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1.
J R Army Med Corps ; 164(6): 410-413, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29764915

RESUMEN

Wearable technologies are making considerable advances into the mainstream as they become smaller and more user friendly. The global market for such devices is forecasted to be worth over US$5 billion in 2018, with one in six people owning a device. Many professional sporting teams use self-monitoring to assess physiological parameters and work rate on the pitch, highlighting the potential utility for military command chains. As size of device reduces and sensitivity improves, coupled with remote connectivity technology, integration into the military environment could be relatively seamless. Remote monitoring of personnel on the ground, giving live updates on their physiological status, would allow commanders or medical officers the ability to manage their soldiers appropriately and improve combat effectiveness. This paper explores a proof of concept for the use of a self-monitoring system in the austere high altitude environment of the Nepalese Himalayas, akin to those experienced by modern militaries fighting in remote locations. It also reviews, in part, the historical development of remote monitoring technologies. The system allowed for physiological recordings, plotted against GPS position, to be remotely monitored in Italy. Examples of the data recorded are given and the performance of the system is discussed, including limitations, potential areas of development and how systems like this one could be integrated into the military environment.


Asunto(s)
Altitud , Dispositivos Electrónicos Vestibles , Humanos , Ciencia Militar
2.
J R Army Med Corps ; 164(1): 41-45, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29279321

RESUMEN

INTRODUCTION: The British Service Dhaulagiri Research Expedition (BSDMRE) took place from 27 March to 31 May 2016. The expedition involved 129 personnel, with voluntary participation in nine different study protocols. Studies were conducted in three research camps established at 3600, 4600 and 5140 m and involved taking and storing blood samples, cardiac echocardiography and investigations involving a balance plate. Research in this remote environment requires careful planning in order to provide a robust and resilient power plan. In this paper we aim to report the rationale for the choices we made in terms of power supply, the equipment used and potential military applicability. METHODS: This is a descriptive account from the expedition members involved in planning and conducting the medical research. RESULTS: Power calculations were used to determine estimates of requirement prior to the expedition. The primary sources used to generate power were internal combustion engine (via petrol fuelled electric generators) and solar panels. Having been generated, power was stored using lithium-ion batteries. Special consideration was given to the storage of samples taken in the field, for which electric freezers and dry shippers were used. All equipment used functioned well during the expedition, with the challenges of altitude, temperature and transport all overcome due to extensive prior planning. CONCLUSIONS: Power was successfully generated, stored and delivered during the BSDMRE, allowing extensive medical research to be undertaken. The challenges faced and overcome are directly applicable to delivering military medical care in austere environments, and lessons learnt can help with the planning and delivery of future operations, training exercises or expeditions.


Asunto(s)
Investigación Biomédica , Suministros de Energía Eléctrica , Expediciones , Fuentes Generadoras de Energía , Humanos , Medicina Militar , Energía Solar , Reino Unido
3.
Horm Metab Res ; 48(10): 658-663, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27643447

RESUMEN

Gradual ascent to high altitude is typically associated with reduced resting aldosterone and unchanged cortisol, features that may facilitate acclimatization but are poorly understood. The aim of the study was to investigate the cortisol and aldosterone response to adrenocorticotrophic hormone at altitude. Eleven subjects underwent a 250 µg short synacthen test at sea-level and again after trekking to 3 600 m in Nepal. Cortisol and aldosterone were measured by conventional assay from blood samples taken immediately prior to the administration of synacthen (T0) and then 30 (T30) and 60 (T60) min later. At 3 600 m resting basal cortisol and aldosterone levels were both significantly lower than they were at sea-level (p=0.004, p=0.003, respectively). Cortisol values at T30 and T60 were not different between sea-level and 3 600 m but the increment after synacthen was significantly greater (p=0.041) at 3 600 m due to a lower basal value. Aldosterone at T30 and T60 was significantly lower (p=0.003 for both) at 3 600 m than at sea-level and the increment following synacthen was also significantly less (p=0.003) at 3 600 m. At 3 600 m there appears to be a divergent adrenal response to synthetic adrenocorticotrophic hormone with an intact cortisol response but a reduced aldosterone response, relative to sea-level. This may reflect a specific effect of hypoxia on aldosterone synthesis and may be beneficial to acclimatization.


Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Aldosterona/sangre , Altitud , Hormonas/farmacología , Hidrocortisona/sangre , Hipoxia/tratamiento farmacológico , Hormona Adrenocorticotrópica/administración & dosificación , Adulto , Presión Atmosférica , Femenino , Estudios de Seguimiento , Hormonas/administración & dosificación , Humanos , Hipoxia/sangre , Masculino , Pronóstico
4.
J R Army Med Corps ; 162(6): 470-472, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25687257

RESUMEN

Travel to high altitude and the incumbent exposure to hypobaric hypoxia leads to a prothrombotic state. This may increase the likelihood of thromboembolic events, including stroke, in otherwise healthy individuals. While there have been sporadic anecdotal reports of 'stroke-like' syndromes at high altitude for over 100 years, there are surprisingly few detailed reports supported by imaging.This report describes a case of posterior circulation infarct thought to be due to a paradoxical embolus through a patent foramen ovale. The relationship between high-altitude physiology, increased incidence of thromboembolism and the significance of patent foramen are discussed in the report.


Asunto(s)
Mal de Altura/diagnóstico , Infarto Encefálico/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Embolia Paradójica/diagnóstico por imagen , Foramen Oval Permeable/diagnóstico por imagen , Hemiplejía/diagnóstico por imagen , Mal de Altura/complicaciones , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/etiología , Infarto Encefálico/etiología , Angiografía Cerebral , Diagnóstico Diferencial , Ecocardiografía , Embolia Paradójica/etiología , Foramen Oval Permeable/complicaciones , Hemiplejía/etiología , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Adulto Joven
5.
J R Army Med Corps ; 162(6): 465-469, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26604255

RESUMEN

BACKGROUND: Acute mountain sickness (AMS) is a common problem of trekkers to high altitude. The UK military train at high altitude through adventurous training (AT) or as exercising troops. The ascent of Point Lenana at 4985 m on Mount Kenya is frequently attempted on AT. This study sought to establish the incidence of AMS within this population, to aid future planning for military activities at altitude. METHODS: A voluntary questionnaire was distributed to all British Army Training Unit Kenya based expeditions attempting to ascend Mount Kenya during the period from February to April 2014. The questionnaire included twice daily Lake Louise and Borg (perceived exertion scale) self-scoring. All expeditions were planned around a 5-day schedule, which included reserve time for acclimatisation, illness and inclement weather. RESULTS: Data were collected on 47 participants, 70% of whom reached the summit of Point Lenana. 62% (29/47) self-reported AMS (defined as Lake Louise score (LLS) ≥3) on at least one occasion during the ascent, and 34% (10/29) suffered severe AMS (LLS ≥6). Those who attempted the climb within 2 weeks of arrival in Kenya had a higher incidence of AMS (12/15 (80%) vs 17/32 (53%), p=0.077). Participants recording a high Borg score were significantly more likely to develop AMS (16/18 vs 9/21, p=0.003). CONCLUSIONS: This represents the first informative dataset for Mount Kenya ascents and altitude. The incidence of AMS during AT on Mount Kenya using this ascent profile is high. Adapting the current ascent profile, planning the ascent after time in country and reducing perceived exertion during the trek may reduce the incidence of AMS.


Asunto(s)
Aclimatación , Mal de Altura/epidemiología , Expediciones , Personal Militar , Montañismo , Enfermedad Aguda , Adolescente , Adulto , Femenino , Humanos , Incidencia , Kenia/epidemiología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Reino Unido/epidemiología , Adulto Joven
6.
J R Nav Med Serv ; 102(1): 33-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-29984977

RESUMEN

British military personnel are frequently exposed to high altitude (HA) (>1500m). Operations in Afghanistan have occurred at altitudes of up to 3000m and there remains the possibility of rapid deployment of non-acclimatised troops to HA areas. British military personnel also deploy to HA frequently on Adventurous Training (AT) and there are numerous expeditions every year to the Greater Ranges. As such, there remains a reasonable likelihood of the development of high altitude illness (HAI) with potentially life-threatening consequences. This article aims to provide an overview of the adaptive (acclimatisation) and pathological (acute HAI) responses to HA exposure, with particular reference to military deployments.


