Asthma Clinical Trial: Dupliumab

Antibody clinical trial for asthma; abstract;

Background Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown. Methods We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed. Results The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%). Conclusions In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).

Colobronchial Fistula.

Here we see why investigating strange physical symptoms is important: a case of a colobronchial fistula.  

Skin Microbiome Review

A review of the skin microbiome, with information on relevant dermatological disorders, including acne is here.  One can expect the skin microbiome, like the gut microbiome, to be linked to an increasingly diverse array of human health conditions. Abstract:

Functioning as the exterior interface of the human body with the environment, skin acts as a physical barrier to prevent the invasion of foreign pathogens while providing a home to the commensal microbiota. The harsh physical landscape of skin, particularly the desiccated, nutrient-poor, acidic environment, also contributes to the adversity that pathogens face when colonizing human skin. Despite this, the skin is colonized by a diverse microbiota. In this Review, we describe amplicon and shotgun metagenomic DNA sequencing studies that have been used to assess the taxonomic diversity of microorganisms that are associated with skin from the kingdom to the strain level. We discuss recent insights into skin microbial communities, including their composition in health and disease, the dynamics between species and interactions with the immune system, with a focus on Propionibacterium acnes, Staphylococcus epidermidis and Staphylococcus aureus.

Money matters: educate yourself

Here is a great link to financial podcasts I just found.  

The list is posted on the blog of Jim, who is retiring at the end of 2018 at the age of 43, and moving to Panama!


As the weather deteriorates, I do some my evening walks inside my open plan living room-kitchen and educate myself by listening to some great financial podcasts.

It is never too late to learn!

Resistance Training For COPD

Aerobic exercise seems to be helpful for chronic obstructive pulmonary disease (COPD). Does resistance training also help? Here is a study, abstract:

OBJECTIVE: Emerging research suggests that aerobic-based physical activity may help to promote survival among chronic obstructive pulmonary disease patients. However, the extent to which engagement in resistance training on survival among chronic obstructive pulmonary disease patients is relatively unknown. Therefore, the purpose of this study was to examine the independent associations of muscle strengthening activities on all-cause mortality among a national sample of U.S. adults with chronic obstructive pulmonary disease. We hypothesize that muscle strengthening activities will be inversely associated with all-cause mortality.
METHODS: Data from the 2003-2006 NHANES were employed, with follow-up through 2011. Aerobic-based physical activity was objectively measured via accelerometry, muscle strengthening activities engagement was assessed via self-report, and chronic obstructive pulmonary disease was assessed via physician-diagnosis.
RESULTS: Analysis included 385 adults (20 + yrs) with chronic obstructive pulmonary disease, who represent 13.3 million chronic obstructive pulmonary disease patients in the USA. The median follow-up period was 78 months (IQR=64-90), with 82 chronic obstructive pulmonary disease patients dying during this period. For a two muscle strengthening activity sessions/week increase (consistent with national guidelines), chronic obstructive pulmonary disease patients had a 29% reduced risk of all-cause mortality (HR=0.71; 95% CI: 0.51-0.99; P = 0.04).
CONCLUSION: Participation in muscle strengthening activities, independent of aerobic-based physical activity and other potential confounders, is associated with greater survival among chronic obstructive pulmonary disease patients.

So, yes, it seems like resistance training is helpful. COPD patients, when discussing treatment plans with their physicians, should ask about resistance training if the physician does not bring it up themselves. One possibility is that a combination of aerobic and resistance training is best. Generally speaking, over the past few decades, increasing evidence is accumulating that resistance training is helpful for many aspects of health. I can remember “the old days” in which medical authorities recommended aerobic exercise only, and resistance training was viewed as something for “weird bodybuilders,” but today more informed medical professionals and other experts promote the benefits of resistance training.

Two Spaces Better Than One

Apparently, using two spaces at the end of a sentence facilitates reading better than one space, and this effect is most prominent for people who themselves use two spaces when writing.  Abstract:

The most recent edition of the American Psychological Association (APA) Manual states that two spaces should follow the punctuation at the end of a sentence. This is in contrast to the one-space requirement from previous editions. However, to date, there has been no empirical support for either convention. In the current study, participants performed (1) a typing task to assess spacing usage and (2) an eye-tracking experiment to assess the effect that punctuation spacing has on reading performance. Although comprehension was not affected by punctuation spacing, the eye movement record suggested that initial processing of the text was facilitated when periods were followed by two spaces, supporting the change made to the APA Manual. Individuals' typing usage also influenced these effects such that those who use two spaces following a period showed the greatest overall facilitation from reading with two spaces.

