ABSTRACT
Cytomegalovirus (CMV) is an important cause of morbidity and mortality in the immunocompromised host. In transplant recipients, a variety of clinically important "indirect effects" are attributed to immune modulation by CMV, including increased mortality from fungal disease, allograft dysfunction and rejection in solid organ transplantation, and graft-versus-host-disease in stem cell transplantation. Monocytes, key cellular targets of CMV, are permissive to primary, latent and reactivated CMV infection. Here, pairing unbiased bulk and single cell transcriptomics with functional analyses we demonstrate that human monocytes infected with CMV do not effectively phagocytose fungal pathogens, a functional deficit which occurs with decreased expression of fungal recognition receptors. Simultaneously, CMV-infected monocytes upregulate antiviral, pro-inflammatory chemokine, and inflammasome responses associated with allograft rejection and graft-versus-host disease. Our study demonstrates that CMV modulates both immunosuppressive and immunostimulatory monocyte phenotypes, explaining in part, its paradoxical "indirect effects" in transplantation. These data could provide innate immune targets for the stratification and treatment of CMV disease.
ABSTRACT
Rapamycin has been used as a clinical immunosuppressant for many years; however, the molecular basis for its selective effects on lymphocytes remains unclear. We investigated the role of two canonical effectors of the mammalian target of rapamycin (mTOR): ribosomal S6 kinases (S6Ks) and eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs). S6Ks are thought to regulate cell growth (increase in cell size), and 4E-BPs are thought to control proliferation (increase in cell number), with mTORC1 signaling serving to integrate these processes. However, we found that the 4E-BP-eIF4E signaling axis controlled both the growth and proliferation of lymphocytes, processes for which the S6Ks were dispensable. Furthermore, rapamycin disrupted eIF4E function selectively in lymphocytes, which was due to the increased abundance of 4E-BP2 relative to that of 4E-BP1 in these cells and the greater sensitivity of 4E-BP2 to rapamycin. Together, our findings suggest that the 4E-BP-eIF4E axis is uniquely rapamycin-sensitive in lymphocytes and that this axis promotes clonal expansion of these cells by coordinating growth and proliferation.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Carrier Proteins/metabolism , Eukaryotic Initiation Factor-4E/metabolism , Lymphocytes/drug effects , Nucleocytoplasmic Transport Proteins/metabolism , Phosphoproteins/metabolism , Signal Transduction , Animals , Cell Cycle Proteins , Cell Enlargement , Cell Membrane/metabolism , Cell Proliferation , Crosses, Genetic , Eukaryotic Initiation Factors , Female , Gene Expression Regulation , Guanosine Triphosphate , Immunosuppressive Agents/pharmacology , Lymphocytes/cytology , Male , Mice , Mice, Inbred C57BL , Sirolimus/pharmacologyABSTRACT
OBJECTIVE: The aim of the present study was to evaluate the quality of integrated child health care management (ICHCM) promoted by the World Health Organization (WHO) after an in-service training course. METHODS: The training was carried out in a rural and an urban health unit and in the paediatric ward of the local reference hospital. Tutorial courses were given to small groups (4-6 students) over a 5-day period (40 h in total). The courses consisted of demonstrations, discussions, analyses, applications and evaluations of the ICHCM (in-service training). The training was evaluated by comparing the quality of ICHCM given by each physician in their work place on three different occasions: 15 days before the course began (pre-course evaluation), 15 days after the course (post-course evaluation) and 6 months after the course had ended (follow-up evaluation). Each physician was observed in each period during his or her consultation with a child under 5 years of age who presented with acute diarrhoea or acute respiratory infection. A series of possible behaviours by physicians was checked against a list of behaviours that would indicate effective training. RESULTS: The average grades obtained by the 24 physicians evaluated (pre- and post-course) increased from 74.5 to 96.6 (22.1 points, P < 0.01). Physicians whose baseline grade was <80 had the greatest increases. Their averages grades increased from 68.2 to 91.3 (23.1 points, P < 0.001). The overall change for the whole group was sustained for up to 6 months (post-course 96.6 points and follow-up 90.9 points, P > 0.05). CONCLUSION: The quality of ICHCM improved after the in-service training. No additional resources were necessary in the clinical units. This type of training can be extended to other countries or health programmes.
Subject(s)
Child Health Services/organization & administration , Diarrhea/therapy , Education, Medical, Continuing , Inservice Training , Quality of Health Care , Respiratory Tract Infections/therapy , Acute Disease , Adult , Child , Female , Humans , Male , Mexico , Program EvaluationABSTRACT
Con el propósito de evaluar el tratamiento del paciente pediátrico con diarrea aguda en unidades del segundo nivel de atención, se revisaron 345 expedientes clínicos de cuatro hospitales del Instituto Mexicano del Seguro Social del sur de la Ciudad de México y 144 de los hospitales del Sector Salud en el Estado de Tlaxcala, de niños menores de cinco años hospitalizados por este diagnóstico durante 1991. Las variables estudiadas fueron las características clínicas y el diagnóstico al ingreso, el tratamiento médico durante la hospitalización, la evolución de la enfermedad, las complicaciones y las condiciones al egreso. Se calificó la justificación de la conducta terapéutica y se realizó análisis descriptivo de todos los datos comparando los hospitales de la Ciudad de México con los de Tlaxcala. La mayoría de los casos correspondió a niños menores de un año, con cuadros cortos y con algún grado de deshidratación. En dos terceras partes de los casos no se justificó la hospitalización. El tratamiento otorgado durante la misma fue en general inadecuado, ya que a pesar de que en la mayor parte de los niños se indicó hidratación oral con vida suero oral, se utilizó innecesariamente venoclisis y por tiempo prolongado, hubo indicación frecuente de ayuno o modificaciones dietéticas, prescripción indiscriminada de antimicrobianos y realización excesiva de estudios de laboratorio. Se recomienda que todos los hospitales que atienden niños con diarrea aguda cuenten con salas docente-asistenciales de hidratación oral, donde se efectúe una asistencia adecuada y se otorgue capacitación a las madres de los pacientes y al personal de salud, incluyendo a los médicos
