The genetic spectrum of familial hypercholesterolemia in South-Eastern Poland

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population. MATERIALS AND METHODS: 161 unrelated subjects with a clinical diagnosis of FH from the south-eastern region of Poland were recruited. High resolution melt and direct sequencing of PCR products were used to screen 18 exons of LDLR, a region of exon 26 in the APOB gene and exon 7 of PCSK9. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions and insertions in LDLR. Genotypes of six LDL-C raising SNPs were used for a polygenic gene score calculation. RESULTS: We found 39 different pathogenic mutations in the LDLR gene with 10 of them being novel. 13 (8%) individuals carried the p.Arg3527Gln mutation in APOB, and overall the detection rate was 43.4%. Of the patients where no mutation could be found, 53 (84.1%) had a gene score in the top three quartiles of the healthy comparison group suggesting that they have a polygenic cause for their high cholesterol. CONCLUSIONS: These results confirm the genetic heterogeneity of FH in Poland, which should be considered when designing a diagnostic strategy in the country. As in the UK, in the majority of patients where no mutation can be found, there is likely to be a polygenic cause of their high cholesterol level

Verification of the formulation and efficacy of Danggui Buxue Tang (a decoction of Radix Astragali and Radix Angelicae Sinensis): an exemplifying systematic approach to revealing the complexity of Chinese herbal medicine formulae

This article exemplifies a systematic approach to revealing the complexity of Chinese herbal medicine formulae through three levels of scientific research: standardization of herbs, verification of ancient formulae and mechanism studies. We use Danggui Buxue Tang (DBT) as an example for this approach. Among thousands of traditional Chinese medicine herbal formulae, almost all of which consist of multiple herbs, DBT is one of the simplest. Containing only two herbs, namely Radix Astragali (RA) and Radix Angelicae Sinensis (RAS), DBT is traditionally used to treat ailments in women. The weight ratio of RA to RAS in DBT was prescribed to be 5:1 as early as in 1247 AD. In addition to advanced chemical analysis of herbal constituents, DNA genotyping techniques have been developed for reliable standardization of RA and RAS. Chemical evaluation shows that main active constituents in DBT, including astragaloside IV, calycosin, formononetin and ferulic acid, were most abundant after extraction at the RA to RAS ratio of 5:1, whereas other tested RA to RAS ratios only gave sub-optimal levels of the active constituents. Biological evaluation indicates that bioactivities of DBT, e.g. immuno-modulatory, oesteotropic and estrogenic effects are also best exerted at the RA to RAS ratio of 5:1. Correlation analysis demonstrates statistically significant relationship between the tested chemical constituents and tested bioactivities. Up- and down-regulation of expression of some genes as potential biomarkers has been detected by using gene chip technology. This systematic approach on the basis of herbal standardization, chemical and biological verification and mechanism studies, as exemplified in this article, will be useful to reveal the complexity of not only DBT but also other Chinese medicine herbal formulae

Remaining Useful Life Modelling with an Escalator Health Condition Analytic System

The refurbishment of an escalator is usually linked with its design life as recommended by the manufacturer. However, the actual useful life of an escalator should be determined by its operating condition which is affected by the runtime, workload, maintenance quality, vibration, etc., rather than age only. The objective of this project is to develop a comprehensive health condition analytic system for escalators to support refurbishment decisions. The analytic system consists of four parts: 1) online data gathering and processing; 2) a dashboard for condition monitoring; 3) a health index model; and 4) remaining useful life prediction. The results can be used for a) predicting the remaining useful life of the escalators, in order to support asset replacement planning and b) monitoring the real-time condition of escalators; including alerts when vibration exceeds the threshold and signal diagnosis, giving an indication of possible root cause (components) of the alert signal.Comment: 14 pages, 12 figures, 7 table

Medium-term Outcomes of Myocarditis and Pericarditis following BNT162b2 Vaccination among Adolescents in Hong Kong

