Persistent Prothrombotic State in a Patient With Alström Syndrome.

We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome.

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. OBJECTIVE: We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. METHODS: We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. RESULTS: 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05-1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. CONCLUSION: Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought. PROSPERO DATABASE: CRD42019132045.

Addressing uncertainties in correlative imaging of exogenous particles with the tissue microanatomy with synchronous imaging strategies.

Exposure to exogenous particles is of increasing concern to human health. Characterizing the concentrations, chemical species, distribution, and involvement of the stimulus with the tissue microanatomy is essential in understanding the associated biological response. However, no single imaging technique can interrogate all these features at once, which confounds and limits correlative analyses. Developments of synchronous imaging strategies, allowing multiple features to be identified simultaneously, are essential to assess spatial relationships between these key features with greater confidence. Here, we present data to first highlight complications of correlative analysis between the tissue microanatomy and elemental composition associated with imaging serial tissue sections. This is achieved by assessing both the cellular and elemental distributions in three-dimensional space using optical microscopy on serial sections and confocal X-ray fluorescence spectroscopy on bulk samples, respectively. We propose a new imaging strategy using lanthanide-tagged antibodies with X-ray fluorescence spectroscopy. Using simulations, a series of lanthanide tags were identified as candidate labels for scenarios where tissue sections are imaged. The feasibility and value of the proposed approach are shown where an exposure of Ti was identified concurrently with CD45 positive cells at sub-cellular resolutions. Significant heterogeneity in the distribution of exogenous particles and cells can be present between immediately adjacent serial sections showing a clear need of synchronous imaging methods. The proposed approach enables elemental compositions to be correlated with the tissue microanatomy in a highly multiplexed and non-destructive manner at high spatial resolutions with the opportunity for subsequent guided analysis.

Atherosclerosis in Fabry Disease-A Contemporary Review.

Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

Tumefactive fibroinflammatory lesion of the maxilla: Successful resection and microvascular reconstruction after failed medical therapy.

Tumefactive fibroinflammatory lesions (TFILs) of the head and neck are rare and benign but locally aggressive lesions. The etiology and pathogenesis of these lesions are unknown. Medical management is regarded the first line of treatment. Surgical management has been rarely reported for head and neck lesions. A 51-year-old female presented with a 6-month history of left facial swelling and pain that subsequently developed into progressive inframalar hollowing and asymmetry. Biopsies confirmed tumefactive fibroinflammatory lesion of the maxilla. Initial treatment with high-dose steroids led to temporary partial involution; however, symptoms progressed. Cyclophosphamide and then rituximab were commenced, with minimal response. Imaging showed progression toward the infratemporal fossa. The patient subsequently underwent a resection and microvascular free flap reconstruction This patient had a successful surgical outcome and resolution of serum inflammatory markers with no evidence of recurrence after 18-month follow-up. A multidisciplinary approach is crucial to ensure a pragmatic patient-specific management plan is developed. Surgical resection and reconstruction can be successful in these lesions and should be considered if medical therapy has failed.

Consensus clinical management guidelines for Alström syndrome.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Osteomyelitis of the mandible secondary to malignant infantile osteopetrosis in an adult.

Malignant infantile osteopetrosis (MIOP), an autosomal-recessive disorder, is extremely rare, presenting early in life with extreme sclerosis of the skeleton and reduced activity of osteoclasts. It was first described by Albers Schonberg in 1904. Disease manifestations include compensatory extramedullary haematopoiesis at sites such as the liver and spleen, hepatosplenomegaly, anaemia and thrombocytopaenia. Neurological manifestations can also occur due to narrowing of osseous foramina resulting in visual impairment, hearing loss, facial palsy and hydrocephalus. In addition, growth retardation and recurrent infections requiring long-term antibiotic use are common. The incidence of MIOP is 1/2 000 000 and if untreated, then it has a fatal outcome, with the majority of cases occurring within the first 5 years of life. At present, the only potentially curative option is a haematopoietic stem cell transplant. We present a 21-year-old woman, diagnosed with malignant infantile osteopetrosis, due to a mutation in the T-cell immune regulator 1 gene when aged 6 weeks, presenting with chronic osteomyelitis of her left mandible. As malignant infantile osteopetrosis has a high mortality in infancy, we felt it prudent to report this rare case in a patient surviving to adulthood.

Implications of X-ray beam profiles on qualitative and quantitative synchrotron micro-focus X-ray fluorescence microscopy.

