GPI-anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?

Glycosylphosphatidylinositol anchoring disorders (GPI-ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA-encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI-ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI-ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI-AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI-AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI-AD. All were diagnosed with PIGA-encephalopathy and three had a disease-causing variant at the same residue. The literature reports five additional children with GPI-AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI-ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.     

Cortical ablation induces time‐dependent changes in rat pituitary somatotrophs and upregulates growth hormone receptor expression in the injured cortex

The pituitary appears to be vulnerable to brain trauma, and its dysfunction is a common feature after traumatic brain injury. The role of pituitary growth hormone (GH) in brain repair after injury has been envisaged, but more studies must be performed to understand completely the importance of GH in these processes. Because some of the neuroprotective effects of GH are mediated directly through the GH receptor (GHR), we examined GHR expression in the rat cerebral cortex after sensorimotor cortex ablation. RT‐PCR, immunohistochemistry, and double immunofluorescence had been performed to analyze the correlation between GHR expression in the injured cortex and activity of GH cells in the pituitary. Our results showed that the volume of GH‐immunopositive cells was reduced at days 2 and 7 postsurgery (dps), and volume density of GH cells was significantly decreased at 14 dps, all compared with appropriate sham controls. At 30 dps all investigated parameters had returned to control level. In the injured cortex, GHR expression was transiently upregulated. Increased GHR immunoreactivity was observed in reactive astrocytes at 7 and particularly at 14 dps. In neuronal cells, an increase of GHR immunoreactivity was seen in neuronal cell bodies and well‐defined primary dendrites at 14 and especially at 30 dps. The results presented here suggest that, during recovery from brain injury, changes in activity of pituitary GH cells result in upregulation of GHR that may have a role in neuronal arborization and glial proliferation in the injured cortex. © 2014 Wiley Periodicals, Inc.     

Pontomedullary lacerations and concomitant head and neck injuries: their underlying mechanism. A prospective autopsy study

It is a well-documented fact that pontomedullary lacerations (PML) occur as a result of severe craniocervical injury, but their underlying mechanism has yet to be fully clarified. The aim of this prospective study has been to give greater insight into the underlying mechanism of PML through determining the site of blunt head-impact, as well as the presence of concomitant head and neck injuries in cases of brainstem PML. A total of 56 cases with partial PML have been analysed for this study. The case group was composed of 40 men and 16 women, averaging in age 44.2 ± 19.2 years and consisting of 7 motorcyclists, 4 bicyclists, 18 car occupants, 16 pedestrians, and 10 victims of falls from a height, as well as 1 victim of a fall from standing height. The presented study has shown that there are several possible mechanisms of PML. Impact to the chin, with or without a skull base fracture, most often leads to this fatal injury, due to the impact force transmission either through the jawbone or vertebral column; most likely in combination with a fronto-posterior hyperextension of the head. Additionally, lateral head-impacts with subsequent hinge fractures and PML may also be a possible mechanism. The jawbone and other facial bones are able to act as shock absorbers, and their fracture may diminish the energy transfer towards the skull and protect the brain and brainstem from injury. The upper cervical spine can act as damper and energy absorber as well, and may prevent any occurrence of fracture to the base of the skull.     

Coronary flow of the infarct artery assessed by transthoracic Doppler after primary percutaneous coronary intervention predicts final infarct size

Coronary microcirculatory function after primary percutaneous coronary intervention (pPCI) in patients with acute myocardial infarction is important determinant of infarct size (IS). Our aim was to investigate the utility of coronary flow reserve (CFR) and diastolic deceleration time (DDT) of the infarct artery (IRA) assessed by transthoracic Doppler echocardiography after pPCI for final IS prediction. In 59 patients, on the 2nd day after pPCI for acute anterior myocardial infarction, transthoracic Doppler analysis of IRA blood flow was done including measurements of CFR, baseline DDT and DDT during adenosine infusion (DDT adeno). Killip class, myocardial blush grade, resolution of ST segment elevation, peak creatine kinase-myocardial band and conventional echocardiographic parameters were determined. Single-photon emission computed tomography myocardial perfusion imaging was done 6 weeks later to define final IS (percentage of myocardium with fixed perfusion abnormality). IS significantly correlated with CFR (r = ?0.686, p < 0.01), DDT (r = ?0.727, p < 0.01), and DDT adeno (r = ?0.780, p < 0.01). CFR and DDT adeno in multivariate analysis remained independent IS predictors after adjustment for other covariates and offered incremental prognostic value in models based on conventional clinical, angiographic, electrocardiographic and enzymatic variables. In predicting large infarction (IS > 20 %), the best cut-off for CFR was <1.73 (sensitivity 65 %, specificity 96 %) and for DDT adeno ≤720 ms (sensitivity 81 %, specificity 96 %). CFR and DDT during adenosine are independent and powerful early predictors of final IS offering incremental prognostic information over conventional parameters of myocardial and microvascular damage and tissue reperfusion.     

