A Genetic Validation of the Neurodegeneration Biomarkers Tau-A and Tau-C - A Mendelian Randomization Study.

BACKGROUND: Disease modifying treatments for dementia are only just surfacing, and their development is still significantly hindered by the lack of validated tools for identification of subjects with subclinical disease. Much interest has been taken in developing accessible non-invasive serum biomarkers of neurodegeneration. Recent studies have identified caspase-3-cleaved tau (Tau-C), and ADAM-10 cleaved tau (Tau-A) as possible markers of preclinical neurodegenerative disease. OBJECTIVES: To explore if serum levels of Tau-A and Tau-C change as a consequence of neurodegeneration. DESIGN AND SETTING: Cohort study with measurement of biomarkers and genome sequencing at baseline with follow-up after an average of 14 years. PARTICIPANTS: Postmenopausal Danish women from the Prospective Epidemiological Risk Factor (PERF) cohort (n=4968) Methods: Genotyping data was used to perform a Mendelian randomization analysis of serum levels of Tau-A and Tau-C in relation to a diagnosis of dementia at follow-up. A dementia diagnosis was defined as a composite of an all-cause dementia diagnosis derived from the Danish National Health registries, a self-reported diagnosis of dementia and/or cognitive test scores suggestive of dementia. Serum levels of Tau-A and Tau-C were measured blinded in samples from baseline in a CAP certified lab. The association with dementia was assessed using bi-directional one- and two- sample Mendelian randomization. RESULTS: A lead single nucleotide polymorphism (SNP) was identified for Tau-A (rs10414043) and Tau-C (rs429358), respectively were identified. Both were located in the APOE/C1 cluster on chromosome 19. APOE and EPOC1 variants were associated with lower levels of Tau-A and Tau-C levels - effect size -0.13, 95%CI [-0.17 - -0.09] log2 (ng/mL), p=7.05e-11 for rs10414043 association with Tau-A and effect size -0.12, 95%CI [-0.15 - -0.08] log2 (ng/mL), p=2e-11 for rs429358 association with Tau-C. When incorporating genetic data from a larger genetic study we found that Alzheimer's disease was marginally associated with a decreased Tau-A and Tau-C levels (Odds Ratio 0.97, 95%CI [0.93 - 1.00]. No association was found in the forward Mendelian randomization analysis. CONCLUSIONS: By combining genotype data with serum measurements of the novel biomarkers Tau-A and Tau-C, we conclude that Tau-A and Tau-C levels change because of neurodegeneration. We also conclude that lower serum-values of the biomarkers are associated with the presence of genetic variants commonly found in individuals suffering from late-onset Alzheimer's Dementia. These findings add to the growing data pointing towards Tau-A and Tau-C as valuable biomarkers for neurodegeneration.

Impact of the radiation effect on the energy storage density and wake-up behaviors of antiferroelectric-like Al-doped HfO2 thin films.

The effect of the γ-ray total dose radiation on the energy storage density (ESD) and the phase transition of antiferroelectric-like (AFE-like) Al-doped HfO2 (HfAlO) thin films was investigated. The ESD property and wake-up behavior of the phase transition during the field cycling of the AFE-like HfAlO thin films were quantified before and after the radiation. The efficiency of the AFE-like thin films for energy storage slightly decreases as the total dose increases from 200 krad (Si) to 5 Mrad (Si), which is attributed to the radiation-induced trapped defects at the interfaces of HfAlO/TiN. Both the J-E, C-V, and εr-f characteristics of the AFE-like HfAlO thin films were also measured before and after the radiation at the same electrodes. These results further confirm that the ferroelectricity of the thin films can be reduced due to the radiation oxide trapped defects. It is worth noting that an enhanced wake-up behavior of the AFE-like HfAlO thin films can be observed after the radiation, which indicates that the transition from the antiferroelectric phase to the ferroelectric phase could be accelerated by the increased radiation-induced defects.

Identification of heterogenous treatment response trajectories to anti-IL6 receptor treatment in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p < 0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p < 0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.

Interfacial exchange coupling and magnetization reversal in perpendicular [Co/Ni]N/TbCo composite structures.

