Hemorragia intraparenquimatosa relacionada con embolismo venoso secundario a isquemia mesentérica / Intraparenchymal hemorrhage related to cerebral venous air embolism secondary to mesenteric ischemia

Introducción: La presencia de aire en estructuras vasculares cerebrales puede condicionar una sintomatología neurológica y una importante morbilidad. Suele producirse como consecuencia de procedimientos terapéuticos invasivos y es muy infrecuente que el desencadenante sea otro. Caso clínico: Mujer de 76 años con antecedente de fibrilación auricular anticoagulada con acenocumarol. Acudió a urgencias por dolor abdominal de inicio brusco, vómitos y diarrea. Tras iniciar tratamiento sintomático y evidenciar analíticamente infradosificación del anticoagulante, presentó bruscamente focalidad neurológica. La tomografía computarizada craneal evidenció una hemorragia intraparenquimatosa aguda. Se trasladó a la paciente a la unidad de ictus del hospital de referencia. En cuestión de unas horas, presentó inestabilidad hemodinámica por shock séptico de causa abdominal. La tomografía computarizada abdominal evidenció extensa neumatosis intestinal y una interrupción al paso de contraste subsidiario de una isquemia mesentérica. Se intentó una trombectomía mecánica para embolizar el trombo a un nivel más distal, pero la paciente falleció. Conclusiones: La isquemia mesentérica puede causar una importante neumatosis intestinal, que, por un mecanismo retrógrado a través del sistema portal, consiga la llegada de burbujas de aire al sistema venoso cerebral, causando un ictus agudo.(AU)

Introduction: The presence of air in vascular structures of the brain can lead to neurological symptoms and significant morbidity. It usually occurs as a consequence of invasive therapeutic procedures and is very rarely triggered by any other cause. Case report: We report the case of a 76-year-old woman with a history of atrial fibrillation anticoagulated with acenocoumarol who visited the Emergency department because of sudden-onset abdominal pain, vomiting and diarrhoea. After starting symptomatic treatment and finding analytical evidence of underdosing of the anticoagulant, she suddenly presented with neurological focus. A cranial computed tomography scan revealed an acute intraparenchymal haemorrhage. The patient was transferred to the stroke unit of the referral hospital. Within a few hours, she developed haemodynamic instability due to a septic shock that had its origin in the abdomen. A computed tomography scan of the abdomen evidenced extensive pneumatosis intestinalis and an obstruction of contrast indicating mesenteric ischaemia. A mechanical thrombectomy was performed in an attempt to embolise the thrombus at a more distal level, but the patient died. Conclusions: Mesenteric ischaemia can cause significant pneumatosis intestinalis, which, by a retrograde mechanism through the portal system, can cause air bubbles to reach the cerebral venous system, leading to acute stroke.(AU)

[Intraparenchymal hemorrhage related to cerebral venous air embolism secondary to mesenteric ischemia]. / Hemorragia intraparenquimatosa relacionada con embolismo venoso secundario a isquemia mesentérica.

INTRODUCTION: The presence of air in vascular structures of the brain can lead to neurological symptoms and significant morbidity. It usually occurs as a consequence of invasive therapeutic procedures and is very rarely triggered by any other cause. CASE REPORT: We report the case of a 76-year-old woman with a history of atrial fibrillation anticoagulated with acenocoumarol who visited the Emergency department because of sudden-onset abdominal pain, vomiting and diarrhoea. After starting symptomatic treatment and finding analytical evidence of underdosing of the anticoagulant, she suddenly presented with neurological focus. A cranial computed tomography scan revealed an acute intraparenchymal haemorrhage. The patient was transferred to the stroke unit of the referral hospital. Within a few hours, she developed haemodynamic instability due to a septic shock that had its origin in the abdomen. A computed tomography scan of the abdomen evidenced extensive pneumatosis intestinalis and an obstruction of contrast indicating mesenteric ischaemia. A mechanical thrombectomy was performed in an attempt to embolise the thrombus at a more distal level, but the patient died. CONCLUSIONS: Mesenteric ischaemia can cause significant pneumatosis intestinalis, which, by a retrograde mechanism through the portal system, can cause air bubbles to reach the cerebral venous system, leading to acute stroke.

