Using mass spectrometric immunoassay, the abundance of SAA truncations relative to the native variants was examined in plasma of 91 participants with type 2 diabetes and chronic kidney disease and 69 ...participants without diabetes.
The ratio of SAA 1.1 (missing N-terminal arginine) to native SAA 1.1 was lower in diabetics compared to non-diabetics (p = 0.004), and in males compared to females (p<0.001). This ratio was negatively correlated with glycated hemoglobin (r = -0.32, p<0.001) and triglyceride concentrations (r = -0.37, p<0.001), and positively correlated with HDL cholesterol concentrations (r = 0.32, p<0.001).
The relative abundance of the N-terminal arginine truncation of SAA1.1 is significantly decreased in diabetes and negatively correlates with measures of glycemic and lipid control.
To determine the effect of prior oophorectomy in healthy postmenopausal women on the rate of loss of bone mineral density (BMD) and rate of increase in carotid artery intima-media thickness (CIMT).
...Secondary analysis from a randomized controlled trial.
University-based research clinic.
Two hundred twenty-two healthy postmenopausal women in the Greater Los Angeles area.
Baseline and annual screening of BMD and assessment of CIMT every 6 months for a total of 3 years.
Changes in BMD and CIMT during postmenopausal years.
Among women who were menopausal for more than 10 years, the rate of CIMT progression was statistically significantly less in women with intact ovaries compared with those in women with prior oophorectomy. In women 5-10 years postmenopause, there was a trend toward a slower loss of BMD in those who retained their ovaries, and in women more than 10 years postmenopause there was significantly less BMD loss in those who retained their ovaries.
As time from menopausal transition increases, retained ovaries are associated with a slower rate of bone loss and a slower rate of thickening of the carotid artery wall compared with rates in menopausal women with oophorectomy.
Introduction
Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and ...well‐established preclinical safety efficacy make it a viable candidate.
Methods
A randomized, double‐blinded, placebo‐controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once‐per‐week for 12 weeks with a 1‐month follow‐up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini‐Mental State Examination score of 20–26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers.
Results
A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 22%) and fatigue (n = 3 17%). A single non‐serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose‐response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/−7.31), 42.05 ng/mL (+/−14.55), 60.07 ng/mL (+/−12.8), and 137.48 ng/mL (+/−38.69), respectively. The MTD was established based on evidence of allopregnanolone‐induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging–based imaging outcomes were evident.
Conclusions
Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial.
Trial registration
ClinicalTrials.gov‐NCT02221622
Autism is a heritable but genetically complex disorder characterized by deficits in language and in reciprocal social interactions, combined with repetitive and stereotypic behaviors. As with many ...genetically complex disorders, numerous genome scans reveal inconsistent results. A genome scan of 345 families from the Autism Genetic Resource Exchange (AGRE) (AGRE_1), gave the strongest evidence of linkage at 17q11-17q21 in families with no affected females. Here, we report a full-genome scan of an independent sample of 91 AGRE families with 109 affected sibling pairs (AGRE_2) that also shows the strongest evidence of linkage to 17q11-17q21 in families with no affected females. Taken together, these samples provide a replication of linkage to this chromosome region that is, to our knowledge, the first such replication in autism. Fine mapping at 2-centimorgan (cM) intervals in the combined sample of families with no affected females reveals a linkage peak at 66.85 cM, which places this locus at 17q21.
► We produced a neutralizing antibody against clade 1 of H5 influenza virus. ► The antibody recognized the loop at amino acid positions 140–145 of HA1. ► The amino acids at 142, 144, and 145 were ...critical for the antibody recognition. ► The antibody cross-neutralized the clade 2.2.1 but not clade 2.1.3.2 or 2.3.4 of H5 virus. ► The amino acids at 142 and 145 were conserved in the clade 2.2.1 virus.
