FLT3-targeted therapy restores GATA1 pathway function in NPM1/FLT3-ITD mutated acute myeloid leukaemia.

One-third of newly diagnosed adult acute myeloid leukaemia (AML) carry FLT3 mutations, which frequently occur together with nucleophosmin (NPM1) mutations and are associated with worse prognosis. FLT3 inhibitors are widely used in clinics with limitations due to drug resistance. AML cells carrying FLT3 mutations in both mouse models and patients present low expression of GATA1, a gene involved in haematopoietic changes preceding AML. Here, we show that FLT3 inhibition induces cellular responses and restores the GATA1 pathway and functions in NPM1/FLT3-ITD mutated AML, thus providing a new mechanism of action for this drug.

MR Imaging Signs of Gadolinium Retention Are Not Associated with Long-Term Motor and Cognitive Outcomes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: The long-term impact of gadolinium retention in the dentate nuclei of patients undergoing administration of seriate gadolinium-based contrast agents is still widely unexplored. The aim of this study was to evaluate the impact of gadolinium retention on motor and cognitive disability in patients with MS during long-term follow-up. MATERIALS AND METHODS: In this retrospective study, clinical data were obtained from patients with MS followed in a single center from 2013 to 2022 at different time points. These included the Expanded Disability Status Scale score to evaluate motor impairment and the Brief International Cognitive Assessment for MS battery to investigate cognitive performances and their respective changes with time. The association with qualitative and quantitative MR imaging signs of gadolinium retention (namely, the presence of dentate nuclei T1-weighted hyperintensity and changes in longitudinal relaxation R1 maps, respectively) was probed using different General Linear Models and regression analyses. RESULTS: No significant differences in motor or cognitive symptoms emerged between patients showing dentate nuclei hyperintensity and those without visible changes on T1WIs (P = .14 and 0.92, respectively). When we tested possible relationships between quantitative dentate nuclei R1 values and both motor and cognitive symptoms, separately, the regression models including demographic, clinical, and MR imaging features explained 40.5% and 16.5% of the variance, respectively, without any significant effect of dentate nuclei R1 values (P = .21 and 0.30, respectively). CONCLUSIONS: Our findings suggest that gadolinium retention in the brains of patients with MS is not associated with long-term motor or cognitive outcomes.

Towards the integration of ecophysiology with fisheries stock assessment for conservation policy and evaluating the status of the Mediterranean Sea.

Recent European Union (EU) regulations have been introduced to discourage the capture of undersized specimens with the aim of reducing the bycatch mortality imposed by commercial fisheries. We argue that we still lack accurate data regarding basic information required to properly implement these regulations for most Mediterranean ecosystems, including the true mortality imposed by fisheries, escape rates from fishing gears and the capability of specimens to survive following discard. We suggest that additional reliance on physiological biomarkers could assist in all aspects of the data collection required to support implementation of the EU discard ban (aka landing obligation), particularly in determining which species should receive special dispensation from this policy. Ideally, this new approach, here termed the 'Fisheries Environmental and Physiological Stress Analysis' (FEPSA), would become an important step for any fish stock assessment within the ecosystem approach to fisheries management and the recognition of Good Environmental Status, as established by the EU in the Marine Strategy Framework Directive (2008/56/EC). In particular, the main goal of FEPSA would be applying the study of physiological stressors to exploited stocks to estimate the so-called collateral fishing mortality, which includes the mortality experienced by fish that escape after interacting with fishing gears or that are discarded, with some degree of injury or physiological stress. The approach outlined here, which is described for bottom trawls but adaptable to any other type of fishing gear, is not a trivial undertaking but is a requirement for collecting the data required by recent EU fisheries policies. While we agree that the threats to marine biodiversity posed by fishing and associated discard practices require strong policy interventions, we emphasize that the research programs needed to support such initiatives, including the landing obligation, should be given equal priority. This is particularly true for Mediterranean fisheries, which are at a complex intersection of jurisdictional boundaries, numerous additional ecosystem threats including widespread pollution, thermal variation and hypoxia, and are historically understudied as compared to fisheries and species in more northern climates.

