Prion pathology in the brainstem: clinical target areas in prion disease

Prion diseases are fatal transmissible neurodegenerative disorders characterized by spongiform changes, neuronal loss, reactive astrocytosis, and deposition of disease associated prion protein (PrP). Our aim was to investigate "clinical target areas" for prion disease, responsible for disease onset, progression, and the clinical phenotype, using PrP overexpressing MloxP and PrP depleted NFH-Cre/MloxP transgenic mouse lines. Upon infection with different prion strains NFH-Cre/MloxP mice have significantly longer survival than MloxP mice (first set of experiments: Me7, ~29 weeks vs. ~17 weeks; Mouse-adapted BSE , ~33 weeks vs. ~20 weeks; second set of experiments: RML, ~35 weeks vs.12 weeks; Me7 ~29 weeks, vs. ~17 weeks; MRC2 ~31 weeks vs. ~22 week. As we found that the first pathological changes in the brains of Me7 and Mouse–adapted BSE infected mice are localized in the brainstem, and clinical signs of prion disease point to brainstem failure, we quantitatively scored spongiosis, abnormal PrP accumulation and astrogliosis at early and late stage of disease in specific brainstem nuclei of RML and Me7 infected MloxP and NFH-Cre/MloxP mice. The first target areas showing abnormal PrP accumulation and gliosis in both prion infections are the locus coeruleus (LC), the nucleus of the solitary tract (NTS) and the pre-Bötzinger complex (PBC). We then studied the pathology progression, scoring prion pathology in these and other brainstem nuclei of infected MloxP and NFH-Cre/MloxP mice in the course of the disease. We show that neural degeneration in the LC, NTS, and PBC correlate with clinical signs characteristic of terminally ill mice. We therefore propose that these areas are potential clinical target areas of prion disease. We also studied the spatial and temporal characteristics of Cre-mediated recombination. With immunohistochemistry in reporter mice, we estimated that in the LC, NTS, and PBC, Cre-mediated recombination is 60% or lower, and this can explain why mice proceed to terminal stage of the disease. In NFH-Cre/MloxP mice we found that recombination is a progressive event and in the hippocampus it is complete by 5 weeks post-natally, differently from previous data. Finally, we produced anti PrP RNAi –encoding lentivirus which could be used as focal therapy in the clinical target areas we propose

Acute kidney injury and acute kidney disease in high-dose cisplatin-treated head and neck cancer

Background: In locally advanced head and neck squamous cell carcinoma (LA-SCCHN) at least 200mg/m2 (standard dose 300 mg/m2) of cisplatin concomitant with radiotherapy represents the standard of care, both in postoperative and conservative settings. Nevertheless, high dose administration every 3 weeks is often replaced with low dose weekly cisplatin to avoid toxicities like kidney injury, though often failing to reach the therapeutic dose. Our aim was to investigate the incidence of renal impairment in the real-life setting, integrating high dose cisplatin with adequate supportive therapy, and to explore both Acute Kidney Injury (AKI) and Acute Kidney Disease (AKD), a recently described clinical renal syndrome that encompasses functional alterations of the kidney lasting fewer than 3 months. Methods: One hundred and nine consecutive patients affected by LA-SCCHN and treated with at least a cumulative dosage of 200 mg/m2 of cisplatin concomitant with radiotherapy were enrolled in this prospective observational study. Results: AKI was reported in 12.8% of patients, 50% of whom were stage 1 (KDIGO criteria), while 25.7% of the cohort developed AKD. Patients with baseline estimated Glomerular Filtration Rate (eGFR) < 90 ml/min showed a higher incidence of AKD (36.2% vs 17.7%). Hypertension, baseline eGFR, and therapy with Renin-angiotensin-aldosterone system inhibitors proved to be significant factors associated with both AKI and AKD. Conclusion: AKI and AKD are not rare complications of high-dose cisplatin, but an appropriate prevention strategy and accurate monitoring of patients during treatment could lead to a reduction of the burden of these conditions

2D seismic tomography of Somma-Vesuvius: Description of the experiment and preliminary results

