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Archive for the ‘Micronutrients’ Category


3-D Printed Liver

Curator: Larry H. Bernstein, MD, FCAP

 

 

3D-printing a new lifelike liver tissue for drug screening

Could let pharmaceutical companies quickly do pilot studies on new drugs
February 15, 2016    http://www.kurzweilai.net/3d-printing-a-new-lifelike-liver-tissue-for-drug-screening

Images of the 3D-printed parts of the biomimetic liver tissue: liver cells derived from human induced pluripotent stem cells (left), endothelial and mesenchymal supporing cells (center), and the resulting organized combination of multiple cell types (right). (credit: Chen Laboratory, UC San Diego)

 

University of California, San Diego researchers have 3D-printed a tissue that closely mimics the human liver’s sophisticated structure and function. The new model could be used for patient-specific drug screening and disease modeling and could help pharmaceutical companies save time and money when developing new drugs, according to the researchers.

The liver plays a critical role in how the body metabolizes drugs and produces key proteins, so liver models are increasingly being developed in the lab as platforms for drug screening. However, so far, the models lack both the complex micro-architecture and diverse cell makeup of a real liver. For example, the liver receives a dual blood supply with different pressures and chemical constituents.

So the team employed a novel bioprinting technology that can rapidly produce complex 3D microstructures that mimic the sophisticated features found in biological tissues.

The liver tissue was printed in two steps.

  • The team printed a honeycomb pattern of 900-micrometer-sized hexagons, each containing liver cells derived from human induced pluripotent stem cells. An advantage of human induced pluripotent stem cells is that they are patient-specific, which makes them ideal materials for building patient-specific drug screening platforms. And since these cells are derived from a patient’s own skin cells, researchers don’t need to extract any cells from the liver to build liver tissue.
  • Then, endothelial and mesenchymal supporting cells were printed in the spaces between the stem-cell-containing hexagons.

The entire structure — a 3 × 3 millimeter square, 200 micrometers thick — takes just seconds to print. The researchers say this is a vast improvement over other methods to print liver models, which typically take hours. Their printed model was able to maintain essential functions over a longer time period than other liver models. It also expressed a relatively higher level of a key enzyme that’s considered to be involved in metabolizing many of the drugs administered to patients.

“It typically takes about 12 years and $1.8 billion to produce one FDA-approved drug,” said Shaochen Chen, NanoEngineering professor at the UC San Diego Jacobs School of Engineering. “That’s because over 90 percent of drugs don’t pass animal tests or human clinical trials. We’ve made a tool that pharmaceutical companies could use to do pilot studies on their new drugs, and they won’t have to wait until animal or human trials to test a drug’s safety and efficacy on patients. This would let them focus on the most promising drug candidates earlier on in the process.”

The work was published the week of Feb. 8 in the online early edition of Proceedings of the National Academy of Sciences.


Abstract of Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

Fernando

I wonder how equivalent are these hepatic cells derived from human induced pluripotent stem cells (hiPSCs) compared with the real hepatic cell populations.
All cells in our organism share the same DNA info, but every tissue is special for what genes are expressed and also because of the specific localization in our body (which would mean different surrounding environment for each tissue). I am not sure about how much of a step forward this is. Induced hepatic cells are known, but this 3-D print does not have liver shape or the different cell sub-types you would find in the liver.

I agree with your observation that having the same DNA information doesn’t account for variability of cell function within an organ. The regulation of expression is in RNA translation, and that is subject to regulatory factors related to noncoding RNAs and to structural factors in protein folding. The result is that chronic diseases that are affected by the synthetic capabilities of the liver are still problematic – toxicology, diabetes, and the inflammatory response, and amino acid metabolism as well. Nevertheless, this is a very significant step for the testing of pharmaceuticals. When we look at the double circulation of the liver, hypoxia is less of an issue than for heart or skeletal muscle, or mesothelial tissues. I call your attention to the outstanding work by Nathan O. Kaplan on the transhydrogenases, and his stipulation that there are significant differences between organs that are anabolic and those that are catabolic in TPNH/DPNH, that has been ignored for over 40 years. Nothing is quite as simple as we would like.

Fernando commented on 3-D printed liver

3-D printed liver Larry H. Bernstein, MD, FCAP, Curator LPBI 3D-printing a new lifelike liver tissue for drug …

I wonder how equivalent are these hepatic cells derived from human induced pluripotent stem cells (hiPSCs) compared with the real hepatic cell populations.
All cells in our organism share the same DNA info, but every tissue is special for what genes are expressed and also because of the specific localization in our body (which would mean different surrounding environment for each tissue). I am not sure about how much of a step forward this is. Induced hepatic cells are known, but this 3-D print does not have liver shape or the different cell sub-types you would find in the liver.

 

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A Reconstructed View of Personalized Medicine

Author: Larry H. Bernstein, MD, FCAP

 

There has always been Personalized Medicine if you consider the time a physician spends with a patient, which has dwindled. But the current recognition of personalized medicine refers to breakthrough advances in technological innovation in diagnostics and treatment that differentiates subclasses within diagnoses that are amenable to relapse eluding therapies.  There are just a few highlights to consider:

  1. We live in a world with other living beings that are adapting to a changing environmental stresses.
  2. Nutritional resources that have been available and made plentiful over generations are not abundant in some climates.
  3. Despite the huge impact that genomics has had on biological progress over the last century, there is a huge contribution not to be overlooked in epigenetics, metabolomics, and pathways analysis.

