Uncovering the Mechanism of Aggregation of Human Transthyretin.

The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify β-strands F and H as necessary for TTR aggregation. Based on the crystal structures of these segments, we designed two non-natural peptide inhibitors that block aggregation. This work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy

Randomized clinical trial of the effects of screening and brief intervention for illicit drug use: the Life Shift/Shift Gears study.

BackgroundAlthough screening, brief intervention, and referral to treatment (SBIRT) has shown promise for alcohol use, relatively little is known about its effectiveness for adult illicit drug use. This randomized controlled trial assessed the effectiveness of the SBIRT approach for outcomes related to drug use among patients visiting trauma and emergency departments (EDs) at two large, urban hospitals.MethodsA total of 700 ED patients who admitted using illegal drugs in the past 30 days were recruited, consented, provided baseline measures of substance use and related problems measured with the Addiction Severity Index-Lite (ASI-Lite), and then randomized to the Life Shift SBIRT intervention or to an attention-placebo control group focusing on driving and traffic safety (Shift Gears). Both groups received a level of motivational intervention matched to their condition and risk level by trained paraprofessional health educators. Separate measurement technicians conducted face-to-face follow-ups at 6 months post-intervention and collected hair samples to confirm reports of abstinence from drug use. The primary outcome measure of the study was past 30-day drug abstinence at 6 months post-intervention, as self-reported on the ASI-Lite.ResultsOf 700 participants, 292 (42%) completed follow-up. There were no significant differences in self-reported abstinence (12.5% vs. 12.0% , p = 0.88) for Life Shift and Shift Gears groups, respectively. When results of hair analyses were applied, the abstinence rate was 7 percent for Life Shift and 2 percent for Shift Gears (p = .074). In an analysis in which results were imputed (n = 694), there was no significant difference in the ASI-Lite drug use composite scores (Life Shift +0.005 vs. Shift Gears +0.017, p = 0.12).ConclusionsIn this randomized controlled trial, there was no evidence of effectiveness of SBIRT on the primary drug use outcome.Trial registrationClinicalTrials.gov NCT01683227

Measurement invariance of the pay satisfaction questionnaire across three countries

In recent years, pay satisfaction has been increasingly studied in an international con-text, prompting the importance of examining whether the Pay Satisfaction Question-naire (PSQ) is invariant across countries other than the United States. This study investigated the measurement invariance across three countries, namely, the United States (N 321), Belgium (N 301), and Cyprus (N 132). Results showed that the measurement structure of the PSQ was invariant across these different countries because there was no departure from measurement invariance in terms of factor form, factor pattern coefficients, factor variances, and factor covariances. These results show promise for the equivalence of PSQ ratings across different countries. Future research is needed to test the equivalence further across other countries and samples

Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis

Factors responsible for initial success or failure of coronary thrombolysis and persistent recanalization or early reocclusion have not been thoroughly elucidated. Both adequate initial clot lysis and preclusion of rethrombosis are required. Failure may reflect clot lysis followed immediately or somewhat later by rethrombosis. To determine whether differences in the intensity and persistence of the activation of thrombin are determinants of success or failure of recanalization, plasma fibrinopeptide A, a fibrinogen product liberated by thrombin, was serially assayed in 19 patients treated with intravenous streptokinase. In patients exhibiting recanalization (n = 9), plasma fibrinopeptide A decreased after administration of streptokinase but before administration of heparin. In patients without initially apparent recanalization, fibrinopeptide A increased, suggesting ongoing thrombosis, and subsequently decreased promptly after heparin. In patients with initial recanalization followed by overt reocclusion the pattern was different. Despite recanalization, fibrinopeptide A continued to rise markedly. Elevations persisted despite administration of heparin. Thus, inhibition of activation of thrombin is associated with successful recanalization. Conversely, persistent activation of thrombin may be a predisposing factor to both apparent initial failure of recanalization and nvprt early reocclusion

Association of daily step count and serum testosterone among men in the United States

Purpose To describe the association between daily activity (i.e., daily step counts and accelerometer intensity measures) and serum TT levels in a representative sample of US adults aged 18 years or older. Methods A retrospective cohort study was carried out utilizing the NHANES (National Health and Nutrition Examination Survey) 2003–2004 cycle. Physical activity was measured with a waist-worn uniaxial accelerometer (AM-7164; ActiGraph) for up to 7 days using a standardized protocol. Using linear and multivariable logistic regression controlling for relevant social, demographic, lifestyle, and comorbidity characteristics, we assessed the association between daily step counts and TT. Results A total of 279 subjects with a median age 46 (IQR: 33–56) were included in the analysis. 23.3% of the cohort had a low serum TT level (TT < 350 ng/dl). Compared to men who took <4000 steps per day, men who took >4000 or >8000 steps/day had a lower odd of being hypogonadal (OR 0.14, 95% CI: 0.07–0.49 and 0.08, 95%CI: 0.02–0.44, respectively). While a threshold effect was noted on average, TT increased 7 ng/dL for each additional 1000 steps taken daily (β-estimate: 0.007, 95% CI: 0.002–0.013). Conclusions Patients with the lowest daily step counts had higher odds of being hypogonadal. The current work supports a possible association between daily steps, total testosterone, and hypogonadism for men in the US

Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS

ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for ∼20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease has been difficult, given that more than 140 different SOD1 mutants have been observed in fALS patients. In addition, the molecular origin of sporadic ALS (sALS) is unclear. By dissecting the amino acid sequence of SOD1, we identified four short segments with a high propensity for amyloid fibril formation. We find that fALS mutations in these segments do not reduce their propensity to form fibrils. The atomic structures of two fibril-forming segments from the C terminus, ^(101)DSVISLS^(107) and ^(147)GVIGIAQ^(153), reveal tightly packed β-sheets with steric zipper interfaces characteristic of the amyloid state. Based on these structures, we conclude that both C-terminal segments are likely to form aggregates if available for interaction. Proline substitutions in 101DSVISLS107 and ^(147)GVIGIAQ^(153) impaired nucleation and fibril growth of full-length protein, confirming that these segments participate in aggregate formation. Our hypothesis is that improper protein maturation and incompletely folded states that render these aggregation-prone segments available for interaction offer a common molecular pathway for sALS and fALS

The use of CAM by women suffering from nausea and vomiting during pregnancy

BACKGROUND: Nausea and vomiting during pregnancy (NVP) affects two-thirds of pregnant women to varying degrees and over the years many modalities have been used to try to alleviate this often debilitating condition. There is a paucity of information in the literature about the use or efficacy of complementary and alternative medicine (CAM) for the treatment of this condition that affects so many women. Our primary objective was to examine the prevalence of CAM usage by women suffering from NVP. Our secondary objective was to ascertain if women had any supervision in the use of these treatments. METHODS: Women who called The Motherisk NVP helpline, were asked after the counseling session to complete a questionnaire, which included demographic data as well as information about their CAM use. RESULTS: Seventy women completed the questionnaire. 61% reported using CAM therapies, of which the three most popular were: ginger, vitamin B6 and acupressure. 21% of those who reported using CAM, had consulted CAM practitioners, 8% their physicians or pharmacists and 71% discussed the usage with family, friends and other allied health professionals. Women who did not use CAM stated they would probably use these modalities if there was more information about the safety in pregnancy. CONCLUSION: Pregnant women with NVP are mirroring the trend in the general population of the use of CAM. They are also using CAM therapies with little supervision from practitioners experienced in the use of these modalities