RESUMEN

PURPOSE: Passive elevation of body temperature can induce an acute inflammatory response that has been proposed to be beneficial; however, it can be perceived as uncomfortable. Here, we investigate whether local cooling of the upper body during hot water immersion can improve perception without inhibiting the interleukin-6 (IL-6) response. METHODS: Nine healthy male participants (age: 22 ± 1 years, body mass: 83.4 ± 9.4 kg) were immersed up to the waist for three 60-min water immersion conditions: 42 °C hot water immersion (HWI), 42 °C HWI with simultaneous upper-body cooling using a fan (FAN), and 36 °C thermoneutral water immersion (CON). Blood samples to determine IL-6 plasma concentration were collected pre- and post-water immersion; basic affect and thermal comfort were assessed throughout the intervention. RESULTS: Plasma IL-6 concentration was higher for HWI and FAN when compared with CON (P < 0.01) and did not differ between HWI and FAN (P = 0.22; pre to post, HWI: 1.0 ± 0.6 to 1.5 ± 0.7 pg·ml-1, FAN: 0.7 ± 0.5 to 1.1 ± 0.5 pg·ml-1, CON: 0.5 ± 0.2 to 0.5 ± 0.2 pg·ml-1). At the end of immersion, basic affect was lowest for HWI (HWI: - 1.8 ± 2.0, FAN: 0.2 ± 1.6, CON 1.0 ± 2.1, P < 0.02); thermal comfort for HWI was in the uncomfortable range (3.0 ± 1.0, P < 0.01 when compared with FAN and CON), whereas FAN (0.7 ± 0.7) and CON (-0.2 ± 0.7) were in the comfortable range. CONCLUSION: Local cooling of the upper body during hot water immersion improves basic affect and thermal comfort without inhibiting the acute IL-6 response.

Asunto(s)

Frío , Calor , Inmersión , Interleucina-6/sangre , Regulación de la Temperatura Corporal/fisiología , Humanos , Masculino , Agua , Adulto Joven

RESUMEN

Assisted living is a popular alternative to residential care, promoting independence and enabling self-care through a supportive living environment. Practitioner understanding of quality of life (QoL) experiences are vital to facilitate good physical and mental health in assisted living. An idiographic case study approach explored resident experiences by combining photo-elicitation and interpretive phenomenological analysis. QoL was understood through three themes: facilitation of identity coherence and transition, the essential nature of socialising, and perceptions of a supportive environment. Assisted living has the potential to act as a bearer for cues of identity continuity with nostalgic devices facilitating environment transition and limiting biographical disruption. Furthermore, opportunities for social contact offer a protective function for residents adapting to negative life challenges such as bereavement. To foster health and QoL in withdrawn residents' facilities should develop peer support programmes with benefits for both mentor and mentee.

Asunto(s)

Hogares para Ancianos , Calidad de Vida , Anciano , Humanos , Investigación Cualitativa

RESUMEN

BACKGROUND: Childhood cancer is neglected within global health. Oxford Pediatrics Linking Oncology Research with Electives describes early outcomes following collaboration between low- and high-income paediatric surgery and oncology centres. The aim of this paper is twofold: to describe the development of a medical student-led research collaboration; and to report on the experience of Wilms' tumour (WT). METHODS: This cross-sectional observational study is reported as per STROBE guidelines. Collaborating centres included three tertiary hospitals in Tanzania, Rwanda and the UK. Data were submitted by medical students following retrospective patient note review of 2 years using a standardised data collection tool. Primary outcome was survival (point of discharge/death). RESULTS: There were 104 patients with WT reported across all centres over the study period (Tanzania n = 71, Rwanda n = 26, UK n = 7). Survival was higher in the high-income institution [87% in Tanzania, 92% in Rwanda, 100% in the UK (X2 36.19, p < 0.0001)]. Given the short-term follow-up and retrospective study design, this likely underestimates the true discrepancy. Age at presentation was comparable at the two African sites but lower in the UK (one-way ANOVA, F = 0.2997, p = 0.74). Disease was more advanced in Tanzania at presentation (84% stage III-IV cf. 60% and 57% in Rwanda and UK, respectively, X2 7.57, p = 0.02). All patients had pre-operative chemotherapy, and a majority had nephrectomy. Post-operative morbidity was higher in lower resourced settings (X2 33.72, p < 0.0001). Methodology involving medical students and junior doctors proved time- and cost-effective. This collaboration was a valuable learning experience for students about global research networks. CONCLUSIONS: This study demonstrates novel research methodology involving medical students collaborating across the global south and global north. The comparison of outcomes advocates, on an institutional level, for development in access to services and multidisciplinary treatment of WT.