A Reconstructed View of Personalized Medicine

There has been much interest in ‘junk DNA’, non-coding areas of our DNA are far from being without function. DNA has two basic categories of nitrogenous bases: the purines (adenine [A] and guanine [G]), and the pyrimidines (cytosine [C], thymine [T], and  no uracil [U]),  while RNA contains only A, G, C, and U (no T).  The Watson-Crick proposal set the path of molecular biology for decades into the 21st century, culminating in the Human Genome Project.

There is no uncertainty about the importance of “Junk DNA”.  It is both an evolutionary remnant, and it has a role in cell regulation.  Further, the role of histones in their relationship the oligonucleotide sequences is not understood.  We now have a large output of research on noncoding RNA, including siRNA, miRNA, and others with roles other than transcription. This requires major revision of our model of cell regulatory processes.  The classic model is solely transcriptional.

  • DNA-> RNA-> Amino Acid in a protein.

Redrawn we have

  • DNA-> RNA-> DNA and
  • DNA->RNA-> protein-> DNA.

Neverthess, there were unrelated discoveries that took on huge importance.  For example, since the 1920s, the work of Warburg and Meyerhoff, followed by that of Krebs, Kaplan, Chance, and others built a solid foundation in the knowledge of enzymes, coenzymes, adenine and pyridine nucleotides, and metabolic pathways, not to mention the importance of Fe3+, Cu2+, Zn2+, and other metal cofactors.  Of huge importance was the work of Jacob, Monod and Changeux, and the effects of cooperativity in allosteric systems and of repulsion in tertiary structure of proteins related to hydrophobic and hydrophilic interactions, which involves the effect of one ligand on the binding or catalysis of another,  demonstrated by the end-product inhibition of the enzyme, L-threonine deaminase (Changeux 1961), L-isoleucine, which differs sterically from the reactant, L-threonine whereby the former could inhibit the enzyme without competing with the latter. The current view based on a variety of measurements (e.g., NMR, FRET, and single molecule studies) is a ‘‘dynamic’’ proposal by Cooper and Dryden (1984) that the distribution around the average structure changes in allostery affects the subsequent (binding) affinity at a distant site.

What else do we have to consider?  The measurement of free radicals has increased awareness of radical-induced impairment of the oxidative/antioxidative balance, essential for an understanding of disease progression.  Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Various studies have confirmed that metals activate signaling pathways and the carcinogenic effect of metals has been related to activation of mainly redox sensitive transcription factors, involving NF-kappaB, AP-1 and p53.

I have provided mechanisms explanatory for regulation of the cell that go beyond the classic model of metabolic pathways associated with the cytoplasm, mitochondria, endoplasmic reticulum, and lysosome, such as, the cell death pathways, expressed in apoptosis and repair.  Nevertheless, there is still a missing part of this discussion that considers the time and space interactions of the cell, cellular cytoskeleton and extracellular and intracellular substrate interactions in the immediate environment.

There is heterogeneity among cancer cells of expected identical type, which would be consistent with differences in phenotypic expression, aligned with epigenetics.  There is also heterogeneity in the immediate interstices between cancer cells.  Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. In the case of breast cancer, there is interaction with estrogen , and we refer to an androgen-unresponsive prostate cancer.

Finally,  the interaction between enzyme and substrates may be conditionally unidirectional in defining the activity within the cell.  The activity of the cell is dynamically interacting and at high rates of activity.  In a study of the pyruvate kinase (PK) reaction the catalytic activity of the PK reaction was reversed to the thermodynamically unfavorable direction in a muscle preparation by a specific inhibitor. Experiments found that in there were differences in the active form of pyruvate kinase that were clearly related to the environmental condition of the assay – glycolitic or glyconeogenic. The conformational changes indicated by differential regulatory response were used to present a dynamic conformational model functioning at the active site of the enzyme. In the model, the interaction of the enzyme active site with its substrates is described concluding that induced increase in the vibrational energy levels of the active site decreases the energetic barrier for substrate induced changes at the site. Another example is the inhibition of H4 lactate dehydrogenase, but not the M4, by high concentrations of pyruvate. An investigation of the inhibition revealed that a covalent bond was formed between the nicotinamide ring of the NAD+ and the enol form of pyruvate.  The isoenzymes of isocitrate dehydrogenase, IDH1 and IDH2 mutations occur in gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. In this case, there is steric hindrance by Asp279 where the isocitrate substrate normally forms hydrogen bonds with Ser94.

Personalized medicine has been largely viewed from a lens of genomics.  But genomics is only the reading frame.  The living activities of cell processes are dynamic and occur at rapid rates.  We have to keep in mind that personalized in reference to genotype is not complete without reconciliation of phenotype, which is the reference to expressed differences in outcomes.