Olfactory function and cognition in relapsing-remitting and secondary-progressive multiple sclerosis.

BACKGROUND: Both cognition and olfaction are impaired in multiple sclerosis (MS). However, little is known about the relationship between smell identification ability and measures of cognitive function in this disease. OBJECTIVE: To assess olfactory function in MS and to evaluate its relationship with cognitive and physical disability. METHODS: Fifty-five MS patients and 20 healthy controls (HCs) were tested. The University of Pennsylvania smell identification test (UPSIT) was administered to assess olfactory function. Cognitive function was tested using the symbol digit modalities test (SDMT), California verbal learning test-II (CVLT II), brief visuospatial memory test (BVMT), paced auditory serial addition test (PASAT), and controlled oral word association test (COWAT). Fatigue and depressive symptoms were evaluated using the Modified Fatigue Impact Scale and the Beck Depression Inventory II, respectively. RESULTS: MS patients had lower UPSIT scores than those of the HCs (28.76 ±â€¯5.48 vs 31.7 ±â€¯2.18, p = 0.02), with secondary-progressive and cognitively impaired MS patients showing the greatest impairment. Scores on the SDMT, CVLTII, BVMT and COWAT were related to the olfactory test scores. CONCLUSION: We confirm that olfactory function is impaired in MS, particularly in progressive phenotypes, and show, for the first time, that such dysfunction is related to a broad range of cognitive measures. Our data suggest that olfactory dysfunction might be considered as an indirect measure of MS severity. Longitudinal studies are needed to confirm this possibility.

Detection of bovine Deltapapillomavirus DNA in peripheral blood of healthy sheep (Ovis aries).

Blood samples from 65 sheep were tested for the presence of bovine Deltapapillomavirus (δPVs) DNA. The sheep were divided into three groups. Sheep in groups 1 and 2 were from Sardinia and Campania, respectively, and were in contact with cattle and grazed on lands contaminated with bracken fern. Sheep in Group 3 lived in closed pens and had no contact with cattle. These sheep were fed hay that did not contain bracken fern. Bovine δPV E5 DNA was detected in blood from 24 of 27 (89%) sheep in Group 1. A single bovine δPV type was detected in the blood from nine (33%) sheep, including the detection of bovine δPV-1 DNA in four sheep, bovine δPV-2 in four and δPV-13 in one sheep. Two δPV types were detected in 33% of the sheep, and three bovine δPV types were detected in 22% of the sheep. Bovine δPVs were detected in 17 of 20 (85%) sheep from Group 2. The detection rate by a single δPV type was 40% with just δPV-1 DNA amplified from two, just δPV-2 DNA from four, and just δPV-13 DNA from two sheep. Two and three δPVs were detected in 30% and 15%, respectively. All sequenced amplicons showed a 100% identity with papillomaviral E5 DNA deposited in GenBank. Bovine δPV-14 DNA sequences were not detected from any sheep. No bovine δPV DNA was revealed in blood samples from sheep in Group 3. The detection of bovine δPV DNA in the blood of sheep means that sheep may be able to be infected by these PVs. This suggests that bovine δPVs could potentially be a previously unrecognized cause of disease in sheep. Furthermore, it is possible that sheep could act as a reservoir for these viruses.

Migraine with aura: which patients are most at risk of stroke?

The complex association between migraine (M) and ischemic stroke (IS) is discussed. Epidemiological studies and meta-analyses show that M with aura (MA) and not M without aura, doubles the risk of IS. The risk is higher for female gender, young age and higher headache attacks frequency. Smoking habit and oral contraceptives, especially if associated, increase stroke risk. The underlying pathogenetic mechanisms are not completely understood, but it is hypothesized that a particular brain susceptibility to cortical spread depression could explain the association between MA and IS. The absolute risk of IS in migraineurs is relatively low and an antithrombotic primary prevention is not indicated, but it is mandatory to investigate and treat associated risk factors for IS and, in young MA women, consider only progestinic oral contraceptives, if needed, and smoking cessation.