In this study, we examined the clinical and electrophysiological outcomes of adolescents in Hong Kong who developed myocarditis or pericarditis following BNT162b2 vaccination for COVID-19, and followed-up for 60 to 180 days after their initial diagnosis. Clinical assessments included electrocardiogram (ECG) and echocardiogram at the initial admission and follow-up were compared. Treadmill testing was also performed in some cases. Between 14 June 2021 and 16 February 2022, 53 subjects were approached to participate in this follow-up study, of which 28 patients were followed up for >60 days with a median follow-up period of 100 days (range, 61-178 days) and were included in this study. On admission, 23 patients had ECG abnormalities but no high-grade atrioventricular block. Six patients had echocardiogram abnormalities, including reduced contractility, small rim pericardial effusions, and hyperechoic ventricular walls. All patients achieved complete recovery on follow-up. After discharge, 10 patients (35.7%) reported symptoms, including occasional chest pain, shortness of breath, reduced exercise tolerance, and recurrent vasovagal near-syncope. At follow-up, assessments, including ECGs, were almost all normal. Among the three patients with possible ECG abnormalities, all their echocardiograms or treadmill testings were normal. Sixteen patients (57.1%) underwent treadmill testing at a median of 117 days post-admission, which were also normal. However, at follow-up, there was a significant mean bodyweight increase of 1.81kg (95%CI 0.47-3.1 kg, p=0.01), possibly due to exercise restriction. In conclusion, most adolescents experiencing myocarditis and pericarditis following BNT162b2 vaccination achieved complete recovery. Some patients developed non-specific persistent symptoms, and bodyweight changes shall be monitored

Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C

The term laminopathies defines a group of genetic disorders caused by defects in the nuclear envelope, mostly the lamins. Lamins are the main constituents of the nuclear lamina, a filamentous meshwork associated with the inner nuclear membrane that provides mechanical stability and plays important roles in processes such as transcription, DNA replication and chromatin organization. More than 300 mutations in lamin A/C have been associated with diverse clinical phenotypes, understanding the molecular basis of these diseases may provide a rationale for treating them. Here we describe the generation of induced pluripotent stem cells (iPSCs) from a patient with inherited dilated cardiomiopathy and 2 patients with distinct accelerated forms of aging, atypical Werner syndrome and Hutchinson Gilford progeria, all of which are caused by mutations in lamin A/C. These cell lines were pluripotent and displayed normal nuclear membrane morphology compared to donor fibroblasts. Their differentiated progeny reproduced the disease phenotype, reinforcing the idea that they represent excellent tools for understanding the role of lamin A/C in normal physiology and the clinical diversity associated with these diseases

X-ray Signatures of Non-Equilibrium Ionization Effects in Galaxy Cluster Accretion Shock Regions

The densities in the outer regions of clusters of galaxies are very low, and the collisional timescales are very long. As a result, heavy elements will be under-ionized after they have passed through the accretion shock. We have studied systematically the effects of non-equilibrium ionization for relaxed clusters in the LambdaCDM cosmology using one-dimensional hydrodynamic simulations. We found that non-equilibrium ionization effects do not depend on cluster mass but depend strongly on redshift which can be understood by self-similar scaling arguments. The effects are stronger for clusters at lower redshifts. We present X-ray signatures such as surface brightness profiles and emission lines in detail for a massive cluster at low redshift. In general, soft emission (0.3-1.0 keV) is enhanced significantly by under-ionization, and the enhancement can be nearly an order of magnitude near the shock radius. The most prominent non-equilibrium ionization signature we found is the O VII and O VIII line ratio. The ratios for non-equilibrium ionization and collisional ionization equilibrium models are different by more than an order of magnitude at radii beyond half of the shock radius. These non-equilibrium ionization signatures are equally strong for models with different non-adiabatic shock electron heating efficiencies. We have also calculated the detectability of the O VII and O VIII lines with the future International X-ray Observatory (IXO). Depending on the line ratio measured, we conclude that an exposure of ~130-380 ksec on a moderate-redshift, massive regular cluster with the X-ray Microcalorimeter Spectrometer (XMS) on the IXO will be sufficient to provide a strong test for the non-equilibrium ionization model.Comment: 18 pages, 11 figures, accepted for publication in the Astrophysical Journa

A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease

Background: Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). Methods and results: We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (. P-value for heterogeneity=0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. Conclusions: In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD

Quantification of Beat-To-Beat Variability of Action Potential Durations in Langendorff-Perfused Mouse Hearts