Asunto(s)
Mal de Altura/diagnóstico , Mal de Altura/prevención & control , Personal Militar , Aclimatación , Mal de Altura/etiología , Humanos
7.
J R Nav Med Serv ; 102(2): 99-103, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-29894138

RESUMEN

Anaphylaxis is a severe, life-threatening, generalised hypersensitivity reaction. It affects 1 in 1,333 (~0.08%) of the English population during their lives, with 1% of cases being fatal. Management, underpinned by guidance from the Resuscitation Council (UK), focuses on a thorough clinical assessment and prompt administration of intramuscular adrenaline. Symptoms may recur, so patients must be observed for a period of no less than six hours. In a deployed environment evacuation must be swift and into a safe environment capable of providing critical care support. There are clear occupational implications following a case of anaphylaxis, and a confirmed case may affect service personnel's fitness to deploy. This article will summarise the management of anaphylaxis in Royal Naval personnel.


Asunto(s)
Anafilaxia/tratamiento farmacológico , Epinefrina/uso terapéutico , Medicina Naval/métodos , Simpatomiméticos/uso terapéutico , Albuterol/uso terapéutico , Broncodilatadores/uso terapéutico , Manejo de la Enfermedad , Glucocorticoides/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Inyecciones Intramusculares , Planificación de Atención al Paciente , Guías de Práctica Clínica como Asunto , Derivación y Consulta , Autocuidado , Automanejo , Triptasas/sangre
8.
Eur J Appl Physiol ; 115(1): 91-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25213006

RESUMEN

PURPOSE: A diuresis is a key part of acclimatisation to high altitude (HA). Arginine vasopressin (AVP) is a hormone involved in salt and water balance and may potentially have a role in the development of altitude illness. ProAVP (copeptin) is more stable than AVP and is assayed by a straightforward, automated method. We investigated the relationship of AVP to copeptin and the copeptin response to exercise and altitude illness in a large cohort during a field study at HA. METHODS: 48 subjects took part in a 10-day trek at HA. Venous blood samples were taken at 3,833, 4,450 and 5,129 m post-trek (exercise) and the following day at rest. Daily recordings of symptoms of altitude illness, oxygen saturations and perceived exertion were carried out. RESULTS: AVP and copeptin levels increased with exercise and correlated closely (ρ 0.621 p < 0.001), this was strongest in the stressed state when AVP secretion was highest, at 5,129 m post-exercise (ρ 0.834 p < 0.001). On two-way ANOVA, both altitude (F = 3.5; p = 0.015) and exercise (F = 10.2; p = 0.002) influenced copeptin levels (interaction F = 2.2; p = 0.08). AVP levels were influenced by exercise (F = 14.4; p = 0.0002) but not altitude (F = 2.0; p = 0.12) with no overall group interactions (F = 1.92.6; p = 0.06). There was no association between copeptin or arginine vasopressin and altitude illness. Copeptin correlated with the Borg RPE score and was significantly higher in the group with a Borg score ≥15 (7.9 vs. 3.7 p < 0.001). CONCLUSION: We have shown that arginine vasopressin and copeptin levels correlate and are suppressed below 5,129 m. Furthermore, we have demonstrated that exertion, rather than altitude illness or increasing osmolality, is the stimulus for increases in copeptin.


Asunto(s)
Altitud , Arginina Vasopresina/sangre , Glicopéptidos/sangre , Percepción , Esfuerzo Físico , Equilibrio Hidroelectrolítico/fisiología , Aclimatación/fisiología , Adulto , Femenino , Humanos , Masculino , Concentración Osmolar
9.
J R Nav Med Serv ; 101(2): 138-42, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26867414

RESUMEN

Exercise HIMALAYAN SERPENT was open to junior doctors from the United Kingdom (UK) Armed Forces and aimed to educate potential expedition doctors on aspects of high altitude and wilderness medicine as well as conducting adventurous training (AT) and medical research. This was the first time such an exercise had been undertaken and this article explores the views of those junior doctors taking part to assess whether the exercise met the aims and objectives it set out.


