Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Rate and characteristics of urgent hospitalisation in persons with profound intellectual disabilities compared with general population.

BACKGROUND: Little is known about the hospitalisation rate of adults with severe/profound intellectual disability (PID) presenting at emergency services or about the appropriateness of hospital admissions in this population. Examining the possible differences in the patterns of hospitalisation between people with PID and those without intellectual disability (ID) may shed light on aspects of health and illness in these patients and may in turn make it possible to differentiate more clearly between mild-moderate ID and PID. METHODS: After an evaluation of the emergency visits made by adults with PID and by people without ID, patients in both groups requiring one or more hospitalisations were subsequently followed up for 18 months. The appropriateness of the decision to hospitalise was assessed using the ambulatory care-sensitive conditions index. RESULTS: There were no differences in the proportion of people with PID and controls admitted to hospital after their emergency visit. The median hospital stay was higher for PIDs: 7.5 vs. 4 days for controls. People with PID were admitted more than controls for respiratory reasons and somewhat less for other somatic causes unrelated to the nervous system. There were no admissions for psychiatric causes in the group with PID other than unspecified conduct disorders. There were no differences in other diagnostic groups. The rate of inappropriate admissions was similar in the two study groups. CONCLUSIONS: In contrast to previous results reported for the group with ID as a whole, patients with PID consulting the emergency service were not admitted to hospital more frequently than the general population nor did they present a higher rate of inappropriate admissions. These results support the utility of maintaining two distinct groups of people with ID: mild-moderate and severe-profound.

Pain underreporting associated with profound intellectual disability in emergency departments.

BACKGROUND: Little information is available regarding the visits made by persons with profound intellectual disability (PID) to general hospital emergency departments (ED). This study aims to know whether persons with PID who attend ED are given the same type of diagnoses as people with no such disability. METHODS: Over a period of 18 months, we gathered data from all non-scheduled visits to an ED by persons with PID to identify the reason for consultation (according to the classification used by the Spanish Society for Emergency Nursing) and the final diagnosis upon discharge. The results were compared with data obtained from a control group of people with no ID who attended an ED for any reason during the same period. RESULTS: Somatic complaints were the main reason for ED attendance among persons with PID (90% of consultations). These complaints were more often related to the central nervous system than was the case among non-ID patients (16 vs. 4.7%), whereas other kinds of non-central nervous system somatic complaint were less common among persons with PID (74 vs. 91%). A diagnosis implying physical pain was given less often to people with PID than to controls (3 vs. 20%). CONCLUSIONS: The results suggest that persons with PID are less able to conceptualise and communicate information about their symptoms, especially as regards pain, and that this influences the diagnosis they are given when attending an ED. Professionals working in this environment need to be aware of this possibility so as not to underestimate or overlook such symptoms and the illnesses related to them.

Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.

Inherited defects of skull ossification often manifest as symmetric parietal foramina (PFM; MIM 168500). We previously identified mutations of MSX2 in non-syndromic PFM and demonstrated genetic heterogeneity. Deletions of 11p11-p12 (proximal 11p deletion syndrome, P11pDS; MIM 601224) are characterized by multiple exostoses, attributable to haploinsufficiency of EXT2 and PFM. Here we identify ALX4, which encodes a paired-related homeodomain transcription factor, as the PFM disease gene in P11pDS.

Estrogen-related genes and postmenopausal osteoporosis risk.

BACKGROUND: To date, more than 150 candidate genes related to osteoporosis have been described, but osteoporosis has increasingly been considered a polygenic disease modulated by environmental factors. It is thought that osteoporosis predisposition, pathology, and treatment response depend on the interaction between different genes or between genes and environmental factors. OBJECTIVE: The aim of this study was to evaluate the relationship between the presence of single nucleotide polymorphisms (SNPs) in the estrogen metabolic pathway and the development of osteoporosis and to determine whether this relationship is monogenic or whether interactions between genes exist. MATERIALS AND METHODS: A multicentric study with 1980 postmenopausal Spanish women in five Spanish communities was conducted. The women completed a specific questionnaire that inquired about risk factors for osteoporosis. Data on participants' bone mineral density were obtained with dual-energy X-ray densitometers, and genetic data were obtained from frozen peripheral blood. RESULTS: The digenic protection combinations indicated involvement of the wild-type genotype (WT) of the 3'UTR marker for the CYP19A1 gene, the IVS4 marker of the same gene, and the BMP15 and FSHR genes. Among patients who carried two or more of the genotypes considered 'risky', the triple combination among markers of the ESR2 and NRIP1 genes with any of the two mutations of the analyzed markers of the BMP15 gene gave a mean T-score value of -2.32±0.91 (p = 0.02). CONCLUSION: Variants of the new candidate genes (NRIP and BMP15) can predispose patients to osteoporosis.

