Search

Genetic alterations within the cAMP/protein kinase A (PKA) pathway result in a spectrum of adrenocortical disorders. Implicated genes include GNAS, PDE8B, PDE11A, PRKAR1A/B, and PRKACA. To date, pathogenic somatic PRKACA variants and germline PRKACA copy number gain have been associated with the development of cortisol-secreting adrenocortical adenomas and bilateral adrenal hyperplasia, respectively. While perturbations within the PRKAR1A gene are known to cause Carney complex, PKRACA mutations are rarely associated with an extra-adrenal phenotype. We describe a mosaic PRKACA duplication in an infant who presented with a Carney-like complex at the age of 3 months with bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing's syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens its extra-adrenal phenotype. It suggests that the Cushing's syndrome phenotypes arising from somatic and germline PRKACA abnormalities likely exist on a spectrum. We emphasise the importance of ascertaining a genetic diagnosis for PRKACA-mediated disease. Significance statement We describe a mosaic PRKACA duplication in a young infant who presented with a Carney-like complex: bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing's syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens the extra-adrenal phenotype of PRKACA-associated Cushing's syndrome. Our data suggest that Cushing's syndrome phenotypes arising from somatic and germline PRKACA abnormalities can exist on a spectrum. We emphasise the value of ascertaining a genetic diagnosis for PRKACA-mediated adrenal and extra-adrenal disease to guide individualised and targeted care.

Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47phox-deficient CGD (p47phoxCGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34+ cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34+ cells derived from a p47phoxCGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47phoxCGD.

Congenital lung disease comes to the attention of the surgical pathologist through lung biopsy or excision of a lung lobe. The two most frequent clinical indications are removal of a mass, often detected antenatally, or investigation of difficulty in ventilation or oxygenation. The diagnostic possibilities in each instance are different. The mass is most commonly a cystic airway malformation, but a limited number of rare neoplasms enters the differential diagnosis. Biopsy in the case of difficulty in ventilation most often shows delayed alveolar development, but surfactant protein disorder and a small number of lethal developmental abnormalities must be excluded. This review offers a conceptual framework to the general histopathologist confronted with such specimens and presents an approach to assessment in order to achieve the maximum information from the specimen. Correlation with clinical features and radiology is vital.

The histological spectrum of the central fibrous body (CFB) of the heart, particularly in humans, is not fully characterized. Herein, we describe the presence of cartilage and bone within the CFB of 2 explanted heart specimens from patients with known mutation-driven cardiomyopathy involving the TNNI3 and TNNT2 genes, review the existing literature on the identified variants particularly TNNI3 (p.Asn185Thrfs*14) and TNNT2 (p.Arg141Trp), and provide insights into the plausible nature of such histopathological observation based on animal studies and the few reported cases in humans.

Objectives To determine the feasibility and tissue yield of a perinatal incisionless ultrasound‐guided biopsy procedure, the INcisionless Targeted Core Tissue (INTACT) technique, in the context of minimally invasive autopsy. Methods Cases of perinatal death in which the parents consented for minimally invasive autopsy underwent postmortem magnetic resonance imaging and an INTACT biopsy procedure, defined as needle biopsy of organs via the umbilical cord, performed under ultrasound guidance. In each case, three cores of tissue were obtained from seven target organs (both lungs, both kidneys, heart, spleen and liver). Biopsy success was predefined as an adequate volume of the intended target organ for pathological analysis, as judged by a pathologist blinded to the case and biopsy procedure. Results Thirty fetuses underwent organ sampling. Mean gestational age was 30 weeks (range, 18–40 weeks) and mean delivery‐to‐biopsy interval was 12 days (range, 6–22 days). The overall biopsy success rate was 153/201 (76.1%) samples, with the success rates in individual organs being highest for the heart and lungs (93% and 91%, respectively) and lowest for the spleen (11%). Excluding splenic samples, the biopsy success rate was 150/173 (86.7%). Histological abnormalities were found in 4/201 (2%) samples, all of which occurred in the lungs and kidneys of a fetus with pulmonary hypoplasia and multicystic kidney disease. Conclusions Incisionless ultrasound‐guided organ biopsy using the INTACT procedure is feasible, with an overall biopsy success rate of over 75%. This novel technique offers the ideal combination of an imaging‐led autopsy with organ sampling for parents who decline the conventional invasive approach. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.

