Aplasia medular asociada a osimertinib: a propósito de un caso / Bone marrow aplasia associated with osimertinib: a case report

Osimertinib es un inhibidor de tirosina quinasa (ITK) de tercera generación aprobado para el cáncer de pulmón no microcítico localmente avanzado o metastásico con mutación del EGFR. La prevalencia de efectos adversos hematológicos graves asociados a este fármaco es infrecuente según ficha técnica. Se describe el caso de una mujer de 69 años diagnosticada de cáncer de pulmón no microcítico localmente avanzado en tratamiento con osimertinib en primera línea con aparición de trombocitopenia severa que requirió de ingresos hospitalarios, transfusiones de sangre y plaquetas y de tratamiento con eltrombopag sin conseguir resultados favorables para la paciente. (AU)

Osimertinib is a third generation, tyrosine kinase inhibitor (TKI) approved for locally advanced or metastatic non-small cell lung cancer with EGFR mutation. The prevalence of serious haematological adverse events associated with osimertinib is uncommon according to the summary of product characteristics. The case of study describes a 69-year-old woman diagnosed with locally advanced non-small cell lung cancer treated with osimertinib, with onset of severe thrombocytopenia that required hospital admissions, blood and platelet transfusions, and treatment with eltrombopag, without achieving favourable results. (AU)

Surgical management of a loss of pregnancy in the first trimester: Patient experience and influencing factors, a prospective observational study.

OBJECTIVE: Describe the "patient experience" regarding care provided during the surgical management of a loss of pregnancy in the first trimester and identify the factors influencing this experience. MATERIAL AND METHODS: It is an observational prospective study conducted in two type III, academic, maternity wards in Lyon, France, carrying out 8,500 deliveries per year. Adult female patients, having undergone a suction curettage for a loss of pregnancy in the first trimester from 24 December 2020 to 13 June 2021 were inculded. The "patient experience" was assessed using the 15 questions of the Picker Patient Experience (PPE-15) questionnaire, and research was conducted on factors influencing the patient experience. The main outcome was the percentage of patients reporting a problem in response to at least one of the PPE-15 questions. RESULTS: 58 out of 79 patients (73% CI [62-83]) reported at least one problem with their care. The largest proportion of problems was raised in question about "Opportunity for family/loved ones to talk to the doctor" (76% CI [61-87]). The lowest proportion of problems was raised in question about "Treated with respect and dignity" (8% CI [3-16]). No factors influencing the patient experience were identified. DISCUSSION: Almost three out of four patients reported a problem in the experience as a patient. The main areas of improvement reported by patients were the participation of their family/relatives and the emotional support provided by the healthcare team. TWEETABLE ABSTRACT: Better communication with patient families and emotional support could improve patient experience during the surgical management of a loss of pregnancy in the first trimester.

[A Mythological Anamnesis: from AIDS Spiders to the Bats of Ebola or Covid-19 - Revised Version of the Paper Presented at the Colloquium "Cultural and Social Perspectives on Epidemics", musée du quai Branly-Jacques-Chirac, June 27, 2019]. / Une anamnèse mythologique : des araignées du sida aux chauves-souris d'Ebola ou de la Covid-19 ­ Version remaniée de la communication présentée au colloque Regards culturels et sociaux autour des épidémies, musée du quai Branly-Jacques-Chirac le 27 juin 2019.

This article focuses on some representations of the origin of AIDS and Ebola in Burkina Faso, against a new background of Covid-19 which began in early 2020 in connection with two animals: the spider and the bat. These are also, if not first and foremost, heroes of oral literature (from tales to myths) from this region of West Africa. It is up to anthropologists to explore the meandering symbolism and imagination of these liminal animals that move back and forth between the worlds inhabited by humans and the "bush" worlds of non-humans. Here arises a mythological anamnesis. These "trickster" animals challenge categories and understanding of both virologists and anthropologists.

Cet article porte sur quelques représentations de l'origine du sida et d'Ebola en pays lobi burkinabè, avec la Covid-19 en nouvel arrière-plan depuis le début de l'année 2020, en lien avec deux animaux : l'araignée et la chauve-souris. Ce sont aussi, voire d'abord, des héros de la littérature orale (des contes aux mythes) de cette région d'Afrique de l'Ouest. Des anthropologues ont exploré les méandres des symboliques et des imaginaires de ces animaux liminaires qui vont et viennent entre les mondes habités par les humains et les univers de « brousse ¼ des non-humains. Une anamnèse mythologique est mise à jour. Ces animaux rusés se jouent de nos catégories et de notre entendement, virologues et anthropologues ici confondus.

