Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field

Characterization of a Large Group of Individuals with Huntington Disease and Their Relatives Enrolled in the COHORT Study

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington's Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of "high normal" repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.Clinicaltrials.gov NCT00313495

Transmission of Vibrio cholerae Is Antagonized by Lytic Phage and Entry into the Aquatic Environment

Cholera outbreaks are proposed to propagate in explosive cycles powered by hyperinfectious Vibrio cholerae and quenched by lytic vibriophage. However, studies to elucidate how these factors affect transmission are lacking because the field experiments are almost intractable. One reason for this is that V. cholerae loses the ability to culture upon transfer to pond water. This phenotype is called the active but non-culturable state (ABNC; an alternative term is viable but non-culturable) because these cells maintain the capacity for metabolic activity. ABNC bacteria may serve as the environmental reservoir for outbreaks but rigorous animal studies to test this hypothesis have not been conducted. In this project, we wanted to determine the relevance of ABNC cells to transmission as well as the impact lytic phage have on V. cholerae as the bacteria enter the ABNC state. Rice-water stool that naturally harbored lytic phage or in vitro derived V. cholerae were incubated in a pond microcosm, and the culturability, infectious dose, and transcriptome were assayed over 24 h. The data show that the major contributors to infection are culturable V. cholerae and not ABNC cells. Phage did not affect colonization immediately after shedding from the patients because the phage titer was too low. However, V. cholerae failed to colonize the small intestine after 24 h of incubation in pond water—the point when the phage and ABNC cell titers were highest. The transcriptional analysis traced the transformation into the non-infectious ABNC state and supports models for the adaptation to nutrient poor aquatic environments. Phage had an undetectable impact on this adaptation. Taken together, the rise of ABNC cells and lytic phage blocked transmission. Thus, there is a fitness advantage if V. cholerae can make a rapid transfer to the next host before these negative selective pressures compound in the aquatic environment

Continuous and Periodic Expansion of CAG Repeats in Huntington's Disease R6/1 Mice

Huntington's disease (HD) is one of several neurodegenerative disorders caused by expansion of CAG repeats in a coding gene. Somatic CAG expansion rates in HD vary between organs, and the greatest instability is observed in the brain, correlating with neuropathology. The fundamental mechanisms of somatic CAG repeat instability are poorly understood, but locally formed secondary DNA structures generated during replication and/or repair are believed to underlie triplet repeat expansion. Recent studies in HD mice have demonstrated that mismatch repair (MMR) and base excision repair (BER) proteins are expansion inducing components in brain tissues. This study was designed to simultaneously investigate the rates and modes of expansion in different tissues of HD R6/1 mice in order to further understand the expansion mechanisms in vivo. We demonstrate continuous small expansions in most somatic tissues (exemplified by tail), which bear the signature of many short, probably single-repeat expansions and contractions occurring over time. In contrast, striatum and cortex display a dramatic—and apparently irreversible—periodic expansion. Expansion profiles displaying this kind of periodicity in the expansion process have not previously been reported. These in vivo findings imply that mechanistically distinct expansion processes occur in different tissues

AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures

Purpose Acute monoamine depletion paradigms using alpha-methyl-para-tyrosine (AMPT) combined with single photon emission computed tomography (SPECT) have been used successfully to evaluate disturbances in central dopaminergic neurotransmission. However, severe side effects due to relatively high doses (4,500 to 8,000 mg) of AMPT have been reasons for study withdrawal. Thus, we assessed the effectiveness and tolerability of two alternative procedures, using lower doses of AMPT. Methods Six healthy subjects underwent three measurements of striatal dopamine D2 receptor (D2R)-binding potential (BPND) with SPECT and the selective radiolabeled D2R antagonist [123I]IBZM. All subjects were scanned in the absence of pharmacological intervention (baseline) and after two different depletion procedures. In the first depletion session, over 6 h, subjects were administered 1,500 mg of AMPT before scanning. In the second depletion session, over 25 h, subjects were administered 40 mg AMPT/kg body weight. We also administered the Subjective Well-being Under Neuroleptic Treatment Scale, a self-report instrument designed to measure the subjective experience of patients on neuroleptic medication. Results We found no change of mean D2R BPND after the first and short AMPT challenge compared to the baseline. However, we found a significant increase in striatal D2R BPND binding after the AMPT challenge adjusted for bodyweight compared to both other regimen. Although subjective well-being worsened after the prolonged AMPT challenge, no severe side effects were reported. Conclusions Our results imply a low-dosage, suitable alternative to the common AMPT procedure. The probability of side effects and study withdrawal can be reduced by this procedure