BACKGROUND Antroduodenal manometry (ADM) and histopathology are currently employed to aid the diagnosis of pediatric intestinal pseudo-obstruction (PIPO). Limited data are available on the reliability of ADM analysis and its correlation with histopathology. We aimed to develop a protocol for enhanced analysis of ADM contractile patterns, including a scoring system, and explore whether this provided better correlation with histopathology. METHODS Children referred with suspected PIPO between April 2012-December 2019 who underwent both ADM and full-thickness biopsies were included. ADM tracings were analyzed using both standard (conventional ADM) and novel (enhanced ADM) motility parameters. A novel ADM score (GLASS score) was generated based on the enhanced ADM analysis. Conventional and enhanced ADM analyses were then correlated with histopathology. RESULTS Forty patients were included. Using conventional clinical criteria, 29 of these were diagnosed with PIPO and the other 11 with non-PIPO diagnoses. Twenty-three of the PIPO patients had abnormal histopathology: 6 myopathy, 4 neuropathy, 3 neuro-myopathy, and 10 non-specific changes. No agreement in diagnosis was found between conventional ADM analysis and histopathology (ϰ = 0.068; p = 0.197), whereas the latter significantly correlated with enhanced ADM analysis (ϰ = 0.191; p = 0.003). The enhanced ADM score was significantly higher in PIPO versus non-PIPO (16.0 vs. 8.0; p

Aims The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. Methods and results In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P, Graphical Abstract Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. SARC+: sarcomere positive; SARC−: sarcomere negative.

The practice of healing by anyone other than qualified doctors or pharmacists has been allegedly illegal in France since the nineteenth century. In this judicial order, the state delegated the power to oversee the boundaries of medicine to doctors and pharmacists, allowing them, with support from criminal courts, to determine which therapeutic techniques should remain their exclusive right. In practice, this apparently neat legal system was never clear-cut; therapists without medical qualifications continued to infringe upon spaces that doctors and pharmacists saw as their preserve, often carving out zones of juridical tolerance. In the 1980s and 1990s, negotiations over the legality or illegality of different kinds of healing intensified. Alternative therapies, such as acupuncture and herbalism, had gained in popularity and their practitioners were keen to negotiate a legal position that would make their work licit. While some succeeded, others got entangled in a new governmental framework that characterized alternative medicines as gateways to “sects.” This article examines these developments and explains how new juridical techniques to govern certaintherapies arose in the 1990s. These operated through decentralized surveillance systems that enrolled new actors. These included agencies dedicated to monitoring sects; associations of victims; and individuals such as users, their families, or health professionals. Together, they aimed to “prevent” deviant behavior, thereby fostering what is today one of the most peculiar features of the way the French state regulates alternative healing, which it considers potentially “cult-like.”

Amelanotic/hypomelanotic variant of cellular blue naevus (CBN) can present a challenge for the clinician and histopathologist. We report a case of amelanotic/hypomelanotic variant of CBN that presented as a painless scrotal swelling in a child. We review the literature on amelanotic/hypomelanotic CBN, the key histological features and important differential diagnoses.

Examination of the malformed heart requires sequential segmental analysis in which the three paired segments of the heart (atria, ventricles, great arteries) are recognized by their most constant feature. Their connections to each other are established with certainty and associated abnormalities are described. The basic anatomy of the commonest congenital heart defect - ventricular septal defect is described in detail. A knowledge of the normal anatomy of the interventricular septum makes understanding the variation in the morphology of ventricular septal defect easier to understand. The paediatric aspects of cardiomyopathy are described with particular emphasis on those conditions that have a particular relevance to childhood: histiocytoid cardiomyopathy, mitogenic cardiomyopathy, mitochondrial cardiomyopathy, ventricular non-compaction and cardiomyopathy associated with muscular dystrophy and Friedreichs ataxia.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Methods and results We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ± 13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake. Conclusion In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.