Monte Carlo simulation of the dose distribution of ICRP adult reference computational phantoms for acquisitions with a 320 detector-row cone-beam CT scanner.

PURPOSE: The purpose of this study was to develop and validate a Monte Carlo (MC) simulation tool for patient dose assessment for a 320 detector-row CT scanner, based on the recommendations of International Commission on Radiological Protection (ICRP). Additionally, the simulation was applied on four clinical acquisition protocols, with and without automatic tube current modulation (TCM). METHODS: The MC simulation was based on EGS4 code and was developed specifically for a 320 detector-row cone-beam CT scanner. The ICRP adult reference phantoms were used as patient models. Dose measurements were performed free-in-air and also in four CTDI phantoms: 150 mm and 350 mm long CT head and CT body phantoms. The MC program was validated by comparing simulations results with these actual measurements acquired under the same conditions. The measurements agreed with the simulations across all conditions within 5%. Patient dose assessment was performed for four clinical axial acquisitions using the ICRP adult reference phantoms, one of them using TCM. RESULTS: The results were nearly always lower than those obtained from other dose calculator tools or published in other studies, which were obtained using mathematical phantoms in different CT systems. For the protocol with TCM organ doses were reduced by between 28 and 36%, compared to the results obtained using a fixed mA value. CONCLUSIONS: The developed simulation program provides a useful tool for assessing doses in a 320 detector-row cone-beam CT scanner using ICRP adult reference computational phantoms and is ready to be applied to more complex protocols.

The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle.

Chromosomes are dynamic structures that must be reversibly condensed and unfolded to accommodate mitotic division and chromosome segregation. Histone modifications are involved in the striking chromatin reconfiguration taking place during mitosis. However, the mechanisms that regulate activity and function of histone-modifying factors as cells enter and exit mitosis are poorly understood. Here, we show that the anaphase-promoting complex or cyclosome (APC/C) is involved in the mitotic turnover of TRRAP (TRansformation/tRanscription domain-Associated Protein), a common component of histone acetyltransferase (HAT) complexes, and that the pre-mitotic degradation of TRRAP is mediated by the APC/C ubiquitin ligase activators Cdc20 and Cdh1. Ectopic expression of both Cdh1 and Cdc20 reduced the levels of coexpressed TRRAP protein and induced its ubiquitination. TRRAP overexpression or stabilization induces multiple mitotic defects, including lagging chromosomes, chromosome bridges and multipolar spindles. In addition, lack of sister chromatid cohesion and impaired chromosome condensation were found after TRRAP overexpression or stabilization. By using a truncated form of TRRAP, we show that mitotic delay is associated with a global histone H4 hyperacetylation induced by TRRAP overexpression. These results demonstrate that the chromatin modifier TRRAP is targeted for destruction in a cell cycle-dependent fashion. They also suggest that degradation of TRRAP by the APC/C is necessary for a proper condensation of chromatin and proper chromosome segregation. Chromatin compaction mediated by histone modifiers may represent a fundamental arm for APC/C orchestration of the mitotic machinery.

Monitorización continua de glucosa en la diabetes tipo 2. Posibles indicaciones / Potential indications of continuous glucose monitoring in type 2 diabetes

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Pautas de tratamiento insulínico en el paciente diabético hospitalizado / Practical insulin management of the diabetic patient in the hospital setting

El reconocimiento de la hiperglucemia como factor clave en el pronóstico vital del paciente ingresado por patología vascular aguda y la introducción de nuevos análogos de insulina han hecho revisar los protocolos de tratamiento del paciente diabético ingresado. A partir de antiguos esquemas de tratamiento con pautas de insulina supuestamente correctoras, se está intentando implementar sistemas terapéuticos que, siendo seguros, ofrezcan al paciente un mejor grado de control sin sobrecargar la tarea diaria de los profesionales sanitarios. En primer lugar, se han de defi nir claramente los objetivos de glucemia y valorar el grado de control y de insulinopenia previo. En segundo lugar, se ha de mantener o mejorar el esquema de tratamiento anterior al ingreso, especialmente en pacientes con terapia intensiva o tratados con infusores de insulina. Por otro lado, hay que considerar que las necesidades de insulina constituyen una variable cambiante a lo largo del ingreso, lo que difi cultará la estabilidad del control y obligará a revisiones muy frecuentes de la pauta de tratamiento. En resumen, estas pautas se basan en dos pilares: el tratamiento con insulina intravenosa (i.v.) en fase crítica y el esquema basal-bolo en las pautas de insulina subcutáneas (s.c.). Así, debe garantizarse el aporte básico de insulina que inhiba la movilización de sustratos en ausencia de ingestiones y que permita disponer de una insulinemia posprandial eficaz. Otro punto importante es el riesgo de hiper- o hipoglucemia en la transición de las unidades de críticos a las salas convencionales, y de éstas al domicilio

