Plasmodium vivax cerebral malaria with pancytopenia in the peruvian amazon: case report. / Malaria cerebral con pancitopenia por plasmodium vivax en la amazonía peruana: reporte de caso.

Plasmodium vivax causes 81% of all malaria cases and is the most common species in the Peruvian Amazon. We present the case of a male patient with cerebral malaria caused by Plasmodium vivax, who had general malaise and fever, and then presented seizures more than twice a day with loss of consciousness and motor functional limitation. Plasmodium vivax trophozoites were detected by thick blood smear, besides, we also observed low counts of all three blood cell types. Treatment began with artesunate and clindamycin for five days, then one unit of packed red blood cells was transfused; treatment continued with primaquine for seven days. The patient showed clinical improvement with neurological sequelae in one lower limb.

Plasmodium vivax es la especie más común en la Amazonía peruana y ocasiona el 81% del total de casos de malaria. Presentamos el caso de un paciente adulto varón con malaria cerebral por Plasmodium vivax, que inicia con malestar general y fiebre, luego presenta convulsiones más de dos veces al día con pérdida de consciencia y limitación funcional motora. Se le realiza gota gruesa donde se observa trofozoítos de Plasmodium vivax y depresión de las tres series sanguíneas. Se inicia tratamiento con artesunato y clindamicina por cinco días, se le transfunde un paquete globular, y continua con primaquina por siete días. El paciente muestra mejoría clínica con secuela neurológica en extremidad inferior izquierda.

Malaria cerebral con pancitopenia por plasmodium vivax en la amazonía peruana: reporte de caso / Plasmodium vivax cerebral malaria with pancytopenia in the peruvian amazon: case report

RESUMEN Plasmodium vivax es la especie más común en la Amazonía peruana y ocasiona el 81% del total de casos de malaria. Presentamos el caso de un paciente adulto varón con malaria cerebral por Plasmodium vivax, que inicia con malestar general y fiebre, luego presenta convulsiones más de dos veces al día con pérdida de consciencia y limitación funcional motora. Se le realiza gota gruesa donde se observa trofozoítos de Plasmodium vivax y depresión de las tres series sanguíneas. Se inicia tratamiento con artesunato y clindamicina por cinco días, se le transfunde un paquete globular, y continua con primaquina por siete días. El paciente muestra mejoría clínica con secuela neurológica en extremidad inferior izquierda.

ABSTRACT Plasmodium vivax causes 81% of all malaria cases and is the most common species in the Peruvian Amazon. We present the case of a male patient with cerebral malaria caused by Plasmodium vivax, who had general malaise and fever, and then presented seizures more than twice a day with loss of consciousness and motor functional limitation. Plasmodium vivax trophozoites were detected by thick blood smear, besides, we also observed low counts of all three blood cell types. Treatment began with artesunate and clindamycin for five days, then one unit of packed red blood cells was transfused; treatment continued with primaquine for seven days. The patient showed clinical improvement with neurological sequelae in one lower limb.

Edaphoclimatic Descriptors of Wild Tomato Species (Solanum Sect. Lycopersicon) and Closely Related Species (Solanum Sect. Juglandifolia and Sect. Lycopersicoides) in South America.