Asunto(s)
Medicina Militar/educación , Medicina Silvestre/educación , Humanos , Nepal , Reino Unido
10.
J R Nav Med Serv ; 101(2): 143-6, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26867415

RESUMEN

Undertaking medical research during military adventurous training expeditions presents a unique set of challenges to medical personnel, and for those considering doing so in the future the task may seem daunting. This article details some of the challenges faced whilst undertaking high altitude research on a recent Defence Medical Services (DMS) adventurous training expedition to the Dhaulagiri circuit in Nepal. By discussing what led to some of the problems encountered, how they were overcome, and in some instances how they could have been avoided in the first place, it is hoped that the article will act as a guide for others who plan on undertaking future research in a similar environment.


Asunto(s)
Medicina Militar/educación , Medicina Silvestre/educación , Humanos , Nepal , Reino Unido
11.
Horm Metab Res ; 44(4): 302-5, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22368038

RESUMEN

High altitude exposure normally leads to a marked natriuresis and diuresis. Acute mountain sickness is often associated with fluid retention, to which an elevated cortisol may contribute. Most investigators report a rise in resting cortisol with ascent, but little data exist regarding the cortisol response to a day trekking. We therefore measured salivary cortisol during ascent to > 5000 m in a cohort of between 42-45 subjects following a 6-h trek (samples taken between 15:30-16:30 h) and between 15-20 subjects at rest (morning samples taken between 08:00-09:00 h). Morning resting cortisol [nmol/l, mean±sd, (range)] was 5.5±2.9 (2.13-13.61) at 1300 m; 4.7±6.8 (1.4-27.02) at 3400 m, and significantly (p=0.002) rose between 4270 m [3.5±2.1 (1.4-8.34)] and 5150 m [14.5±30.3 (1.9-123.1)]. Post-exercise cortisol [nmol/l, mean±sd, (range)] dropped between 3400 m [7±6 (1.5-33.3)] and 4270 m [4.2±4.8 (1.4-29.5)] (p=0.001) followed by a significant rise in post-exercise cortisol between 4270 m [4.2±4.8 (1.4-29.5)] and 5 150 m [9.2±10.2 (1.4-61.3)] (p<0.001). There were no significant associations between severity of acute mountain sickness and cortisol levels. There was a significant though weak correlation between cortisol post-exercise at 5150 m and oxygen saturation at 5150 m (rho= - 0.451, p=0.004). In conclusion, this is the largest cohort to have their resting and post-exercise cortisol levels ascertained at high altitude. We confirm the previous findings of an elevated resting morning cortisol at > 5000 m, but present the novel finding that the cortisol response to a day trekking at HA appears suppressed at 4270 m.


Asunto(s)
Mal de Altura/metabolismo , Ejercicio Físico/fisiología , Hidrocortisona/metabolismo , Hipoxia/metabolismo , Descanso/fisiología , Adulto , Femenino , Humanos , Hidrocortisona/análisis , Masculino , Persona de Mediana Edad , Saliva/química , Saliva/metabolismo , Adulto Joven
12.
J R Army Med Corps ; 158(2): 110-4, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22860500

RESUMEN

The aim of military adventurous training (AT) is "to develop, through authorised challenging pursuits and within an outdoor environment, leadership and the qualities necessary to enhance the performance of military personnel during peace and war". An increasing amount of effort is being applied by all three services to increase participation in AT to achieve these, largely immeasurable, aims. Existing guidance to Commanding Officers dictates that, where possible, 20% of a unit strength should undertake some form of AT annually with 5% taking part in an overseas expedition. In a speech in 2008 Alan Johnson, the then Secretary of State for Health, acknowledged that for Armed Forces medical personnel 'just as important as clinical skills are issues such as leadership, communication, adaptability and teamwork." Controlled exposure to risk, discomfort and personal hardship is a common theme for both AT activities and military deployments. Both General Medical Council competencies for all doctors and the Royal College of Anaesthetists military module include elements which can effectively be taught and developed through training in an outdoors environment. These skills include communication skills, leadership, risk assessment and interdisciplinary working. In this review the value of AT in training doctors to develop those attributes is examined.