TITLE: Hemorragia intraparenquimatosa relacionada con embolismo venoso secundario a isquemia mesentérica.Introducción. La presencia de aire en estructuras vasculares cerebrales puede condicionar una sintomatología neurológica y una importante morbilidad. Suele producirse como consecuencia de procedimientos terapéuticos invasivos y es muy infrecuente que el desencadenante sea otro. Caso clínico. Mujer de 76 años con antecedente de fibrilación auricular anticoagulada con acenocumarol. Acudió a urgencias por dolor abdominal de inicio brusco, vómitos y diarrea. Tras iniciar tratamiento sintomático y evidenciar analíticamente infradosificación del anticoagulante, presentó bruscamente focalidad neurológica. La tomografía computarizada craneal evidenció una hemorragia intraparenquimatosa aguda. Se trasladó a la paciente a la unidad de ictus del hospital de referencia. En cuestión de unas horas, presentó inestabilidad hemodinámica por shock séptico de causa abdominal. La tomografía computarizada abdominal evidenció extensa neumatosis intestinal y una interrupción al paso de contraste subsidiario de una isquemia mesentérica. Se intentó una trombectomía mecánica para embolizar el trombo a un nivel más distal, pero la paciente falleció. Conclusiones. La isquemia mesentérica puede causar una importante neumatosis intestinal, que, por un mecanismo retrógrado a través del sistema portal, consiga la llegada de burbujas de aire al sistema venoso cerebral, causando un ictus agudo.

The JAK2 46/1 haplotype does not predispose to CALR-mutated myeloproliferative neoplasms.

Somatic mutations in the CALR gene were recently discovered in a substantial proportion of Philadelphia-negative chronic myeloproliferative neoplasm (cMPN) patients lacking JAK2 and MPL mutations. Somatically acquired defects are not the only pathogenic mechanism involved in these disorders. Since germline JAK2 46/1 haplotype predisposes to cMPN-associated mutations, including JAK2V617F and MPLW515K7L, we evaluated whether the 46/1 haplotype also confers susceptibility to CALR-mutated cMPN, both in sporadic and familial cases. The single-nucleotide polymorphism rs10974944, which tags 46/1, was investigated in 155 sporadic MPN patients and 270 unrelated controls, as well as in 11 familial cMPN cases and 36 unaffected relative controls. As described elsewhere, the 46/1 haplotype was overrepresented, both in sporadic and familial cMPN. In sporadic cMPN, the JAK2 46/1 haplotype was closely associated with JAK2V617F (p = 0.0003) but not with JAK2-nonmutated cases. Analysis of CALR-mutated sporadic cMPN (n = 22) showed no association between CALR mutations and 46/1 haplotype (p = 0.87). Regarding the familial cMPN, the prevalence of carriers of the G allele was higher in familial (81.8%) than in sporadic (62%) cMPN, but it did not differ significantly (p = 0.3). Although we described a family with carriers of both JAK2V617F and CALR mutations, due to the low number of CALR-mutated familial cases, we could not determinate whether the JAK2 46/1 haplotype predisposes or does not to CALR-mutated familial cMPN. We conclude, for the first time, that the 46/1 haplotype, unlike JAK2V617F and MPLW515K7L, is not associated with CALR-mutated cMPN.