Asunto(s)

Neoplasias Renales/terapia , Tumor de Wilms/terapia , Investigación Biomédica , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Colaboración Intersectorial , Masculino , Estudios Retrospectivos , Estudiantes de Medicina

RESUMEN

Haemorrhage remains a leading cause of maternal death. We conducted an audit to identify strategies to improve the management at our local NHS Trust. A data collection form was based on our local guideline. A coded database search was conducted for all deliveries where the estimated blood loss was ≥2000 ml (from June 1 2015 to December 31 2015), returning 68 search results (13.7/1000 births). Fifty-six records were included. Poor compliance (<75%) was seen in some key areas including the major obstetric haemorrhage (MOH) call activation (52%), the presence of an anaesthetic consultant (63%) and tranexamic acid administration (46%). Thirty out of 56 cases (54%) were acutely transfused. Women, who were not transfused acutely, appeared to be more likely to need a secondary transfusion if no MOH call had been activated (9/27 (33%) versus 3/29 (10%), p = .052). A key area for improvement was the activation of MOH calls. Following this audit, we adjusted our guideline to make it more clinically useful and staff training sessions were held, including simulation training. Impact statement What is already known on this subject? A postpartum haemorrhage (PPH) is an obstetric emergency. A structured approach is important to optimise the care of the mothers during this dangerous time, and has been shown to reduce the transfusion requirements. However, clinical practice may not adhere to the guideline recommendations. What the results of this study add? With the objective evidence of increased rates of PPH ≥2000 ml at our institution, our work identifying the flaws in management was a critical component of the work to improve the outcomes. This study gives impetus to find innovative ways to improve adherence to guidelines, and inspired an update of our local guideline to improve the applicability and utility. This project suggests a new marker for the adequacy of an acute management (a requirement for secondary blood transfusion without having received an acute transfusion), and raises questions about what constitutes optimum PPH management. What the implications are of these findings for clinical practice and/or further research? The primary and secondary transfusion data raised new questions to investigate in the future: does the involvement of consultants and the escalation of care via the instigation of major haemorrhage protocols improve decision-making and patient outcomes? Does the necessity for a secondary transfusion indicate a suboptimal acute care?

Asunto(s)

Parto Obstétrico/efectos adversos , Hemorragia Posparto/epidemiología , Adulto , Auditoría Clínica , Femenino , Adhesión a Directriz/estadística & datos numéricos , Humanos , Hemorragia Posparto/etiología , Hemorragia Posparto/prevención & control , Embarazo

RESUMEN

BACKGROUND AND PURPOSE: Concentrations of extracellular glycine in the CNS are regulated by two Na(+)/Cl(-) -dependent glycine transporters, GlyT1 and GlyT2. Selective inhibitors of GlyT1 have been developed for the treatment of schizophrenia, whilst selective inhibitors of GlyT2 are analgesic in animal models of pain. We have assessed a series of endogenous lipids as inhibitors of GlyT1 and GlyT2. EXPERIMENTAL APPROACH: Human GlyT1 and GlyT2 were expressed in Xenopus laevis oocytes, and the inhibitory actions of a series of acylcarnitines on glycine transport were measured using electrophysiological techniques. KEY RESULTS: Oleoyl-L-carnitine inhibited glycine transport by GlyT2, with an IC(50) of 340 nM, which is 15-fold more potent than the previously identified lipid inhibitor N-arachidonyl-glycine. Oleoyl-L-carnitine had a slow onset of inhibition and a slow washout. Using a series of chimeric GlyT1/2 transporters and point mutant transporters, we have identified an isoleucine residue in extracellular loop 4 of GlyT2 that conferred differences in sensitivity to oleoyl-L-carnitine between GlyT2 and GlyT1. CONCLUSIONS AND IMPLICATIONS: Oleoyl-L-carnitine is a potent non-competitive inhibitor of GlyT2. Previously identified GlyT2 inhibitors show potential as analgesics and the identification of oleoyl-L-carnitine as a novel GlyT2 inhibitor may lead to new ways of treating pain.