A multidisciplinary project for the investigation of Mt. Vesuvius structure was started in 1993. The core of the project is represented by a high resolution seismic tomography study by using controlled and natural sources. The main research objective is to investigate the feeding system of the volcano and to retrieve details of the upper crustal structure in the area. A first 2D active seismic experiment was performed in May 1994, with the aim of studing the feasibility of using tomographic techniques for exploring the volcano interiors. Particularly, this experiment was designed to obtain information on the optimal sources-receivers configuration and on the depth extension of the volume sampled by shot-generated seismic waves. 66 three-component seismic stations and 16 single-component analogue instruments were installed by several Italian and French groups to record signals generated by three on-land, underground explosions. Sources and geophones were deployed along a 30-km NW-SE profile passing through the volcano crater. Receivers were placed at an average spacing of 250 m in the middle of the recording line and at 500 m outside. The arrival time data base was complemented by first P and S readings of microearthquakes which occurred in the recent past within the volcano. The first arrival data set was preliminarily used to determine the shallow structure of the volcano by applying Thurber's (1983) tomographic inversion technique. This analysis shows evidence for a high-velocity body which extends vertically from about 400 m below the crater down to at least 3000 m and for a shallow 300-500 m thick low-velocity cover which borders the edifice. Data from the distant shot show evidence for arrivals of deep reflected/converted phases and provide information on the deeper structure under the volcano. The results from the interpretation of 2D data are used for planning a 3D tomographic survey which will be carried out in 1996

Mediterranean plant germination reports – 5

This is the fifth issue of the series of germination reports from Mediterranean areas (sensu Med-Checklist). It comprises germination protocols for 18 taxa: Hieracium and Pilosella from South Italy by Di Gristina & al. (Nos. 103-106); Genista from Sardinia by Deplano & al. (No. 107); Antirrhinum, Anthyllis, Digitalis, Echium, Jasione, Nothoscordum, Silene and Verbascum by Martínez-Oliver & al. (Nos. 108-116); Dianthus, Helichrysum and Silene from Sicily by Scafidi & Salmeri (Nos. 117-120)

Autologous hematopoietic cell transplantation for T-cell prolymphocytic leukemia: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

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The use of digital pathology and image analysis in clinical trials

Digital pathology and image analysis potentially provide greater accuracy, reproducibility and standardisation of pathology‐based trial entry criteria and endpoints, alongside extracting new insights from both existing and novel features. Image analysis has great potential to identify, extract and quantify features in greater detail in comparison to pathologist assessment, which may produce improved prediction models or perform tasks beyond manual capability. In this article, we provide an overview of the utility of such technologies in clinical trials and provide a discussion of the potential applications, current challenges, limitations and remaining unanswered questions that require addressing prior to routine adoption in such studies. We reiterate the value of central review of pathology in clinical trials, and discuss inherent logistical, cost and performance advantages of using a digital approach. The current and emerging regulatory landscape is outlined. The role of digital platforms and remote learning to improve the training and performance of clinical trial pathologists is discussed. The impact of image analysis on quantitative tissue morphometrics in key areas such as standardisation of immunohistochemical stain interpretation, assessment of tumour cellularity prior to molecular analytical applications and the assessment of novel histological features is described. The standardisation of digital image production, establishment of criteria for digital pathology use in pre‐clinical and clinical studies, establishment of performance criteria for image analysis algorithms and liaison with regulatory bodies to facilitate incorporation of image analysis applications into clinical practice are key issues to be addressed to improve digital pathology incorporation into clinical trials

A real-world approach to Evidence-Based Medicine in general practice: a competency framework derived from a systematic review and Delphi process

Background Evidence-Based Medicine (EBM) skills have been included in general practice curricula and competency frameworks. However, GPs experience numerous barriers to developing and maintaining EBM skills, and some GPs feel the EBM movement misunderstands, and threatens their traditional role. We therefore need a new approach that acknowledges the constraints encountered in real-world general practice. The aim of this study was to synthesise from empirical research a real-world EBM competency framework for general practice, which could be applied in training, in the individual pursuit of continuing professional development, and in routine care. We sought to integrate evidence from the literature with evidence derived from the opinions of experts in the fields of general practice and EBM. Methods We synthesised two sets of themes describing the meaning of EBM in general practice. One set of themes was derived from a mixed-methods systematic review of the literature; the other set was derived from the further development of those themes using a Delphi process among a panel of EBM and general practice experts. From these two sets of themes we constructed a real-world EBM competency framework for general practice. Results A simple competency framework was constructed, that acknowledges the constraints of real-world general practice: (1) mindfulness - in one’s approach towards EBM itself, and to the influences on decision-making; (2) pragmatism – in one’s approach to finding and evaluating evidence; and (3) knowledge of the patient – as the most useful resource in effective communication of evidence. We present a clinical scenario to illustrate how a GP might demonstrate these competencies in their routine daily work. Conclusion We have proposed a real-world EBM competency framework for general practice, derived from empirical research, which acknowledges the constraints encountered in modern general practice. Further validation of these competencies is required, both as an educational resource and as a strategy for actual practice.</p