Interfacial exchange coupling and magnetization reversal characteristics in the perpendicular heterostructures consisting of an amorphous ferrimagnetic (FI) TbxCo(100-x) alloy layer exchange-coupled with a ferromagnetic (FM) [Co/Ni]N multilayer have been investigated. As compared with pure TbxCo(100-x) alloy, the magnetization compensation composition of the heterostructures shift to a higher Tb content, implying Co/Ni also serves to compensate the Tb moment in TbCo layer. The net magnetization switching field Hc⊥ and interlayer interfacial coupling field Hex, are not only sensitive to the magnetization and thickness of the switched TbxCo(100-x) or [Co/Ni]N layer, but also to the perpendicular magnetic anisotropy strength of the pinning layer. By tuning the layer structure we achieve simultaneously both large Hc⊥ = 1.31 T and Hex = 2.19 T. These results, in addition to the fundamental interest, are important to understanding of the interfacial coupling interaction in the FM/FI heterostructures, which could offer the guiding of potential applications in heat-assisted magnetic recording or all-optical switching recording technique.

Inhibitory effect of liposomal quercetin on acute hepatitis and hepatic fibrosis induced by concanavalin A.

Immune response plays an important role in the development of hepatic fibrosis. In the present study, we investigated the effects of quercetin on hepatitis and hepatic fibrosis induced by immunological mechanism. In the acute hepatitis model, quercetin (2.5 mg/kg) was injected iv into mice 30 min after concanavalin A (Con A) challenge. Mice were sacrificed 4 or 24 h after Con A injection, and aminotransferase tests and histopathological sections were performed. Treatment with quercetin significantly decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Consistent with this observation, treatment with quercetin markedly attenuated the pathologic changes in the liver. A hepatic fibrosis model was also generated in mice by Con A challenge once a week for 6 consecutive weeks. Mice in the experimental group were treated with daily iv injections of quercetin (0.5 mg/kg). Histopathological analyses revealed that treatment with quercetin markedly decreased collagen deposition, pseudolobuli development, and hepatic stellate cells activation. We also examined the effects of quercetin on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor beta (TGF-ß) pathways by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). NF-κB and TGF-ß production was decreased after treatment with quercetin, indicating that the antifibrotic effect of quercetin is associated with its ability to modulate NF-κB and TGF-ß production. These results suggest that quercetin may be an effective therapeutic strategy in the treatment of patients with liver damage and fibrosis.

Inhibitory effect of liposomal quercetin on acute hepatitis and hepatic fibrosis induced by concanavalin A

Immune response plays an important role in the development of hepatic fibrosis. In the present study, we investigated the effects of quercetin on hepatitis and hepatic fibrosis induced by immunological mechanism. In the acute hepatitis model, quercetin (2.5 mg/kg) was injected iv into mice 30 min after concanavalin A (Con A) challenge. Mice were sacrificed 4 or 24 h after Con A injection, and aminotransferase tests and histopathological sections were performed. Treatment with quercetin significantly decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Consistent with this observation, treatment with quercetin markedly attenuated the pathologic changes in the liver. A hepatic fibrosis model was also generated in mice by Con A challenge once a week for 6 consecutive weeks. Mice in the experimental group were treated with daily iv injections of quercetin (0.5 mg/kg). Histopathological analyses revealed that treatment with quercetin markedly decreased collagen deposition, pseudolobuli development, and hepatic stellate cells activation. We also examined the effects of quercetin on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor beta (TGF-β) pathways by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). NF-κB and TGF-β production was decreased after treatment with quercetin, indicating that the antifibrotic effect of quercetin is associated with its ability to modulate NF-κB and TGF-β production. These results suggest that quercetin may be an effective therapeutic strategy in the treatment of patients with liver damage and fibrosis.

Two cases of severe intoxication associated with analytically confirmed use of the novel psychoactive substances 25B-NBOMe and 25C-NBOMe.