Calcium and reactive oxygen species as messengers in endotoxin action on adrenocortical cells.

The effect of Escherichia coli 0111:B4 endotoxin (lipopolysaccharide, LPS) on the intracellular Ca2+ and reactive oxygen metabolite content of both rat isolated fasciculata-reticularis and glomerulosa cells was evaluated by flow cytometry to know the role of these mechanisms in the initiation of cell injury produced by LPS on adrenocortical cells during endotoxic shock. A rapid increase of intracellular calcium was induced by endotoxin in both cell types. In fasciculata-reticularis cells, this [Ca2+]i increase was mainly due to an important mobilization of intracellular stores. Dose-dependent increases in [Ca2+]i were also observed when both cell types were incubated with LPS for 20 min in the presence of extracellular calcium. This treatment abolished the increase in intracellular calcium induced by ACTH and angiotensin II. On the other hand, the endotoxin produced a fast and dose-dependent increase in reactive oxygen species in both cell types, higher in glomerulosa than in fasciculata-reticularis cells. LPS-pretreated cells showed more susceptibility to the oxidative stress induced by Fe2+. These results can be related to functional alterations previously described showing the involvement of calcium and reactive oxygen species as messengers in the endotoxin action on adrenocortical cells.

Rat glomerulosa cells in primary culture and E. coli lipopolysaccharide action.

During endotoxic shock there is a dysfunction of the adrenal gland; both corticosterone and aldosterone secretion are altered. The aim of the present study is to use glomerulosa cells in primary culture as a target of lipopolysaccharide (LPS) action. Glomerulosa cells cultured in basal conditions are able to proliferate; bFGF and ACTH have antagonic effects, bFGF increases proliferation whereas ACTH is antimitogenic. LPS has a biphasic effect, in the short term it is antimitogenic and in the long term increases the proliferation rate. LPS inhibits ACTH-induced corticosterone secretion in a dose-dependent manner in glomerulosa cells in culture similar to that in fasciculata cells, but it does not exert an important direct effect on aldosterone secretion. These results show that LPS exerts different effects in ACTH and ANG II signal transduction pathways and in the two enzymes which catalyze the late step in the steroidogenesis, 11beta-hydroxylase and aldosterone synthase, which could be in agreement with the existence of both enzymes, regulated independently, in rat zona glomerulosa cells.

Subendometrial contractility in menstrual phase visualized by transvaginal sonography in patients with endometriosis.

OBJECTIVE: To describe the propagation direction of the subendometrial myometrial contractile wave in menstrual phase sonographically assessed in patients with and without endometriosis. DESIGN: Prospective study. SETTING: Patients and normal volunteers in a university hospital. PATIENTS: Sixteen women with (study group) and 21 without (control group) endometriosis. INTERVENTIONS: Patients were examined by transvaginal sonography (midsaggital plane of the uterus) and recorded on videotape for a 5-minute period. MAIN OUTCOME MEASURE: Direction of propagation of contraction waves. RESULTS: The endometriosis group showed a predominant retrograde pattern whereas the control group showed a normal antegrade. CONCLUSION: This abnormal cervix-to-fundus myometrial activity could well increase the amount of peritoneal shedding of endometrial menstrual debris, increasing the probabilities of its heterotopic implantation.

Alobar holoprosencephalic embryo detected via transvaginal sonography.

The incorporation of high-frequency transvaginal probes in commercial ultrasonic equipment allows now for the earlier detection of fetal malformations and the possibility of interrupting pregnancy when such an anomaly is incompatible with postnatal life. We describe here a case of alobar holoprosencephaly associated with serious facial anomalies, diagnosed via transvaginal sonography during the 10th week of amenorrhea. A cytogenetic study was carried out by transabdominal chorial biopsy and diagnostic confirmation by necropsy was made after termination. In order to be able to counsel patients on the advisability of future pregnancies we stress the importance of making a cytogenetic study of the embryo.

Position of the Spanish Menopause Society regarding the management of perimenopause.

Perimenopause is an imprecise period in woman over 40 years of age, which comprises the time between the moment that the first changes in the menstrual cycle appear and the year following the definitive cessation of the menses. Besides irregular bleeding, many women also complain of hot flashes and other characteristic symptoms of postmenopause. Moreover, most of them are concerned about the future impact that these events may have on their health, such as needing health exams or continuing to use contraceptive methods. A panel of experts from the Spanish Menopause Society has met to establish diagnostic and therapeutic guidelines for this period based on the best available evidence.

