Genome-scale definition of the transcriptional programme associated with compromised PU.1 activity in acute myeloid leukaemia.

Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML-RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild-type PU.1. PU.1 induction caused transition from leukaemia phenotype to monocytic differentiation. Global binding maps for PU.1, CEBPA and the histone mark H3K27Ac with and without PU.1 induction showed that mutant PU.1 retains DNA-binding ability, but the induction of wild-type protein dramatically increases both the number and the height of PU.1-binding peaks. Correlating chromatin immunoprecipitation (ChIP) Seq with gene expression data, we found that PU.1 recruitment coupled with increased histone acetylation induces gene expression and activates a monocyte/macrophage transcriptional programme. PU.1 induction also caused the reorganisation of a subgroup of CEBPA binding peaks. Finally, we show that the PU.1 target gene set defined in our model allows the stratification of primary human AML samples, shedding light on both known and novel AML subtypes that may be driven by PU.1 dysfunction.

Outcomes of percutaneous tracheostomy.

AIM: Percutaneous dilatational tracheostomy (PDT) is one of the most commonly performed procedures in critically ill patients receiving mechanical ventilation. Although many papers have compared different PDT techniques, few records on the outcome of tracheostomized patients after intensive care unit (ICU) discharge are available. METHODS: Prospective observational study to evaluate efficacy, safety and long-term consequences of PDT performed over a 6-year period (January 2002-December 2007) in a combined medical/surgical ICU in Rho, Milan, Italy. A total of 181 patients were subjected to PDT, 26.5% with the Ciaglia technique and 73.5% with the Percu-twist technique. RESULTS: The main endpoints that were examined were complications related to PDT and the final outcome of tracheostomized patients. Early complications included minor bleeding in 4 patients, stomal infection in 8 patients, and the occurrence of hypoxic/desaturation events during the procedure in 3 cases. Late complications included: tracheal stenosis in a single case, recurrent stomal granuloma in 2 cases, and tracheal mucosa injury caused by the endotracheal tube cuff in 3 patients. All patients who were decannulated late underwent bronchoscopic follow-up at 3, 6 and 12 months. Hospital discharge: of the 137 patients alive at the time of discharge from the hospital, 115 were decannulated (40 early decannulation, 75 late decannulation). In total, 22 patients were never decannulated (14 breathed spontaneously whereas 8 needed ventilator support). In the group of patients that were decannulated late, the mortality rate at 1 year was 20.6%. CONCLUSIONS: PDT-related early complications without clinical consequences were observed. Conversely, late complications were infrequent but had significant clinical implications. Although late decannulation is the major risk for complications, in 83.9% of cases tracheostomy is only a temporary measure.

Anatomy of the episodic buffer: a voxel-based morphometry study in patients with dementia.

In 2000 Baddeley proposed the existence of a new component of working memory, the episodic buffer, which should contribute to the on-line maintenance of integrated memory traces. The author assumed that this component should be critical for immediate recall of a short story that exceeds the capacity of the phonological store. Accordingly, patients with Alzheimer's dementia (AD) should suffer of a deficit of the episodic buffer when immediate recall of a short story is impossible. On the other hand, the episodic buffer should be somewhat preserved in such patients when some IR can occur (Baddeley and Wilson, 2002). We adopted this logic for a voxel-based morphometry study. We compared the distribution of grey-matter density of two such groups of AD patients with and of a group of age-matched controls. We found that both AD groups had a significant atrophy of the left mid-hippocampus; on the other hand, the anterior part of the hippocampus was significantly more atrophic in patients who were also impaired on the immediate prose recall task. Six out of ten patients with no immediate recall were spared at "central executive" tasks. Taken together our findings suggest that the left anterior hippocampus contributes to the episodic buffer of the revised working memory model. We also suggest that the episodic buffer is somewhat independent from the central executive component of working memory.

[Cornea donation: role of the local coordinator in monitoring and implementation]. / Attività di prelievo di cornea. Ruolo del coordinatore locale nel monitoraggio e nell'implementazione.