Mercury in fishes from Augusta Bay (southern Italy): risk assessment and health implication.

Our study reports on the total mercury (HgT) concentrations measured in the muscles and livers of several benthic, demersal and pelagic fish species caught inside and outside of Augusta Bay (southern Italy), a semi-enclosed marine area, highly contaminated by the uncontrolled (since the 1950s to 1978s) discharge of the largest European petrochemical plant. Mercury levels in fish tissues are discussed with regard to specific habitat, size and/or age of the specimens and HgT distribution in the bottom sediments. Results suggest a still active Hg release mechanism from the polluted sediments to the marine environment. Also, the high HgT concentrations measured in fishes caught in the external area of the bay imply a potential role of Augusta Bay as a pollutant source for the Mediterranean ecosystem. Finally, values of hazard target quotient (THQ) and estimated weekly intake (EWI) demonstrate that consumption of fishes caught inside the bay represents a serious risk for human health. Also, data indicate that intake of fishes caught from the external area of the bay, especially for that concern demersal and benthic species, could be represent a significant component of risk for the local population.

LGI1 microdeletion in autosomal dominant lateral temporal epilepsy.

OBJECTIVES: To characterize clinically and genetically a family with autosomal dominant lateral temporal epilepsy (ADLTE) negative to LGI1 exon sequencing test. METHODS: All participants were personally interviewed and underwent neurologic examination. Most affected subjects underwent EEG and neuroradiologic examinations (CT/MRI). Available family members were genotyped with the HumanOmni1-Quad v1.0 single nucleotide polymorphism (SNP) array beadchip and copy number variations (CNVs) were analyzed in each subject. LGI1 gene dosage was performed by real-time quantitative PCR (qPCR). RESULTS: The family had 8 affected members (2 deceased) over 3 generations. All of them showed GTC seizures, with focal onset in 6 and unknown onset in 2. Four patients had focal seizures with auditory features. EEG showed only minor sharp abnormalities in 3 patients and MRI was unremarkable in all the patients examined. Three family members presented major depression and anxiety symptoms. Routine LGI1 exon sequencing revealed no point mutation. High-density SNP array CNV analysis identified a genomic microdeletion about 81 kb in size encompassing the first 4 exons of LGI1 in all available affected members and in 2 nonaffected carriers, which was confirmed by qPCR analysis. CONCLUSIONS: This is the first microdeletion affecting LGI1 identified in ADLTE. Families with ADLTE in which no point mutations are revealed by direct exon sequencing should be screened for possible genomic deletion mutations by CNV analysis or other appropriate methods. Overall, CNV analysis of multiplex families may be useful for identifying microdeletions in novel disease genes.

Multiple cerebral aneurysms associated with atrial myxoma. A case report.

Cardiac myxoma is a tumor of mesenchymal origin accounting for half of all primary cardiac neoplasms. Intracranial involvement by atrial myxoma is a rare cause of neurologic deficit. When the myxoma arises in the left atrium, systemic emboli from a cardiac myxoma can lead to infarction, cerebral hemorrhage and aneurysm formation. In the light of the potentially preventable nature of these lesions, the diagnosis of myxomatous aneurysms should be considered in any patient with neurologic symptoms and a history of cardiac myxoma. Because aneurysms are often stable over several years, conservative management with careful clinical and radiological follow-up with MRI and angiography seems sensible. We describe a case in which MR imaging and angiography were used to diagnose multiple cerebral aneurysms caused by left atrial myxoma.

Unawareness of "illnesses": a case of right-sided hemiballism.

The Authors describe a non-demented patient who, after a left subthalamic haemorrhage causing hemiballism, was completely unaware of both neurological (i.e., dyskinesias) and non-neurological (i.e., cough) symptoms occurring after the stroke. In contrast, he was perfectly able to acknowledge pathological conditions affecting him before the brain damage. Neuropsychological assessment showed no cognitive defects, but revealed the presence of frontal behaviours (e.g., perseverations and utilization behaviours). This unusual clinical picture was ascribed to damage of frontal-subcortical circuits involved in conscious representation of current bodily states.