Evaluación físico matemática de la dinámica cardiaca arrítmica mediante la aplicación de la ley exponencial caótica / Physical mathematical evaluation of the arrhythmic cardiac dynamic by means of the application of the chaotic exponential law / Avaliação físico matemática da dinâmica cardíaca arrítmica mediante a aplicação da lei exponencial caótica

Objetivo: confirmar la aplicabilidad clínica de la ley exponencial de ayuda diagnóstica específicamente en arritmias y evaluar la concordancia diagnóstica del mismo con respecto al Gold Estándar, por medio del cálculo de la sensibilidad, especificidad y el coeficiente Kappa. Metodología: se realizó un estudio de 40 Holter, 10 corresponden a sujetos normales y 30 diagnosticados con diferentes tipos de arritmias. Se realizó una simulación teórica de todas las frecuencias cardiacas de mínimo 21 horas a partir de los valores máximos y mínimos de frecuencias registrados, para construir el atractor de la dinámica cardiaca. Seguidamente se calculó la dimensión fractal del atractor y se cuantificó la ocupación espacial de cada uno ellos en el espacio generalizado de Box-counting. Finalmente, se aplicaron los parámetros matemáticos que diferencian dinámicas cardiacas normales de enfermas y agudas, así como en evolución hacia la enfermedad. Resultados: los casos con arritmias diagnosticados matemáticamente con dinámica aguda fueron seis, se encontraron 24 casos entre los rangos de 73 y 200 de ocupación de la rejilla Kp, que corresponden a casos de evolución hacia agudización de la dinámica. El diagnóstico físico-matemático, después de ser comparado con el Gold Estándar, presentó una sensibilidad y especificidad del 100% y un coeficiente Kappa de uno. Conclusiones: la aplicación de esta metodología al estudio de la dinámica cardiaca caótica, evidencia su utilidad como herramienta de ayuda diagnóstica para la predicción y prevención de eventos arrítmicos agudos que pueden implicar situaciones con riesgo vital.

Objective: To confirm the clinical applicability of the diagnostic methodology based on the power law of cardiac dynamic systems, specifically for detecting arrhythmias, evaluating its concordance with respect to the Gold Standard, by means of the sensitivity, specificity, and Kappa coefficient. Methods: Forty Holter were studied, of which 10 corresponded to normal subjects and 30 to patients diagnosed with different types of arrhythmias. A theoretical simulation of all cardiac frequencies (of at least 21 hours) was performed from the maximum and minimum frequency values registered, to build the cardiac dynamics attractor and its fractal dimension was calculated; the spatial occupation of each one of them was quantified in the generalized Box-Counting space. Finally, the mathematical parameters to differentiate normality of acute cardiac disease and of the evolution toward disease were applied. Results: There were six cases with mathematically-diagnosed acute arrhythmias, 24 cases were between 73 and 200 occupied ranges for the Kp grid that correspond to cases of evolution toward disease. This physical-mathematical diagnosis was compared with the Gold Standard and yielded a sensitivity and specificity of 100% and a Kappa coefficient of 1. Conclusions: The application of this method to the study of chaotic cardiac dynamics evidences its usefulness as a tool of diagnostic aid for the prediction of acute arrhythmic events which may imply situations of vital risk.

Objetivo: confirmar a aplicabilidade clínica da lei exponencial de ajuda diagnóstica especificamente em arritmias e avaliar a concordância diagnóstica do mesmo com respeito ao Gold Estándar, por meio do cálculo da sensibilidade, especificidade e o coeficiente Kappa. Metodologia: se realizou um estudo de 40 Holter, 10 correspondem a sujeitos normais e 30 diagnosticados com diferentes tipos de arritmias. Se realizou una simulação teórica de todas as frequências cardíacas de mínimo 21 horas a partir dos valores máximos e mínimos de frequências registrados, para construir o atractor da dinâmica cardíaca. Seguidamente se calculou a dimensão fractal do atractor e se quantificou a ocupação espacial de cada um deles no espaço generalizado de Box-counting. Finalmente, se aplicaram os parâmetros matemáticos que diferenciam dinâmicas cardíacas normais de doentes e agudas, assim como em evolução para a doença. Resultados: os casos com arritmias diagnosticados matematicamente com dinâmica aguda foram seis, se encontraram 24 casos entre as faixas de 73 e 200 de ocupação da grade Kp, que correspondem a casos de evolução para o agravamento da dinâmica. O diagnóstico físico-matemático, depois de ser comparado com o Gold Estándar, apresentou uma sensibilidade e especificidade de 100% e um coeficiente Kappa de um. Conclusões: a aplicação desta metodologia ao estudo da dinâmica cardíaca caótica, evidência sua utilidade como ferramenta de ajuda diagnóstica para a predição e prevenção de eventos arrítmicos agudos que possam implicar situações com risco vital.