Asunto(s)

Carnitina/análogos & derivados , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Glicina/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Carnitina/química , Carnitina/farmacología , Relación Dosis-Respuesta a Droga , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Estructura Molecular , Oocitos/metabolismo , Técnicas de Placa-Clamp , Xenopus laevis

RESUMEN

A 57-year-old man presented at our institution with central chest pain. Serial ECGs showed dynamic T-wave changes, suggesting the possibility of unstable angina. Urgent coronary angiography revealed an unexpected finding of a radio-opaque lesion seen in the xiphisternal region during screening. Oesophogastroduodenoscopy confirmed this to be a 10p coin. The coin passed through the gastrointestinal tract without complications and the patient's symptoms and ECG changes resolved. This unusual case is a reminder that many diseases may electrocardiographically imitate an acute coronary syndrome.

Asunto(s)

Angina Inestable/diagnóstico , Dolor en el Pecho/diagnóstico por imagen , Dolor en el Pecho/etiología , Angiografía Coronaria , Electrocardiografía , Endoscopía del Sistema Digestivo , Esófago , Cuerpos Extraños/diagnóstico , Esternón , Apófisis Xifoides , Síndrome Coronario Agudo/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

LIM (Lin-11, Isl-1, Mec-3), RING (Really interesting new gene), PHD (Plant homology domain) and MYND (myeloid, Nervy, DEAF-1) domains are all zinc-binding domains that ligate two zinc ions. Unlike the better known classical zinc fingers, these domains do not bind DNA, but instead mediate interactions with other proteins. LIM-domain containing proteins have diverse functions as regulators of gene expression, cell adhesion and motility and signal transduction. RING finger proteins are generally associated with ubiquitination; the presence of such a domain is the defining feature of a class of E3 ubiquitin protein ligases. PHD proteins have been associated with SUMOylation but most recently have emerged as a chromatin recognition motif that reads the methylation state of histones. The function of the MYND domain is less clear, but MYND domains are also found in proteins that have ubiquitin ligase and/or histone methyltransferase activity. Here we review the structure-function relationships for these domains and discuss strategies to modulate their activity.

Asunto(s)

Proteínas de Unión al ADN/fisiología , Proteínas de Homeodominio/fisiología , Dedos de Zinc/fisiología , Animales , Sitios de Unión , Proteínas de Unión al ADN/química , Proteínas de Homeodominio/química , Humanos , Conformación Proteica , Pliegue de Proteína , Dominios RING Finger/fisiología , Homología de Secuencia de Aminoácido

RESUMEN

The mammary gland undergoes extensive epithelial expansion and differentiation during pregnancy, leading ultimately to the development of functional milk-producing alveolar lobules. This phase of mammary gland remodeling is controlled primarily by the cooperative interplay between hormonal signals initiated by both progesterone and prolactin. Abrogation of mammary epithelial expression of receptors for either one of the hormones results in failure of alveologenesis and an absence of pregnancy-induced tertiary ductal side branches in the case of progesterone receptor-null (PRKO) mammary glands. By combining gene array approaches to identify PR- and prolactin (PRL)-dependent downstream signaling pathways and by using genetic mouse models to address the consequences of abrogation and/or misexpression of potential downstream genes, recent studies have begun to illuminate key signaling pathways that mediate the morphogenic effects of these hormones during pregnancy-induced mammary gland remodeling. Analysis of deregulated expression of PR-dependent gene transcripts in PRKO mammary glands has revealed that convergence between progesterone and prolactin signaling occurs in part through progesterone-dependent induction of mammary epithelial PRL receptors to prime the mammary epithelium to respond to PRL. Additional genes activated by PRs encode epithelial paracrine growth factor signals that regulate ductal and alveolar epithelial proliferation and survival, lineage-restricted transcription factors that control luminal and alveolar cell fate establishment and maintenance, and gap junction proteins that play a critical role in alveolar morphogenesis by establishment of epithelial cell polarity. Finally, two distinct isoforms of PRs (PR-A and PR-B) are coexpressed in the mammary gland and display extensively overlapping but partially distinct gene regulatory properties in relaying the progesterone signal.