Recurrent Intraventricular Hemorrhages Caused by an AVM Detected by Angiography with Initially Normal Angiogram.

Primary intraventricular haemorrhage (PIVH) is an uncommon type of non-traumatic cerebral haemorrhage limited to the ventricular system arising in adults and children, with diverse aetiology and variable course. Vascular malformations account for 34% of PIVH, whereas no cause is found in 21-47%. When a primary intraventricular haemorrhage is detected in a young patient an underlying lesion such as an arteriovenous malformation (AVM) must be ruled out. The diagnosis may be suspected when there is sudden onset of headache, nausea and vomiting with or without a reduced level of consciousness. Nevertheless, even if clinical features suggest the diagnosis of PIVH, cerebral computed tomography (CT) scan is required for confirmation, and magnetic resonance imaging (MRI) and catheter angiography are necessary to establish the aetiology. We describe a case of isolated recurrent intraventricular haemorrhages caused by AVM detected by diagnostic intracranial angiography with no abnormality demonstrated on angiography four years earlier.

Electroclinical evolution in ring chromosome 20 epilepsy syndrome: a case with severe phenotypic features followed for 25 years.

Intractable epilepsy and peculiar EEG patterns characterize ring chromosome 20 syndrome [r(20)], while dysmorphic features, mental retardation and behavioural disturbances are widely variable. The clinical evolution of r(20) over time is not well defined as relatively few cases have been reported. Here we describe a patient with severe clinical features followed for a 25-year period. The patient was subjected to clinical, psychometric and EEG evaluation twice a year from the age of 21 years. Cytogenetic studies, using chromosome analysis and fluorescence in situ hybridization (FISH) and several immunological investigations were performed. Ring chromosome 20 was found in 50% of examined metaphases with the deletion of subtelomeric regions 20p and 20q. Our patient presented with marked dysmorphic features, severe mental retardation, tetraparesis, dysarthria and intractable epilepsy with onset during the first year of life. During follow up, EEG findings and clinical features progressively worsened: a progressive disorganization of background EEG activity occurred and mental and motor impairment evolved. The severity of clinical expression depended on the extent of chromosomal deletion and on the haploinsufficiency of other important related genetic loci due to ring instability. The progressive worsening of both clinical and EEG features over a long period, which has also been reported by other authors, further characterized this syndrome.

Development of a questionnaire for the assessment of sources of stress in Spanish soccer referees

El objetivo de este estudio consistió en la elaboración de un instrumento de evaluación que identificara las principales fuentes de estrés en los árbitros de fútbol españoles, y que posibilitara la identificación de individuos con niveles elevados de estrés en este tipo de población. El Cuestionario de Estrés de Árbitros de Fútbol (CEAF) se desarrolló a partir de una muestra de 138 árbitros, y el análisis de componentes principales con rotación varimax produjo una solución de 5 factores que explicaban el 65.7% de la varianza. La versión definitiva del cuestionario obtuvo un aIpha de Cronbach de 0.88. Los estresores más importantes se relacionaban con la competencia arbitral percibida y con la evaluación que el árbitro recibe del informador en los partidos

The aim of the present study was to elaborate a self-report questionnaire to identify Spanish soccer referees' sources of stress and to provide a tool for the detection of referees with high levels of stress. The Soccer Referee Stress Questionnaire was administered to a sample of 138 referees, and a principal component analysis with varimax rotation revealed a S-factor solution that accounted for 65.7% of the variance. The final version of the test had a Cronbach's alpha of 0.88. The most important sources of stress were related to the referee's perceived competence and, to the referee-supervisor's rating ofmatches

Sentinel headache.