Asunto(s)
Comunicación , Educación Médica , Liderazgo , Aprendizaje , Personal Militar/educación , Conducta Cooperativa , Emociones , Expediciones , Procesos de Grupo , Humanos , Comunicación Interdisciplinaria
13.
J R Army Med Corps ; 158(2): 120-2, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22860502

RESUMEN

OBJECTIVES: In the United Kingdom, approximately eight million peripheral cannulations are performed each year. Intravenous cannulae are made from either polytetrafluoroethylene (Teflon) or polyurethane. Polyurethane has a lower incidence of thrombophlebitis, however the physical characteristics of polyurethane may make the cannulae difficult to use at higher ambient temperatures. This effect maybe of importance to those involved in cannulation in extreme environments and especially for military doctors deployed in current theatres of operations. METHODS: In a randomised single blinded study we investigated the different characteristics of Teflon and polyurethane cannulae (Vasofix Safety Cannulae, B Braun) at three different temperatures (-10 degrees C, 21 degrees C and 40 degrees C). RESULTS: There is no statistically significant difference in the ease or speed of cannulation of either polyurethane or Teflon safety cannulae in extremes of temperature. CONCLUSIONS: This study provides evidence that performance of polyurethane safety cannulae are not impaired by temperature extremes.


Asunto(s)
Catéteres/efectos adversos , Frío , Calor , Politetrafluoroetileno/efectos adversos , Poliuretanos/efectos adversos , Cateterismo , Humanos , Método Simple Ciego , Estadísticas no Paramétricas , Tromboflebitis/etiología , Factores de Tiempo
14.
Biol Lett ; 7(2): 168-72, 2011 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-21177694

RESUMEN

BACKGROUND: Real science has the potential to not only amaze, but also transform the way one thinks of the world and oneself. This is because the process of science is little different from the deeply resonant, natural processes of play. Play enables humans (and other mammals) to discover (and create) relationships and patterns. When one adds rules to play, a game is created. THIS IS SCIENCE: the process of playing with rules that enables one to reveal previously unseen patterns of relationships that extend our collective understanding of nature and human nature. When thought of in this way, science education becomes a more enlightened and intuitive process of asking questions and devising games to address those questions. But, because the outcome of all game-playing is unpredictable, supporting this 'messyness', which is the engine of science, is critical to good science education (and indeed creative education generally). Indeed, we have learned that doing 'real' science in public spaces can stimulate tremendous interest in children and adults in understanding the processes by which we make sense of the world. The present study (on the vision of bumble-bees) goes even further, since it was not only performed outside my laboratory (in a Norman church in the southwest of England), but the 'games' were themselves devised in collaboration with 25 8- to 10-year-old children. They asked the questions, hypothesized the answers, designed the games (in other words, the experiments) to test these hypotheses and analysed the data. They also drew the figures (in coloured pencil) and wrote the paper. Their headteacher (Dave Strudwick) and I devised the educational programme (we call 'i,scientist'), and I trained the bees and transcribed the childrens' words into text (which was done with smaller groups of children at the school's local village pub). So what follows is a novel study (scientifically and conceptually) in 'kids speak' without references to past literature, which is a challenge. Although the historical context of any study is of course important, including references in this instance would be disingenuous for two reasons. First, given the way scientific data are naturally reported, the relevant information is simply inaccessible to the literate ability of 8- to 10-year-old children, and second, the true motivation for any scientific study (at least one of integrity) is one's own curiousity, which for the children was not inspired by the scientific literature, but their own observations of the world. This lack of historical, scientific context does not diminish the resulting data, scientific methodology or merit of the discovery for the scientific and 'non-scientific' audience. On the contrary, it reveals science in its truest (most naive) form, and in this way makes explicit the commonality between science, art and indeed all creative activities. PRINCIPAL FINDING: 'We discovered that bumble-bees can use a combination of colour and spatial relationships in deciding which colour of flower to forage from. We also discovered that science is cool and fun because you get to do stuff that no one has ever done before. (Children from Blackawton)'.