PPARγ Pro12Ala polymorphism and risk of acute coronary syndrome in a prospective study of Danes

<p>Abstract</p> <p>Background</p> <p>Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the western world. Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in the regulation of the energy balance, adipocyte differentiation and lipid biosynthesis. The aim was to investigate if the polymorphism <it>PPARγ2 </it>Pro¹²Ala, which encodes a less efficient transcription factor, was associated with risk of acute coronary disease and if there were interactions between this polymorphism and factors that modify PPARγ activity, such as alcohol intake, smoking, and use of non-steroidal anti-inflammatory medicine.</p> <p>Methods</p> <p>A case-cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals.</p> <p>Results</p> <p>Homozygous male variant allele carriers of <it>PPARγ2 </it>Pro¹²Ala were at higher risk of ACS (HR = 2.12, 95% CI: 1.00–4.48) than homozygous carriers of the Pro-allele. Among men, there was a statistically significant interaction between genotypes and alcohol intake such that homozygous variant allele carriers with a low alcohol intake were at higher risk of ACS (HR = 25.3, CI: 16.5–38.7) compared to homozygous common allele carriers (p for interaction < 0.0001). Overall, the association was only observed among homozygous variant allele carriers. Thus, all the observed associations were obtained in subgroups including small numbers of cases. It is therefore possible that the observed associations were due to chance.</p> <p>Conclusion</p> <p>In the present study, there were no consistent associations between PPARγ Pro¹²Ala and risk of ACS, and no consistent interaction with alcohol, BMI, NSAID or smoking in relation to ACS.</p

Induction of Neuronal Death by Microglial AGE-Albumin: Implications for Alzheimer’s Disease

Advanced glycation end products (AGEs) have long been considered as potent molecules promoting neuronal cell death and contributing to neurodegenerative disorders such as Alzheimer’s disease (AD). In this study, we demonstrate that AGE-albumin, the most abundant AGE product in human AD brains, is synthesized in activated microglial cells and secreted into the extracellular space. The rate of AGE-albumin synthesis in human microglial cells is markedly increased by amyloid-β exposure and oxidative stress. Exogenous AGE-albumin upregulates the receptor protein for AGE (RAGE) and augments calcium influx, leading to apoptosis of human primary neurons. In animal experiments, soluble RAGE (sRAGE), pyridoxamine or ALT-711 prevented Aβ-induced neuronal death in rat brains. Collectively, these results provide evidence for a new mechanism by which microglial cells promote death of neuronal cells through synthesis and secretion of AGE-albumin, thereby likely contributing to neurodegenerative diseases such as AD

A collaboratively derived international research agenda on legislative science advice

© 2019, The Author(s). The quantity and complexity of scientific and technological information provided to policymakers have been on the rise for decades. Yet little is known about how to provide science advice to legislatures, even though scientific information is widely acknowledged as valuable for decision-making in many policy domains. We asked academics, science advisers, and policymakers from both developed and developing nations to identify, review and refine, and then rank the most pressing research questions on legislative science advice (LSA). Experts generally agree that the state of evidence is poor, especially regarding developing and lower-middle income countries. Many fundamental questions about science advice processes remain unanswered and are of great interest: whether legislative use of scientific evidence improves the implementation and outcome of social programs and policies; under what conditions legislators and staff seek out scientific information or use what is presented to them; and how different communication channels affect informational trust and use. Environment and health are the highest priority policy domains for the field. The context-specific nature of many of the submitted questions—whether to policy issues, institutions, or locations—suggests one of the significant challenges is aggregating generalizable evidence on LSA practices. Understanding these research needs represents a first step in advancing a global agenda for LSA research

The Dopamine Augmenter L-DOPA Does Not Affect Positive Mood in Healthy Human Volunteers

Dopamine neurotransmission influences approach toward rewards and reward-related cues. The best cited interpretation of this effect proposes that dopamine mediates the pleasure that commonly accompanies reward. This hypothesis has received support in some animal models and a few studies in humans. However, direct assessments of the effect of transiently increasing dopamine neurotransmission have been largely limited to the use of psychostimulant drugs, which elevate brain levels of multiple neurotransmitters in addition to dopamine. In the present study we tested the effect of more selectively elevating dopamine neurotransmission, as produced by administration of the immediate dopamine precursor, L-DOPA (0, 100/25, 200/50 mg, Sinemet), in healthy human volunteers. Neither dose altered positive mood. The results suggest that dopamine neurotransmission does not directly influence positive mood in humans