Epidemiological characteristics,baseline clinical features,and outcomes of critically ill patients treated in a coronavirus disease 2019 tertiary center in continental Croatia

AimTo describe epidemiological characteristics and baseline clinical features, laboratory findings at intensive care unit (ICU) admission, and survival rates of critically ill coronavirus disease 2019 (COVID-19) patients treated at a tertiary institution specialized for COVID-19 patients.MethodsThis retrospective study recruited 692 patients (67.1% men). Baseline demographic data, major comorbidities, anthropometric measurements, clinical features, and laboratory findings at admission were compared between survivors and non-survivors.ResultsThe median age was 72 (64-78) years. The median body mass index was 29.1 kg/m². The most relevant comorbidities were diabetes mellitus (32.6%), arterial hypertension (71.2%), congestive heart failure (19.1%), chronic kidney disease (12.6%), and hematological disorders (10.3%). The median number of comorbidities was 3 and median Charlson Comorbidity Index (CCI) was 5. A total of 61.8% patients received high-flow nasal oxygen therapy (HFNO) and 80.5% received mechanical ventilation (MV). Median duration of HFNO was 3, and that of MV was 7 days. ICU mortality rate was 72.7%. Survivors had significantly lower age, number of comorbidities, CCI, sequential organ failure assessment score, serum ferritin, C-reactive protein, D-dimer, and procalcitonin, interleukin-6, lactate, white blood cell, and neutrophil counts. They also had higher lymphocyte counts, PaO₂/FiO₂ ratio, and glomerular filtration rate at admission. Length of ICU stay was 9 days. The median survival was 11 days for mechanically ventilated patients, and 24 days for patients who were not mechanically ventilated.ConclusionThe parameters that differentiate survivors from non-survivors are in agreement with published data. Further multivariate analyses are warranted to identify individual mortality risk factors.

The first case of coronavirus disease 2019 (COVID-19) in Croatia was confirmed on February 25, 2020 (1). Very soon, on March 11, the World Health Organization (WHO) declared a COVID-19 pandemic (2). As of February 25, 2021, there were more than 240 000 confirmed cases and 5489 deaths in Croatia.As a part of the national strategy against COVID-19 pandemic, the Ministry of Health and Civil Protection Headquarters decided that University Hospital Dubrava (UH) is to be repurposed into a Primary Respiratory Center for patients with confirmed COVID-19 infection. The intensive center of primary respiratory intensive center (PRIC-IC) is a subunit of UH Dubrava reserved for the treatment of patients with severe symptoms of COVID-19 who require mechanical ventilation, vasoactive hemodynamic support, continuous renal replacement therapy, and other aspects of intensive care (3). UH Dubrava became a COVID-19 tertiary center treating a third of all COVID-19 positive ICU patients in the country.As the pandemic was surging through Europe, the number of critically ill COVID-19 patients in UH Dubrava continued to grow, and ICU capacities needed expansion. During winter months, six intensive care units in PRIC were operating at the same time: Three were run by intensivists from UH Dubrava and three by intensivists from other hospitals in Zagreb, including University Hospital Center Zagreb, University Hospital Center Sestre Milosrdnice, University Hospital Sveti Duh, University Hospital Merkur, and Children''s Hospital Zagreb. The outcomes of critically ill patients treated in PRIC-IC therefore represent the work of intensivists from all hospitals in Zagreb.Although scientific knowledge of COVID-19 increases daily, limited information is available regarding early identification of individuals who are at risk of developing severe symptoms. Previous studies reported certain demographic features and clinical characteristics of patients who were likely to develop severe symptoms of COVID-19 and thus require mechanical ventilation (4-7). Studies worldwide reported high mortality rates for patients requiring mechanical ventilation, ranging from 40% to 97% (4,8-10). Unfortunately, some of these reports were preliminary and included patients without a completed ICU stay. The aim of our cohort retrospective study is to describe the demographic characteristic, clinical features, laboratory values, and outcomes among critically ill COVID-19 patients treated in PRIC-IC, UH Dubrava.     

The utility of a computerised clinical decision support system intervention in home medicines review: A mixed-methods process evaluation