Asunto(s)
Abejas/fisiología , Visión de Colores , Reconocimiento Visual de Modelos , Animales , Conducta Animal , Conducta Espacial
15.
J R Army Med Corps ; 157(1): 5-7, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21465903

RESUMEN

Science and mountain exploration are closely linked throughout history. A large array of studies of varying complexity have been performed in conditions of hypobaric hypoxia, some on field studies, some in hypobaric chambers. The military has contributed greatly to this body of evidence both through operations in high altitude regions of the world, hypobaric chamber studies and through field studies as part of adventurous training expeditions. The hope is that by investigating hypoxia in fit participants in field or chamber studies insights may be gained into the adaptation to hypoxia during critical illness and novel approaches for treatment developed. Field studies in the mountains are challenging to design and undertake and need to balance practicalities (e.g. limited power supply) with scientific objectives. This article examines the history and rationale for high altitude research and discusses the challenges of organising a field study.


Asunto(s)
Altitud , Medicina Militar , Montañismo , Mal de Altura/fisiopatología , Humanos , Hipoxia/fisiopatología , Investigación
16.
J R Army Med Corps ; 157(1): 23-8, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21465906

RESUMEN

The role of the cardiovascular system is to deliver oxygenated blood to the tissues and remove metabolic effluent. It is clear that this complex system will have to adapt to maintain oxygen deliver in the profound hypoxia of high altitude. The literature on the adaptation of both the systemic and pulmonary circulations to high altitude is reviewed.


Asunto(s)
Mal de Altura/fisiopatología , Altitud , Fenómenos Fisiológicos Cardiovasculares , Montañismo/fisiología , Presión Sanguínea , Gasto Cardíaco , Frecuencia Cardíaca , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Esfuerzo Físico/fisiología , Volumen Plasmático , Circulación Pulmonar
17.
J R Army Med Corps ; 157(1): 38-42, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21465909

RESUMEN

Hypobaric hypoxia is associated with an increase in erythropoesis and an increased thrombotic risk. This is true of long haul air travel, mountaineering expeditions and longer stays at altitude. Studies looking at clotting on mountaineering expeditions are further complicated by the effects of exercise, plasma volume changes and the catecholamine response to hypoxia. This review examines the evidence for changes in clotting factors and functional clotting at altitude and considers the implications of altitude travel for those with pre-existing medical conditions.


Asunto(s)
Mal de Altura/sangre , Altitud , Coagulación Sanguínea , Montañismo/fisiología , Mal de Altura/fisiopatología , Eritropoyesis/fisiología , Humanos , Hipoxia/sangre , Hipoxia/complicaciones , Hipoxia/fisiopatología , Esfuerzo Físico/fisiología , Trombosis/sangre , Trombosis/etiología , Trombosis/fisiopatología
18.
J Exp Med ; 184(4): 1573-8, 1996 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-8879232

RESUMEN

Transgenic mice expressing self major histocompatibility complex (MHC) class I (H-2Kb) antigen solely in lymphoid cell lineages do not acquire tolerance to H-2Kb expressed on skin grafts. H-2Kb-specific cytotoxic T cell responses were completely abrogated in these mice, even after they had rejected skin grafts. Moreover, thymocytes expressing T cell receptors that confer H-2Kb reactivity on cytotoxic CD8+ T cells were eliminated. The ability to reject grafts correlated with the presence of a novel population of H-2Kb-reactive CD4+ T cells. At least some of these CD4+ T cells recognize peptides derived from H-2Kb by processing. We conclude that self MHC I antigens induce tolerance in the CD8 T cell compartment via negative selection when expressed exclusively by lymphoid cells. In contrast, tolerance to MHC class II-restricted self peptides derived by processing of such MHC I antigens is not induced in the CD4 T cell compartment. This suggests that effective transfer of self antigens from lymphoid cells to MHC II-positive cells that can process and present them as self peptides to thymocytes or CD4+ T cells does not take place in vivo. Thus, sequestration of self antigens and MHC II molecules in distinct cell types in the thymic microenvironment allows potentially autoreactive and functionally competent CD4+ T cells that recognize cryptic MHC II-restricted self peptides to mature into the peripheral T cell repertoire under normal physiological circumstances.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos H-2/inmunología , Tolerancia Inmunológica , Timo/inmunología , Animales , Presentación de Antígeno , Antígenos CD2/genética , Antígenos CD2/inmunología , Linfocitos T CD8-positivos/inmunología , Supresión Clonal , Citotoxicidad Inmunológica , Células Dendríticas , Antígenos H-2/genética , Antígenos de Histocompatibilidad Clase II , Activación de Linfocitos , Ratones , Ratones Endogámicos , Ratones Transgénicos , Péptidos/inmunología , Timo/citología , Distribución Tisular
19.
J Exp Med ; 172(5): 1425-31, 1990 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-2230651