Asunto(s)

Glándulas Mamarias Humanas/crecimiento & desarrollo , Progesterona/metabolismo , Transducción de Señal , Animales , Humanos , Glándulas Mamarias Humanas/metabolismo , Morfogénesis

RESUMEN

PURPOSE: Docetaxel is highly active in the treatment of patients with breast cancer. The principal dose-limiting toxicities of the 3-weekly regimen are neutropenia and febrile neutropenia. In a previous phase I dose-escalation study with granulocyte colony-stimulating factor (G-CSF) support, the recommended dose was determined to be docetaxel 160 mg/m(2) 3-weekly. The objectives of this phase II study were to determine the response rate and toxicity of this dose and schedule, given as first-line in patients with advanced breast cancer. Mobilisation of peripheral blood stem cells (PBSCs) was also investigated. PATIENTS AND METHODS: Eligible women had metastatic breast cancer and were aged 18-75 years with ECOG performance status < or =2. Strict criteria for liver function were followed, and adjuvant chemotherapy must have been completed at least 6 months previously. Treatment was docetaxel 160 mg/m(2) over 60-90 min every 21 days with G-CSF 5 micro g/kg/day until neutrophil recovery, for up to six cycles. A 3-day corticosteroid prophylaxis was given. Bloods samples to determine PBSC levels [CD34+, granulocyte-macrophage colony-forming cells (GM-CFC) and burst-forming units-erythroid (BFU-E)] were taken on days 6, 8, 9 and 11 following docetaxel. RESULTS: Twenty-five women with median age 50 years (range 35-66) were included. Seventeen (68%) had previously received adjuvant chemotherapy. In total, 112 cycles were delivered (median four per patient), with dose reductions required in 12.5% of cycles. G-CSF was given for a median of 6 days. The median neutrophil nadir was 0.5 x 10(9)/l and occurred a median 5 days after treatment. The median duration of grade 3 or 4 neutropenia was 2 days (range 1-7). Grade 4 neutropenia occurred in 44% of patients, but there was only one episode of febrile neutropenia. Five patients were taken off study due to toxicities that included oedema, neurosensory toxicity and asthenia. Confirmed partial response was seen in nine patients (37.5%; 95% confidence interval 19% to 59%). CD34+ cells, GM-CFC and BFU-E levels peaked at day 8 following docetaxel administration. The median CD34+ cell peak was 6.5 x 10(4)/ml, with only 20% of patients <2 x 10(4)/ml, a level below which leukapheresis is not usually attempted. CONCLUSIONS: Docetaxel 160 mg/m(2) was delivered with G-CSF support with a very low rate of febrile neutropenia. Non-haematological toxicity was significant, causing five patients to go off study. Effective mobilisation of PBSCs was seen. The response rate of 37.5% was less than that obtained in first-line studies using standard-dose docetaxel 100 mg/m(2), suggesting that there is no additional benefit in dose escalation of this cytotoxic agent in breast cancer patients using this schedule.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Taxoides/uso terapéutico , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Ensayo de Unidades Formadoras de Colonias , Docetaxel , Quimioterapia Combinada , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Persona de Mediana Edad , Neutropenia/inducido químicamente , Taxoides/efectos adversos , Resultado del Tratamiento