BackgroundUse of high-risk medications is common and associated with adverse effects in older adults, including those living with dementia. A Computerised Clinical Decision Support System (CCDSS) called G-MEDSS© (Goal-directed Medication Review Electronic Decision Support System) contains tools that identify medications with anticholinergic and sedative effects and align older adult's health and medication goals of care with medication management strategies.ObjectivesTo describe the utility of a CCDSS called G-MEDSS in Home Medicines Review (HMR) by an accredited clinical pharmacist (ACP) using a mixed-methods process evaluation method.MethodsA mixed-methods process evaluation was conducted as part of a nation-wide cluster-randomised clinical trial evaluating the effectiveness of implementing G-MEDSS in HMR. Data were collected from ACPs and HMR recipients (the patient) using a feedback survey (ACPs and HMR recipients) and one-on-one telephone interviews (HMR recipients). Quantitative and qualitative data were combined at the start of analysis. Content analysis of the qualitative data was conducted, and emerging categories were linked to quantitative data.ResultsFeedback surveys were completed by eight ACPs and 26 HMR recipients; 11 HMR recipients completed one-on-one telephone interviews. Overall, ACPs and HMR recipients who received the intervention reported a positive attitude towards the utility of G-MEDSS in HMR. ACPs reported that G-MEDSS enhanced their ability to make evidence-based recommendations about anticholinergic and sedative medications, and to better align HMR recommendations with HMR recipients’ goals of care. However, ACPs described that it was difficult to obtain goals of care from HMR recipients. HMR recipients gave mixed reports about the ACPs consultations: some HMR recipients reported that they were engaged in discussions about their views on medications, whilst other participants reported that discussions about their concerns towards medications and goals was limited.ConclusionsThis study suggests that a CCDSS, such as G-MEDSS, demonstrates good utility to assist ACPs to identify and assess anticholinergic and sedative medications. Given the mixed feedback from the ACPs on the different components of the G-MEDSS, further refinement of these tools and their use in combination in practice may be needed.     

The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta

CRH targets the human myometrium during pregnancy. The efficiency of CRH actions is determined by expression of functional receptors (CRH-R), which are dynamically regulated. Studies in myometrial tissue biopsies using quantitative RT-PCR demonstrated that the onset of labor, term or preterm, is associated with a significant 2- to 3-fold increase in CRH-R1 mRNA levels. Detailed analysis of myometrial CRH-R1 mRNA variants showed a decline of the pro-CRH-R1 mRNA encoding the CRH-R1beta variant during labor and increased mRNA levels of CRH-R1d mRNA. Studies in myometrial cells identified IL-1beta as an important regulator of myometrial CRH-R1 gene expression because prolonged treatment of myometrial cells with IL-1beta (1 ng/ml) for 18 h induced expression of CRH-R1 mRNA levels by 1.5- to 2-fold but significantly attenuated CRH-R1beta mRNA expression by 70%. In contrast, IL-1beta had no effect on CRH-R1d mRNA expression. Studies using specific inhibitors suggest that ERK1/2, p38 MAPK, and downstream nuclear translocation of nuclear factor-kappaB mediate IL-1beta effects on myometrial CRH-R1 gene. However, the increased CRH-R1 mRNA expression was associated with a dampening of the receptor efficacy to activate the adenylyl cyclase/cAMP signaling cascade. Thus, our findings suggest that IL-1beta is an important regulator of CRH-R1 expression and functional activity, and this interaction might play a role in the transition of the uterus from quiescence to active contractions necessary for the onset of parturition.     

Diagnostic significance of three‐dimensional echocardiography in asymptomatic unicuspid aortic valve

Unicuspid aortic valve (UAV) is a rare congenital anomaly of aorta associated with a faster progress of valvular dysfunction, aortic dilatation and with necessity for more frequent controls and precise evaluation Asymptomatic 35 year old man had abnormal systolic diastolic murmur on aortic valve during routine examination. Initial diagnostic with transthoracic echocardiography (TTE) supposed bicuspid aortic valve, while three‐dimensional transesophageal echocardiography (3D TEE) and multidetector computed tomography defined unicuspid, unicomissural aortic valve with moderate aortic stenosis and regurgitation. This case report confirmed that 3D TEE gives us opportunity for early, improved and precise diagnosis of UAV.     

Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice

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Polyacylurethanes as Novel Degradable Cell Carrier Materials for Tissue Engineering

Polycaprolactone (PCL) polyester and segmented aliphatic polyester urethanes based on PCL soft segment have been thoroughly investigated as biodegradable scaffolds for tissue engineering. Although proven beneficial as long term implants, these materials degrade very slowly and are therefore not suitable in applications in which scaffold support is needed for a shorter time. A recently developed class of polyacylurethanes (PAUs) is expected to fulfill such requirements. Our aim was to assess in vitro the degradation of PAUs and evaluate their suitability as temporary scaffold materials to support soft tissue repair. With both a mass loss of 2.5–3.0% and a decrease in molar mass of approx. 35% over a period of 80 days, PAUs were shown to degrade via both bulk and surface erosion mechanisms. Fourier Transform Infra Red (FTIR) spectroscopy was successfully applied to study the extent of PAUs microphase separation during in vitro degradation. The microphase separated morphology of PAU1000 (molar mass of the oligocaprolactone soft segment = 1000 g/mol) provided this polymer with mechano-physical characteristics that would render it a suitable material for constructs and devices. PAU1000 exhibited excellent haemocompatibility in vitro. In addition, PAU1000 supported both adhesion and proliferation of vascular endothelial cells and this could be further enhanced by pre-coating of PAU1000 with fibronectin (Fn). The contact angle of PAU1000 decreased both with in vitro degradation and by incubation in biological fluids. In endothelial cell culture medium the contact angle reached 60°, which is optimal for cell adhesion. Taken together, these results support the application of PAU1000 in the field of soft tissue repair as a temporary degradable scaffold.