RESUMEN

Experiments in vitro suggest that although interleukin 5 (IL-5) stimulates the late stages of eosinophil differentiation, other cytokines are required for the generation of eosinophil progenitor cells. In this study transgenic mice constitutively expressing the IL-5 gene were established using a genomic fragment of the IL-5 gene coupled to the dominant control region from the gene encoding human CD2. Four independent eosinophilic transgenic lines have thus far been established, two of which with 8 and 49 transgene copies, are described in detail. These mice appeared macroscopically normal apart from splenomegaly. Eosinophils were at least 65- and 265-fold higher in blood from transgenics, relative to normal littermates, and approximately two- or sevenfold more numerous relative to blood from mice infected with the helminth Mesocestoides corti. Much more modest increases in blood neutrophil, lymphocyte, and monocyte numbers were noted in transgenics, relative to normal littermates (less than threefold). Thus IL-5 in vivo is relatively specific for the eosinophil lineage. Large numbers of eosinophils were present in spleen, bone marrow, and peritoneal exudate, and were highest in the line with the greatest transgene copy number. Eosinophilia was also noted in histological sections of transgenic lungs, Peyer's patches, mesenteric lymph nodes, and gut lamina propria but not in other tissues examined. IL-5 was detected in the sera of transgenics at levels comparable to those seen in sera from parasite-infected animals. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were not found. IL-5 mRNA was detected in transgenic thymus, Peyer's patches, and superficial lymph nodes, but not in heart, liver, brain, or skeletal muscle or in any tissues from nontransgenics. Bone marrow from transgenic mice was rich in IL-5-dependent eosinophil precursors. These data indicate that induction of the IL-5 gene is sufficient for production of eosinophilia, and that IL-5 can induce the full pathway of eosinophil differentiation. IL-5 may therefore not be restricted in action to the later stages of eosinophil differentiation, as suggested by earlier in vitro studies.


Asunto(s)
Eosinofilia/metabolismo , Interleucina-5/metabolismo , Ratones Transgénicos/sangre , Animales , Líquido Ascítico/patología , Recuento de Células Sanguíneas , Médula Ósea/patología , Línea Celular , Células Cultivadas , Infecciones por Cestodos/sangre , Eosinofilia/parasitología , Expresión Génica , Células Madre Hematopoyéticas/patología , Interleucina-5/genética , Mesocestoides/aislamiento & purificación , Ratones , Ratones Transgénicos/parasitología , Bazo/patología
20.
J Exp Med ; 189(9): 1363-72, 1999 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-10224276

RESUMEN

We have recently shown that expression of the enzyme indoleamine 2, 3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell-derived signals IFN-gamma and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.


Asunto(s)
Macrófagos/metabolismo , Linfocitos T/citología , Triptófano Oxigenasa/metabolismo , Triptófano/análogos & derivados , Ciclo Celular , División Celular , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo , ADN/biosíntesis , Fase G1 , Expresión Génica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa , Activación de Linfocitos , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Linfocitos T/metabolismo , Triptófano/metabolismo , Triptófano/farmacología , Triptófano Oxigenasa/genética
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