CONTEXT: A new group of novel psychoactive substance, the N-methoxybenzyl (NBOMe) derivatives of substituted phenethylamine, has recently emerged on the drug market, among which 25I-NBOMe and 25B-NBOMe have previously been implicated in clinical intoxications and fatalities. We report two cases of acute intoxication associated with these substances. CASE DETAILS: Two male patients (17 and 31 years of age) had ingested drugs labelled as 'NBOMe' or 'Holland film' and developed confusion, agitation, hypertension, tachycardia, hyperthermia, sweating and dilated pupils. Other features included convulsion, rhabdomyolysis and deranged liver function. The patients required benzodiazepines and other drugs for the control of symptoms. Urine samples from both patients were analysed using liquid-chromatography tandem mass spectrometry (LC-MS/MS) following glucuronidase digestion and solid-phase extraction. Identification was based upon comparison of the retention time and enhanced product ion scan with reference standards. In both urine samples, 25B-NBOMe was detected. Additionally, 25C-NBOMe was identified in one of the urine samples. DISCUSSION: The NBOMe compounds are highly potent 5HT2A receptor agonists and are also agonists at alpha-adrenergic receptors, which likely account for their serotonergic and sympathomimetic symptoms. The clinical testing of NBOMe drugs is not commonly available. Clinicians as well as laboratory staff play an important role in facilitating the detection of this group of potentially dangerous emerging drugs.

Successful treatment of severe fetal chylothorax resistant to repeated pleuroamniotic shunting by OK-432 pleurodesis.

We report the first case of successful fetal pleurodesis with OK-432 for recurrent severe fetal primary chylothorax after failing repeated pleuroamniotic shunting. Shunting and pleurodesis could be complementary to each other in the treatment of fetal chylothorax.

Serotonin syndrome following overdose of a non-prescription slimming product containing sibutramine: a case report.

INTRODUCTION: Non-prescription slimming products are popular and can be easily purchased from the Internet. However, adulteration of these products with undeclared substances including prescription drugs is not uncommon. We report a case of serotonin syndrome after an overdose of a non-prescription product containing sibutramine. CASE REPORT: A 21-year-old woman presented with somnolence, sinus tachycardia, generalised increase in tone, hyper-reflexia and clonus more prominent in the lower limbs after an intentional overdose of a non-prescription slimming product obtained from the Internet. The product was later found to contain sibutramine and other substances such as animal thyroid tissues, caffeine and phenolphthalein. Quantitative analysis of patient's serum on presentation revealed a sibutramine concentration of 112 ng/mL, which far exceeded the reported peak serum concentration after a single oral dose of 15 mg (the maximum daily recommended dose). No other culpable agent was identified. The overall clinical presentation was compatible with serotonin syndrome associated with sibutramine overdose. The patient made a full recovery after supportive management. DISCUSSION AND CONCLUSION: This case highlighted the health threat posed by non-prescription slimming products sold over the Internet. Sibutramine overdose can result in serotonin syndrome, as in overdose of other serotonergic agents. Early recognition and timely supportive treatment are essential to ensure a good clinical outcome.

Birth-weight prediction using three-dimensional sonographic fractional thigh volume at term in a Chinese population.

OBJECTIVES: To develop and validate new birth-weight prediction models in Chinese pregnant women using fractional thigh volume. METHODS: Healthy late third-trimester fetuses within 5 days of delivery were prospectively examined using two- (2D) and three- (3D) dimensional ultrasonography. Measurements were performed using 2D ultrasound for standard fetal biometry and 3D ultrasound for fractional thigh volume (TVol) and middle thigh circumference. The intraclass correlation coefficient (ICC) was used to analyze the inter- and intraobserver reliability of the 3D ultrasound measurements of 40 fetuses. Five birth-weight prediction models were developed using linear regression analysis, and these were compared with previously published models in a validation group. RESULTS: Of the 290 fetuses studied, 100 were used in the development of prediction models and 190 in the validation of prediction models. The inter- and intraobserver variability for TVol and middle thigh circumference measurements was small (all ICCs ≥ 0.95). The prediction model using TVol, femur length (FL), abdominal circumference (AC) and biparietal diameter (BPD) provided the most precise birth-weight estimation, with a random error of 4.68% and R(2) of 0.825. It correctly predicted 69.5 and 95.3% of birth weights to within 5 and 10% of actual birth weight. By comparison, the Hadlock model with standard fetal biometry (BPD, head circumference, AC and FL) gave a random error of 6.41%. The percentage of birth-weight prediction within 5 and 10% of actual birth weight was 46.3 and 82.6%, respectively. CONCLUSION: Consistent with studies on Caucasian populations, a new birth-weight prediction model based on fractional thigh volume, BPD, AC and FL, is reliable during the late third trimester in a Chinese population, and allows better prediction than does the Hadlock model.