Synchrotron radiation X-ray fluorescence microscopy is frequently used to investigate the spatial distribution of elements within a wide range of samples. Interrogation of heterogeneous samples that contain large concentration ranges has the potential to produce image artefacts due to the profile of the X-ray beam. The presence of these artefacts and the distribution of flux within the beam profile can significantly affect qualitative and quantitative analyses. Two distinct correction methods have been generated by referencing the beam profile itself or by employing an adaptive-thresholding procedure. Both methods significantly improve qualitative imaging by removing the artefacts without compromising the low-intensity features. The beam-profile correction method improves quantitative results but requires accurate two-dimensional characterization of the X-ray beam profile.

Biphasic malignant tumours of the abdominal cavity.

Carcinosarcomas (CS) are uncommon, highly aggressive, biphasic tumours consisting of both sarcomatous and carcinomatous elements. They appear to originate from a common cell of origin, either via transformation from a single premature precursor or conversion of a mature epithelial cell through an epithelial-mesenchymal transition. CS should be considered a unique cancer subtype with cells typically displaying diffuse mitotic activity and widespread atypical mitoses predisposing to early metastasis and a tendency to local recurrence following resection. This review addresses the pathophysiology of CS and discusses its presentation, natural history and management at a variety of sites within the abdominal cavity and retroperitoneum.

Surgical management of macroglossia secondary to amyloidosis.

The authors report a case of amyloidosis-induced macroglossia treated with surgical reduction of the tongue using a keyhole to inverted T method with particular emphasis on the postoperative sequelae. Significant tongue swelling persisted for longer than anticipated requiring tracheostomy to remain in situ for 14 days.

Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome: an observational study.

BACKGROUND: Alström syndrome is a rare inherited ciliopathy with progressive multisystem involvement. Dilated cardiomyopathy is common in infancy and recurs or presents de novo in adults with high rates of premature cardiovascular death. Although Alström syndrome is characterised by fibrosis in solid organs such as the liver, the pathogenesis of related cardiomyopathy are not clear. To date it is not known whether diffuse interstitial myocardial fibrosis is present before the onset of heart failure symptoms or changes in conventional parameters of left ventricular function. METHODS: In this observational study, 26 patients with Alström syndrome (mean age 27 ± 9 years, 65 % male, 24 h ABPM 130 ± 14 / 77 ± 9 mmHg) without symptomatic cardiovascular disease were recruited from a single centre and compared to matched healthy controls. All subjects underwent cardiac MRI (1.5 T) to assess ventricular function, diffuse interstitial myocardial fibrosis by measurement of extracellular volume on T1-mapping (MOLLI) and coarse replacement fibrosis using standard late gadolinium enhancement imaging. RESULTS: Global extracellular volume was increased in Alström syndrome with wider variation compared to controls (0.30 ± 0.05 vs. 0.25 ± 0.01, p < 0.05). Left ventricular long axis function and global longitudinal strain were impaired in Alström syndrome without change in ejection fraction, ventricular size or atrial stress (NT-proBNP) (p < 0.05). Global extracellular volume was associated with reduced peak systolic longitudinal strain (r = -0.73, p < 0.01) and strain rate (r = -0.57, p < 0.01), increased QTc interval (r = 0.49, p < 0.05) and serum triglycerides (r = 0.66, p < 0.01). Nine (35 %) patients had diffuse mid-wall late gadolinium enhancement in a non-coronary artery distribution. CONCLUSION: Diffuse interstitial myocardial fibrosis is common in Alström syndrome and is associated with impaired left ventricular systolic function. Serial studies are required to determine whether global extracellular volume may be an independent imaging biomarker of vulnerability to dilated cardiomyopathy and heart failure.

Optic neuropathy secondary to eosinophilic angiocentric fibrosis.

Eosinophilic angiocentric fibrosis (EAF) is a rare fibroinflammatory disorder with a predilection for upper respiratory tract submucosa. We report a 45-year-old man with progressive unilateral visual loss secondary to a retroorbital soft tissue mass with histological features consistent with EAF. The patient experienced marked improvement in vision after endoscopic optic nerve decompression through sphenoethmoidectomy.

Regulation of pituitary tumor transforming gene (PTTG) expression and phosphorylation in thyroid cells.