BACKGROUND: In order to contribute to the dissemination of an organ and tissue donation culture, the authors report the results of a retrospective investigation into the donation of corneas for transplantation relative to the period from January 1997 to December 2001 at a leading hospital in the Milan area. METHODS: All cases of intra-hospital death (n=2137) were considered. The adoption of a selection protocol for potential donors, in accordance with the indications of the North Italy Transplant program, and constant monitoring on the part of the local coordinator, led to the collection of 348 corneal flaps using the procedure whereby all deaths have to be notified to the Health Department. RESULTS: Over this period, the donors/deaths ratio increased from 2.1 to 17.6%, while the collection index (real donors/potential donors including those wrongly excluded) increased from 40.8% in 1999-2000 to 67.8% in 2001. Most involved in the donor selection activity were the intensive care centres with an increase for Resuscitation of 12.7% and for First Aid of 33%, to a lesser extent non-intensive centres (increase of 11.2%). The causes of exclusion from cornea collection in the last three-year period were clinical contraindications in 51.2% of cases (sepsis, blood transfusions, diseases of the central nervous system of unknown aetiology), failure to activate the procedures in 17.4% of cases, opposition in 17%, unsuitability of the corneal tissues in 11.3%, inadequate age in 3%. CONCLUSIONS: The results obtained indicate good prospects for technical implementation and for the development of a donation culture in respect of other organs and tissues.

[Initial epidemiological data on the clinical effects in health workers employed in the manual lifting of patients in wards]. / Primi dati epidemiologici sugli effetti clinici negli operatori sanitari addetti alla movimentazione manuale di pazienti nei reparti di degenza.

An investigation was carried out by teams from various centres coordinated by the EPM (Ergonomics of Posture and Movement) Research Unit on 54 different hospitals in various regions of northern and central Italy. The teams examined a total of 3341 health workers whose job involved manual handling of patients (553 male and 2788 females, 1568 working in hospitals and 1773 in geriatric residences). Numerous meetings were held to ensure that the methods of assessing the exposure indexes and spinal impairment were identical in the various teams. The final data were processed centrally at the EPM Research Unit. The sample analyzed may be considered as representative of the situation in hospitals in Italy, at least for northern and central Italy. The mean age was 36 years, mean length of service in the department 6 years and mean length of job duration not exceeding 10 years; staff turnover was high. Physical examination revealed that 8.4% of the workers had had at least one episode of acute low back pain in the previous 12 months: i.e., 4 times the values of the reference groups. Also in the case of clinical-functional spondyloarthropathies of the lumbosacral spine, in the females there was a significantly higher prevalence than in the reference groups. All disorders were more severe in sectors more at risk, i.e., old peoples homes, rehabilitation centres, orthopaedic and surgical departments, and in any case higher in old peoples homes and geriatric residences. The initial data concerning the ratio between presence of spinal disease and risk index were also positive.

[The management of the risk due to the manual lifting of patients in a hospital risk-management program]. / La gestione del rischio da movimentazione manuale dei pazienti in un programma di gestione dei rischi ospedalieri.

Application of Law 626/94 in the health care area is still only partial and in many respects practically in the initial stages. This is due to a number of causes, including the special features of this sector and the extreme variability and diffusion of the risk factors involved. Assessment of risk, especially the newest ones (from manual patient handling to biological agents) involves considerable difficulties, also because the usual methods cannot be applied. The process of assessment and especially the management of risks in this sector is an extremely complex problem, and to address it requires the creation of an organized structure within the hospital consisting of a general manager, or a person delegated by the same, the medical director, the administrative director, the certified occupational physician, the director of prevention and protection. This management team must be flexible in character, draw up strategic plans according to priority criteria, periodically assess the state of advancement of the plans that will be carried out in phases. It is also necessary to ensure the active cooperation of worker safety representatives and of other experts who may be involved in the various topics addressed from time to time. The authors propose a method used in a three-year project, still under way, for the assessment of risk due to manual patient handling in a major Italian hospital; the data obtained from an assessment made in 58 wards were the following: about 60% of the wards showed a medium-high exposure level, 24% negligible exposure levels and 13.8% zero exposure due to the absence of disabled patients. On the basis of the initial data obtained from health surveillance programmes on a group of 431 exposed subjects, about 10% were judged fit with limitations due to spinal disorders. The main problems that have arisen (management, organisation, training, transfer of workers with limited job fitness, accreditation) are discussed. The method proposed for management of risk due to manual handling of patients is considered suitable for other risk factors, within the framework of a more far reaching programme for application of Law 626/94, as a means of permanent management of risk in a particularly complex working environment such as that of a hospital.