The global spread of highly pathogenic avian influenza A H5N1 viruses raises concerns about more widespread infection in the human population. Pre-pandemic vaccine for H5N1 clade 1 influenza viruses has been produced from the A/Viet Nam/1194/2004 strain (VN1194), but recent prevalent avian H5N1 viruses have been categorized into the clade 2 strains, which are antigenically distinct from the pre-pandemic vaccine. To understand the antigenicity of H5N1 hemagglutinin (HA), we produced a neutralizing monoclonal antibody (mAb12–1G6) using the pre-pandemic vaccine. Analysis with chimeric and point mutant HAs revealed that mAb12–1G6 bound to the loop (amino acid positions 140–145) corresponding to an antigenic site A in the H3 HA. mAb12–1G6 failed to bind to the mutant VN1194 HA when only 3 residues were substituted with the corresponding residues of the clade 2.1.3.2 A/Indonesia/5/05 strain (amino acid substitutions at positions Q142L, K144S, and S145P), suggesting that these amino acids are critical for binding of mAb12–1G6. Escape mutants of VN1194 selected with mAb12–1G6 carried a S145P mutation. Interestingly, mAb12–1G6 cross-neutralized clade 1 and clade 2.2.1 but not clade 2.1.3.2 or clade 2.3.4 of the H5N1 virus. We discuss the cross-reactivity, based on the amino acid sequence of the epitope.
A 12-year-old boy presented with acute neck swelling diagnosed as submandibular sialadenitis secondary to influenza; it resolved quickly with supportive care. Recognition of this as a clinical entity ...during the influenza season may help guide management.
The H5N1 subtype of the highly pathogenic (HP) avian influenza virus has been recognized for its ability to cause serious pandemics among humans. In the present study, new monoclonal antibodies ...(mAbs) against viral proteins were established for the immunological detection of H5N1 influenza virus for research and diagnostic purposes. B-cell hybridomas were generated from mice that had been hyperimmunized with purified A/Vietnam/1194/2004 (NIBRG-14) virion that had been inactivated by UV-irradiation or formaldehyde. After screening over 4,000 hybridomas, eight H5N1-specific clones were selected. Six were specific for hemagglutinin (HA) and had in vitro neutralization activity. Of these, four were able to broadly detect all tested clades of the H5N1 strains. Five HA-specific mAbs detected denatured HA epitope(s) in Western blot analysis, and two detected HP influenza virus by immunofluorescence and immunohistochemistry. A highly sensitive antigen-capture sandwich ELISA system was established by combining mAbs with different specificities. In conclusion, these mAbs may be useful for rapid and specific diagnosis of H5N1 influenza. Therapeutically, they may have a role in antibody-based treatment of the disease.
Isoflavonoids (IFL) may protect against chronic diseases, including cancer. IFL exposure is traditionally measured from plasma (PL), but the reliability of urine is uncertain. We assessed whether IFL ...excretion in overnight urine (OU) or spot urine (SU) reliably reflects IFLs in PL and the usefulness of the three matrices to determine soy intake compliance.
In a randomized, double-blind, placebo-controlled soy intervention trial with 350 postmenopausal women, IFLs (daidzein, genistein, glycitein, equol, O-desmethylangolensin, dihydrodaidzein, dihydrogenistein) were analyzed by liquid chromatography/mass spectrometry in OU, SU, and PL collected at baseline and every 6 months over 2.5 years.
High between-subject intraclass correlations between all three matrices (median, 0.94) and high between-subject Pearson correlations (median r(OU-PL) = 0.80; median r(SU-PL) = 0.80; median r(OU-SU) = 0.92) allowed the development of equations to predict IFL values from any of the three matrices. Equations developed from a randomly selected 87% of all available data were valid because high correlations were found on the residual 13% of data between equation-generated and measured IFL values (median r(OU-PL) = 0.86; median r(SU-PL) = 0.78; median r(OU-SU) = 0.84); median absolute IFL differences for OU-PL, SU-PL, and OU-SU were 8.8 nmol/L, 10.3 nmol/L, and 0.28 nmol/mg, respectively. All three matrices showed highly significant IFL differences between the placebo and soy intervention group at study end (P < 0.0001) and highly significant correlations between IFL values and counted soy doses in the intervention group.
OU and SU IFL excretion reflect circulating PL IFL levels in healthy postmenopausal women accurately.
Noninvasively-collected urine can be used to reliably determine systemic IFL exposure and soy intake compliance.
VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate ...whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20–36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.
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