 

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Breast Cancer Extratumor Microenvironment has Effect on Progression

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Tumor Microenvironment Diversity Predicts Breast Cancer Outcomes

GEN News Highlights   Feb 17, 2016   http://www.genengnews.com/gen-news-highlights/tumor-microenvironment-diversity-predicts-breast-cancer-outcomes/81252378/

 

Intratumor heterogeneity, it is known, can complicate cancer treatments. Now it appears the same may be true of tumor microenvironment heterogeneity. According to a new study from the Institute of Cancer Research (ICR), London, breast cancers that develop within an “ecologically diverse” breast cancer microenvironment are particularly likely to progress and lead to death.

The study took an unusual approach: It combined ecological scoring methods with genome-wide profiling data. This approach, besides showing clinical utility in the evaluation of breast cancer outcomes, demonstrated that even so contextual a discipline as genomics can benefit from being placed within a larger context. In this case, the context is essentially Darwinian, albeit at a small scale.

Natural selection is typically studied at the level of ecosystems consisting of animals and plants. In the current study, however, it was assessed at the level of the tumor microenvironment, which consists of cancer cells, immune system lymphocytes, and stromal cells.

The ICR scientists, led by Yinyin Yuan, Ph.D., presented their work February 16 in the journal PLoS Medicine, in an article entitled “Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.” The article describes how the scientists developed a tumor ecosystem diversity index (EDI), a scoring system that indicates the degree of microenvironmental heterogeneity along three spatial dimensions in solid tumors. EDI scores take account of “fully automated histology image analysis coupled with statistical measures commonly used in ecology.”

“[EDI] was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set,” wrote the authors. “In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types.”

By using the EDI, the ICR team was able to identify several particularly aggressive subgroups of breast cancer. In fact, the EDI was a stronger predictor of survival than many established markers for the disease.

The ICR researchers also looked at the EDI in addition to genetic factors. For example, the researchers found that the prognostic value of EDI was enhanced with the addition of TP53 mutation status. By integrating EDI data and genome-wide profiling data, the researchers identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors. These tumors, which showed high microenvironmental diversity, substratified patients into poor prognostic groups.

“Our findings show that mathematical models of ecological diversity can spot more aggressive cancers,” said Dr. Yuan. “By analyzing images of the environment around a tumor based on Darwinian natural selection principles, we can predict survival in some breast cancer types even more effectively than many of the measures used now in the clinic.

“In the future, we hope that by combining cell diversity scores with other factors that influence cancer survival, such as genetics and tumor size, we will be able to tell apart patients with more or less aggressive disease so we can identify those who might need different types of treatment.”

“This ingenious study…teaches us a valuable lesson,” added Paul Workman, Ph.D., chief executive of the ICR. “[We] should always remember that cancer cells are not developing and growing in isolation, but are part of a complex ecosystem that involves normal human cells, too. By better understanding these ecosystems, we aim to create new ways to diagnose, monitor and treat cancer.”

 

Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

 

Background

The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters.

Methods and Findings

We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10−4, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size.

Conclusions

To our knowledge, this is the first study to couple unbiased measures of microenvironmental heterogeneity with genomic alterations to predict breast cancer clinical outcome. We propose a clinically relevant role of microenvironmental heterogeneity for advanced breast tumors, and highlight that ecological statistics can be translated into medical advances for identifying a new type of biomarker and, furthermore, for understanding the synergistic interplay of microenvironmental heterogeneity with genomic alterations in cancer cells.

Background

The human body contains millions of cells, all of which grow, divide, and die in an orderly fashion to build tissues during early life and to replace worn-out or dying cells and repair injuries during adult life. Sometimes, however, normal cells acquire genetic changes (mutations) that allow them to divide uncontrollably and to move around the body (metastasize), resulting in cancer. Because any cell in the body can acquire the mutations needed for cancer development, there are many types of cancer. For example, breast cancer, the most common cancer in women, begins when the cells in the breast that normally make milk become altered. Moreover, different types of cancer progress and evolve differently—some cancers grow quickly and kill their “host” soon after diagnosis, whereas others can be successfully treated with drugs, surgery, or radiotherapy. The behavior of individual cancers depends both on the characteristics of the cancer cells within the tumor and on the interactions between the cancer cells and the normal stromal cells (the connective tissue cells of organs) and other cells (for example, immune cells) that surround and feed cancer cells (the tumor microenvironment).

Why Was This Study Done?

Although recent studies have highlighted the importance of the tumor microenvironment for disease-related outcomes, little is known about how the heterogeneity of the tumor microenvironment—the diversity of non-cancer cells within the tumor—affects outcomes. Mathematical modeling suggests that tumors with heterogeneous and homogeneous microenvironments have different growth patterns and that heterogeneous microenvironments are more likely to be associated with aggressive cancers than homogenous microenvironments. However, the lack of methods to quantify the spatial variability and cellular composition across solid tumors has prevented confirmation of these predictions. Here, the researchers develop a computational system for quantifying microenvironmental heterogeneity in breast cancer based on tumor morphology (shape and form) in histological sections (tissue samples taken from tumors that are examined microscopically). They then use this system to analyze the associations between clinical outcomes, molecular changes, and microenvironmental heterogeneity in breast cancer.