RESUMEN

Azoxystrobin was evaluated in replicated small-plot trials from 1995 to 1999 for control of citrus black spot (CBS) on 'Valencia' oranges caused by Guignardia citricarpa. Applications of different rates of tank mixes of azoxystrobin and mancozeb during the susceptible period from October to January were compared with an untreated control as well as the standard four applications of mancozeb with or without mineral oil (1.20 g a.i./liter + 0.5% [vol/vol]/liter and 1.60 g a.i./liter of water, respectively). Two applications of azoxystrobin in tank mixtures with mancozeb and mineral oil (0.5% [vol/vol]/liter) in mid-November and mid-January at rates of 0.10, 0.15, and 0.20 g a.i./liter controlled CBS by more than 98 to 99%, 99 to 100% and 95 to 98%, respectively. Concomitantly, where mineral oil was not added to the fungicide mixture, azoxystrobin and mancozeb resulted only in 73 to 95%, 74 to 93% and 92.2 to 92.3% CBS control, respectively. Tank mixtures of benomyl, mancozeb, and mineral oil reduced CBS by only 29%, which could be attributed to the presence of benomyl-resistant pathogen isolates in the experimental orchard. Azoxystrobin applied at rates of 0.05, 0.075, and 0.10 g a.i./liter in tank mixtures with mancozeb (1.2 g a.i./liter) and mineral oil (0.5% [vol/vol]/liter of water) or Agral 90 (0.5% [vol/vol]/liter of water) were equally effective, reducing CBS by more than 99%. When mineral oil was compared to different adjuvants in tank mixtures with azoxystrobin and mancozeb, only mineral oil resulted in 100% clean exportable fruit. There was no difference between Sunspray 6E and Bac oil when mixed with azoxystrobin and mancozeb on the degree of disease control. Furthermore, the concentration of mineral oil in water can be lowered from 0.5% (vol/vol)/liter of water to 0.3% (vol/vol)/liter of water without a loss in efficacy against CBS. It is therefore, recommended that azoxystrobin (0.075 g a.i./liter) must be applied in tank mixtures with mancozeb (1.2 g a.i./liter) and mineral oil, which can be applied at either 0.5% (vol/vol)/liter of water or 0.3% (vol/vol)/liter of water.

Asunto(s)

Arteriopatías Oclusivas/terapia , Arteriosclerosis/terapia , Arteria Femoral , Fotoquimioterapia/métodos , Anciano , Anciano de 80 o más Años , Arteriopatías Oclusivas/tratamiento farmacológico , Arteriosclerosis/tratamiento farmacológico , Cateterismo/métodos , Terapia Combinada , Humanos , Pierna/irrigación sanguínea , Cuidados a Largo Plazo , Persona de Mediana Edad , Proyectos Piloto , Prevención Secundaria

Asunto(s)

Reestenosis Coronaria/prevención & control , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Enfermedad de la Arteria Coronaria/patología , Reestenosis Coronaria/etiología , Reestenosis Coronaria/patología , Humanos , Fármacos Fotosensibilizantes/farmacocinética , Proyectos Piloto , Ratas , Stents , Porcinos , Túnica Íntima

RESUMEN

The nuclear receptor for the female hormone progesterone (PR) is widely expressed in uterine cancer. PR is expressed as two proteins (PRA and PRB) with different functions, and in vitro evidence reveals PRA to inhibit PRB function, so the cellular ratio of PRA:PRB is likely to be an important determinant of progesterone action. The relative expression of PRA and B and their involvement in the pathogenesis of endometrial cancer is not known. The aims of this study were to determine PRA and B expression by dual immunofluorescent histochemistry in endometrial adenocarcinomas compared with expression in normal and hyperplastic glands, and to correlate expression in tumors with clinical features including grade. Significantly lower PR levels were found in tumors compared with normal glands and areas of complex atypical hyperplasia within the same specimen. The normal glands expressed both of the isoforms at similar levels, whereas there was increased predominance of one isoform in hyperplastic areas and in tumors, which suggested that the loss of coordinated expression of PR isoforms was an early event in tumor progression. The majority of tumors [27 (58%) of 46] expressed only one PR isoform, and the proportion expressing either PRA or B was the same [14 (30%) of 46, and 13 (28%) of 46, respectively]. One-half of all tumors ([23 (50%) of 46] expressed either PRA only or a predominance of PRA, and a few tumors [10 (22%) of 46] expressed comparable levels of PRA and B. Similar levels of PRA and B were noted only in FIGO grade 1 tumors, whereas higher grades (2 and 3) were associated with a predominance of one isoform. In summary, expression of only one PR isoform was common in endometrial cancers, which indicates that the decreased PR levels observed in these cancers arise from the loss of one PR isoform. Expression of a single PR isoform was associated with higher clinical grade, which suggests a relationship between the loss of PR isoform expression and features of poorer prognosis. Disruption of relative PR isoform expression was observed in complex atypical hyperplasia, which suggests that early alterations in the ratio of PRA:PRB may precede and/or be implicated in the development of endometrial adenocarcinoma. Alterations in the ratio of PR isoform expression are likely to cause disordered regulation of target genes, resulting in altered progestin action in the uterus, and this may be involved in the pathogenesis of endometrial cancer.

