A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.

BACKGROUND The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T). METHODS/DESIGN The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. DISCUSSION The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. TRIAL REGISTRATION The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511)

Multidimensional characterization of global food supply from 1961 to 2013

Food systems are increasingly globalized and interdependent, and diets around the world are changing. Characterization of national food supplies and how they have changed can inform food policies that ensure national food security, support access to healthy diets and enhance environmental sustainability. Here we analysed data for 171 countries on the availability of 18 food groups from the United Nations Food and Agriculture Organization to identify and track multidimensional food supply patterns from 1961 to 2013. Four predominant food-group combinations were identified that explained almost 90% of the cross-country variance in food supply: animal source and sugar, vegetable, starchy root and fruit, and seafood and oilcrops. South Korea, China and Taiwan experienced the largest changes in food supply over the past five decades, with animal source foods and sugar, vegetables and seafood and oilcrops all becoming more abundant components of the food supply. In contrast, in many Western countries the supply of animal source foods and sugar declined. Meanwhile, there was remarkably little change in the food supply in countries in the sub-Saharan Africa region. These changes led to a partial global convergence in the national supply of animal source foods and sugar, and a divergence in those of vegetables and of seafood and oilcrops. Our analysis generated a novel characterization of food supply that highlights the interdependence of multiple food types in national food systems. A better understanding of how these patterns have evolved and will continue to change is needed to support the delivery of healthy and sustainable food system policies

National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio: a pooled analysis of 458 population-based studies in Asian and Western countries

Background Although high-density lipoprotein (HDL) and non-HDL cholesterol have opposite associations with coronary heart disease, multi-country reports of lipid trends only use total cholesterol (TC). Our aim was to compare trends in total, HDL and non-HDL cholesterol and the total-to-HDL cholesterol ratio in Asian and Western countries. Methods We pooled 458 population-based studies with 82.1 million participants in 23 Asian and Western countries. We estimated changes in mean total, HDL and non-HDL cholesterol and mean total-to-HDL cholesterol ratio by country, sex and age group. Results Since ∼1980, mean TC increased in Asian countries. In Japan and South Korea, the TC rise was due to rising HDL cholesterol, which increased by up to 0.17 mmol/L per decade in Japanese women; in China, it was due to rising non-HDL cholesterol. TC declined in Western countries, except in Polish men. The decline was largest in Finland and Norway, at ∼0.4 mmol/L per decade. The decline in TC in most Western countries was the net effect of an increase in HDL cholesterol and a decline in non-HDL cholesterol, with the HDL cholesterol increase largest in New Zealand and Switzerland. Mean total-to-HDL cholesterol ratio declined in Japan, South Korea and most Western countries, by as much as ∼0.7 per decade in Swiss men (equivalent to ∼26% decline in coronary heart disease risk per decade). The ratio increased in China. Conclusions HDL cholesterol has risen and the total-to-HDL cholesterol ratio has declined in many Western countries, Japan and South Korea, with only a weak correlation with changes in TC or non-HDL cholesterol

Exogenous coenzyme Q10 modulates MMP-2 activity in MCF-7 cell line as a breast cancer cellular model

<p>Abstract</p> <p>Background/Aims</p> <p>Matrix Metalloproteinases 2 is a key molecule in cellular invasion and metastasis. Mitochondrial ROS has been established as a mediator of MMP activity. Coenzyme Q₁₀contributes to intracellular ROS regulation. Coenzyme Q₁₀beneficial effects on cancer are still in controversy but there are indications of Coenzyme Q₁₀complementing effect on tamoxifen receiving breast cancer patients.</p> <p>Methods</p> <p>In this study we aimed to investigate the correlation of the effects of co-incubation of coenzyme Q10 and N-acetyl-L-cysteine (NAC) on intracellular H2O2 content and Matrix Metalloproteinase 2 (MMP-2) activity in MCF-7 cell line.</p> <p>Results and Discussion</p> <p>Our experiment was designed to assess the effect in a time and dose related manner. Gelatin zymography and Flowcytometric measurement of H2O2 by 2'7',-dichlorofluorescin-diacetate probe were employed. The results showed that both coenzyme Q10 and N-acetyl-L-cysteine reduce MMP-2 activity along with the pro-oxidant capacity of the MCF-7 cell in a dose proportionate manner.</p> <p>Conclusions</p> <p>Collectively, the present study highlights the significance of Coenzyme Q₁₀effect on the cell invasion/metastasis effecter molecules.</p