Wild species related to cultivated tomato are essential genetic resources in breeding programs focused on food security to face future challenges. The ecogeographic analysis allows identifying the species adaptive ranges and most relevant environmental variables explaining their patterns of actual distribution. The objective of this research was to identify the diversity, ecological descriptors, and statistical relationship of 35 edaphoclimatic variables (20 climatic, 1 geographic and 14 edaphic variables) from 4,649 accessions of 12 wild tomato species and 4 closely related species classified in Solanum sect. Lycopersicon and clustered into four phylogenetic groups, namely "Lycopersicon group" (S. pimpinellifolium, S. cheesmaniae, and S. galapagense), "Arcanum group" (S. arcanum, S. chmielewskii, and S. neorickii), "Eriopersicon group" (S. habrochaites, S. huaylasense, S. corneliomulleri, S. peruvianum, and S. chilense), "Neolycopersicon group" (S. pennellii); and two phylogenetically related groups in Solanum sect. Juglandifolia (S. juglandifolium and S. ochranthum), and section Lycopersicoides (S. lycopersicoides and S. sitiens). The relationship between the climate and edaphic variables were determined by the canonical correlation analysis, reaching 89.2% of variation with the first three canonical correlations. The most significant climatic variables were related to humidity (annual evapotranspiration, annual precipitation, and precipitation of driest month) and physicochemical soil characteristics (bulk density, pH, and base saturation percentage). In all groups, ecological descriptors and diversity patterns were consistent with previous reports. Regarding edaphoclimatic diversity, 12 climate types and 17 soil units were identified among all species. This approach has promissory applications for biodiversity conservation and uses valuable genetic resources related to a leading crop.

Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSE: Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL. METHODS: This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4). RESULTS: Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. CONCLUSION: The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.

Granulomatosis de Wegener, una afección poco frecuente / Wegener's granulomatosis, a rare condition

Introducción: la granulomatosis de Wegener es una vasculitis sistémica, poco frecuente, cuyo sustrato etiopatogénico es la inflamación de los vasos sanguíneos impidiendo la libre circulación del flujo sanguíneo. Clinicamente se caracteriza por presencia de manifestaciones respiratorias, nasales, auditivas y renales; frecuentemente se asocian trastornos infecciosos y alérgicos. Objetivo: socializar los principales elementos etiopatogénicos, manifestaciones clínicas y exámenes complementarios que permiten definir el granulomatosis de Wegener. Caso clínico: se presenta el caso de una paciente de 32 años de edad la cual es referida desde la atención primaria de salud, por presentar manifestaciones clínicas y de laboratorio que permiten confirmar el diagnóstico de una granulomatosis de Wegener. Conclusiones: la granulomatosis de Wegener es una rara enfermedad que, aunque se presenta fundamentalmente en pacientes femeninas entre 40 y 50 años, puede presentarse en pacientes de cualquier edad sin distinguir preferencia por el sexo. Sus principales manifestaciones clínicas son la toma respiratoria y renal acompañada de manifestaciones generales. El uso de esteroides constituye la piedra angular del tratamiento, al cual se adicionan medicamentos para el control de la enfermedad como es el caso del methotrexate.

Introduction: Wegener's granulomatosis is a rare systemic vasculitis, whose etiopathogenic substrate is the inflammation of the blood vessels, preventing the free circulation of blood flow. Clinically it is characterized by the presence of respiratory, nasal, auditory and renal manifestations; Infectious and allergic disorders are frequently associated. Objective: to socialize the main etiopathogenic elements, clinical manifestations and complementary examinations that allow us to define Wegener's granulomatosis. Clinical case: the case of a 32-year-old female patient is reported from primary health care, due to clinical and laboratory manifestations that confirm the diagnosis of Wegener's granulomatosis. Conclusions: Wegener's granulomatosis is a rare disease that, although it occurs mainly in female patients between 40 and 50 years, can occur in patients of any age without distinguishing preference for sex. Its main clinical manifestations are respiratory and renal uptake accompanied by general manifestations. The use of steroids is the cornerstone of the treatment, to which are added medications for the control of the disease such as methotrexate.