Asunto(s)

Carcinoma Endometrioide/metabolismo , Neoplasias Endometriales/metabolismo , Receptores de Progesterona/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/patología , Estudios de Cohortes , Hiperplasia Endometrial/metabolismo , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Isoformas de Proteínas

Asunto(s)

Antialérgicos/efectos adversos , Antimaláricos/efectos adversos , Astemizol/efectos adversos , Cloroquina/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Adulto , Electrocardiografía , Humanos , Síndrome de QT Prolongado/diagnóstico , Masculino , Pronóstico , Torsades de Pointes/etiología

RESUMEN

OBJECTIVE: mpl(-/-) mice have a profound defect in platelets and megakaryocytes and a defect in hematopoietic progenitor cells and stem cells. However, no specific subset of the progenitor/stem cell compartment has been shown to be particularly affected by this deficiency in mpl(-/-) mice. In this article, we identified a specific subset of bone marrow progenitor/stem cells that was altered in mpl(-/-) mice. MATERIALS AND METHODS: In vitro and in vivo hematopoietic assays were utilized to examine the response to interleukin-11 in mice lacking the receptor for thrombopoietin (TPO) (mpl(-/-) mice). RESULTS: The interleukin (IL)-11-responsive subset of progenitor cells was not detected in clonal cultures of bone marrow cells from mpl(-/-) mice. However, mpl(-/-) mice responded to IL-11 in vivo as evidenced by a rise in platelet count and an increase in spleen weight. Experiments were performed to address this paradox: administration of 5-fluorouracil with consequent "expansion" of early hematopoietic cells resulted in the appearance of IL-11-responsive cells in mpl(-/-) mice when assayed in in vitro cultures. CONCLUSIONS: Thus, although mpl(-/-) mice have the capacity to produce IL-11-responsive progenitor cells, under steady state conditions their expansion is dependent on TPO. This is the first evidence that a specific subset of bone marrow progenitor/stem cells is altered in mpl(-/-) mice.

Asunto(s)

Células Madre Hematopoyéticas/efectos de los fármacos , Interleucina-11/farmacología , Proteínas de Neoplasias , Receptores de Citocinas , Transducción de Señal , Trombopoyetina/fisiología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Sinergismo Farmacológico , Fluorouracilo/farmacología , Células Madre Hematopoyéticas/citología , Humanos , Interleucina-3/farmacología , Interleucina-6/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Recuento de Plaquetas , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/fisiología , Receptores de Trombopoyetina , Bazo/citología , Factor de Células Madre/farmacología , Trombopoyetina/deficiencia , Trombopoyetina/genética