Background Congenital hyperinsulinism is a rare disease and patients not responding to medical treatment need near-total or partial pancreatectomy, dependent on whether they have diffuse or focal hyperinsulinism, respectively. While laparoscopic technique for distal and for total pancreatectomy has been developed, minimally invasive resection of the pancreatic neck with pancreatico-jejunostomy has not been reported in children before. Case summary A 2-year old boy suffered from congenital hyperinsulinism, which was refractory to high-dose medical treatment. The nuclear-medicine scan revealed a focal lesion of the pancreatic neck, hence partial pancreatectomy was indicated. On laparoscopy, a slightly prominent tissue mass was apparent in the area of the pancreatic neck. We proceeded with laparoscopic mobilisation of the pancreas from the underlying splenic vessels and resected the pancreatic neck and adjacent parts of the body and the head. After macroscopic resection of the mass, the patient's intraoperative blood glucose levels increased to a point where insulin had to be substituted. To drain the pancreatic tail, we formed an end-to-side anastomosis in the proximal Jejunum and brought the open end to the pancreatic tail and performed a laparoscopic pancreatico-jejunostomy. The patient tolerated the procedure well and had no remaining signs or symptoms of hyperinsulinism. Conclusion This is the first report of a laparoscopic middle-segmental pancreatic resection with laparoscopic assisted Roux-en-Y pancreatico-jejunostomy in a child. For benign pancreatic lesions proximal to the body and tail, the described minimally invasive technique should be considered.

BACKGROUND: Arrhythmogenic Cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC, but with insufficient evidence to support their pathogenicity.; METHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutation were prospectively screened by whole exome sequencing.; RESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in three index patients (2%). We assessed the clinical phenotypes within their families and confirmed co-segregation. One carrier required heart transplantation, two died suddenly and one died of non-cardiac causes. All cases had right and left ventricular (LV) involvement. LV late gadolinium enhancement was present in all and circumferential sub-epicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short proto-filaments and small fibrous aggregates.; CONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis. Copyright © 2020. Published by Elsevier Inc.

We performed a prospective, observational, cohort study of children newly diagnosed with children’s interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3–7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88–96). Death (n=20, 16%) was the most common in those 2

ObjectiveTo define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.MethodsPatients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death.ResultsNinety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.ConclusionsWe found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Interstitial lung disease (ILD) in pediatric patients is different from that in adults, with a vast array of pathologic conditions unique to childhood, varied modes of presentation, and a different range of radiologic appearances. Although rare, childhood ILD (chILD) is associated with significant morbidity and mortality, most notably in conditions of disordered surfactant function, with respiratory failure in 100% of neonates with surfactant protein B dysfunction and 100% mortality without lung transplantation. The authors present a summary of lung development and anatomy, followed by an organized approach, using the structure and nomenclature of the 2013 update to the chILD Research Network classification system, to aid radiologic diagnosis of chILD. Index radiologic cases with contemporaneous histopathologic findings illustrate a summary of recent imaging studies covering the full spectrum of chILD. chILD is best grouped by age at presentation from infancy (diffuse developmental disorders, lung growth abnormalities, specific conditions of unknown origin, surfactant dysfunction mutations) to later childhood (disorders of the normal host, disorders related to systemic disease processes, disorders related to immunocompromise). Appreciation of the temporal division of chILD into infant and later childhood onset, along with a sound understanding of pulmonary organogenesis and surfactant homeostasis, will aid in providing useful insight into this important group of pediatric conditions. Application of secondary lobular anatomy to interpretation of thin-section computed tomographic images is pivotal to understanding patterns of ILD and will aid in selecting and narrowing a differential diagnosis. ©RSNA, 2017.