Linfoma no Hodgkin de amígdalas en un paciente con lupus eritematoso sistémico / Non-Hodgkin's lymphoma of tonsils in a patient with systemic lupus erythematous

Introducción: las enfermedades reumáticas aumentan el riesgo de aparición de distintas comorbilidades y estado de salud inadecuado en los pacientes. Dentro de estas comorbilidades las más peligrosas, por la frecuencia que se producen y por el desenlace final de las mismas lo constituyen las enfermedades neoplásicas. Objetivos: socializar los elementos clínicos, de laboratorio e histopatológicos que permiten la sospecha clínica y el diagnóstico de linfoma no Hodgkin en pacientes con enfermedades reumáticas. Caso clínico: paciente femenina de 54 años de edad, con diagnóstico de lupus eritematoso sistémico y síndrome de Sjögren secundario que acude con manifestaciones clínicas dadas por sudores nocturnos profusos, toma del estado general, fiebre vespertina y adenopatías cervicales. Se le realiza el diagnóstico de linfoma no Hodgkin en amígdala derecha. Conclusiones: las enfermedades reumáticas aumentan el riesgo de aparición de enfermedades neoplásicas. El seguimiento periódico, la adherencia farmacológica y el monitoreo constante de manifestaciones generales y elementos de sospecha de procesos malignos, son las acciones fundamentales que se pueden realizar para prevenir o diagnósticas precozmente la aparición de afecciones neoplásicas en pacientes reumáticos(AU)

Introduction: rheumatic diseases increase the risk of the appearance of different comorbidities and inadequate health status in patients. Within these comorbidities the most dangerous, by the frequency that occur and by the final outcome of them are neoplastic diseases. Objectives: to socialize the clinical, laboratory and histopathological elements that allow clinical suspicion and the diagnosis of non-Hodgkin's lymphoma in patients with rheumatic diseases. Case report: A 54-year-old female patient with a diagnosis of systemic lupus erythematous and secondary Sjogren's syndrome who presented with clinical manifestations due to profuse nocturnal sweats, general condition, afternoon fever and cervical lymphadenopathy. He is diagnosed with non-Hodgkin's lymphoma in the right amygdala. Conclusions: rheumatic diseases increase the risk of the appearance of neoplastic diseases. The periodic follow-up, the pharmacological adherence and the constant monitoring of general manifestations and elements of suspicion of malignant processes, are the fundamental actions that can be performed to prevent or early diagnosis the appearance of neoplastic affections in rheumatic patients(AU)

Relación entre la actitud hacia el trabajo en equipo con la calidad de atención desde la percepción usuario en salud. Hospital Cesar Vallejo Mendoza - Santiago de Chuco, 2016 / Relationship between the attitude towards teamwork and the quality of care from the user perception in health. Cesar Vallejo Mendoza Hospital - Santiago de Chuco, 2016

Esta investigación es de tipo sustantivo descriptivo trabajado con un diseño descriptivo correlacional. El presente estudio tiene como objetivo determinar la relación entre las actitudes hacia el trabajo en equipo y la calidad de la atención desde la percepción del usuario en salud del Hospital César Vallejo Mendoza de Santiago de Chuco durante el periodo de setiembre a diciembre del 2016, de una población de usuarios de salud entre las edades de 18 a más, de la cual se obtuvo una muestra de 363 usuarios. Los participantes fueron evaluados con los siguientes instrumentos: Encuesta de percepción de la calidad de atención y Escala de Actitudes hacia el trabajo en equipo. El análisis estadístico reveló en las actitudes hacia el trabajo en equipo y la percepción de la calidad de atención una correlación directa, de grado considerable y altamente significativa (p<.01) entre las actitudes hacia el trabajo en equipo con las dimensiones capacidad de respuesta y empatía, asimismo, una correlación directa, de grado medio y altamente significativa (p<.01) con la calidad de atención y sus dimensiones fiabilidad, seguridad y tangibilidad percibida por los usuarios del Hospital César Vallejo Mendoza de Santiago de Chuco

This research is of descriptive noun type worked with a descriptive correlational design. The objective of this study is to determine the relationship between attitudes towards teamwork and the quality of care from the perception of the health user of the César Vallejo Mendoza Hospital in Santiago de Chuco during the period from September to December 2016, Of a population of health users between the ages of 18 and over, from which a sample of 363 users was obtained. Participants were evaluated with the following instruments: Survey of perception of the quality of care and Scale of Attitudes toward teamwork. Statistical analysis revealed in the attitudes towards teamwork and the perception of quality of care a direct correlation, of considerable and highly significant degree (p<.01) between attitudes toward teamwork with the dimensions of responsiveness (P<.01) with quality of care and its dimensions of reliability, safety and tangible aspects perceived by users of the César Vallejo Mendoza Hospital in Santiago de Chuco.