Caracterización de tres mutaciones en el gen de la antitrombina / Identification of three mutations in the antithrombin gene

La antitrombina es el principal anticoagulante hemostático. Desde que el hematólogo Egeber descubriera en 1965 la primera deficiencia de antitrombina asociada a un aumento del riesgo trombótico, numerosos trabajos han identificado familias con deficiencia de antitrombina asociada a una significativa incidencia de trombosis venosa. Este trabajo recoge el estudio de 3 familias trombofílicas españolas con deficienciacongénita de antitrombina. En dos identificamos mutaciones en el gen de la antitrombina no descritas hasta la fecha: InsT7429-30 y Lys125Arg. En la tercera detectamos una variante, la antitrombina Cambridge II (Ala384Ser) identificada con elevada frecuencia en población británica. Valoramos su frecuencia en población española y su papel en el desarrollode trombosis venosa mediante un estudio de asociación caso-control en 1018 pacientes de trombosis venosa y 1018controles. Comprobamos que la antitrombina Cambridge II es una alteración no restringida a población británica, estando presente en el 0.2% de la población española pero en un 1.7% de los pacientes con trombosis venosa. Así, el alelo mutado incrementó 9.75 veces el riesgo trombótico. Además, esta mutación es la principal causa de deficiencia de antitrombina en pacientes con trombosis venosa. Finalmente destacamos que la antitrombina Cambridge II únicamente puede ser detectada por métodos moleculares. Todos estos resultados aconsejan el estudio de la antitrombina Cambridge II en los estudios trombofílicos rutinarios

Antithrombin is the most important haemostatic anticoagulant. Since, in 1965 Egeber described the first antithrombin deficiency associated with an increase of thrombotic risk, many studies have identified families with antithrombin deficiency that caused a significantly increase in the risk of venous thrombosis. We studied three thrombofilic families with congenital antithrombin deficiency. In two of them, we identified mutations in antithrombin gene not described previously: InsT7429-30 and Lys125Arg. In the third family, we detected a variant, antithrombin Cambridge II (Ala384Ser) that had a high frequency in British population. We have evaluated the prevalence of this mutation in Spanish population, and its role in venous thrombosis in a case-control study including 1018 patients with venous thrombosis and 1018 healthy controls. We confirmed that antithrombin Cambridge II is not restricted to British population, as we observed this mutation in 0.2% of Spanish population and in 1.7% of patients with venous thrombosis. The mutated allele increased 9.75 fold the risk of venous thrombosis. Moreover, this mutation was the main cause of antithrombin deficiency among patients with venous thrombosis. Finally, we point that this variant can only be detected by molecular methods. All our data support the study of antithrombin Cambridge II in routine thrombophilic tests

The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol.

BACKGROUND: The efficacy of oral anticoagulant therapy is largely conditioned by both environmental and genetic factors. OBJECTIVES: To attempt to define the genetic profile involved in the response to this treatment. PATIENTS AND METHODS: We selected 100 men younger than 75 years, with non-valvular atrial fibrillation, who started anticoagulation with acenocoumarol following the same protocol: 3 mg for three consecutive days. Then, doses were individually adjusted to achieve a steady International Normalized Ratio (INR). The basal plasma level and the level after 3 days were obtained, and the INR was determined. We studied five functional polymorphisms: FVII -323 Del/Ins, CYP2C*9, VKORC1 c1173t, calumenin (CALU) R4Q and CALU a29809g. The dose required for a steady INR was also recorded. RESULTS: Only the VKORC1 genotype had significant impact on the efficacy of therapy. Carriers of the 1173t allele were significantly more sensitive to therapy for 3 days [INR 2.07 (1.59-2.87) vs. 1.74 (1.30-2.09); P = 0.015] and they needed lower acenocoumarol doses to stabilize their INR (15.8 +/- 5.6 vs. 19.5 +/- 6.0 mg week(-1); P = 0.004). Its effect was exacerbated by combination with the CALU a29809g polymorphism. Carriers of both variants (27% of the sample) achieved the highest INR [2.26 (1.70-3.32)] and required the lowest dose (14.1 +/- 5.1 mg week(-1)). This genetic profile was particularly relevant in patients with INR >or= 3.5 at the start of therapy (P = 0.005; odds ratio = 6.67, 95% confidence interval = 1.32-37.43). CONCLUSIONS: Our results suggest that CALU a29809g might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy, and confirm that specific genetic profiles defined by different polymorphisms will determine the initial response and dose required to achieve a stable and safe INR.