What Did the Researchers Do and Find?

The researchers used automated image analysis and statistical analysis to develop the ecosystem diversity index (EDI), a numerical measure of microenvironmental heterogeneity in solid tumors. They compared the EDI with prognosis (likely outcome), key mutations, genome-wide copy number (tumor cells often contain abnormal numbers of copies of specific genes), and expression profiling data (the expression of several key proteins is altered in tumors) in a test set of 510 samples from patients with breast cancer and in a validation set of 516 additional samples. Among high-grade breast cancers (grade 3 cancers; the grade of a cancer indicates what the cells look like; high-grade breast cancers have a poor prognosis), but not among low-grade breast cancers (grades 1 and 2), a high EDI (high microenvironmental heterogeneity) was associated with a poor prognosis. Specifically, patients with grade 3 tumors and a high EDI had a ten-year disease-specific survival rate of 51%, whereas the remaining patients with grade 3 tumors had a ten-year survival rate of 70%. Notably, the combination of a high EDI with specific DNA alterations—mutations in a gene called TP53 and loss of genes on Chromosomes 4p14 and 5q13—improved the accuracy of prognosis among patients with grade 3 breast cancer and stratified them into subgroups with disease-specific five-year survival rates of 35%, 9%, and 32%, respectively.

What Do These Findings Mean?

These findings establish a method for measuring the spatial heterogeneity of the microenvironment of solid tumors and suggest that the measurement of tumor microenvironmental heterogeneity can be coupled with information about genomic alterations to provide an accurate way to predict outcomes among patients with high-grade breast cancer. The association between EDI, specific genomic alterations, and outcomes needs to be confirmed in additional patients. However, these findings suggest that microenvironmental heterogeneity might provide an additional biomarker to help clinicians identify those patients with advanced breast cancer who have a particularly bad prognosis. The ability to identify these patients is important because it will help clinicians target aggressive treatments to individuals with a poor prognosis and avoid the overtreatment of patients whose prognosis is more favorable. Finally, and more generally, these findings describe a new way to investigate the interactions between the tumor microenvironment and genomic alterations in cancer cells.

Additional Information

This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001961.

