Detection and surveillance of left atrial thrombosis by transesophageal echocardiography

Out of 1,141 successive transoesophageal echocardiographic studies performed prospectively between 01/05/1993 and 31/12/1995, 26 cases of left atrial thrombosis were observed (2.2%); 5 were in the left atrium (20%), 19 in the left atrial appendage (73%) and the thrombi were in both atrium and left atrial appendage in 2 cases (7%). The 26 patients included 15 women and 11 men, with an average age of 69 +/- 16 years (range 25-89 years); 22 patients (84%) had permanent atrial fibrillation and 4 were in sinus rhythm. Only 5 of the patients were on oral anticoagulant therapy. All had underlying cardiac disease: 11 mitral valve diseases; 10 dilated cardiomyopathies; 2 hypertrophic cardiomyopathies; 3 other cardiac diseases. The indication for transoesophageal echocardiography was systemic embolism in 13 cases (50%); before D.C. cardioversion in 10 cases (38%) and before percutaneous mitral valvuloplasty in 3 cases. The thrombus was adherent in 18 cases (69%) and mobile in 8 cases (31%). Spontaneous contrast was observed in 23 cases (88%). Intravenous heparin was given as soon as the diagnosis was made. In 4 patients, thrombectomy was indicated in view of the threatening nature of the thrombus and/or the necessity for associated valve replacement. In 22 patients, heparin was relayed by oral anticoagulants on the 10th day of treatment. Control transoesophageal echocardiography was not performed because of the patient's refusal or poor general condition. The other 15 patients were reexamined 1 to 5 times between the 4th day and 12th month: a regression was observed in 13 cases (86%) which was complete in 11 and partial in 2 cases. No cases of embolism occurred during follow-up but six patients died: 1 of the operated cases and 5 of the patients treated medically (3 cardiac failures and 2 cerebral haemorrhages). The authors conclude that left atrial thrombosis is rare in the absence of classical embolic cardiac disease. With the exception of the surgical indication of a life-threatening thrombus and/or associated surgical mitral valve disease, anticoagulant therapy results in complete or partial regression of the thrombus visualised by transoesophageal echocardiography which is essential for follow-up. The prognosis depends on the severity of the underlying heart disease.     

Fungal thrombus of the right atrium on a central venous catheter. Apropos of a case]

The authors report the case of a 9 year old child in an intensive care unit after multiple trauma, presenting with a candida septicaemia and a central venous catheter. Echocardiography, performed because of the inefficacy of medical treatment, showed a right atrial thrombus. Surgical ablation was decided because of its extreme mobility and persisting infection, and resulted in cure of the patient.     

SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus–induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2–induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2–induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN–dependent immunity against SARS-CoV-2 infection.     

Congenital hyperinsulinism

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet β cells. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon. HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis: pancreatic ₁₈F-fluoro-l-DOPA PET-CT and molecular analysis. Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy. Diffuse HI involves all the pancreatic β cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable. The genetics of focal islet-cells hyperplasia associates a paternally inherited mutation of the ABCC8 or the KCNJ11 genes, with a loss of the maternal allele specifically in the hyperplasic islet cells. The genetics of diffuse isolated HI is heterogeneous and may be recessively inherited (ABCC8 and KCNJ11) or dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH). Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to potassium channel defect (ABCC8 and KCNJ11), most of these HI are sensitive to diazoxide. The main points sum up the management of HI: i) prevention of brain damages by normalizing glycemia and ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.     

COVID-19 severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3–73.1) in three French transplant centers. After a median follow-up of 13 days (7–30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2–14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.     

Transaldolase deficiency: a new cause of hydrops fetalis and neonatal multi-organ disease

Transaldolase (TALDO) deficiency is a newly recognized metabolic disease, which has been reported so far in 2 patients presenting with liver failure and cirrhosis. We report a new sibship of 4 infants born to the same consanguineous parents; all presented at birth or in the antenatal period with dysmorphic features, cutis laxa and hypertrichosis, hepatomegaly, splenomegaly, liver failure, hemolytic anemia, thrombocytopenia, and genitourinary malformations. The clinical courses were variable: the first child died of liver failure at 4 months of age; the second pregnancy was medically terminated at 28 weeks gestation because of hydrops fetalis with oligohydramnios. The third child is doing well at age 7 with liver fibrosis and mild kidney failure. The fourth child is now 21 months old and has hepatosplenomegaly, mild anemia, and thrombocytopenia. Urine assessment of polyols showed elevations of erythritol, arabitol, and ribitol consistent with TALDO deficiency. TALDO activity was undetectable in the patients' tissues, and mutation in the TALDO1 gene was found in the 4 patients.     

Clinical and biochemical heterogeneity associated with fumarase deficiency

Fumarase deficiency (FD), caused by biallelic alteration of the Fumarase Hydratase gene (FH), and a rare metabolic disorder that affects the Krebs cycle, causes severe neurological impairment and fumaric aciduria. Less than 30 unrelated cases are known to date. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). We report three additional patients with dramatically different clinical presentations of FD and novel missense mutations in the FH gene. One patient had severe neonatal encephalopathy, polymicrogyria, <1% enzyme activity, and mildly increased levels of urinary fumarate. The second patient had microcephaly, mental retardation, 20% of fumarase activity, and intermediate levels of urinary fumarate. The third patient had mild mental retardation, polymicrogyria, 42–61% enzyme activity in different cell types and massive amounts of urinary fumarate. In silico analysis predicted minor yet significant structural changes in the encoded proteins. The nuclear translocation of hypoxia‐inducible factor (HIF)‐1alpha (HIF1A) in cultured fibroblasts was similar to controls. These results extend the range of clinical and biochemical variation associated with FD, supporting the notion that patients with moderate increases in fumarate excretion should be investigated for this disease. The tumoral risk in the patients and their relatives requires adequate screening protocols. Hum Mutat 32:1–7, 2011. © 2011 Wiley‐Liss, Inc.     

Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension

In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.