A multivariate analysis of serum nutrient levels and lung function

<p>Abstract</p> <p>Background</p> <p>There is mounting evidence that estimates of intakes of a range of dietary nutrients are related to both lung function level and rate of decline, but far less evidence on the relation between lung function and objective measures of serum levels of individual nutrients. The aim of this study was to conduct a comprehensive examination of the independent associations of a wide range of serum markers of nutritional status with lung function, measured as the one-second forced expiratory volume (FEV₁).</p> <p>Methods</p> <p>Using data from the Third National Health and Nutrition Examination Survey, a US population-based cross-sectional study, we investigated the relation between 21 serum markers of potentially relevant nutrients and FEV₁, with adjustment for potential confounding factors. Systematic approaches were used to guide the analysis.</p> <p>Results</p> <p>In a mutually adjusted model, higher serum levels of antioxidant vitamins (vitamin A, beta-cryptoxanthin, vitamin C, vitamin E), selenium, normalized calcium, chloride, and iron were independently associated with higher levels of FEV₁. Higher concentrations of potassium and sodium were associated with lower FEV₁.</p> <p>Conclusion</p> <p>Maintaining higher serum concentrations of dietary antioxidant vitamins and selenium is potentially beneficial to lung health. In addition other novel associations found in this study merit further investigation.</p

Highly Frequent Mutations in Negative Regulators of Multiple Virulence Genes in Group A Streptococcal Toxic Shock Syndrome Isolates

Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock and multiorgan failure; it has a high mortality rate. Although a number of studies have attempted to determine the crucial factors behind the onset of STSS, the responsible genes in group A Streptococcus have not been clarified. We previously reported that mutations of csrS/csrR genes, a two-component negative regulator system for multiple virulence genes of Streptococcus pyogenes, are found among the isolates from STSS patients. In the present study, mutations of another negative regulator, rgg, were also found in clinical isolates of STSS patients. The rgg mutants from STSS clinical isolates enhanced lethality and impaired various organs in the mouse models, similar to the csrS mutants, and precluded their being killed by human neutrophils, mainly due to an overproduction of SLO. When we assessed the mutation frequency of csrS, csrR, and rgg genes among S. pyogenes isolates from STSS (164 isolates) and non-invasive infections (59 isolates), 57.3% of the STSS isolates had mutations of one or more genes among three genes, while isolates from patients with non-invasive disease had significantly fewer mutations in these genes (1.7%). The results of the present study suggest that mutations in the negative regulators csrS/csrR and rgg of S. pyogenes are crucial factors in the pathogenesis of STSS, as they lead to the overproduction of multiple virulence factors

Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants

Background Raised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. We estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher. Methods For this analysis, we pooled national, subnational, or community population-based studies that had measured blood pressure in adults aged 18 years and older. We used a Bayesian hierarchical model to estimate trends from 1975 to 2015 in mean systolic and mean diastolic blood pressure, and the prevalence of raised blood pressure for 200 countries. We calculated the contributions of changes in prevalence versus population growth and ageing to the increase in the number of adults with raised blood pressure. Findings We pooled 1479 studies that had measured the blood pressures of 19·1 million adults. Global age-standardised mean systolic blood pressure in 2015 was 127·0 mm Hg (95% credible interval 125·7–128·3) in men and 122·3 mm Hg (121·0–123·6) in women; age-standardised mean diastolic blood pressure was 78·7 mm Hg (77·9–79·5) for men and 76·7 mm Hg (75·9–77·6) for women. Global age-standardised prevalence of raised blood pressure was 24·1% (21·4–27·1) in men and 20·1% (17·8–22·5) in women in 2015. Mean systolic and mean diastolic blood pressure decreased substantially from 1975 to 2015 in high-income western and Asia Pacific countries, moving these countries from having some of the highest worldwide blood pressure in 1975 to the lowest in 2015. Mean blood pressure also decreased in women in central and eastern Europe, Latin America and the Caribbean, and, more recently, central Asia, Middle East, and north Africa, but the estimated trends in these super-regions had larger uncertainty than in high-income super-regions. By contrast, mean blood pressure might have increased in east and southeast Asia, south Asia, Oceania, and sub-Saharan Africa. In 2015, central and eastern Europe, sub-Saharan Africa, and south Asia had the highest blood pressure levels. Prevalence of raised blood pressure decreased in high-income and some middle-income countries; it remained unchanged elsewhere. The number of adults with raised blood pressure increased from 594 million in 1975 to 1·13 billion in 2015, with the increase largely in low-income and middle-income countries. The global increase in the number of adults with raised blood pressure is a net effect of increase due to population growth and ageing, and decrease due to declining age-specific prevalence. Interpretation During the past four decades, the highest worldwide blood pressure levels have shifted from high-income countries to low-income countries in south Asia and sub-Saharan Africa due to opposite trends, while blood pressure has been persistently high in central and eastern Europe

Perspectives on the Trypanosoma cruzi-host cell receptor interaction

Chagas disease is caused by the parasite Trypanosoma cruzi. The critical initial event is the interaction of the trypomastigote form of the parasite with host receptors. This review highlights recent observations concerning these interactions. Some of the key receptors considered are those for thromboxane, bradykinin, and for the nerve growth factor TrKA. Other important receptors such as galectin-3, thrombospondin, and laminin are also discussed. Investigation into the molecular biology and cell biology of host receptors for T. cruzi may provide novel therapeutic targets

Towards a Critical Sociology of Dominant Ideologies: An Unexpected Reunion between Pierre Bourdieu and Luc Boltanski

This article aims to demonstrate the enduring relevance of Pierre Bourdieu and Luc Boltanski’s ‘La production de l’idéologie dominante’ [‘The production of the dominant ideology’], which was originally published in Actes de la recherche en sciences sociales in 1976. More than three decades later, in 2008, a re-edited version of this study was printed in book format as La production de l’idéologie dominante, which was accompanied by a detailed commentary, written by Luc Boltanski and entitled Rendre la réalité inacceptable. À propos de « La production de l’idéologie dominante » [Making Reality Unacceptable. Comments on ‘The production of the dominant ideology’]. In addition to containing revealing personal anecdotes and providing important sociological insights, this commentary offers an insider account of the genesis of one of the most seminal pieces Boltanski co-wrote with his intellectual father, Bourdieu. In the Anglophone literature on contemporary French sociology, however, the theoretical contributions made both in the original study and in Boltanski’s commentary have received little – if any – serious attention. This article aims to fill this gap in the literature, arguing that these two texts can be regarded not only as forceful reminders of the fact that the ‘dominant ideology thesis’ is far from obsolete but also as essential for understanding both the personal and the intellectual underpinnings of the tension-laden relationship between Bourdieu and Boltanski. Furthermore, this article offers a critical overview of the extent to which the unexpected, and partly posthumous, reunion between ‘the master’ (Bourdieu) and his ‘dissident disciple’ (Boltanski) equips us with powerful conceptual tools, which, whilst illustrating the continuing centrality of ‘ideology critique’, permit us to shed new light on key concerns in contemporary sociology and social theory. Finally, the article seeks to push the debate forward by reflecting upon several issues that are not given sufficient attention by Bourdieu and Boltanski in their otherwise original and insightful enquiry into the complexities characterizing the daily production of ideology