Citation: Natrajan R, Sailem H, Mardakheh FK, Arias Garcia M, Tape CJ, Dowsett M, et al. (2016) Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.
PLoS Med 13(2): e1001961.     http://dx.doi.org:/10.1371/journal.pmed.1001961
Fig 1. In silico tumor dissection pipeline for quantifying spatial diversity in the tumor ecosystem.
Fig 1. In silico tumor dissection pipeline for quantifying spatial diversity in the tumor ecosystem. (A) Flow diagram depicting the overall study design. (B) Schematic of our pipeline for quantifying spatial diversity in pathological samples. H&E sections are morphologically classified and divided into regions to be spatially scored. The number of clusters k in the regional scores is indicative of the number of sub-populations of cell types in the tumor regions. (C) Examples of tumor regions with low and high diversity scores using the Shannon diversity index, accounting for cancer cells (outlined in green), lymphocytes (blue), and stromal cells (red). Cell classification is automated by image analysis. (D) The 3-D landscape of cell diversity scores on an example H&E section; the x- and y-axes are the geometric axes of the image, and the z-axis is cell diversity computed on a region-by-region basis. (E) The distribution of regional scores in a tumor from the METABRIC study with two regional clusters identified using Gaussian mixture clustering (grey shading: histogram; dashed black line: density; solid black lines: mixture components/clusters).
Fig 2. Application of EDI to 1,026 breast tumors from the METABRIC study.
Fig 2. Application of EDI to 1,026 breast tumors from the METABRIC study. (A) The frequencies of EDI scores in breast tumors. (B) H&E staining, distribution of classified cells (green: cancer; blue: lymphocyte; red: stromal cells), and the heatmap of regional diversity scores for a tumor with the highest EDI score (EDI = 5). (C) Representative regions from each of the clusters k1–k5 are shown in a tumor with EDI = 5, with cluster k1 having the lowest diversity score and k5 the highest. By mapping regional clusters to the H&E image, we can begin to interpret these clusters with different cell diversity. We observed predominantly cancer cells in k1, increasingly more stromal cells and ductal in situ carcinoma cells (DCIS) in k2, and a vessel in k3. Cluster k4 features extensive stromal lymphocytes between ductal in situ carcinoma components, while k5 shows tumor-infiltrating lymphocytes (TIL) associated with invasive carcinoma cells.
Fig 3. Reproducibility, stability, and independence of the EDI-high group in 507 grade 3 breast tumors.
Fig 3. Reproducibility, stability, and independence of the EDI-high group in 507 grade 3 breast tumors. (A) Kaplan–Meier curves of disease-specific survival to illustrate the prognosis of EDI-high samples compared to other grade 3 samples in two independent patient cohorts. Shown below the graph are the number of patients (the number of disease-specific events) per group for EDI-low (grey) and EDI-high (red). (B) Agreement of the EDI subtyping between 100% data and resampling with progressively fewer tumor regions in 200 repeats. (C) Distribution of known subtypes in grade 3 tumors stratified by EDI; asterisks mark subtypes enriched in the EDI-high group. (D) Kaplan–Meier curves illustrating the duration of disease-specific survival according to tumor size (left) and improvement of stratification with the addition of EDI information (right).
Accumulating evidence suggests that the interactions of cancer cells and stromal cells within their microenvironment govern disease progression, metastasis, and, ultimately, the evolution of therapeutic resistance [1–3]. Recent reports have highlighted the significance of the contribution of stromal gene expression and morphological structure as powerful prognostic determinants for a number of tumor types, emphasizing the importance of the tumor microenvironment in disease-related outcomes [4–7]. In breast cancer, a number of studies have demonstrated the prognostic correlation of individual cell types, including the immune cell infiltrate that predicts response to therapy [8–10], and the high percentage of tumor stroma that predicts poor prognosis in triple-negative disease but good prognosis in estrogen receptor (ER)–positive disease [11,12]. Nevertheless, different types of cells coexist with varying degrees of heterogeneity within a tumor. This fundamental feature of human tumors and the combinatorial effects of cell types have been largely ignored, and the collective implications for clinical outcome remain elusive. Consistent observations from mathematical models have highlighted that tumors with diverse microenvironments show growth patterns dramatically different from those of tumors with homogeneous environments [13] and are more likely to be associated with aggressive cancer phenotypes [2] that select for cell migration and eventual metastasis by allowing cancer cells to evolve more rapidly [14]. These observations highlight the need to understand the collective physiological characteristics and heterogeneity of tumor microenvironments. However, there is a lack of methods to quantify the high spatial variability and diverse cellular composition across different solid tumors. Moreover, the interplay of genomic alterations in cancer cells and microenvironmental heterogeneity and its subsequent role in treatment response have not been explored. Our aims were (i) to develop a computational system for quantifying microenvironmental heterogeneity based on tumor morphology in routine histological sections, (ii) to define the clinical implications of microenvironmental heterogeneity, and (iii) to integrate this histologybased index with RNA gene expression and DNA copy number profiling data to identify molecular changes associated with microenvironmental heterogeneity.
The Ecosystem Diversity Index To characterize the tumor ecosystem based on cell compositions, we developed a new index to be used in conjunction with our image analysis tool [16]. First, we used our automated morphological classification method [16] to identify and classify cells into cancer, lymphocyte, or stromal cell classes in H&E sections (Fig 1B). We next divided sections into smaller spatial regions and quantified the diversity of the tumor ecosystem in a tumor region j using the Shannon diversity index: dj ¼ Sm i pi logpi ; ð1Þ where m is the number of cell types and pi is the proportion of the ith cell type (Fig 1B and 1C). A high value of the Shannon diversity index dj reports a heterogeneous environment populated by many cell types, whilst a low value indicates a homogeneous environment (Fig 1C). Compared to other methods such as the Simpson index, the Shannon diversity index accounts for rare species and, hence, is less dominated by main species [17]. Subsequently, we derived the ecosystem diversity index (EDI) by applying unsupervised clustering that identifies the optimum number of clusters in the dataset in an unbiased manner, in order to group tumor regions and quantify the degree of spatial heterogeneity. Let D = d1,d2,…,dn be the Shannon index for n regions in a tumor. We used Gaussian mixture models to fit data D: D SK k¼1okNðmk; s2 kÞ: ð2Þ where μk, ,s2 k, and ωk are the mean, variance, and weight of a Gaussian distribution k, and K is the number of clusters. The Bayesian information criterion was then used to select the best number of clusters K [18]. We used K = 1–5 as the range of K to avoid small EDI groups (S1 Text). The final value of K thus is a measurement of heterogeneity and the score of EDI for a tumor.
Fig 5. The relationship between ecological heterogeneity and cancer genomic aberrations in 507 grade 3 tumors. (A) Genome-wide copy number aberrations in grade 3 breast tumors and genomic coordinates of genes with copy number aberrations enriched in the EDI-high group. Lengths of black lines denote level of enrichment significance with copy number gains (above the horizontal line) or losses (below the horizontal line). (B) Kaplan–Meier curves illustrating the duration of disease-specific survival in grade 3 breast cancer patients according to copy number loss of the 4p14 region (left) and the EDI-high group with additional information of 4p14 copy number loss (right). (C) Kaplan–Meier curves illustrating the duration of disease-specific survival according to copy number loss of the 5q13 region (left) and the EDI-high group with additional information of 5q13 copy number loss (right).
This study has a number of limitations. The motivation for our computational development was to use a data-driven model and measure the degree of spatial heterogeneity in tumor pathological specimens. In this model, only three major cell types in breast tumors were considered. Further sub-classification of the different types of stromal and immune cells by immunohistochemistry may add additional discriminatory value to our model. For dissecting spatial heterogeneity, we chose to use square regions with equal sizes. We found that EDI was correlated with the size of the region chosen for calculation of the Shannon diversity index, and as such the spatial heterogeneity is scale dependent. This phenomenon has been well described in a number of studies in ecology that show that a scale needs to be chosen that is appropriate for the ecological process under study [38,39], further highlighting the analogy between tumor studies and ecology. Similar to the recent observation that breast cancer subclonal heterogeneity is correlated with tumor size [35], we also found an association between microenvironmental heterogeneity and tumor size; hence, EDI may have more limited value in smaller tumors. However, small tumors were present in the EDI-high group, and addition of EDI within tumors grouped by size further stratified their prognosis. We found that EDI was prognostic only in grade 3 tumors in our study, which could be a limitation, given the possible discordance in grading between pathologists.
The identification of additional biomarkers in subgroups of patients that identify them as high risk is important for patient management and to avoid overtreatment for low-risk patients. We envision that the use of our measure of microenvironment heterogeneity, together with key genomic alterations, will enable the diagnosis of patients at very high risk of relapse and facilitate the enrollment of these patients into additional clinical trials for novel therapies or treatment intensification. Our novel computational approach provides a fully automated tool that is relatively easy to implement. Integration of this measure with genomic profiling provides additional prognostic information independent of known clinical parameters. The results of this study highlight the possibility of a grade-3-specific prognostic tool that may aid in further classification of high-grade breast cancer patients beyond standard assays such as ER and HER2 status.