The acknowledgement of hyperglycemia as a key factor in the life expectancy of patients suffering from acute vascular events together with the introduction of the new insulin analogues has led to the revision of the guidelines for insulin administration to the hospitalized diabetic patient. The current goal is to implement practical protocols to improve glycemic control in the hospital setting without increasing the burden of the people involved in patient care. First of all, the target blood glucose level has to be well defined, taking into account the prior control and the degree of insulin deficiency. Secondly, it is necessary to maintain or even improve the previous treatment, particularly for patients under intensive insulin schedules or wearing insulin pumps. Additionally, insulin requirements change throughout the hospital stay. Thus, the insulin doses have to be reviewed and adjusted frequently. In summary, the two cornerstones of inpatient insulin therapy are: the use of intravenous insulin infusion during the acute process and a basal-bolus regimen for subcutaneous treatment. These strategies deliver sufficient insulin to prevent substrate mobilization while fasting and provide effective postprandial insulin levels. Another aspect to be taken into account is the risk of hyperglycemia or hypoglycemia when the patient is transferred from the critical care unit to the conventional care setting, and from hospital to ambulatory care

Marcadores de lesión endotelial implicados en la trombosis y fibrinolisis en la diabetes mellitus / Markers of endothelial damage involved in thrombosis and fibrinolysis in diabetes mellitus

La diabetes mellitus es un factor de riesgo conocido de enfermedad vascular. Las primeras fases de esta afección vascular implican la disfunción del endotelio vascular. El estudio funcional del endotelio supone una intervención demasiado laboriosa y costosa para formar parte de la valoración regular del paciente de riesgo. En consecuencia, ha crecido el interés en los últimos años en la valoración de la lesión endotelial por medio de la determinación de diferentes marcadores solubles. Los más estudiados son aquellos marcadores de síntesis predominantemente endotelial implicados en los procesos de trombosis y fibrinolisis. En este artículo se revisan aquellos que se han relacionado con la lesión endotelial en la diabetes: trombomodulina, tissue factor pathway inhibitor, factor von Willebrand, activador tisular del plasminógeno e inhibidor del activador del plasminógeno-1 (AU)

[Etiologic diagnosis and behaviour when confronted with abnormal hair growth in a child]. / Diagnostic étiologique et conduite à tenir devant une anomalie de la pilosité chez l'enfant.

Knowledge of the physiology of hair follicle growth and its relationship to the endocrine and the metabolic system is essential in understanding abnormalities in hair development or hirsutism. Although there is no sexual dysmorphism in the distribution of hair follicles, there are many factors that induce hair growth. The first clinical measure is to differentiate all the intrinsic causes from auxologic and normal psychomotor development related to ethnic, racial and hereditary differences (generalized congenital or idiopathic hypertrichosis) and congenital causes within the context of a multi-malformation syndrome in which hirsutism is associated with mental retardation (Cornélia de Lange's syndrome), major hypotrophy (leprechaunism) or with abnormalities of the limbs (Rubinstein Taybi's syndrome or mucopolysaccharidosis). In these cases, the hormone balance is normal and genetic and/or metabolic explorations are required. Secondly, virilism may occur with hirsutism combining pubis and axillary hair growth, hypertrophy of the clitoris, and android characteristics. This results from hyperandrogenia with increased circulation of plasma androgens. Dynamic hormone tests (ACTH test and dectanyl suppression test), together with sonography help to determine the adrenal (hyperplasia, more frequent than tumors), gonadic (tumors, cysts or gonadic dysgenesis) or paraneoplastic origins (choriocarcinoma). In practice, most hirsutism is considered as idiopathic.

Simulating rotational grazing management.

