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BackgroundRelapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.MethodsWe did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204.FindingsWe enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.InterpretationEstriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial.FundingNational Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

The melting of the Greenland ice sheet (GrIS) in summer has rapidly and significantly increased in recent decades, especially for the northern GrIS. Circulation related to GrIS melting is important for understanding the contribution of the GrIS to the global sea level. In this paper, we used the SOM method to obtain three spatial patterns of GrIS melting based on model output data: overall melting, northern melting, and southern melting patterns. We also examined their linkages to the observed atmospheric circulation. GrIS melting is primarily related to Greenland blocking (GB), while different types of GB are responsible for different melting patterns. The overall and northern melting patterns are both associated with high-latitude GB, which is associated with the decay and westward movement of mid-latitude and high-latitude European blocking (EB), respectively. It is found that the generation of mid-latitude and high-latitude EBs are related to mid-latitude eastern North Atlantic warming and Greenland–Norskehavet–North Sea warming, respectively, while the movement of EB is related t upstream weakened zonal wind anomalies. Furthermore, the southern melting pattern is linked to mid-latitude GB, which is associated with the wave train from the East Pacific to Southern Greenland through North America and further related to the mid-latitude of East Pacific warming. [ABSTRACT FROM AUTHOR]

This study introduces a versatile electrolyte additive, nicotinamide, for zinc anodes, aiming to facilitate uniform deposition and suppress water-induced side reactions. The molecular structure, consisting of a pyridine ring and an amide function group, endows NTA molecules with the ability to regulate electrolyte pH, enhance nucleation overpotential, and constrain 2D diffusion of Zn2+. As a result, the full battery configuration with this additive achieved an impressive lifespan of over 10 000 cycles. [ABSTRACT FROM AUTHOR]

Background: The neurotrophic tyrosine kinase (NTRK) gene family includes NTRK1, NTRK2, and NTRK3, which encode tropomyosin receptor kinases TrkA, TrkB, and TrkC, respectively. This study aimed to initially assess the genomic and proteomic profiles of NTRK genes and Trk receptors in liver hepatocellular carcinoma (LIHC). Methods: The ONCOMINE, UALCAN, GEPIA, cBioPortal, FusionGDB, SurvivalMeth, and the Human Protein Atlas databases were searched for NTRK gene expression and protein data in LIHC. Immunohistochemistry was used to detect pan-Trk expression across a commercial microarray containing 96 hepatocellular carcinoma (HCC) and 94 para-cancerous tissue spots. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for pan-Trk. Student's t- and chi-square tests were the main statistical analyses used. Results: The transcriptional levels of NTRK genes in LIHC were not significantly different from healthy controls. Using UALCAN and GEPIA, only high expression of NTRK2 was significantly associated with longer disease-free survival (P = 0.004). The alteration frequencies were low (7% in NTRK1, 1.7% in NTRK2, and 2% in NTRK3). The methylation levels of NTRK genes were all significantly different as analyzed by UALCAN; the high-risk group displayed an unfavorable prognosis compared with the low-risk group for NTRK1 (P = 0.033) and NTRK3 (P = 0.005). The median H-score of pan-Trk in HCC and para-cancerous tissues was not statistically different (186.31 ± 23.86 and 192.38 ± 21.06, P = 0.065). No differences were observed in clinicopathological features of HCC with the median H-score for pan-Trk expression (p > 0.05). The survival rate of patients with pan-Trk expression was also not significantly different. Conclusion: The alteration frequency was low in NTRK genes, including gene fusion and methylation levels. Therefore, pan-Trk expression in HCC tissue has limited value in clinicopathological features and prognosis. [ABSTRACT FROM AUTHOR]

A detailed investigation of microstructures of authigenic illite has been carried out using high-resolution TEM. Near-atomic images of 1M and 2[M.sub.1] polytypes of illite with incidence [100] and [110] were observed. We unambiguously determine 1Millite in both individual particles and microtwinned domains. Newly formed 2[M.sub.1] domains are surrounded by former packets of 1[M.sub.d] of 1M illite. Such intergrowth of different illite-polytypic domains on a scale of several layers suggests that they are mctastable. The lateral-coherent 1M and 2[M.sub.1] illite domains are aligned along the same orientation and crystallographically continuous normal to [001]*. This is a new phenomenon observed for polytypic intergrowth and transition. The intralayer-stepwise change of stagger direction in a series of successive layers and consequently the interlayer-stacking angle change resulting in polytypic transition are hypothesized as an 'intralayer-stepwise transition' model. It explains the process of illite polytypic transition in the solid state. Keywords: Illite polytype, HRTEM, microstructure, intralayer-stepwise transition

Green and black tea have shown promise in the chemoprevention of prostate cancer. The objective of this study was to determine the bioavailability and bioactivity of tea polyphenols (PP) and theaflavins in human serum and human and mouse tissues. A decaffeinated black tea diet was administered to C57BL/6 mice. PPs and theaflavins were found in the small and large intestine, liver, and prostate in conjugated and free forms. The relative prostate bioavailability of theaflavin was 70% higher than that of epigallocatechin gallate (EGCG). In the second mouse study, a green tea (GT) diet was administered followed by the control diet for 1-5 d. Epicatechin (EC), EGCG, and epicatechin gallate (ECG) concentrations in prostate tissue were significantly decreased after 1 d of consuming the control diet. Epigallocatechin gallate (EGC), however, did not decrease significantly. For the human study, 20 men scheduled for surgical prostatectomy were randomly assigned to consume 1.42 L daily of GT, BT, or a caffeinematched soda control (SC) for 5 d before radical prostatectomy. Tea PPs were greater in prostate samples from men consuming BT and GT than in men consuming SC (P = 0.0025). Although tea PP were not detectable in serum, ex vivo LNCaP prostate cancer cell proliferation was less when cells were grown in media containing patient serum collected after BT (P < 0.001) and GT (P = 0.025) consumption relative to baseline serum This is the first human study to show that tea polyphenols and theafiavins are bioavailable in the prostate where they may be active in the prevention of prostate cancer. KEY WORDS: * tea polyphenols * theaflavins * prostate cancer * ex vivo LNCaP bioassay