Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM

Risk-based prioritization of pharmaceuticals in the natural environment in Iraq

Numerous studies have demonstrated the occurrence of pharmaceuticals in the natural environment, raising concerns about their impact on non-target organisms or human health. One region where little is known about the exposure and effects of pharmaceuticals in the environment is Iraq. Due to the high number of pharmaceuticals used by the public health sector in Iraq (hospitals and care centres) and distributed over the counter, there is a need for a systematic approach for identifying substances that should be monitored in the environment in Iraq and assessed in terms of environmental risk. In this study, a risk-based prioritization approach was applied to 99 of the most dispensed pharmaceuticals in three Iraqi cities, Baghdad, Mosul and Basrah. Initially, information on the amounts of pharmaceuticals used in Iraq was obtained. The top used medicines were found to be paracetamol, amoxicillin and metformin with total annual consumption exceeding 1000 tonnes per year. Predicted environmental concentrations (PECs) and predicted no-effect concentrations (PNECs), derived from ecotoxicological end-points and effects related to the therapeutic mode of action, were then used to rank the pharmaceuticals in terms of risks to different environmental compartments. Active pharmaceutical ingredients used as antibiotics, antidepressants and analgesics were identified as the highest priority in surface water, sediment and the terrestrial environment. Antibiotics were also prioritized according to their susceptibility to kill or inhibit the growth of bacteria or to accelerate the evolution and dissemination of antibiotic-resistant genes in water. Future work will focus on understanding the occurrence, fate and effects of some of highly prioritized substances in the environment

New-Onset Exertional Dyspnea in a Young Patient With Previous Blunt Chest Trauma

CASE PRESENTATION: A 16-year-old male patient was admitted to our Cardiology Department for new-onset exertional dyspnea (NYHA functional class II-III). He had no family history of cardiovascular diseases, no cardiovascular risk factors, and an unremarkable medical history, except for a blunt chest trauma after a motorbike accident 2 years earlier

Time-dependent detrimental effects of distal embolization on myocardium and microvasculature during primary percutaneous coronary intervention.

OBJECTIVES: The authors sought to investigate the impact of distal embolization (DE) on myocardial damage and microvascular reperfusion, according to time-to-treatment, using contrast-enhanced cardiac magnetic resonance (CE-CMR). BACKGROUND: DE, occurring during primary percutaneous coronary intervention (p-PCI), appears to increase myocardial necrosis and to worsen microvascular perfusion, as shown by surrogate markers. However, data regarding the behavior of DE on jeopardized myocardium, and in particular on necrosis extent and distribution, are still lacking. METHODS: In 288 patients who underwent p-PCI within 6 h from symptom onset, the authors prospectively assessed the impact of DE on infarct size and microvascular damage, using CE-CMR. The impact of DE was assessed according to time-to-treatment: for group 1, <3 h; for group 2, 653 and 646 h. RESULTS: DE occurred in 41 (14.3%) patients. Baseline clinical characteristics were not different between the 2 groups. At CE-CMR, patients with DE showed larger infarct size (p = 0.038) and more often transmural necrosis compared with patients without DE (p = 0.008) when time-to-treatment was <3 h, but no impact was proven after this time (p = NS). Patients with DE showed more often microvascular obstruction, as evaluated at first-pass enhancement, than patients without DE (100% vs. 66.5%, p = 0.001) up to 6 h from symptom onset. CONCLUSIONS: These findings suggest that the detrimental impact of DE occurring during p-PCI on myocardial damage is largely influenced by ischemic time, increasing the extent of necrosis in patients presenting within the first hours after symptom onset, and having limited or no impact after this time window

Certainties and Uncertainties of Cardiac Magnetic Resonance Imaging in Athletes

Prolonged and intensive exercise induces remodeling of all four cardiac chambers, a physiological process which is coined as the “athlete’s heart”. This cardiac adaptation, however, shows overlapping features with non-ischemic cardiomyopathies, such as dilated, arrhythmogenic and hypertrophic cardiomyopathy, also associated with athlete’s sudden cardiac death. Cardiac magnetic resonance (CMR) is a well-suited, highly reproducible imaging modality that can help differentiate athlete’s heart from cardiomyopathy. CMR allows accurate characterization of the morphology and function of cardiac chambers, providing full coverage of the ventricles. Moreover, it permits an in-depth understanding of the myocardial changes through specific techniques such as mapping or late gadolinium enhancement. In this narrative review, we will focus on the certainties and uncertainties of the role of CMR in sports cardiology. The main aspects of physiological adaptation due to regular and intensive sports activity and the application of CMR in highly trained athletes will be summarized

At-admission risk stratification for in-hospital life-threatening ventricular arrhythmias and death in non-ST elevation myocardial infarction patients.

Identification of patients with non-ST elevation acute myocardial infarction (NSTEMI) at higher risk of in-hospital life-threatening ventricular arrhythmias (LT-VA) and death is crucial for determining appropriate levels of care/monitoring during hospitalisation. We assessed predictors of in-hospital LT-VA and all-cause mortality in a consecutive series of NSTEMI patients. We prospectively studied 1325 consecutive patients (69.7% males, median age 70 (61-79) years) presenting with NSTEMI and undergoing continuous electrocardiographic monitoring. The primary study end-point was the occurrence of spontaneous (unrelated to coronary interventions) in-hospital LT-VA, including sustained ventricular tachycardia and ventricular fibrillation; the secondary end-point was in-hospital mortality from all causes. Of 1325 patients, 21 (1.5%) experienced LT-VA and 62 (4.7%) died from either arrhythmias (n=1) or other causes (n=61). Seven of the 20 patients who survived LT-VA subsequently died of heart failure. Independent predictors of in-hospital LT-VA were the Global Registry of Acute Coronary Events (GRACE) score >140 (odds ratio (OR)=7.5; 95% confidence interval (CI) 1.7-33.3; p=0.008) and left ventricular ejection fraction (LV-EF)140 (OR=14.6; 95% CI 3.4-62) and LV-EF 140 and LV-EF<35%, while it was respectively 0.2% and 0% among the 627 (47.3%) with GRACE score ≤140 and LV-EF ≥35%. Simple risk stratification at admission based on GRACE score and echocardiographic LV-EF allows early identification of NSTEMI patients at higher risk of both in-hospital LT-VA and all-cause mortality