Patients with subarachnoid haemorrhage (SAH) frequently describe the occurrence of an underestimated or even ignored severe headache in the days or weeks preceding the bleeding. If recognised early, this warning headache might lead to specific investigations and, if indicated, a surgical approach might avoid a dramatic haemorrhagic event. In a recent and exhaustive systematic review, the incidence of a sentinel headache (SH) was evaluated in a range of 10-43% of SAH patients. SH seems to be due to a minor bleeding from a leak of a berry aneurysm and usually occurs in the preceding two weeks. Such a period is similar to the one for rebleeding in SAH and supports the hypothesis of the warning leak. Nevertheless, a warning headache can precede a SAH in unruptured aneurysm even without a minor bleeding. Underestimation or misdiagnosis of SH depends on incorrect evaluation of the headache characteristics (unusual, severe, abrupt, thunderclap), overestimation of cranial CT sensitivity (false negative increasing over the elapsing time), failure to perform lumbar puncture (LP) in patients with negative CT, incorrect evaluation of CSF findings (xanthochromia may be absent in the first 12 h) and failure to differentiate traumatic tap from true SAH. Considering the diagnosis of SH in all cases of a severe, sudden-onset (thunderclap) headache, and performing all the appropriate diagnostic exams, including LP if necessary, could prevent subsequent massive bleeding and its invalidating or fatal consequences.

Severe systemic allergic reaction induced by accidental skin contact with cow milk in a 16-year-old boy. A case report.

The symptoms of food allergy are rarely induced by skin contact. A 16-year-old boy was referred to our Allergology Centre after an episode of systemic symptoms triggered by accidental skin contact with a drop of cow milk (CM) dripped from a sandwich containing fresh cheese. The patient had been allergic to CM from the age of 24 months and had experienced several episodes of urticaria-angioedema after the ingestion of tiny or "hidden" amounts of CM proteins. In vivo and in vitro diagnostic procedures showed intense sensitisation to all CM proteins (1/100 dilutions of allergenic extracts produced large wheals, and class 4 specific IgE antibodies. Total IgE antibodies were elevate (770.0 UI/). A moderate degree of bronchial hyperresponsiveness was found (PC20 metacholine: 3.90 milligrams). This case report suggests that patients with a high degree of sensitisation to CM proteins should be alert to the danger of skin contact and should beware of "hidden" CM allergens.

Bioptically demonstrated Lafora disease without EPM2A mutation: a clinical and neurophysiological study of two sisters.

Lafora disease (LD) is an autosomal recessive inherited form of progressive myoclonic epilepsy with dementia and ataxia, usually presenting in the second decade of life and inexorably progressing until death. Neuropathological hallmarks are Lafora bodies, intracytoplasmic inclusions that can be found in neurons and in other tissues. LD gene (EPM2A), mapping on chromosome 6, encodes for a tyrosine phosphatase protein called laforin. However, up to 20% cases of LD are not genetically linked to chromosome 6. We report two sisters affected from bioptically diagnosed LD but without evidence of EPM2A mutation. Although familial cases of LD are already reported in literature, our observation leads to some considerations on clinical-electrophysiological evolution as well as to remark the genetic heterogeneity of this condition. In addition, we report the good effect of the Levetiracetam for the treatment of myoclonus in these patients, also demonstrated by the electrophysiological findings.

[Round atelectasis of the lung: clinicopathological study of 6 cases and review of the literature]. / Atelettasia rotonda del polmone: studio clinicopatologico di 6 casi e revisione della letteratura.

OBJECTIVE: To report about 6 new patients with round atelectasis of the lung, 1 of them professionally exposed to asbestos and another to silicates. RESULTS: The patients, 5 males and 1 female, presented with a peripheral, rounded pulmonary opacity, simulating a neoplasm. The examination of the surgical specimen revealed a pleuritis, with multiple pleural folding: the underlying lung parenchima was compressed, but otherwise unremarkable. CONCLUSIONS: Round atelectasis is relatively unusual for the pathologist. However, the correct diagnosis is potentially important, because the lesion can be the sign of a significant asbestos exposure.