 

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Adenosine Receptor Agonist Increases Plasma Homocysteine

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases

Spring Zhou Editor at Scientific Research Publishing

I would like to share this paper with you. Any comments on this article are welcome.

 

An increase in total homocysteine (Hcy) levels (protein-bound and free Hcy in the serum) has been identified as a risk factor for vascular diseases. Hcy is a product of the methionine cycle and is a precursor of glutathione in the transsulfuration pathway. The methionine cycle mainly occurs in the liver, with Hcy being exported out of the liver and subsequently bound to serum proteins. When the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA; 0.1 or 0.3 mg/kg body weight) was intraperitoneally administered to mice that had been fasted for 16 h, total Hcy levels in the serum significantly increased 1 h after its administration. The NECA treatment may have inhibited transsulfuration because glutathione levels were significantly decreased in the liver. After the intraperitoneal administration of a high dose of NECA (0.3 mg/kg body weight), elevations in total Hcy levels in the serum continued for up to 10 h. The mRNA expression of methionine metabolic enzymes in the liver was significantly reduced 6 h after the administration of NECA. NECA-induced elevations in total serum Hcy levels may be maintained in the long term through the attenuated expression of methionine metabolic enzymes.

 

Comments:

  1.  Is level of protein consumption a factor?
  2. Is reliance on plant food products a factor?
  3. What are the levels of transthyretin?
  4. Is there a concomitant decrease in vitamin A or vitamin D?

 

 

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases

Shigeko Fujimoto Sakata*, Koichi Matsuda, Yoko Horikawa, Yasuto Sasaki     Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan.

http://www.scirp.org/journal/PaperInformation.aspx    DOI: 10.4236/pp.2015.610048