Silica nanoparticles induce cardiotoxicity interfering with energetic status and Ca2+ handling in adult rat cardiomyocytes.

Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+ handling, which showed impaired contractility and intracellular Ca2+ transient amplitude during ß-adrenergic stimulation in SiO2 treatment. The time to 50% Ca2+ decay increased 39%, and the Ca2+ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+ release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+ handling.

Diagnosis and Treatment of Chronic Myeloid Leukemia in the Imatinib Mesylate Era: Report of the Experience at "La Raza" Medical Center in Mexico.

BACKGROUND: With the advent of tyrosine kinase inhibitors (TKIs), the prognosis of chronic myeloid leukemia (CML) has undergone significant changes in all age groups and at different clinical stages over the past 15 years. Consequently, although disease incidence has remained stable, cumulative prevalence is increasing. PATIENTS AND METHODS: We reviewed our experience with imatinib mesylate (IM) as a first- and second-line treatment for different CML stages to examine demographic and clinical characteristics of patients, cytogenetic and molecular response rates, as well as overall survival (OS), progression-free survival, and event-free survival of patients at the Specialties Hospital of the National Medical Center "La Raza," which belongs to the Mexican Social Security Institute and serves a population with medium to low socioeconomic status. RESULTS: We analyzed data of 302 CML patients who received IM as a first- (n = 234) or second-line treatment (n = 68). Overall, 198 of 302 patients (66%) reached a complete cytogenetic response and at least 115 of 302 (38%) achieved a major molecular response. Among 302 IM-treated patients, 55 (18%) achieved a molecular response 4.5 (MR4.5) or major; at the time of writing this report, 283 (93.7%) were alive and 19 (6.29%) had died. At 60 months, OS was 94%. CONCLUSION: IM offers long-term OS expectations not previously observed with any other therapy, in addition to a good quality of life. However, more than a third of the patients require further treatment with a second-generation TKI; consequently, expectations for treatment-free remission and long-term OS are reduced. Timely change to second-generation TKIs could improve such expectations.

Administración de los costos en la calidad de los servicios de seda Huánuco periodo 1995-2004 / Administrator of costs in service quality seda Huanuco period 1995-2004

El trabajo investigativo se realizó con el objetivo de conocer la realidad de los costos de calidad de los servicios que brinda la Empresa de Servicios de Abastecimiento de Agua y Alcantarillado (Seda Huánuco) y por la importancia que ésta tiene en la calidad del servicio; ya que es una empresa municipal de derecho privado, constituida como sociedad anónima, a cargo de las municipalidades de Huánuco, Leoncio Prado y Amarilis, con autonomía técnica, administrativa, económica y financiera. Sus servicios son de necesidad y utilidad pública y de preferente interés social. La investigación se realizó mediante la recopilación y análisis de las fuentes de información así como la contrastación de la información histórica entre los años 1995 y 2004, obteniendo como resultado que la ciudad de Huánuco con sus casi 200 000 habitantes tiene los servicios de saneamiento con bajos niveles de cobertura y calidad; así, sólo el 30 por ciento de la población urbana tiene acceso al servicio de agua potable y el 20 por ciento goza del servicio de alcantarillado y no se tratan las aguas servidas. A esto se suma que existe una pérdida en la red de aproximadamente 50 por ciento del agua lo cual noes facturada; llegando a la conclusión de que la empresa objeto de estudio cuenta con una inadecuada distribución de los recursos, deficiente gestión empresarial, falta de planeamiento económico financiero e ingerencia política en las decisiones.

