of protein kinase C (PKC) by overnight treatment with PMA prevented gadolinium (Gd3+) from attenuating PGE1- and enhancing PTH-stimulated cAMP production, indicating involvement of PKC-dependent pathways. Cations, however, activated signal transduction pathways not coupled to phosphatidylinositol-specific phospholipase C (PI-PLC), since there was no corresponding increase in inositol phosphate formation or intracellular calcium concentrations. In addition, pertussis toxin treatment failed to prevent Gd(3+)-mediated suppression of PGE1-stimulated cAMP, suggesting actions independent of Gm. Thus, polyvalent cations may either stimulate or inhibit hormone-mediated cAMP accumulation in osteoblasts. These differential actions provide a potential explanation for the paradoxical trophic and toxic effects of cations on osteoblast function that occur in vivo under different hormonal conditions.

Asunto(s)

Cationes/farmacología , AMP Cíclico/biosíntesis , Osteoblastos/metabolismo , Toxina de Adenilato Ciclasa , Alprostadil/antagonistas & inhibidores , Análisis de Varianza , Células Cultivadas , Toxina del Cólera/antagonistas & inhibidores , Toxina del Cólera/farmacología , Colforsina/antagonistas & inhibidores , Colforsina/farmacología , Gadolinio/farmacología , Norepinefrina/antagonistas & inhibidores , Hormona Paratiroidea/agonistas , Toxina del Pertussis , Fosfatidilinositol Diacilglicerol-Liasa , Fosfoinositido Fosfolipasa C , Hidrolasas Diéster Fosfóricas/análisis , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Proteína Quinasa C/fisiología , Factores de Virulencia de Bordetella/antagonistas & inhibidores , Factores de Virulencia de Bordetella/farmacología

RESUMEN

We recently demonstrated that stimulation of DNA synthesis in MC3T3-E1 osteoblasts involves cross-talk between protein kinase C (PKC)-dependent pathways and activation of possible nonreceptor tyrosine kinases. In the current investigation we examined whether the Raf-1/MAP kinase kinase (MKK)/mitogen-activated protein kinase (MAPK) cascade integrates cross-talk between G protein-coupled second messengers and protein tyrosine phosphorylation in osteoblasts. We investigated the effects on DNA synthesis, protein tyrosine phosphorylation, and Raf-1, MKK, and MAPK activities of PKC activation by phorbol 12-myristate 13-acetate (PMA) and of cAMP elevation by forskolin (FSK) in MC3T3-E1 osteoblasts. We found that PMA-stimulated DNA synthesis was associated with increments in tyrosine phosphorylation of p44mapk (ERK1) and p42mapk (ERK2) and activation of Raf-1, MKK, and MAPK in these cells. FSK treatment of osteoblasts, which raised intracellular cAMP levels and inhibited DNA synthesis, blocked PKC-stimulated tyrosine phosphorylation of p44mapk (ERK1) and p42mapk (ERK2) as well as inhibited PKC-stimulated MAPK and Raf-1 activities. Despite this, PMA activated the intermediate MKK step of the Raf-1/MKK/MAPK cascade in the presence of FSK. The differential inhibition of PMA-stimulated Raf-1 and MKK activities by FSK suggests that PKC activates both Raf-1-dependent and -independent pathways in MC3T3-E1 osteoblasts. Moreover, the noncoordinate effects of FSK on PMA-stimulated MKK and MAPK activities indicates the presence of a additional distal cAMP-dependent inhibitory mechanisms.

Asunto(s)

Colforsina/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas Activadas por Mitógenos , Mitógenos/farmacología , Osteoblastos/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Línea Celular , AMP Cíclico/metabolismo , ADN/biosíntesis , Activación Enzimática/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos , Proteína Quinasa 3 Activada por Mitógenos , Quinasas de Proteína Quinasa Activadas por Mitógenos , Osteoblastos/efectos de los fármacos , Fosforilación , Fosfotirosina/metabolismo , Proteína Quinasa C/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-raf , Transducción de Señal , Acetato de Tetradecanoilforbol/farmacología