You "Wnt" To Limit Teeth

Wnt signaling limits tooth number; abstract:

Tooth agenesis is one of predominant developmental anomalies in humans, usually affecting the permanent dentition generated by sequential tooth formation, and in most cases caused by mutations perturbing epithelial Wnt/β-catenin signaling. Also loss-of-function mutations in the Wnt feedback inhibitor AXIN2 lead to human tooth agenesis. We investigated the functions of Wnt/β-catenin signaling during sequential formation of molar teeth using mouse models. Continuous initiation of new teeth, observed after genetic activation of Wnt/β-catenin signaling in the oral epithelium, was accompanied by enhanced expression of Wnt antagonists and a downregulation of Wnt/β-catenin signaling in the dental mesenchyme. Genetic and pharmacological activation of mesenchymal Wnt/β-catenin signaling negatively regulated sequential tooth formation, an effect partly mediated by Bmp4. Runx2, a gene whose loss-of-function mutations result in sequential formation of supernumerary teeth in the human cleidocranial dysplasia syndrome, suppressed the expression of Wnt inhibitors Axin2 and Drapc1 in dental mesenchyme. Our data indicate that increased mesenchymal Wnt signaling inhibits the sequential formation of teeth, and suggest that Axin2/Runx2 antagonistic interactions modulate the level of mesenchymal Wnt/β-catenin signaling, underlying the contrasting dental phenotypes caused by human AXIN2 and RUNX2 mutations.

Corn meal with veggies and chickpeas

As I have written before, Being free improves your health, and being healthy preserves your freedom.

To be financially free and otherwise free (think doctor-free), you need to be healthy and self-reliant. One way to achieve this is to know how to cook healthy and cheap meals. 

High-fiber meals can contribute to healthy weight and have many other benefits.

In my pursuit to develop new recipes with high fiber content, I experimented with corn meal and here is one recipe that would recommend:

Corn meal with veggies and chickpeas

Ingredients:
1 cup of corn meal
4 - 5 carrots
celery (any amount, optional)
1 or 2 (15 oz) cans of chickpeas
3 - 4 Tbsp olive oil
garlic (3-4 cloves), salt, cayenne pepper and paprika to taste (these go with the beans)
3 - 4 Tbsp of apple cider vinegar
1 tsp of honey

Directions:
Prepare "corn meal mush" according to the directions on the box. Usually, to four cups of boiling water, add one cup of corn meal. Add the corn meal slowly, with continuous stirring. After the mush becomes thicker, bring to a slow boil and cook for 4 - 5 minutes (with stirring). The mush can be prepared in advance. I had the corn meal mush prepared the day before I assembled the dish and kept it refrigerated.

Drain the chickpeas and cook in a pan with some olive oil. Stir frequently, after 5 - 7 minutes add the crushed garlic, cayenne pepper, paprika, and salt to taste. Stir and cook until all beans are completely dry and a bit toasted. Remove the beans to a plate.

Prepare the veggies by cutting them in strips. Cook in the same pan (from the chickpeas) with olive oil. After 3 - 4 minutes, add the apple cider vinegar with the honey and salt. Close the pan to steam the vegetables. When most of the liquid is absorbed, the veggies are ready (this timing can vary according to your preference for crunchy or not).

Assemble the dishes with corn meal on the bottom. Sprinkle with the chickpeas and the veggies.

By the way, corn meal mush is versatile. I love it when it is still hot and steamy and I add some crumbled feta cheese. The cheese almost melts and the taste is divine. You can also serve it as a dessert with a swirl of honey on top.

Check my other recipes with high fiber content.

Economic Costs Of An Inactive Aging Population

Aging, inactive populations result in costs, including economic costs, on nation and society.  This applies to Germany and most other developed nations) and approaches to stimulate physical activity and promote good health among the aging population.  Abstract:

BACKGROUND:

Aging societies represent a major challenge for health care systems all over the world. As older people tend to be more physically inactive, economic costs of inactivity are likely to increase notably. The present study aims to investigate this relationship between an aging society and economic costs of inactivity using the example of Germany.

