Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium

Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology.

Although sudden cardiac death (SCD) is one of the most important modes of death in Western countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed and the accurate diagnosis of the causes of SCD is now of particular importance. Pathologists are responsible for determining the precise cause and mechanism of sudden death but there is still considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology has developed these guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate investigation of SCD. The present version is an update of our original article, published 10 years ago. This is necessary because of our increased understanding of the genetics of cardiovascular diseases, the availability of new diagnostic methods, and the experience we have gained from the routine use of the original guidelines. The updated guidelines include a detailed protocol for the examination of the heart and recommendations for the selection of histological blocks and appropriate material for toxicology, microbiology, biochemistry, and molecular investigation. Our recommendations apply to university medical centers, regionals hospitals, and all healthcare professionals practicing pathology and forensic medicine. We believe that their adoption throughout Europe will improve the standards of autopsy practice, allow meaningful comparisons between different communities and regions, and permit the identification of emerging patterns of diseases causing SCD. Finally, we recommend the development of regional multidisciplinary networks of cardiologists, geneticists, and pathologists. Their role will be to facilitate the identification of index cases with a genetic basis, to screen appropriate family members, and ensure that appropriate preventive strategies are implemented

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

How to optimise the yield of forensic and clinical post-mortem microbiology with an adequate sampling: a proposal for standardisation

Purpose: Post-mortem microbiology (PMM) is an important tool in forensic pathology, helping to determine the cause and manner of death, especially in difficult scenarios such as sudden unexpected death (SD). Currently, there is a lack of standardization of PMM sampling throughout Europe. We present recommendations elaborated by a panel of European experts aimed to standardize microbiological sampling in the most frequent forensic and clinical post-mortem situations. Methods: A network of forensic microbiologists, pathologists and physicians from Spain, England, Belgium, Italy and Turkey shaped a flexible protocol providing minimal requirements for PMM sampling at four practical scenarios: SD, bioterrorism, tissue and cell transplantation (TCT) and paleomicrobiology. Biosafety recommendations were also included. Results: SD was categorized in 4 subgroups according to the age of the deceased and circumstances at autopsy: (1) included SD in infancy and childhood (0-16 years); (2) corresponded to SD in the young (17-35 years); (3) comprised SD at any age with clinical symptoms; and (4) included traumatic/iatrogenic SD. For each subgroup, a minimum set of samples and general recommendations for microbiological analyses were established. Sampling recommendations for main bioterrorism scenarios were provided. In the TCT setting, the Belgian sampling protocol was presented as an example. Finally, regarding paleomicrobiology, the sampling selection for different types of human remains was reviewed. Conclusions: This proposal for standardization in the sampling constitutes the first step towards a consensus in PMM procedures. In addition, the protocol flexibility to adapt the sampling to the clinical scenario and specific forensic findings adds a cost-benefit value.status: publishe

Cardiac pathologic findings in three unusual cases of sudden cardiac death related to anorexiant drugs

Amphetamine congeners can be prescribed as anorexiant drugs, despite their potential side effects, including cardiac toxicity. However, the morphologic features of cardiac damage related to protracted use of these compounds are unknown. We provide a detailed description of cardiac autopsy findings in three cases of sudden death associated with protracted use of high-doses of phendimetrazine and/or phenylpropanolamine or bupropion prescribed as anorexiants, in association with other compounds. The main cardiac findings were similar in all three cases: i) mild-moderate hypertrophy of the left ventricle and/or the septum; ii) myocardial non-ischemic scarring (mid-mural and/or sub-epicardial) appearing as discrete foci or with a band/like morphology; iii) mild-moderate intramural small vessel disease, in absence of significant epicardial coronary artery stenosis; iv) acute/recent inflammatory lesions consistent with toxic myocarditis. In summary, the detailed pathology examination of the heart in these three cases revealed myocardial lesions identical to those reported in catecholamine myocardial damage, in all their various stages of evolution. In presence of a clinical history of long-term intake of anorexiants of this category, it is most important at autopsy to recognize and correctly interpret the acute and chronic myocardial lesions of the type herein described, since they represent an anatomical substrate for arrhythmic death

Cardiac hypertrophy at autopsy

Since cardiac hypertrophy may be considered a cause of death at autopsy, its assessment requires a uniform approach. Common terminology and methodology to measure the heart weight, size, and thickness as well as a systematic use of cut off values for normality by age, gender, and body weight and height are needed. For these reasons, recommendations have been written on behalf of the Association for European Cardiovascular Pathology. The diagnostic work up implies the search for pressure and volume overload conditions, compensatory hypertrophy, storage and infiltrative disorders, and cardiomyopathies. Although some gross morphologic features can point to a specific diagnosis, systematic histologic analysis, followed by possible immunostaining and transmission electron microscopy, is essential for a final diagnosis. If the autopsy is carried out in a general or forensic pathology service without expertise in cardiovascular pathology, the entire heart (or pictures) together with mapped histologic slides should be sent for a second opinion to a pathologist with such an expertise. Indication for postmortem genetic testing should be integrated into the multidisciplinary management of sudden cardiac death. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00428-021-03038-0

Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: Report of 22 cases

Background & Aims: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. Methods: Twenty-two males (70±8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150±50mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. Results: From 1993 to 2013, 22 patients were retrieved. Latency was 163±97days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18±13×ULN, ALP 0.7±0.7×ULN and total serum bilirubin 14±10mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). Conclusions: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.Fil: Bessone, Fernando. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Lucena, M. L.. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; EspañaFil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Stephens, Camilla. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; EspañaFil: Medina Cáliz, Inmaculada. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; España. Universidad de Málaga; EspañaFil: Frider, Bernardo. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Tsariktsian, Guillermo. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Hernández, Nelia. Universidad de la República; UruguayFil: Bruguera, Miquel. Liver Unit; EspañaFil: Gualano, Gisela. Hospital Alejandro Posadas; ArgentinaFil: Fassio, Eduardo. Hospital Alejandro Posadas; ArgentinaFil: Montero, Joaquin. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Reggiardo, María V.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Ferretti, Sebastian Eduardo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Colombato, Luis. Hospital Británico de Buenos Aires; ArgentinaFil: Tanno, Federico. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Ferrer, Jaime. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Zeno, Lelio. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Tanno, Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Andrade, Raúl J.. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; Españ