RESUMEN

Aluminum (Al3+) stimulates de novo bone formation in dogs and is a potent stimulus for DNA synthesis in non-transformed osteoblasts in vitro. The recent identification of a G-protein coupled cation-sensing receptor (BoPCaR), which is activated by polyvalent agonists [e.g., gadolinium (Gd3+) > neomycin > calcium (Ca2+)], suggests that a similar physiologically important cation sensing receptor may be present in osteoblasts and pharmacologically activated by Al3+. To evaluate that possibility, we assessed whether known BoPCaR agonists stimulate DNA synthesis in MC3T3-E1 osteoblasts and examined the additive effects of Al3+ and BoPCaR agonists on DNA synthesis in MC3T3-E1 osteoblast-like cells. We found that Al3+, Gd3+, neomycin, and Ca2+ stimulated DNA synthesis in a dose-dependent fashion, achieving 50% effective extracellular concentrations (EC50) of 10 microM, 30 microM, 60 microM, and 2.5 mM, respectively. Al3+ displayed non-additive effects on DNA synthesis with the BoPCaR agonists as well as an unrelated G-protein coupled receptor agonist, PGF2 alpha, suggesting shared mechanisms of action. In contrast, the receptor tyrosine kinase agonist, IGF-I (10 eta g/ml), displayed additive proliferative effects when combined with AlCl3, indicating distinct signalling pathways. AlCl3 (25 microM) induced DAG levels 2-fold and the phosphorylation of the myristoylated alanine-rich C kinase (MARCKS) substrate 4-fold, but did not increase intracellular calcium concentrations. Down-regulation of PKC by pre-treatment with phorbol 12-myristate 13-acetate as well as PKC inhibition by H-7 and staurosporine blocked Al(3+)-induced DNA synthesis. Finally, Al3+, Gd3+, neomycin, and Ca2+ activated G-proteins in osteoblast membranes as evidenced by increased covalent binding of [32P]-GTP-azidoanilide to putative G alpha subunits. Our findings suggest that Al3+ stimulates DNA synthesis in osteoblasts through a cation sensing mechanism coupled to G-protein activation and signalling cascades involving DAG and PKC-dependent pathways.

Asunto(s)

Aluminio/farmacología , ADN/biosíntesis , Proteínas de Unión al GTP/fisiología , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Osteoblastos/metabolismo , Receptores de Superficie Celular/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Células 3T3 , Alcaloides/farmacología , Aluminio/farmacocinética , Animales , Transporte Biológico , Calcio/metabolismo , Calcio/farmacología , Células Clonales , Citosol/metabolismo , Diacilglicerol Quinasa , Perros , Gadolinio/farmacología , Sustancias de Crecimiento/farmacología , Isoquinolinas/farmacología , Cinética , Ratones , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada , Neomicina/farmacología , Osteoblastos/efectos de los fármacos , Radioisótopos de Fósforo , Fosforilación , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Piperazinas/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Proteínas/metabolismo , Receptores Sensibles al Calcio , Estaurosporina , Acetato de Tetradecanoilforbol/farmacología

RESUMEN

A 65-year-old woman with the acquired immunodeficiency syndrome (AIDS) complicated by recurrent mucocutaneous herpes simplex virus (HSV) infection developed angioedema on the initiation of her second course of oral acyclovir therapy. Oral rechallenge in hospital three days later confirmed acyclovir hypersensitivity. Vidarabine and foscarnet therapies were abandoned after treatment failure and unacceptable toxicity. Acyclovir desensitization was accomplished using a protocol derived from oral penicillin desensitization regimens. Mucocutaneous HSV infection responded to intravenous acyclovir followed by chronic oral suppression without recurrences of HSV or hypersensitivity. This report is an example of acyclovir hypersensitivity and successful oral desensitization.

Asunto(s)

Aciclovir/inmunología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Aciclovir/administración & dosificación , Aciclovir/efectos adversos , Administración Oral , Anciano , Desensibilización Inmunológica/métodos , Hipersensibilidad a las Drogas/etiología , Femenino , Herpes Simple/complicaciones , Herpes Simple/tratamiento farmacológico , Humanos , Enfermedades Cutáneas Infecciosas/complicaciones , Enfermedades Cutáneas Infecciosas/tratamiento farmacológico

RESUMEN

List items were given as retrieval cues in a free-recall experiment which factorially combined the presence or absence of cues with the amount of time allowed for use of each cue (10 sec or 30 sec). A categorizable list of 75 randomly presented words was learned, and 48 h later a free-recall test trial was given, followed by a final memory search task. During the final task, cued subjects received words from categories that had not been recalled during the free-recall test. With both time intervals, cued subjects recalled more words than noncued subjects, indicating that random presentation of categorized words does not necessarily preclude the observation of a cueing effect with list items, as has been reported previously. The composition of recall, whether from previously recalled or nonrecalled categories, varied as a function of time for both groups. The results were interpreteod in terms of retrieval strategies employed by cued and noncued subjects and the effect of time on these strategies.