RESUMEN

OBJECTIVE: To examine the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in thrombopoiesis. MATERIALS AND METHODS: Thrombopoietin-unresponsi ve mice (mpl null mice), which have a profound reduction in platelets and mature megakaryocytes, were interbred with mice that do not respond to GM-CSF or interleukin 5 (betac null mice), and hematopoiesis was examined. In initial experiments on a mixed genetic background, double mutant mice (betac/mpl null mice) showed an unexpected amelioration of the thrombocytopenia seen in mpl null mice. Platelet counts were elevated approximately twofold in betac/mpl null mice compared with mpl null mice (mpl null 73+/-31; betac/mpl null 164+/-70; n = 10 to 29 mice per genotype, p<0.00001). This was associated with lessening of the deficit of megakaryocytes, progenitor cells, and colony-forming units spleen seen in mpl null mice. This amelioration of the mpl null phenotype in betac/mpl null mice on a mixed genetic background was highly statistically significant. To determine whether this amelioration of phenotype was solely the consequence of loss of betac signaling, progeny of a second intercross on a C57BL/6 background (B6betac/mpl null mice) were examined. When the resulting B6betac/mpl null mice were analyzed and compared with B6mpl null littermates, the increase in platelet count, hematopoietic progenitor cell number, and colony-forming units spleen number was no longer observed. CONCLUSION: There was no additional effect seen as a result of loss of betac signaling. GM-CSF did not play a significant role in thrombopoiesis, even in combination with the absence of thrombopoietin signaling. These results highlight problems that can be encountered when studying introduced mutations in mice. They exemplify the importance of eliminating the influence of modifying genes when attributing biologic differences to specific introduced genetic alterations.

Asunto(s)

Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Hematopoyesis/efectos de los fármacos , Proteínas de Neoplasias , Proteínas Proto-Oncogénicas/genética , Receptores de Citocinas , Animales , Células de la Médula Ósea/patología , Pruebas Hematológicas , Megacariocitos/fisiología , Ratones , Ratones Noqueados , Ratones Mutantes , Fenotipo , Recuento de Plaquetas , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Trombopoyetina , Bazo/patología , Células Madre/efectos de los fármacos

Asunto(s)

Rotura Cardíaca Posinfarto/cirugía , Ecocardiografía Transesofágica , Rotura Cardíaca Posinfarto/diagnóstico por imagen , Humanos , Persona de Mediana Edad

RESUMEN

Mice lacking both the gene encoding the shared receptor for granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 common beta-chain (B(c)) and the gene for the IL-3 specific receptor (BIL3) were generated. This was achieved by targeting the B(c) locus in embryonic stem cells that were heterozygous for a null mutation of BIL3. Cells from mice generated with the doubly targeted embryonic stem cells were unresponsive to all 3 cytokines. Considerable previous data suggested a role for common beta-chain (beta(c)) in modulating signaling of cytokines including erythropoietin (EPO), G-CSF, and stem cell factor (SCF). However, bone marrow cells from mice lacking beta(c) and beta(IL3) showed normal responsiveness to these cytokines. Thus, there was no evidence for a biologically significant interaction between signaling via beta(c) or beta(IL3) and signaling by EPO, G-CSF, or SCF. Previously documented biochemical phenomena, including receptor transmodulation, receptor transphosphorylation, and even direct physical interaction, involving the beta(c)/beta IL-3 receptor systems do not reflect genuine interactions of physiological significance in primary hematopoietic cells. This study provided results that challenge conclusions previously established using a variety of biochemical assays. (Blood. 2000;96:1588-1590)

Asunto(s)

Proteínas Proto-Oncogénicas c-kit/genética , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Receptores de Interleucina-3/genética , Transducción de Señal/genética , Animales , Factor Estimulante de Colonias de Granulocitos/metabolismo , Hematopoyesis/genética , Interleucina-3/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor Cross-Talk , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Receptores de Interleucina-3/metabolismo , Eliminación de Secuencia , Factor de Células Madre/metabolismo