Administration of post-autologous PBSCT rhG-CSF is associated with long-term low concentrations of bone marrow hematopoietic progenitor cells.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been widely used after autologous peripheral blood stem cell transplant (APBSCT) in an attempt to reduce the duration of neutropenia, but whether this treatment has any influence on long-term engraftment remains unknown. We have retrospectively analyzed data from breast cancer patients to compare post-APBSCT rhG-CSF administration in terms of the short-term benefit and myeloid marrow regeneration after 1 year. Group A included 10 patients not treated with post-APBSCT rhG-CSF, while groups B and C comprised 15 and 13 patients treated with this drug from days +1 and +6, respectively. No differences among the three groups were found in age, diagnosis, previous chemo-radiotherapy, CD34+/CD71- cell concentration in pre-transplant bone marrow (BM), mobilization schedule, CD34+ cell yield, conditioning regimen and post-transplant radiotherapy. Post-APBSCT rhG-CSF was shown to accelerate neutrophil recovery, but there were no significant differences in platelet recovery, transfusion requirements, days of fever, antibiotic administration or inhospital stay. With regard to BM hematopoietic precursors 1 year after APBSCT, significantly lower concentrations of total CD34+ cells, committed CD34+/CD33+ subsets, and more immature CD34+/CD71- cells were found in both groups B and C compared with patients not having received the cytokine (group A). Thus, post-APBSCT rhG-CSF administration does not appear to beneficially affect procedure outcome, and might even impair long-term marrow hematopoiesis.

Cloning of the full length pig PIT1 (POU1F1) CDNA and a novel alternative PIT1 transcript, and functional studies of their encoded proteins.

PIT1 is an essential regulatory gene of growth hormone (GH), prolactin (PRL) and thyrotropin beta subunit (TSHbeta). Previously, a partial pig PIT1 cDNA and a genomic clone of the entire 3' end of the PIT1 gene was isolated, and polymorphisms at PIT1 were associated with several performance traits in the pig. In order to understand the biological function of the pig PIT1 gene and its possible application in swine genetics, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to complete the cloning of the full length cDNA for pig PIT1. The pig PIT1 cDNA and its deduced protein sequence have approximately 90% and 95% identity, respectively, with the PIT1 cDNA and protein of other mammals (human, bovine, sheep and rodents). Surprisingly, sequence comparison to other pig PIT1 sequences indicated only approximately 93% identity. Additional sequencing confirmed our sequence, and identified a new polymorphism in exon 4. Phylogenetic analysis of several mammalian PIT1 sequences indicates sequencing errors may account for the discrepancies observed in the other pig sequences reported. Several PIT1 alternative spliced forms were also identified by RT-PCR. They were the delta3PIT1 (missing entire exon 3), delta4PIT1 (missing entire exon 4) and PIT1beta (additional 26 amino acids inserted in front of exon 2) transcripts. The delta4PIT1 and PIT1beta transcripts have been found to encode functionally different proteins in rodents. The delta3PIT1 transcript is a novel isoform of PIT1. Potentially different functions between pig delta3PIT1 and PIT1 were analyzed by expressing these proteins in bacteria. The E. coli-expressed PIT1 and delta3PIT1 proteins were used with rat growth hormone (rGH) and rat prolactin (rPRL) promoter DNA in DNA mobility shift assays. The results showed that pig PIT1 can specifically bind rGH and rPRL promoter regions, but that the pig delta3PIT1 cannot, even at very high protein concentrations. Possible protein-protein interactions between delta3PIT1 and PIT1 were tested by mixing protein extracts before the gel shift assay, and the results showed that delta3PIT1 protein did not affect PIT1 binding to its target DNA. These data demonstrate the functionality of the PIT1 cDNA cloned in this study, and identify a novel delta3PIT1 transcript which encodes a protein that cannot bind rGH/rPRL target sequences.