Systematic review and meta-analysis on coronary calcifications in COVID-19.

Chest CT is valuable to detect alternative diagnoses/complications of COVID-19, while its role for prognostication requires further investigation. Non-pulmonary radiological findings such as cardiovascular calcifications could increase the predictivity of clinical outcomes of COVID-19 patients beyond pulmonary involvement. Several observational studies have reported mixed results on the role of coronary calcifications in COVID-19 patients as a predictor of hospitalization, ventilatory support, and mortality. The purpose of the study is to systematically review the available evidence on the predictive role of cardiovascular calcifications in SARS-CoV2 disease. The meta-analysis confirms the prognostic significance of coronary calcifications on hospital mortality, and coronary calcifications (CAC ≠ 0) were associated with an OR for mortality of 2.19 (95% CI 1.36-3.52). CAC was neutral on respiratory outcomes, but it was associated with an increased trend of cardiovascular events. Coronary calcium appears as a promising biomarker imaging even in short-term outcomes (MACEs, hospital mortality) in a non-cardiovascular disease such as Sars-CoV2 infection. Further large studies are needed to confirm promising results of this imaging biomarker in non-cardiovascular disease.

Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.

Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.

Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders.

The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

[Serum levels of beta-methyldigoxin and contractile efficiency of the myocardium evaluated with systolic polygraphy and determination of cardiac output]. / Livelli serici di beta-metildigossina ed efficienza contrattile del miocardio valutata con la poligrafia della sistole e con la determinazione della portata cardiaca.

0.3 mg/day betamethyldigoxin was given per os in three daily administrations to 8 healthy subjects, and 8 compensated and 8 decompensated heart patients. Prior to the treatment, and 6 hr after the last administration, blood digoxin values were determined radio-immunologically, together with cardiac output, systolic stroke volume, cardiac index (dilution of indocyanine green), and systolic time intervals, by simultaneous recording of the ECG, carotid pulse, and the phonocardiogram. No significant change in output, stroke volume and cardiac index was noted in the healthy subjects, whereas these parameters were distinctly improved in the decompensated patients. Changes in the systolic intervals after treatment were significant in all cases though there was no significant correlation with the blood digoxin levels reached. In particular, the healthy and compensated subjects displayed a reduction in the corrected electromechanical systole (delta Q-S2), the corrected pre-ejection period (delta PEP), the corrected left ventricular ejection time (delta LVET), and their ratio (PEP/LVET), whereas in the decompensated patients the picture differed to the extent that the LVET increased owing to an augment-systolic stroke volume, the other parameters being reduced. In the healthy subjects, the polygraphic data were normal prior to the treatment, while in the compensated patients delta PEP and the PEP/LVET ratio were enhanced, and the delta LVET was less than in the normal subjects. It is felt that recording of the systolic intervals may be regarded as a sound method, owing to its simplicity and its ability to demonstrate latent cardiac failure before haemodynamic changes appear. Simultaneous determination of serum digoxin and the polygraphic data, therefore, opens the way to the commencement of appropriate, safe and timely management of as yet non-decompensated heart patients.

Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts.

Cornelia de Lange Syndrome is a severe genetic disorder characterized by malformations affecting multiple systems, with a common feature of severe mental retardation. Genetic variants within four genes (NIPBL (Nipped-B-like), SMC1A, SMC3, and HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins that are part of the 'cohesin complex'. Cohesins exhibit two temporally separated major roles in cells: one controlling the cell cycle and the other involved in regulating the gene expression. The present study focuses on the role of the zebrafish nipblb paralog during neural development, examining its expression in the central nervous system, and analyzing the consequences of nipblb loss of function. Neural development was impaired by the knockdown of nipblb in zebrafish. nipblb-loss-of-function embryos presented with increased apoptosis in the developing neural tissues, downregulation of canonical Wnt pathway genes, and subsequent decreased Cyclin D1 (Ccnd1) levels. Importantly, the same pattern of canonical WNT pathway and CCND1 downregulation was observed in NIPBL-mutated patient-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function embryos rescued the adverse phenotype and restored the physiological levels of cell death.

Comparison of the antianginal efficacy of four calcium antagonists and propranolol in stable angina pectoris.

The antianginal effects of propranolol 160 mg/day, diltiazem 240 mg/day, nicardipine 80 mg/day, nifedipine 40 to 80 mg/day and verapamil 320 mg/day were compared in 12 patients with chronic stable angina pectoris using a symptom-limited exercise test. Compared to placebo propranolol and calcium antagonists similarly reduced (p less than 0.001) the frequency of antianginal attacks and nitroglycerin consumption, and increased exercise tolerance and time to greater than or equal to 1 mm S-T segment depression. After propranolol the pressure-rate product at submaximal and maximal exercise was significantly decreased. The calcium antagonists produced a significant reduction in the submaximal pressure-rate product, but no significant change in the peak pressure-rate product. Maximum ST depression was significantly lower after propranolol and was unchanged after the calcium antagonists. None of the drugs caused significant adverse effects. The results indicate that in patients with stable effort angina pectoris, diltiazem, nicardipine, nifedipine and verapamil were as effective as propranolol in improving exercise tolerance and time to ischaemia, and they did not alter the peak pressure-rate product. Different antianginal mechanisms may be operative for the various calcium antagonists.

[Incidence and functional role of antithyroid antibodies in hyperthyroidism]. / Incidenza e ruolo funzionale degli anticorpi antitiroide nei pazienti ipertiroidei.

INTRODUCTION: We report our personal experience in patients with biochemical hyperthyroidism and no nodules, studying the correlations between antithyroid autoantibodies titers, thyroid function and clinical symptoms. MATERIAL AND METHODS: We examined 93 patients (13 men and 80 women, mean age: 44.6 years, range: 25-68 years) referred for suspected hyperthyroidism. Thyroid 99mTc scintigraphy was performed and the 20 minutes' uptake index (UI) calculated: all these patients had a scintigraphic pattern of normal or enlarged thyroid with homogeneous radiotracer uptake. The presence and titer of antiperoxidase (TPO) and anti-TSH receptor antibodies (TRAB), FT3, FT4, TSH were assayed. Based on the results, the patients were divided into 4 subgroups: A (high TRAB/high TPO, no. 17), B (low TRAB/high TPO, no. 15), C (high TRAB/low TPO, no. 35), D (low TRAB/low TPO, no. 26). The incidence of hyperthyroidism symptoms was 94% in Group A, 40% in Group B, 89% in Group C, 50% in group D. RESULTS: UI significantly correlated with FT3 (p < .001), FT4 (p < .01) and TRAB (p < .01) titers. FT3 and UI average values were significantly higher in Group A and Group C patients (high TRAB) than in Group B and Group D patients (low TRAB) (p < .01); these parameters were significantly higher also in Group A than in Group B patients (p < .05 for FT3 and p < .03 for UI, respectively). Mean intergroup TSH values did not differ (p = ns) and anti-TPO antibodies did not correlate with FT3, FT4 and TSH titers. CONCLUSIONS: UI behaved as a good marker of hyperthyroidism in all patients and TRAB correlated well with organ function and the clinical picture; however, about 18% of patients exhibited no antibody production. No correlation was found between TPO and thyroid function. The lack of antithyroid antibodies seems to indicate a better clinical course for hyperthyroidism. The patients without TRAB and/or with high anti-TPO titers may follow different clinical courses and need a regular follow-up.