Background: Beat-to-beat variability in action potential duration (APD) is an intrinsic property of cardiac tissue and is altered in pro-arrhythmic states. However, it has never been examined in mice.Methods: Left atrial or ventricular monophasic action potentials (MAPs) were recorded from Langendorff-perfused mouse hearts during regular 8 Hz pacing. Time-domain, frequency-domain and non-linear analyses were used to quantify APD variability.Results: Mean atrial APD (90% repolarization) was 23.5 ± 6.3 ms and standard deviation (SD) was 0.9 ± 0.5 ms (n = 6 hearts). Coefficient of variation (CoV) was 4.0 ± 1.9% and root mean square (RMS) of successive differences in APDs was 0.3 ± 0.2 ms. The peaks for low- and high-frequency were 0.7 ± 0.5 and 2.7 ± 0.9 Hz, respectively, with percentage powers of 39.0 ± 20.5 and 59.3 ± 22.9%. Poincaré plots of APDn+1 against APDn revealed ellipsoid shapes. The ratio of the SD along the line-of-identity (SD2) to the SD perpendicular to the line-of-identity (SD1) was 8.28 ± 4.78. Approximate and sample entropy were 0.57 ± 0.12 and 0.57 ± 0.15, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.80 ± 0.15 and 0.85 ± 0.29, respectively. When compared to atrial APDs, ventricular APDs were longer (ANOVA, P < 0.05), showed lower mean SD and CoV but similar RMS of successive differences in APDs and showed lower SD2 (P < 0.05). No difference in the remaining parameters was observed.Conclusion: Beat-to-beat variability in APD is observed in mouse hearts during regular pacing. Atrial MAPs showed greater degree of variability than ventricular MAPs. Non-linear techniques offer further insights on short-term and long-term variability and signal complexity

State-Dependent Accessibility of the P-S6 Linker of Pacemaker (HCN) Channels Supports a Dynamic Pore-to-Gate Coupling Model

The hyperpolarization-activated cyclic nucleotide-modulated channel gene family (HCN1-4) encodes the membrane depolarizing current that underlies pacemaking. Although the topology of HCN resembles Kv channels, much less is known about their structure-function correlation. Previously, we identified several pore residues in the S5-P linker and P-loop that are externally accessible and/or influence HCN gating, and proposed an evolutionarily conserved pore-to-gate mechanism. Here we sought dynamic evidence by assessing the functional consequences of Cys-scanning substitutions in the unexplored P-S6 linker (residues 352–359), the HCN1-R background (that is, resistant to sulfhydryl-reactive agents). None of A352C, Q353C, A354C, P355C, V356C, S357C, M358C, or S359C produced functional currents; the loss-of-function of Q353C, A354C, S357C, and M358C could be rescued by the reducing agent dithiothreitol. Q353C, A354C, and S357C, but not M358C and HCN1-R, were sensitive to Cd2+ blockade (IC50 = 3–12 μM vs. >1 mM). External application of the positively charged covalent sulfhydryl modifier MTSET irreversibly reduced I−140mV of Q353C and A354C to 27.9 ± 3.4% and 58.2 ± 13.1% of the control, respectively, and caused significant steady-state activation shifts (∆V1/2 = –21.1 ± 1.6 for Q353C and −10.0 ± 2.9 mV for A354C). Interestingly, MTSET reactivity was also state dependent. MTSET, however, affected neither S357C nor M358C, indicating site specificity. Collectively, we have identified novel P-S6 residues whose extracellular accessibility was sterically and state dependent and have provided the first functional evidence consistent with a dynamic HCN pore-to-gate model

Renal cell carcinoma of native kidney in Chinese renal transplant recipients: a report of 12 cases and a review of the literature

Objectives To present and discuss the epidemiological and clinical aspects, as well as therapeutic options and outcome of de novo renal cell carcinoma (RCC) of the native kidneys in a series of Chinese renal transplant recipients. Patients and Methods A retrospective, cohort study examining all renal transplant recipients with the diagnosis of RCC of native kidney followed up in two major regional hospitals in Hong Kong between January 2000 and December 2009. Clinical data includedage, gender, cause of renal failure, symptoms at presentation, duration of transplantation, immunosuppressive therapy, and history of acquired cystic kidney disease (ACKD). Laboratory, radiographic, operative, and pathology reports were used to assess the tumor extent. Results Among the 1,003 renal transplant recipients recruited, 12 transplant recipients had a nephrectomy for a total of 13 RCC. The prevalence of de novo RCC was 1.3%. The mean age at diagnosis of RCC was 48.4 years, and the median time from transplantation to diagnosis was 6.1 years. ACKD was found in 6 (50%) of the patients. All patients except one were asymptomatic. pT1 disease was found in ten patients with a mean tumor size of 3.2 cm. All patients were treated successfully with radical nephrectomy. After a median follow-up of 38 months, two patients (16.7%) died. One died of sepsis, and the other died of metastatic carcinoma. Conclusions With increasing data showing a better prognosis if RCC is detected early by screening, it is time to consider screening all kidney transplant recipients for ACKD and RCC. © The Author(s) 2011. This article is published with open access at Springerlink.com.published_or_final_versionSpringer Open Choice, 21 Feb 201