Dairy systems predominantly based on rotational grazing are notoriously hard to manage. In order to ensure profitability, this type of production requires quite good organisation, planning, and operating capability on the part of the farmer. A simulation-based decision support system, called SEPATOU, has been developed for this purpose. At the core of the decision support approach lies an explicit and rigorous modelling of the management strategy that underlies a dairy farmer's decision-making behaviour (real or hypothetical). The SEPATOU system is a discrete-event simulator that reproduces the day-to-day dynamics of the farmer's decision process and the response of the controlled biophysical system for which models of grass growth, animal consumption, and milk production are used. SEPATOU provides the means to evaluate and compare tentative strategies by simulating their application throughout the production season under different hypothetical weather conditions. The relative worth of a strategy can be assessed by analysing the effects on the biophysical system and their variability across the representative range of possible conditions that is considered. The activities to be managed concern the type and amount of conserved feed, where to fertilise and how much, the choice of fields to harvest, and most importantly, which field to graze next. Typically, SEPATOU is designed to be used by extension services and farming system scientists. It is implemented in C++ and is currently undergoing a validation process with the intended users.

Parathyroid hormone-related peptide stimulates proliferation of highly tumorigenic human SV40-immortalized breast epithelial cells.

Parathyroid hormone-related protein (PTHrP) is the main mediator of humoral hypercalcemia of malignancy (HHM) and it is produced by many tumors, including breast cancers. Breast epithelial cells as well as breast cancer tumors and cell lines have been reported as expressing PTHrP and the PTH/PTHrP receptor, suggesting that PTHrP may act as an autocrine factor influencing proliferation or differentiation of these cell types. We investigated PTHrP gene expression, PTH/PTHrP receptor signaling, and PTHrP-induced mitogenesis in three immortalized human mammary epithelial cell lines that exhibit differential tumorigenicity. The most tumorigenic cells expressed the highest levels of PTHrP messenger RNA (mRNA) and protein. We used reverse-transcription polymerase chain reaction (RT-PCR) and immunoblotting to detect the PTH/PTHrP receptor transcripts and proteins in all of the three cell lines. Treatment with human PTHrP(1-34) [hPTHrP(1-34)] and hPTH(1-34) increased intracellular cyclic adenosine monophosphate (cAMP) but not free Ca2+ in the nontumorigenic line. These agonists increased both cAMP and free Ca2+ levels in the moderately tumorigenic line, but only increased free Ca2+ in the highly tumorigenic line. Application of the PTH/PTHrP receptor antagonist [Asn10,Leu11,D Trp12]PTHrP(7-34) or PTHrP antibodies reduced [3H]thymidine incorporation in a dose-dependent fashion in the highly tumorigenic cell line but did not affect the other lines. Thus, treatment with a PTH/PTHrP receptor antagonist reduced cell proliferation, suggesting that PTHrP signaling mediated by the phospholipase C (PLC) pathway stimulates proliferation of a highly tumorigenic immortalized breast epithelial cell line.

Induction of skin papillomas, carcinomas, and sarcomas in mice in which the connexin 43 gene is heterologously deleted.

It has been suggested that blocked gap junctional intercellular communication plays a crucial part in multistage carcinogenesis. The mouse skin tumor-promoting phorbol esters are potent inhibitors of gap junctional intercellular communication and this inhibition is considered to be a mechanism by which clonal expansion of "initiated" cells is promoted. We examined whether mice in which the gene for a gap junction protein, connexin 43, is heterozygously deleted are more susceptible to chemical carcinogenesis; connexin 43 is expressed in the basal cell layer and the dermis of the skin. When the back skin was painted with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate, the incidence and yields of both papillomas and carcinomas were similar in connexin 43+/- and connexin 43+/+ mice; for this experiment, the original mice with C57BL/6 genetic background was crossed with CD1 strain for three generations. Subcutaneous injection of 7, 12-dimethylbenz[a]anthracene resulted in induction of fibrosarcomas in connexin 43+/- and connexin 43+/+ mice to a similar extent. All papillomas and carcinomas induced with 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate contained the 7,12-dimethylbenz[a] anthracene-specific mutation in the ras gene (A to T transversion at the 61st codon). About 50% of fibrosarcomas also contained this mutation, but in the Ki-ras gene; there was no difference in the prevalence of this mutation in tumors from connexin 43+/- and connexin 43+/+ mice. None of the tumors examined, however, showed any mutation in the connexin 43 gene. These results suggest that the deletion of one allele of the connexin 43 gene does not significantly contribute to, nor alter, the molecular events involved in skin carcinogenesis. These results are compatible with previous observations that nongenetic disruption of function rather than mutations of connexins, commonly occurs in cancer cells.

Estrogen stimulates PTHrP but not PTH/PTHrP receptor gene expression in the kidney of ovariectomized rat.