The research work was undertaken with the objective of knowing the actual cost of quality of services provided by the Enterprise Services Water and Sewerage Authority (SEDA Huanuco) and its importance in service quality,and which is a municipal company under private law, acting as a society anonymous, by the municipalities of Huanuco, Leoncio Prado and Amarilis , wi th autonomy technical, administrative, economic and financial. Its services are necessary and public utility and preferential social interest. The research was conducted by collecting and analysing information sources as well as the test of historical information between the years 1995 and 2004, which resulted in the city of Huanuco with its nearly 200 000 inhabitants have sanitation low levels of coverage and quality; well, only 30 per cent of the urban population hasaccess to potable water service and 20 per cent enjoyed the service and sewage left untreated sewage. In addition, there is a loss in the networkof approximately 50 per cent of water which is not billed; concluded that the company under consideration has an inadequate distribution of resources, poor management, lack of planning economic and political interference in financial decisions.

Different kinases regulate activation of voltage-dependent calcium channels by depolarization in GH3 cells.

The L-type Ca(2+) channel is the primary voltage-dependent Ca(2+)-influx pathway in many excitable and secretory cells, and direct phosphorylation by different kinases is one of the mechanisms involved in the regulation of its activity. The aim of this study was to evaluate the participation of Ser/Thr kinases and tyrosine kinases (TKs) in depolarization-induced Ca(2+) influx in the endocrine somatomammotrope cell line GH3. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured using a spectrofluorometric method with fura 2-AM, and 12.5 mM KCl (K(+)) was used as a depolarization stimulus. K(+) induced an abrupt spike (peak) in [Ca(2+)](i) that was abolished in the presence of nifedipine, showing that K(+) enhances [Ca(2+)](i), preferably activating L-type Ca(2+) channels. H89, a selective PKA inhibitor, significantly reduced depolarization-induced Ca(2+) mobilization in a concentration-related manner when it was applied before or after K(+), and okadaic acid, an inhibitor of Ser/Thr phosphatases, which has been shown to regulate PKA-stimulated L-type Ca(2+) channels, increased K(+)-induced Ca(2+) entry. When PKC was activated by PMA, the K(+)-evoked peak in [Ca(2+)](i), as well as the plateau phase, was significantly reduced, and chelerythrine (a PKC inhibitor) potentiated the K(+)-induced increase in [Ca(2+)](i), indicating an inhibitory role of PKC in voltage-dependent Ca(2+) channel (VDCC) activity. Genistein, a TK inhibitor, reduced the K(+)-evoked increase in [Ca(2+)](i), but, unexpectedly, the tyrosine phosphatase inhibitor orthovanadate reduced not only basal Ca(2+) levels but, also, Ca(2+) influx during the plateau phase. Both results suggest that different TKs may act differentially on VDCC activation. Activation of receptor TKs with epidermal growth factor (EGF) or vascular endothelial growth factor potentiated K(+)-induced Ca(2+) influx, and AG-1478 (an EGF receptor inhibitor) decreased it. However, inhibition of the non-receptor TK pp60 c-Src enhanced K(+)-induced Ca(2+) influx. The present study strongly demonstrates that a complex equilibrium among different kinases and phosphatases regulates VDCC activity in the pituitary cell line GH3: PKA and receptor TKs, such as vascular endothelial growth factor receptor and EGF receptor, enhance depolarization-induced Ca(2+) influx, whereas PKC and c-Src have an inhibitory effect. These kinases modulate membrane depolarization and may therefore participate in the regulation of a plethora of intracellular processes, such as hormone secretion, gene expression, protein synthesis, and cell proliferation, in pituitary cells.

Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment.

INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness.

Angiotensin II phosphorylation of extracellular signal-regulated kinases in rat anterior pituitary cells.