Binding of Escherichia coli lipopolysaccharide to fasciculata-reticularis and glomerulosa cells evaluated by flow cytometry.

Binding of Escherichia coli lipopolysaccharide (LPS) to the two cell types of the adrenal cortex: fasciculata-reticularis and glomerulosa cells has been studied by flow cytometry and using fluorescein-labeled lipopolysaccharide (FITC-LPS). The binding characteristics were different in relation to time course and number of binding sites. Both fasciculata-reticularis and glomerulosa cells bound LPS in a specific and saturable process. Fasciculata-reticularis cells showed a higher affinity for LPS binding than glomerulosa cells as deduced from Hill plots. Unlabeled LPS decreased FITC-LPS binding in both fasciculata-reticularis and glomerulosa cells, suggesting competition of both ligands for a limited number of binding sites. Lipid A seemed not to be essential for binding of LPS to fasciculata-reticularis cells. However, serum constituents inhibited FITC-LPS binding to both cell types, possibly due to cell interaction with HDL. The exposure of cells to LPS during cell culture did not modify the number of binding sites, but revealed cell size and surfaces structure changes.

Prenatal sonographic appearance of foramina parietalia permagna.

Foramina parietalia permagna (FPP) is an extremely uncommon congenital defect, inherited as an autosomal dominant condition. Its characteristics are two symmetrical orifices in the parietal bones (not of fixed size) on both sides of the midline. This defect does not affect either the psychic or the physical development of the affected person. This paper describes the sonographic appearance of FPP in utero as an enlargement of the posterior fontanelle.

[Prenatal diagnosis of holoprosencephaly with postaxial polydactyly, cardiopathy with normal karyotype]. / Pränatale Diagnostik der Holoprosenzephalie mit postaxialer Polydaktylie, Kardiopathie bei normalem Karyotypus.

Holoprosencephaly is a malformation complex, in which the foetal forebrain (prosencephalon) fails to cleave. The aetiology of holoprosencephaly is heterogeneous. In the last years, a new malformation syndrome has been described, including holoprosencephaly, postaxial polydactyly, congenital heart defects and normal karyotype. In this report, a new case of this syndrome, prenatally diagnosed, is discussed, based on ultrasound and foetal blood sampling. The important implications are pointed out in relation to adequate genetic counselling.

Prenatal ultrasound semiography of anencephaly: sonographic-pathological correlations.

A better understanding of the ultrasound findings in each of the different types of fetal anencephaly can help to reduce the number of false-negative diagnoses of this condition during the prenatal period. Errors in the estimation of the remaining cerebral tissue (angiomatous stroma, area cerebrovasculosa) can cause false-negative diagnoses or diagnostic confusion with cases of microcephaly or incomplete ossification of the cranial vault. In a retrospective study, 30 fetuses with anencephaly (diagnosed at 13-38 weeks of gestation) were grouped, in terms of their ultrasound results, according to the Nanagas classification. The ultrasound diagnoses were then correlated with those found through autopsy, to identify any errors in the ultrasound classification.

Massive ovarian oedema.

Eighteen cases of massive ovarian oedema are presented. The age of patients averaged 26 years and 16 presented with an acute abdomen. Hormonal symptoms included virilism in three cases and one with precocious pseudopuberty. Ultrasonographic findings were variable and not diagnostically accurate. When performed, CA 125 levels were not raised. Seventy-two percent of cases occurred in the right ovary and none were bilateral. Torsion occurred in 14 cases. Salpingo-oophorectomy was performed in all cases. To elucidate its pathogenesis, be this either due to intermittent chronic torsion or to a proliferative phenomenon, immunohistochemistry for Ki-67 and PCNA proliferation antigens, alpha-actin and oestrogen and progesterone receptors was performed. The Ki-67 proliferation index ranged between 0% and 3%, demonstrating the low proliferative status of stromal cells. The PCNA indices, however, were unusually high (60% and above). The divergence between these findings is explained by the fact that PCNA positivity may be related to nuclear reparation subsequent to ischaemia. Alpha-actin was consistently positive in stromal cells, reflecting a myofibroblastic transformation of these cells. These findings together with the clinical evidence of torsion in the majority of cases, lead us to consider that ovarian oedema is a reactive, non-proliferative state of specific stromal cells, occurring as a response to torsion and subsequent ischaemia. The stromal cells have positive oestrogen progesterone receptors and may undergo stimulatory changes responsible for the hormonally related symptoms often found associated with massive ovarian oedema.