The aim of the present study was to test the hypothesis that the decreased renal tubular reabsorption of calcium observed in estrogen deficiency is associated with a local regulation of either PTHrP or PTH/PTHrP receptor genes in the kidney. Rats were randomly sham-operated (S) or ovariectomized receiving either vehicle (OVX) or 4 microg E2/kg/day (OVX+E4) or 40 microg E2/kg/d (OVX+E40) during 14 days using alzet minipumps. Plasma PTH and calcium levels were lower in untreated OVX animals than in all other groups (P < 0.01). Plasma PTH was higher in OVX+E40 than in OVX+E4 (P < 0.05). PTHrP mRNA expression in the kidney was unaffected by ovariectomy but was increased in OVX+E40 (0.984 +/- 0.452 for PTHrP/GAPDH mRNAs expression vs. 0.213 +/- 0.078 in sham, P < 0.01). PTH/PTHrP receptor mRNA expression and the cAMP response of renal membranes to PTH were unaffected by ovariectomy and estrogen substitution. In conclusion, renal PTHrP and PTH/PTHrP receptor mRNAs are not modified by ovariectomy. However, 17beta-estradiol increases renal expression of PTHrP mRNA without evident changes in its receptor expression and function. This may help to explain the pharmacological action of estrogen in the kidney, especially how it prevents the renal leak of calcium in postmenopausal women.

G-->A mutations in p53 and Ha-ras genes in esophageal papillomas induced by N-nitrosomethylbenzylamine in two strains of rats.

In human esophageal cancers, no ras gene mutations but a relatively high prevalence of p53 gene mutations have been reported. We found a high prevalence of point mutations in Ha-ras and p53 genes in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in two strains of rats (BD VI and F344). Our analysis showed the point mutation GGA-->GAA (expected from the known mechanisms of action of NMBA) at Ha-ras codon 12 in 22 of 46 (48%) and 22 of 38 (58%) papillomas from BD VI and F344 rats, respectively. There was no significant difference in the prevalence of ras mutations in tumors induced by high doses (5.0 mg/kg) and low doses (2.5 mg/kg) of NMBA. Eleven papillomas from each strain were analyzed for p53 mutations. The prevalent mutations found were G-->A and C-->T transitions. The frequency of p53 mutation was 36% (four of 11) for each strain. No apparent hot-spot codon or exon was found in the p53 gene, and two papillomas contained double mutations in this gene. The high prevalence of G-->A mutations in the rat Ha-ras gene contrasts with that in the human gene, in which no ras mutations have been found in primary tumors, and suggests either that the biology of esophageal carcinogenesis differs in humans and rats or that nitrosamines are not the major etiological risk factor for human esophageal cancers.

Evidence for the synthesis and secretion of APF--a bile lipid associated protein--by isolated rat hepatocytes.

Bile lipids are thought to be secreted in a lipoprotein complex in which they are associated with cholesterol and a protein called the anionic polypeptidic fraction (APF). APF is present in both bile and serum HDL. The association of APF with both bile and lipoprotein strongly suggests that hepatocytes may be responsible for the synthesis and secretion of this protein. In the present work we attempted to verify this by studying the incorporation of [14C]leucine into APF in isolated rat hepatocytes and by immunolocalization in cell cultures. Results obtained showed that synthesis of APF by cells follows the same kinetic pattern as albumin and that it was the third most abundant protein in the bile secretion. Immunolocalization confirmed that APF is synthesized in the endoplasmic reticulum of hepatocytes. This protein which appears to be rapidly secreted could be of great value for the specific detection of the lipids destined for bile secretion.

Intestinal pathology in the dog induced by sublethal doses of amiodarone.

Amiodarone (A), an unique antiarrhythmic agent and amphiphilic drug, induces at sublethal doses dyslipidic storage in animals. The present work demonstrates a distinct intestinal pathology or "Malabsorption Syndrome" in the dog induced by A. Signs of intestinal pathology were observed in all animals receiving 100 mg/kg, but not in those receiving less than 50 mg/kg, after one month. The malabsorption syndrome was demonstrated by a dynamic study of lipid absorption and pathological lesions (partial villous atrophy and the accumulation of macrophages with dyslipidic inclusions.

[Involvement of the spleen in congenital osteopetrosis of the "op" rat: corrective effect of thymus grafts]. / Atteinte de la rate dans l'ostéopétrose congénitale du rat "op": effet curatif de la greffe de thymus

In the osteopetrotic mutant rat "op", the white pulp of the spleen is poor in T lymphocytes, while the red pulp is hyperplastic in reaction to the aplastic bone marrow. Grafting of normal thymus into the mutant corrects these anomalies.