We studied the effects of ANG II on extracellular signal-regulated kinase (ERK)1/2 phosphorylation in rat pituitary cells. ANG II increased ERK phosphorylation in a time- and concentration-dependent way. Maximum effect was obtained at 5 min at a concentration of 10-100 nM. The effect of 100 nM ANG II was blocked by the AT1 antagonist DUP-753, by the phospholipase C (PLC) inhibitor U-73122, and by the MAPK kinase (MEK) antagonist PD-98059. The ANG II-induced increase in phosphorylated (p)ERK was insensitive to pertussis toxin blockade and PKC depletion or inhibition. The effect was also abrogated by chelating intracellular calcium with BAPTA-AM or TMB-8 by depleting intracellular calcium stores with a 30-min pretreatment with EGTA and by pretreatment with herbimycin A and PP1, two c-Src tyrosine kinase inhibitors. It was attenuated by AG-1478, an inhibitor of epidermal growth factor receptor (EGFR) activation. Therefore, in the rat pituitary, the increase of pERK is a Gq- and PLC-dependent process, which involves an increase in intracellular calcium and activation of a c-Src tyrosine kinase, transactivation of the EGFR, and the activation of MEK. Finally, the response of ERK activation by ANG II is altered in hyperplastic pituitary cells, in which calcium mobilization evoked by ANG II is also modified.

Angiotensin and calcium signaling in the pituitary and hypothalamus.

1) In the rat pituitary, angiotensin type 1B receptors (AT1B) are located in lactotrophs and corticotrophs. 2) Activation of AT1B receptors are coupled to Gq/11 (Guanine protein coupled receptor, or GPCR); they increase phospholipase beta C (PLC) activity resulting in inositol 1,4,5 triphosphate (InsP3) and diacylglycerol (DAG) formation. A biphasic increase in [Ca2+]i triggered by InsP3 and DAG ensues. 3) As many GPCRs, AT1B pituitary receptors rapidly desensitize. 4) This was observed in the generation of InsP3, the mobilization of intracellular Ca(2+), and in prolactin release. Both homologous and heterologous desensitization was evidenced. 5) Desensitization of the angiotensin II type 1 (AT1) receptor in the pituitary shares similarities and differences with endogenously expressed or transfected AT1 receptors in different cell types. 6) In the pituitary hyperplasia generated by chronic estrogen treatment there was desensitization or alteration in angiotensin II (Ang II) evoked intracellular Ca2+ increase, InsP3 generation, and prolactin release. This correlates with a downregulation of AT1 receptors. 7) In particular, in hyperplastic cells Ang II failed to evoke a transient acute peak in [Ca2+]i, which was replaced by a persistent plateau phase of [Ca2+]i increase. 8) Different calcium channels participate in Ang II induced [Ca2+]i increase in control and hyperplastic cells. While spike phase in control cells is dependent on intracellular stores sensitive to thapsigargin, in hyperplastic cells plateau increase is dependent on extracellular calcium influx. 9) Signal transduction of the AT1 pituitary receptor is greatly modified by hyperplasia, and it may be an important mechanism in the control of the hyperplastic process. 10) In the hypothalamus and brain stem there is a predominant expression of AT1A and AT2 mRNA. 11) Ang II acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion. 12) Calcium channels play important roles in the Ang II induced behavioral and endocrine responses. 13) Ang II, in physiological concentrations, can activate AT1 receptors to stimulate both Ca2+ release from intracellular stores and Ca2+ influx from the extracellular space to increase [Ca2+]i in polygonal and stellate astroglia of the hypothalamus and brain stem. 14) In primary cell culture of neurons from newborn rat hypothalamus and brain stem, it has also been determined that Ang II elicits an AT1 receptor mediated inhibition of delayed rectifier K(+) current and a stimulation of Ca2+ current. 15) In primary cell cultures derived from the subfornical organ or the organum vasculosum laminae terminalis of newborn rat pups, Ang II produced a pronounced desensitization of the [Ca2+]i response. 16) Hypothalamic and pituitary Ang II systems are involved in different functions, some of which are related. At both levels Ang II signals through [Ca2+]i in a characteristic way.