Objective To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. Methods Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death. Results Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. Conclusions We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Introduction Arrhythmogenic Cardiomyopathy (AC) is typically caused by mutations in the desmosomal genes, however non-desmosomal genes have been increasingly implicated. Desmin gene (DES) mutations have been previously reported in AC, but in many cases there are insufficient data to support their pathogenicity. Purpose We assessed our AC cohort for DES gene mutations and describe the clinical phenotype associated with a recurring variant present in 3 unrelated families. Methods Genetic testing was performed using next-generation sequencing for 41 genes in a total of 138 AC probands with a definite diagnosis of AC based on the revised 2010 Task Force diagnostic criteria. All candidate variants were confirmed using Sanger sequencing. Clinical and genetic cascade screening were expanded to the first-degree relatives of the probands. Retained tissue from deceased individuals was used for genetic testing. All living mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, signal-averaged ECG, echocardiography, cardiac magnetic resonance imaging (MRI) and 24h Holter-monitoring. Results Two DES gene variants, p.Ser298Leu (n=1) and p.Leu115Ile (n=3), were identified in 4 out of the 138 probands (3%). The former coexisted with a pathogenic DSP gene mutation and has not been further evaluated. The latter is a novel variant, absent in control databases (gnomAD) and was the only variant present in 3 unrelated families (see figure). One carrier required heart transplant (A-II-1), two died suddenly (A-III-1, B-II-1) and one died of non-cardiac causes (B-I-2). Detailed clinical information was present in 8 mutation carriers (2 male, age 45±19 years). Seven (88%) had a definite diagnosis and one had a borderline diagnosis of AC. All cases (100%) had right ventricular (RV) wall motion abnormalities, 6 (75%) had a dilated RV, 6 (75%) a dilated LV and 6 (75%) had LV dysfunction (mild in 5 and severe in 1). LV late gadolinium enhancement (LGE) was present in all 6 carriers that had a cardiac MRI with a circumferential sub-epicardial distribution (see figure, case A-III-2). Non-sustained ventricular tachycardia (VT) was present in 7 (88%) and sustained VT in 2 cases (25%). The ventricular ectopic burden per 24h ranged from 426 to 10583 with a median value of 820. Figure 1 Conclusion Variants of the DES gene are rare causes of AC. The novel p.Leu115Ile variant seems to be prevalent in a large UK-based cohort and it causes a biventricular form of AC, with a characteristic scar pattern on MRI and severe outcomes. Acknowledgement/Funding Alexandros Protonotarios is supported by a BHF Clinical Research Training Fellowship no. FS/18/82/34024

In recent years, there have been no books published on paediatric cardiac pathology despite enormous developments in genetics, a marked explosion of paediatric transplant programmes, surges in knowledge of fetal cardiac pathology and understanding of congenital heart disease, and the emergence of a flourishing cardiac imaging discipline. This book will be the first unified and comprehensive source of reference for childhood heart disease, covering the full field of paediatric cardiac pathology, in one volume. Comprising the twenty-five year experience of a single pathologist, the full spectrum of the pathology of heart disease, from the fetus to the adult, is uniquely presented here. Richly illustrated, with over 800 colour photographs, general and paediatric pathologists alike will be able to examine the microscopic features of the conditions described, with a specific focus on metabolic disease for practitioners worldwide.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.

Background Noninvasive imaging autopsy alternatives for fetuses weighing

This article questions the extent to which calculable numbers are indispensable to the government of conduct. By focusing on the role played by disgust in the government of sexual minorities in Uganda, it provides an account of government by emotion, or affective governmentality. This article draws on the literature on disgust, appropriating elements from the various disciplines and perspectives and bringing them under a Foucauldian umbrella. It explores two techniques through which attempts were made to arouse disgust: the sermon and the tabloid exposé. Although such techniques were performed by agents who operated beyond the state, this article contends that the emergence of the Anti-Homosexuality Act 2014 cannot be accounted for without considering the role played by disgust.

Cardiac rhabdomyoma is the most common tumour of the heart in infancy and childhood, representing approximately 60% of all primary cardiac tumours in these age groups. Though they have a tendency to regress with advancing age and are histologically benign, rhabdomyomas may cause mechanical obstruction to blood flow, arrhythmia, congestive cardiac failure and death and may be associated with underlying genetic syndromes such as tuberous sclerosis. We present the case of a primigravida in her early 20s with no significant medical history who was referred to the Fetal Medicine Unit at 34 weeks' gestation following the detection of an irregular fetal heartbeat. An anomaly scan at 20 weeks had been reported as normal.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype. Methods: Label-free proteomic analysis was used initially to compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals (HCM [n=51], controls [n=7], and aortic stenosis [n=7]) by the development and use of targeted multiple reaction monitoring-based triple quadrupole mass spectrometry. Results: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared with controls ( P P P P =0.015), late gadolinium enhancement on cardiac magnetic resonance imaging ( P =0.03) and the presence of a pathogenic sarcomere mutation ( P =0.04). Conclusions: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.