METHODS:

Using data from the German Socio-Economic Panel, this study applied the comparative risk assessment method developed by the WHO to estimate the direct costs of inactivity for the period 2001-2013 differentiated by gender-specific age-groups (15-29; 30-44; 45-64; 65+). Based on population statistics predicting the aging of the German population for the years 2014-2060, this research projects the development of future costs of inactivity and potential effects of interventions promoting physical activity among the German population.

RESULTS:

The results reveal an increase in the level of physical activity during the observed period (2001-2013) which compensated the negative effect of aging and resulted in a decline of inactivity costs. The projections for the years 2014-2060 indicate a constant increase in direct per capita costs until 2060 because of an aging society. Scenarios indicating how a short-term reduction of physical inactivity impacts costs of inactivity reveal the crucial role of the oldest age-group in this context.

CONCLUSION:

The findings indicate that the aging of the German population demands further actions and initiatives to promote physical activity, especially for the oldest age-group.

Microbiota, Diet, And Blood Pressure

Response to diet – for example, for blood pressure – is influenced by the microbiota, just as s much else is.  Abstract:

BACKGROUND:

Interindividual variation in the response to diet is common, but the underlying mechanism for such variation is unclear.

OBJECTIVE:

The objective of this study was to use a metabolic profiling approach to identify a panel of urinary metabolites representing individuals demonstrating typical (homogeneous) metabolic responses to healthy diets, and subsequently to define the association of these metabolites with improvement of risk factors for cardiovascular diseases (CVDs).

DESIGN:

24-h urine samples from 158 participants with pre-hypertension and stage 1 hypertension, collected at baseline and following the consumption of a carbohydrate-rich, a protein-rich, and a monounsaturated fat-rich healthy diet (6 wk/diet) in a randomized, crossover study, were analyzed by proton (1H) nuclear magnetic resonance (NMR) spectroscopy. Urinary metabolite profiles were interrogated to identify typical and variable responses to each diet. We quantified the differences in absolute excretion of metabolites, distinguishing between dietary comparisons within the typical response groups, and established their associations with CVD risk factors using linear regression.

RESULTS:

Globally all 3 diets induced a similar pattern of change in the urinary metabolic profiles for the majority of participants (60.1%). Diet-dependent metabolic variation was not significantly associated with total cholesterol or low density lipoprotein (LDL) cholesterol concentrations. However, blood pressure (BP) was found to be significantly associated with 6 urinary metabolites reflecting dietary intake [proline-betaine (inverse), carnitine (direct)], gut microbial co-metabolites [hippurate (direct), 4-cresyl sulfate (inverse), phenylacetylglutamine (inverse)], and tryptophan metabolism [N-methyl-2-pyridone-5-carboxamide (inverse)]. A dampened clinical response was observed in some individuals with variable metabolic responses, which could be attributed to nonadherence to diet (≤25.3%), variation in gut microbiome activity (7.6%), or a combination of both (7.0%).

CONCLUSIONS:

These data indicate interindividual variations in BP in response to dietary change and highlight the potential influence of the gut microbiome in mediating this relation. This approach provides a framework for stratification of individuals undergoing dietary management. The original OmniHeart intervention study and the metabolomics study were registered at www.clinicaltrials.gov as NCT00051350 and NCT03369535, respectively

TGIF1 In Colorectal Cancer

TGIF1 is another molecular factor discovered to promote colorectal cancer, apparently by upregulating the deregulated Wnt signaling found in most cases of that disease.  This discovery may point to novel therapeutic approaches targeting this factor.  Abstract:

Colorectal cancer (CRC) is one of the most common cancers, but the mechanisms underlying its initiation and progression are largely unknown. TGIF1 (TGFB induced factor homeobox 1) is a transcriptional corepressor that belongs to the three-amino acid loop extension (TALE) superclass of atypical homeodomains. It has been reported that TGIF1 is highly expressed in mammary cancer and non-small cell lung cancer and can enhance tumor progression. However, the role of TGIF1 in colorectal cancer remains unknown. Here, we report that TGIF1 is significantly upregulated in colorectal cancers, and its high expression predicts poor prognosis. Overexpression of TGIF1 markedly promotes the proliferation of colorectal cancer cells both in vivo and in vitro. In addition, TGIF1 activates Wnt/β-catenin signaling, and the homeodomain is indispensable for Wnt activation and β-catenin interaction. Taken together, our results suggest that TGIF1 is a novel colorectal tumor promoter and indicate that TGIF1 enhances colorectal cancer tumorigenesis through activating Wnt signaling.