RESUMEN

OBJECTIVE: Photodynamic therapy (PDT) uses red light (non-thermal, non-ionising) to activate a previously administered photosensitizing drug. This inhibits neointimal hyperplasia in injured arteries in small animals where it appears safe and well tolerated. Our aim was to develop a method for percutaneous application of PDT to iliac and coronary arteries in a large animal model and investigate its influence on the remodeling and intimal hyperplastic response to balloon injury. METHODS: Studies were undertaken on 13 juvenile Large White-Landrace crossbred pigs (15-20 kg). After intravenous administration of the photosensitizing agent 5-amino laevulinic acid (ALA), the arterial tree was accessed via the left common carotid artery and balloon injuries made by over-distension in both common iliacs (thirteen animals) and one or two main coronary arteries (eight animals). Half the injured sites were then illuminated with red laser light transmitted via the catheter. Animals were culled 28 days later and tissue harvested for histomorphometry. RESULTS: Compared with control injured vessels, PDT treated, balloon injured coronary arteries had a larger lumen (1.4 vs. 0.8 mm2, P = 0.002), larger area within the external elastic lamina (2.8 vs. 2.2 mm2, P = 0.006) and smaller area of neointimal hyperplasia (0.4 vs. 0.7 mm2, P = 0.06), 28 days after intervention. Less neointimal hyperplasia and the absence of negative remodeling resulted in the lumen of PDT-treated, injured segments being the same as that of adjacent reference segments (1.5 vs. 1.6 mm2). Similar trends, but with smaller differences, were seen in the iliac vessels. CONCLUSIONS: Intra-arterial, trans-catheter PDT favourably influences the arterial response to balloon injury in both the coronary and peripheral circulations. This technique offers a promising new approach to restenosis after endovascular procedures.

Asunto(s)

Ácido Aminolevulínico/uso terapéutico , Angioplastia Coronaria con Balón/efectos adversos , Vasos Coronarios/lesiones , Arteria Ilíaca/lesiones , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Enfermedad Coronaria/prevención & control , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/patología , Arteria Ilíaca/efectos de los fármacos , Arteria Ilíaca/patología , Porcinos

RESUMEN

PURPOSE: To assess the mobilization potential and safety of recombinant human stem-cell factor (SCF) when coadministered with filgrastim to untreated women with poor-prognosis breast cancer. PATIENTS AND METHODS: Eligible women had breast cancer with 10 or more positive axillary nodes, or estrogen receptor-negative tumor with 4 positive nodes, or stage III disease. Patients were randomized to receive SCF plus filgrastim or filgrastim alone. Filgrastim 12 microg/kg daily was administered for 6 days by continuous subcutaneous infusion. SCF was administered by daily subcutaneous injection at 5, 10, or 15 microg/kg concurrent with filgrastim for 7 days, or 10 microg/kg daily starting 3 days before filgrastim for a total of 10 days (SCF pretreatment). Apheresis was performed on days 5, 6, and 7 of filgrastim administration. Patients then had three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2 every 28 days, each supported by one third of the apheresis product. RESULTS: Sixty-two women were treated. Greater yields occurred in patients who received SCF 10 microg/kg daily plus filgastim than those who received filgrastim alone (P=.013 for CD34+ cells; P=.07 for granulocyte-macrophage colony-forming cells [GM-CFCs]). The difference was more marked with SCF-pretreatment than concurrent SCF. Fewer aphereses were required to reach the predetermined target of peripheral-blood progenitor/stem cells (PBPCs) in women who received SCF. SCF was generally well tolerated. Hematologic recovery was rapid after each of the three cycles of chemotherapy. There was no difference in recovery between the different treatment groups. CONCLUSION: Mobilization of PBPCs by filgrastim is significantly enhanced by coadministration of SCF, and commencing SCF before filgrastim can optimize this effect. SCF has the potential to reduce the number of aphereses required to collect a target number of PBPCs.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Hematopoyesis , Movilización de Célula Madre Hematopoyética , Factor de Células Madre/administración & dosificación , Adulto , Antígenos CD34/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recuento de Células Sanguíneas , Eliminación de Componentes Sanguíneos , Neoplasias de la Mama/sangre , Ensayo de Unidades Formadoras de Colonias , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Células Precursoras Eritroides , Femenino , Filgrastim , Hematopoyesis/efectos de los fármacos , Movilización de Célula Madre Hematopoyética/métodos , Hemoglobinas/análisis , Humanos , Subgrupos Linfocitarios , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Factor de Células Madre/efectos adversos