Objective Less invasive autopsy techniques in cases of fetal or infant death have good acceptability among parents, but the published sampling adequacy in needle biopsy studies is generally poor. Minimally Invasive Autopsy with Laparoscopically assisted sampling (MinImAL) has the potential to increase the diagnostic yield of less invasive autopsy by improving the quality and quantity of tissue samples obtained, whilst permitting visualization, extraction and examination of internal organs through a small incision. The aim of this study was to present the findings of our experience with the MinImAL procedure in cases of fetal, neonatal and pediatric death. Methods This was a retrospective analysis of 103 prospectively recruited unselected cases of fetal, neonatal or pediatric death that underwent the MinImAL procedure at a tertiary referral center over a 5-year period. Following preprocedure 1.5-T whole-body postmortem magnetic resonance imaging, MinImAL autopsy was performed. Procedure duration, sampling adequacy and cause of death were assessed. Chi-square analysis was used to compare the 'unexplained' rate of intrauterine deaths in the cohort with that in a previously published cohort of > 1000 cases of intrauterine death examined by standard autopsy. Results MinImAL autopsy was performed successfully in 97.8% (91/93) of the cases undergoing a complete procedure. There was a satisfactory rate of adequate histological sampling in most major organs; heart (100%, 91 cases), lung (100%, 91 cases), kidney (100%, 91 cases), liver (96.7%, 88 cases), spleen (94.5%, 86 cases), adrenal glands (89.0%, 81 cases), pancreas (82.4%, 75 cases) and thymus (56.0%, 51 cases). Procedure duration was similar to that of standard autopsy in a previously published cohort of intrauterine deaths. The unexplained rate in stillbirths and intrauterine fetal deaths that underwent MinImAL autopsy was not significantly different from that following standard autopsy. Conclusions The MinImAL procedure provides good histological yield from major organs with minimal cosmetic damage and can be learned by an autopsy practitioner. The MinImAL procedure is an appropriate minimally invasive alternative for the investigation of perinatal and pediatric deaths in which consent to full autopsy is withheld, and may have applications in both high- and low/middle-income settings. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC usingWe performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ± 13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake.In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.

What's already known about this topic? Accurate pathological assessment of small gestational age fetuses is challenging. Dating an embryo/fetus is essential to recognise expected human developmental stages and prevent misdiagnosis. What does this study add? Micro‐CT offers a non‐destructive, digital method for dating human embryos. The micro‐CT imaging here is of the earliest gestation human embryo published to date with corresponding pathology. It can provide an alternative to autopsy even at early stages of development.

It is axiomatic that good pathology is essential for good patient care. For too long, pathologists have viewed their central role in diagnosis and clinical management as self-evident to all. Alas, the benefits of high-quality pathological investigation are not always self-evident, and much good work has gone unrecognized or unappreciated. To some extent we have ourselves to blame in that there has been a retreat of the pathologist to the autopsy room or the laboratory with a consequent lack of visibility in the clinical arena. The reduction in the volume and scope of pathology teaching in some undergraduate curricula has led to a lessening of the background pathological knowledge of many clinicians and, thus, the common meeting ground of clinician and pathologist has diminished. In pediatrics perhaps as nowhere else, is the need for a commonality of interest so great. Fortunately, in pediatrics the pathologist, by and large, is more visible in the clinical arena than in any other area. It is necessary for us all to strive to increase the commonality of interest for the benefit of the patient.