Simultaneous real-time imaging of four-chamber and left ventricular outflow tract views using xPlane imaging capability of a matrix array probe.

OBJECTIVES: To determine the feasibility and reliability of using xPlane imaging to examine simultaneously the four-chamber and left ventricular outflow tract (LVOT) views in real time, to assess rotation angles from the four-chamber view to the LVOT view, and to investigate factors affecting the angles. METHODS: In 145 fetuses at 11-37 weeks' gestation, we visualized the four-chamber view in one of three cardiac positions: a subcostal view with the apex at the 3 or 9 o'clock position; an apical view with the apex at the 12 or 6 o'clock position; or a view with the fetal heart apex midway between these two positions. We then used the rotation function of xPlane imaging, using the four-chamber view as the reference plane, to visualize the LVOT view simultaneously in real time on the secondary image plane, on the right side of the split screen, by rotating a reference line from 0° with a rotation step of 5°. The rotation angle necessary for the first appearance of LVOT was recorded as the first rotation angle. The reference line was then rotated until the LVOT was just out of view, and this last rotation angle was recorded as the second rotation angle. The difference between these two angles was recorded as the angle span of the LVOT display. Reliability was assessed by intraclass correlation coefficient (ICC). RESULTS: Of the 145 fetuses examined, 29 had cardiac defects. Using xPlane imaging, the LVOT was visualized successfully after 14 weeks in 95.1% of cases. The first and second rotation angles varied significantly with cardiac position (P < 0.001); when the fetal heart was examined using a subcostal approach with the apex at the 3 or 9 o'clock position, the first rotation angle was smaller than that at the apical view for normal hearts (20° vs. 50°, P < 0.001). There was also a significant difference for the second rotation angle and for the angle span, between fetuses with and without normal LVOT (P = 0.038 and 0.006, respectively). Regarding intra- and interobserver reliability for measurement of first and second rotation angles, the ICCs were high (range, 0.847-0.980). CONCLUSION: Using xPlane imaging, it is feasible to examine simultaneously the four-chamber and LVOT views in real time, and measurement of the rotation angles between these two views is reproducible. The rotation angles depend on the position of the fetal heart, and the normality of the LVOT. Proposed algorithms for examination of the fetal heart with three-/four-dimensional ultrasonography may need to be adapted to optimize visualization of the standard planes.

Haemoglobin level, proportion of haemoglobin Bart's and haemoglobin Portland in fetuses affected by homozygous α0-thalassemia from 12 to 40 weeks' gestation.

OBJECTIVES: To determine haematological parameters in fetuses affected by homozygous α(0)-thalassemia. METHODS: This was a cross-sectional retrospective study reviewing 546 blood samples (268 fetal and 278 neonatal cord) being collected between 1993 and 2006, from 12 weeks' gestation onwards for any indication, including the prenatal diagnosis of homozygous α(0)-thalassemia, other haematological disorders, hydrops or aneuploidy. The proportion of haemoglobin (Hb) fractions was determined by electrophoresis of haemolysate on cellulose acetate in all samples. RESULTS: There were significant differences in the haematological parameters between homozygous α(0)-thalassemia (n = 183) and control (n = 363) which were either heterozygous α(0)-thalassemia (alpha thalassemia trait) or normal. In homozygous α(0)-thalassemia, the median Hb level, proportion of Hb Bart's (γ(4)) and Hb Portland 1(ζ(2)γ(2)) were 6.4 g/dL, 77.5% and 22.5%, respectively. While the Hb level and the proportion of Hb Bart's increased significantly with gestation, the proportion of Hb Portland 1 decreased. The Hb level contributed by Hb Portland 1 remained around 1.4 g/dL throughout gestation. The proportion of mild, moderate and severe anaemia in the affected fetuses was 27.5, 32.7 and 39.8%, respectively. There was no significant difference in these proportions across different gestation (P = 0.231). There were no differences in the haematological parameters between hydropic and non-hydropic fetuses. CONCLUSION: Although the degree of anaemia is mild in around one-quarter of the affected fetuses, the contribution by Hb Portland 1 (ζ(2)γ(2)) to the Hb level was very low throughout gestation, and the affected fetuses may therefore be at risk for hypoxia.