[Chemical and physical characteristics and toxicology of man-made mineral fibers]. / Caratteristiche chimico-fisiche e tossicologia delle fibre minerali artificali.

The evidence for the adverse health effects following exposure to asbestos (i.e. fibrogenic and carcinogenic effect) has prompted widespread removal of asbestos-containing materials and led to banning of asbestos internationally (in Italy, DPR 257/1992), resulting in the increased use of substitutes composed of both naturally occurring and synthetic materials, including man made mineral fibres (MMMFs) and man made organic fibres (MMOF). MMMFs represent a family of synthetic, inorganic vitreous substances derived primarily from glass, rock, slag, or clay. MMMFs are further divided into two categories: 1) man made vitreous fibres (MMVFs), further divided as follows: a) fibrous glass, including mainly continuous filament, special purpose fibres; and microfibres. The materials are typically composed of oxides of silicon, calcium, sodium, potassium, aluminum, and boron. b) Mineral wool, including glass wool, rock wool (derived from magma rock) and slag wool (made from molten slag produced in metallurgical processes such as the production of iron, steel, or copper). The main components of rock wool and slag wool are oxides of silicon, calcium, magnesium, aluminum, and iron. 2) Refractory/ceramic fibres, amorphous or partially crystalline materials made from kaolin clay or oxides of aluminum, silicon or other metal oxides (i.e. oxides of zirconium and yttrium). Less commonly, refractory fibres are also made from non-oxide refractory materials such as silicon carbide, silicon nitride, or boron nitride. Industrial production of MMVFs began in the second half of the 19th century, while ceramic fibres production began more recently, in the early 1970s. Major uses of MMMFs include thermal, acoustic and aerospace insulation, fire proofing, reinforcing material in plastics, cement and textile, optic fibres, air and liquid filtration, friction products, refractory coatings. Serious questions have been raised about health implications of MMMFs. Suspicion about the possible occurrence of adverse effects following exposure to MMMFs arises mainly from some similarities of MMMFs with asbestos (fibrous aspects, inhalability, chemical composition, free radical formation). The fibre characteristics that have been identified as crucial in influencing the pathogenesis of fibre-related adverse respiratory effects can be mainly divided into two groups: fibre dimension, and chemical composition and structure. Fibre dimension plays a determining role in conditioning penetration in the lung. In a broad sense, the term "respirable" means "capable of being carried by breath into the respiratory system". For regulatory purposes, "respirable fibres" (i.e. RFP) are defined in most countries following WHO criteria: length > 5 microns, diameter < 3 microns, length/diameter > 3. MMMFs are generally produced as fibres of diameter higher than asbestos, and too large in diameter to be respirable. Moreover, due to the production process, they are structurally amorphous. Since MMMFs have no crystalline domains, they also have no clearly defined structural faults and they fracture transversely, and randomly. Fragments that are too large to be taken up by macrophages can be resolved in the lung by a leaching--or dissolution--process which leads to a progressive reduction of particle length. In contrast, when abraded, asbestos tends to split longitudinally into new, fine, straight fibres: these fibrils are of much smaller diameter, more respirable, and consequently more hazardous than parent fibres. Fibre chemical composition plays a determining role in conditioning the higher or lower biological activity, durability, biopersistence, and biodegradability. The term "biological activity" means reactivity or ability to interact (possibly due to formation of active oxygen species, identified as a crucial step in the mechanism of action) with biological structures and tissues. Fibre "durability" is strictly related to its solubility. It can be defined as the ability to resist

[Cognitive evaluation of patients with temporal epilepsy, candidates for surgery]. / Valutazione cognitiva dei pazienti con epilessia temporale candidati ad intervento chirurgico.

We provide a short overview on selected aspects of the neuropsychology of patients with temporal lobe epilepsy candidate to surgery. The possible impairment of verbal and non verbal memory is treated in particular. We also present the neuropsychological test battery that we use for the cognitive assessment of such patients before surgery and in the follow-up phase.