Objectives Congenital cardiac malformations are commonly identified at perinatal autopsy, which can be challenging in fetuses of early gestation and in macerated fetuses. Our objective was to examine fetal complex congenital heart disease by microcomputed tomography (micro-CT), using standard autopsy as the gold standard. Methods In this ethically approved study, ex-vivo isolated fetal heart and fetal heart-lung blocks underwent iodine preparation prior to micro-CT, and were fixed in formalin after the micro-CT examination. Images were acquired using a microfocus-CT scanner with individual specimen image optimization. Twenty-one indices assessed normally at autopsy were evaluated for each dataset. Cardiac dissection was performed using a dissecting microscope within 24 h of the micro-CT examination. Results We examined six fetal hearts, comprising five with complex congenital cardiac malformations at a gestational age of 17–23 weeks and an anatomically normal heart of 23 weeks' gestation for reference. All specimens demonstrated excellent internal contrast at micro-CT examination, and the correct overall diagnosis was made in all cases. There was agreement for 114/126 indices assessed on micro-CT and at autopsy dissection (overall concordance of 95.8% (95% CI, 90.5–98.2%)). Micro-CT was particularly useful in the assessment of ventricular morphology in macerated fetuses. Conclusions Micro-CT of small ex-vivo fetal specimens can provide highly accurate three-dimensional rendering of complex congenital fetal heart disease. This approach represents a significant advance in postmortem imaging and confirms the potential of this technology for non-invasive examination of small fetuses and organs. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Normal gastrointestinal function requires an intact enteric musculature and enteric nervous system. There is a group of disorders in which abnormalities of either enteric nerves or muscle, or both, lead to clinical features of intestinal obstruction in the absence of physical obstruction – chronic intestinal pseudo-obstruction. These disorders may be congenital or acquired. The best known of the congenital enteric nervous system disorders is Hirschsprung disease where there is absence of nerve cells in the distal colon. Others include ganglioneuromatosis. Muscular disorders include degenerative leiomyopathy and mitochondrial disorders. The nervous or muscular system may also be affected secondarily in many systemic disorders. Surgical intervention is frequent in cases of chronic intestinal pseudo-obstruction and yields specimens for pathological examination. The pathological investigation of these specimens may yield only non-diagnostic features, but care is needed not to overlook those cases where a specific diagnosis may be made on the basis of the histopathology.

SummaryIntroduction Interstitial lung disease (ILD) in infants is rare. Clinical and radiological features are often non-specific, and overlap with growth disorders and infection. In infants with severe respiratory compromise, lung biopsy is often necessary to guide acute management, but the risk and diagnostic yield of this procedure is incompletely understood. Aims To retrospectively review infants undergoing open lung biopsy for suspected ILD at a large referral center; to determine morbidity and mortality related to the procedure; and to describe subsequent diagnosis and outcome. Methods Lung biopsies performed in infants (aged

Aims To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P

AimsSudden unexpected death in infancy (SUDI) investigation requires extensive ancillary investigations, the results of which, such as postmortem microbiology, can be difficult to interpret. Markers of an inflammatory response, including interleukin 6 (IL-6), c-reactive protein (CRP) and cellular adhesion molecules are elevated in infections, yet little attention has been paid to their assessment after death. This study investigates the role of inflammatory markers in SUDI autopsies for determining cause of death.MethodsCases of SUDI over a 14 year period were identified from an autopsy database and 100 cases were selected for immunohistochemical staining of heart and liver for IL-6, CRP, P-selectin, VCAM-1 and ICAM-1 (CD54), with staining patterns compared between five groups, including infectious and unexplained SUDI.ResultsThere were significant differences between groups. Cases of histological infection demonstrated strongly positive hepatocyte CRP and ICAM-1 expression and increased myocardial staining for CRP. Half of trauma-related deaths demonstrated diffuse hepatic CRP expression but without myocardial CRP staining. Staining of unexplained SUDI cases were predominantly negative, apart from a subgroup in whom Escherichia Coli was identified, who had increased expression of hepatic IL-6.ConclusionsThere were distinct patterns of organ-specific CRP and ICAM-1 expression in SUDI by cause of death. These markers of inflammation were rarely present in unexplained SUDI suggesting either a non-inflammatory cause of death or a failure to mount an effective acute phase response. Immunohistochemical staining offers potential to identify infection-related deaths and provides insight into SUDI mechanisms.

To investigate the demographics, circumstances and autopsy findings in infants and children dying following immersion. A retrospective review of a pediatric autopsy database at a specialist center over a 16-year period (1995–2010) was undertaken to identify deaths between 7 days and 16 years of age in whom death occurred following immersion. 28 infants and children died following immersion during the study period. 82 % were aged

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 μg per kilogram per day). All the patients had a clear glycemic response to sirolimus, although one patient required a small dose of octreotide to maintain normoglycemia. There were no major adverse events during 1 year of follow-up.