Cite this paper

Sakata, S. , Matsuda, K. , Horikawa, Y. and Sasaki, Y. (2015) The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases. Pharmacology & Pharmacy, 6, 461-470. doi: 10.4236/pp.2015.610048.
An increase in total serum homocysteine levels (total Hcy: serum protein-bound and free Hcy) has been identified as a risk factor for cardiovascular disease [1] [2] and liver fibrosis [3]. The normal range of total Hcy in adults is typically 5 – 15 μM, with the mean level being approximately 10 μM [2]. Plasma Hcy concentrations were previously found to be strongly associated with the presence and number of small infarctions, or infarction of the putamen in elderly diabetic patients [4]. High levels of Hcy have been shown to induce endoplasmic reticulum (ER) stress and increase the production of reactive oxygen species (ROS) [5]. Hcy has strong reducibility and modifies disulfide bonds in proteins. Only 1% to 2% of Hcy occurs as thiol homocysteine in the serum; 75% of Hcy has been suggested to bind to proteins through disulfide bonds with protein cysteines [6]. Hcy is formed as an intermediary in methionine metabolism [7] [8]. Methionine metabolism mainly occurs in the livers of mammals. Methionine receives an adenosine group from ATP to become S-adenosylmethionine (AdoMet) in the methionine cycle. This reaction is catalyzed in the liver by liver-specific methionine adenosyltransferase I/III (MAT I/III), which is encoded by the methionine adenosyltransferase 1A (MAT1A) gene [9]. AdoMet then transfers its methyl group to a large number of compounds, a process that is catalyzed by various methyltransferases (e.g., glycine N-methyltransferase: GNMT; DNA methyltransferase; phosphatidylethanolamine N-methyl- transferase), to produce S-adenosylhomocysteine (AdoHcy). Hcy is formed from AdoHcy by AdoHcy hydrolase (SAHH). The reaction that generates Hcy from AdoHcy is reversible, and AdoHcy from Hcy is shown to be thermodynamically favored over the synthesis of Hcy [10]. A previous study reported that Hcy levels were very low in the liver [11]. This reaction then proceeds toward the synthesis of Hcy when the products (Hcy and adenosine) are removed by further metabolism [12]. Three enzymes metabolize Hcy, with the betaine-homocysteine S-methyltransferase (BHMT) and methionine synthase (MS) reactions both yielding methionine. A large proportion of Hcy in the liver is remethylated by BHMT [3]. The third enzyme, cystathionine β-synthase (CBS) catalyzes Hcy to cystathionine in the transsulfuration pathway. Previous studies of whole body methionine kinetics demonstrated that 62% of Hcy was converted to cystathionine during each cycle in males fed a basal diet, resulting in the production of glutathione (GSH), while 38% of Hcy was remethylated to methionine [13]. Hcy is located at an important regulatory branch point: remethylation to methionine; conversion to cystathionine; export from the cells.
A decrease in intracellular ATP levels, accompanied by the accumulation of 5’-AMP and subsequently adenosine, is known to follow ischemia. Adenosine levels in interstitial fluids were shown to increase 100 – 1000- fold from basal levels (10 – 300 nM) with ischemia [14]. Furthermore, adenosine levels in hepatocytes were increased by a hypoxic challenge, with excess amounts of adenosine being exported out of cells [14]. Adenosine levels were also found to increase 10-fold due to hypoxia, stress, and inflammation [15]. Adenosine has been shown to activate A1, A2a, and A3 receptors with EC50 values in the range of 0.2 – 0.7 μM, and also A2b receptors with an EC50 of 24 μM [16]. A1 and A3 receptors have been classified as adenylate cyclase inhibitory receptors, and A2a and A2b receptors as adenylate cyclase-activating receptors [17]. The activation of adenosine receptors accompanied by ischemia may increase total Hcy levels in the serum because hepatic ischemia is known to decrease the content of GSH and activity of MAT [18].
We previously reported that the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA) increased serum glucose levels and the expression of a glucogenic enzyme (glucose 6-phosphatase) in the liver [19] [20]. Based on the dose of NECA administered in these studies and plasma concentrations after the administration of other adenosine agonists [21], it was inferred that the serum NECA concentration was in the μM range and also that NECA activated adenosine A2b receptors. In the present study, we measured methionine metabolites, including Hcy, in NECA-treated mice in order to determine whether the activation of adenosine receptors increased total Hcy levels in the serum. The results obtained clearly demonstrated that NECA increased total Hcy levels in the serum.
Measurement of Methionine Metabolites AdoMet and AdoHcy levels in the liver were measured using an HPLC method [25] and total GSH in the liver was measured using a microtiter plate assay [26], as described previously [23]. Total Hcy and total cysteine levels (total Cys: free and protein-bound cysteine) in the serum were measured using an HPLC method [27]. Briefly, a mixture of 50 μL of serum, 25 μL of an internal standard, and 25 μL of phosphate-buffered saline (PBS, pH 7.4) was incubated with 10 μL of 100 mg/mL TCEP for 30 min at room temperature in order to reduce and release protein-bound thiols. After this incubation, 90 μL of 100 mg/mL trichloroacetic acid containing 1 mmol/L EDTA was added for deproteinization, centrifuged at 15,000 ×g for 10 min, and 50 μL of the supernatant was added to a tube containing 10 μL of 1.55 mol/L NaOH; 125 μL of 0.125 mol/L borate buffer containing 4 mmol/L EDTA, pH 9.5; and 50 μL of 1 mg/mL SBD-F in the borate buffer. The sample was then incubated for 60 min at 60˚C. HPLC was performed on a Waters M-600 pump equipped with a Waters 2475 Multi λ Fluorescence Detector (385 nm excitation, 515 nm emission). The separation of SBD-derivatized thiols was performed on a μ-BONDASPHERE C18 column (Waters, 5 μm, 100 A, 150 × 3.9 mm) with a 20-μL injection volume and 0.1 mol/L acetate buffer, pH 5.5, containing 30 ml/L methanol as the mobile phase at a flow rate of 1.0 mL/min and column temperature of 29˚C.
3.1. Effects of NECA on Total Hcy and Total Cys Levels in the Serum As shown in Table 1, serum total Hcy and total Cys levels significantly increased after 16 h of fasting. The administration of a low dose of NECA (NECA0.1 group) to mice fasted for 16 h resulted in higher serum total Hcy levels than those in the control group at 1 h (Experiment 1). Serum total Hcy levels were also significantly elevated at 3 h (Experiment 2), but were not significantly different from those in the control group at 6 h (Experiment 3). The administration of a high dose of NECA (NECA0.3 group) resulted in significantly higher serum total Hcy levels than those in the control group at 1 h, 3 h, 6 h, and 10 h (Experiments 4, 5, 6, and 7), gradually increasing Hcy levels to 19.7 μM. The effects of NECA on serum total Cys levels were the same as those on total Hcy levels.
Table 1. Effects of NECA on the content of total homocysteine and total cysteine in the serum.