Human pituitary tumor transforming gene (hPTTG) is a multifunctional proto-oncogene implicated in the initiation and progression of several tumors. Phosphorylation of hPTTG is mediated by cyclin-dependent kinase 2 (CDC2), whereas cellular expression is regulated by specificity protein 1 (SP1). The mechanisms underlying hPTTG propagation of aberrant thyroid cell growth have not been fully defined. We set out to investigate the interplay between hPTTG and growth factors, as well as the effects of phosphorylation and SP1 regulation on hPTTG expression and function. In our study, epidermal growth factor (EGF), TGFα, and IGF-1 induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of MAPK and phosphoinositide 3-kinase. Growth factors induced hPTTG independently of CDC2 and SP1 in thyroid carcinoma cells. Strikingly, CDC2 depletion in TPC-1 cells resulted in enhanced expression and phosphorylation of hPTTG and reduced cellular proliferation. In reciprocal experiments, hPTTG overexpression induced EGF, IGF-1, and TGFα mRNAs in primary human thyrocytes. Treatment of primary human thyrocytes with conditioned media derived from hPTTG-transfected cells resulted in autocrine upregulation of hPTTG protein, which was ameliorated by growth factor depletion or growth factor receptor tyrosine kinase inhibitors. A transgenic murine model of thyroid targeted hPTTG overexpression (hPTTG-Tg) (FVB/N strain, both sexes) demonstrated smaller thyroids with reduced cellular proliferation and enhanced secretion of Egf. In contrast, Pttg(-/-) knockout mice (c57BL6 strain, both sexes) showed reduced thyroidal Egf mRNA expression. These results define hPTTG as having a central role in thyroid autocrine signaling mechanisms via growth factors, with profound implications for promotion of transformed cell growth.

Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.

Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized proto-oncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.

Cessation of epilepsy in an 8-year-old girl following removal of carotid body paraganglioma.

We present a case of an 8-year-old girl with established focal epilepsy, whose fits resolved permanently after excision of a carotid body paraganglioma.

Clinicians didn't reliably distinguish between different causes of cardiac death using case histories.

BACKGROUND AND OBJECTIVES: Routine statistics and epidemiologic studies often distinguish between types of cardiac death. Our aim was to assess agreement between doctors on cause of death given identical clinical information, and to assess agreement between a physician panel and the original cause of death as coded on national statistics. METHODS: Clinical information and autopsy reports on 400 cardiac deaths were randomly selected from a defined population in the West Midlands, UK. A panel of eight clinicians was assembled, and batches of 24-25 cases were sent to pairs of these clinicians who, blinded to the certified cause of death, independently of each other assigned underlying cause of death. Physician panel decision was achieved by consensus. Levels of agreement were assessed using the kappa statistic. RESULTS: Reviewers agreed on cause of death in 54% of cases (kappa = 0.34). Consensus decision of reviewers agreed with death certificate diagnosis in 61.5% (kappa = 0.39). Agreement was higher if an autopsy had been performed (kappa = 0.49). CONCLUSION: The process of identifying underlying cause of death is of limited reliability, and therefore, limited accuracy. This has implications for design of epidemiologic studies and clinical trials of cardiovascular disease.

Pituitary tumor transforming gene binding factor: a novel transforming gene in thyroid tumorigenesis.

CONTEXT: There are currently no clear markers for the detection of differentiated thyroid cancer and its recurrence. Pituitary tumor transforming gene (PTTG) is a protooncogene implicated in the pathogenesis of multiple tumor types, which stimulates fibroblast growth factor-2 secretion via PTTG binding factor (PBF). OBJECTIVE: The aim of this study was to ascertain whether PBF expression is associated with thyroid cancer outcome. DESIGN: PBF expression was measured at the mRNA and protein level. Tissue was collected during surgery, with normal samples being taken from the contralateral lobe. In vitro studies ascertained the ability of PBF to transform cells and form tumors in nude mice and its subcellular localization. SETTING: The study was conducted at a primary care/referral center. PATIENTS: Thyroid tumors were collected from a series of 27 patients undergoing surgical excision of papillary and follicular thyroid tumors. INTERVENTION: No intervention was conducted. MAIN OUTCOME MEASURE: The expression of PBF in thyroid cancers compared with normal thyroid, hypothesized before the investigation to be raised in tumors, was the main outcome measure. RESULTS: PBF mRNA expression was higher in differentiated thyroid carcinomas than in normal thyroid (P < 0.001; n = 27) and was independently associated with tumor recurrence (P = 0.002; R(2) = 0.49). PTTG was able to up-regulate PBF mRNA expression in vitro (P < 0.001; n = 12), and stable overexpression of PBF in NIH3T3 cells resulted in significant colony formation (P < 0.001; n = 12). In vivo, stable sc overexpression of PBF induced tumor formation in athymic nude mice. CONCLUSIONS: PBF is an additional prognostic indicator in differentiated thyroid cancer that is transforming in vitro and tumorigenic in vivo.