Comparison of inter- and intraobserver agreement and reliability between three different types of placental volume measurement technique (XI VOCAL, VOCAL and multiplanar) and validity in the in-vitro setting.

OBJECTIVES: To compare XI VOCAL (eXtended Imaging Virtual Organ Computer-aided AnaLysis) for three-dimensional (3D) ultrasound volumetry of the placenta and of phantom objects with a rotational method using VOCAL and with the multiplanar method. METHODS: We acquired 3D volume datasets from 32 fetuses at 11-14 weeks' gestation. Placental volume was calculated twice by each of two observers using XI VOCAL (with 5, 10, 15 and 20 slices), multiplanar (1-mm interval) and VOCAL (with 12 degrees, 18 degrees and 30 degrees rotation) methods. In addition, validity was assessed using the in-vitro setting with three phantom objects of known volume. RESULTS: Both inter- and intraobserver reliabilities were very high for all three methods. There was no systematic bias between any two methods except between XI VOCAL (10 slices) and the multiplanar (1-mm interval) method, with a smaller volume using the former method. The limits of agreement were wide between any two of the three methods. In the in-vitro setting, there was a trend towards less valid measurements with the XI VOCAL technique and fewer slices. With the same number of steps, measurements made with VOCAL (12 degrees and 18 degrees) were more valid than were those made with XI VOCAL (15 and 10 slices, respectively). CONCLUSION: XI VOCAL cannot be used interchangeably with VOCAL or multiplanar techniques in measuring placental volume at 11-14 weeks' gestation.

Fetal biometry by an inexperienced operator using two- and three-dimensional ultrasound.

OBJECTIVE: To compare the reproducibility, accuracy and time required for fetal biometric measurements using two-dimensional (2D) and three-dimensional (3D) ultrasonography by an inexperienced operator. METHODS: Fifty consecutive fetuses were evaluated at a gestational age of 17-34 weeks. For every fetus measurements-including biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL)-were made by an inexperienced operator using 2D ultrasound and then saved 3D volumes. As a control, measurements were also made by an experienced operator using 2D ultrasonography alone. Each fetal biometric parameter was measured twice by each operator. All images were assessed by two experienced reviewers, blinded to the operator's identity, using a scoring system based on objective evaluation criteria. RESULTS: The interobserver, intraobserver and inter- method variability for 2D ultrasonography by the experienced operator (2D-exp), and 2D and 3D ultrasonography by the inexperienced operator (2D-inexp and 3D-inexp) was small (all intraclass correlation coefficients > or = 0.991). A non-significantly higher proportion of fetal biometric measurements by 3D-inexp than 2D-inexp were within 1 mm of the measurements by 2D-exp. There were no differences in the mean image quality scores of fetal biometry between 2D-exp and 2D-inexp, 2D-exp and 3D-inexp. However, the quality score of AC images obtained by 3D-inexp was greater than that obtained by 2D-inexp (5.5 vs. 5.3, P = 0.018). The mean time required to measure BPD, HC, AC and FL was less for 3D-inexp than for 2D-inexp (67.2 vs. 97.0 s, 64.6 vs. 97.0 s, 60.1 vs. 81.5 s and 65.5 vs. 95.1 s, respectively; all P < 0.001), but was significantly greater than for 2D-exp, with corresponding figures of 24.3, 24.3, 27.9 and 27.2 s. CONCLUSION: Fetal biometric measurements obtained by an inexperienced operator using both 2D and 3D ultrasound were reproducible and showed good agreement with those obtained by an experienced operator. The use of 3D ultrasound by an inexperienced operator allows faster measurements to be made than by 2D ultrasound and also seems to facilitate the acquisition of higher-quality images for measurement of AC.