3.2. Effects of NECA on Other Methionine Metabolite Levels in the Liver We previously reported that fasting for 16 h decreased AdoMet and GSH levels, and increased AdoHcy levels in the livers of mice [23]. In the present study, as shown in Table 2, the administration of a low dose of NECA (NECA0.1 group) to mice fasted for 16 h resulted in lower liver GSH levels than those in the control group at 1 h (Experiment 1). Liver GSH levels were also significantly lower at 3 h (Experiment 2), while GSH levels were not significantly different from those in the control group at 6 h (Experiment 3). The administration of a high dose of NECA (NECA0.3 group) resulted in liver GSH levels that were significantly lower than those in the control group at 1 h, 6 h, and 10 h (Experiments 4, 6, and 7). The effects of NECA on total Hcy levels in the serum and GSH levels in the liver were similar at each dose and time. Furthermore, the low and high doses of NECA both led to significantly higher AdoMet levels than those in the control group at 1 h (Experiments 1 and 4). AdoMet levels at 3 h, 6 h, and 10 h were not significantly different from those in the control group (Experiments 2, 3, 5, 6, and 7). AdoHcy levels were significantly lower in the NECA0.3 group than in the control group 6 h and 10 h after the administration of NECA (Experiments 6 and 7), while the administration of a low dose of NECA had less of an impact on AdoHcy levels.

Table 2. Effects of NECA on the content of methionine metabolites in the liver.

3.3. Effects of NECA on mRNA Expression of Methionine Cycle Enzymes in the Liver Figure 1 shows changes in the mRNA expression of methionine cycle enzymes in Experiments 4, 5, and 6. The expression of methionine cycle enzymes did not significantly change 1 h after the administration of NECA. The expression of MAT1A mRNA was significantly decreased in the liver 6 h after the NECA treatment, while that of MAT2A was increased. The changes observed in the expression of MAT in the present study were consistent with previous findings obtained in ischemic livers [18] or with liver regeneration [28]. The expression of GNMT, which eliminates excess AdoMet, was significantly decreased 6 h after the NECA treatment. The expression of CBS, which converts Hcy to cystathionine through the transsulfuration pathway, and BHMT, which converts Hcy to methionine, was also decreased at 6 h.

Figure 1 shows changes in the mRNA expression of methionine cycle enzymes in Experiments 4, 5, and 6. The expression of methionine cycle enzymes did not significantly change 1 h after the administration of NECA. The expression of MAT1A mRNA was significantly decreased in the liver 6 h after the NECA treatment, while that of MAT2A was increased. The changes observed in the expression of MAT in the present study were consistent with previous findings obtained in ischemic livers [18] or with liver regeneration [28]. The expression of GNMT, which eliminates excess AdoMet, was significantly decreased 6 h after the NECA treatment. The expression of CBS, which converts Hcy to cystathionine through the transsulfuration pathway, and BHMT, which converts Hcy to methionine, was also decreased at 6 h.
Figure 1. Effects of NECA on the mRNA expression of methionine cycle enzymes in the mouse liver. Northern hybridization was performed on the liver RNA of mice in experiments 4, 5, and 6. The mean ± SEM of the ratio of each enzyme mRNA to the level of the 18S rRNA signal is shown as an arbitrary unit. Unpaired Student’s t-tests were used to compare NECA- treated groups with the control groups. *p < 0.05, **p < 0.01: significantly different from each control.
4. Discussion In the present study, an increase in total Hcy levels and AdoMet levels, and decrease in GSH levels occurred 1 h after the NECA treatment. These results were not due to changes in the expression of methionine metabolic enzymes, which remained unchanged 1 h after the NECA treatment (Figure 1). The effects of NECA on methionine metabolism are summarized in Figure 2. No previous study has demonstrated that adenosine has the ability to directly affect CBS; however, the overproduction of carbon monoxide (CO), which is generated by heme oxygenase (HO), is found to inhibit transsulfuration [11]. CO has been shown to inhibit CBS activity and increase AdoMet concentrations [11]. Adenosine and NECA were previously reported to markedly induce HO in macrophages [29]. Hcy, which is a substrate of CBS, may be increased by NECA via the CO-induced inhibition of CBS, and GSH may be decreased by the CO-induced inhibition of transsulfuration. However, the mechanism by which NECA affects transsulfuration in the short term has not yet been elucidated.
Figure 2. Effects of NECA on the methionine metabolic pathway. MAT: methionine adenosyltransferase, GNMT: glycine N-methyltransferase, CBS: cystathionine β-synthase, BHMT: betaine-homocysteine S-methyltransferase, MS: methionine synthase (Map is based on Sakata SF 2005).
GSH was maintained at a low level for up to 10 h by the NECA0.3 treatment and transsulfuration may have been continuously inhibited by the NECA0.3 treatment. Total Hcy levels were also continuously increased for up to 10 h by the NECA0.3 treatment, and decreased AdoHcy levels were observed 6 h and 10 h after the NECA0.3 treatment. Long-term elevations in serum total Hcy levels by NECA may be maintained by attenuating the expression of methionine metabolic enzymes via the following mechanisms: The expression of methionine metabolic enzymes in the liver was reduced 6 h after the NECA0.3 treatment (Figure 1); the flow of the methionine cycle may have been decreased by changes in the expression of MAT (decreased liver-specific MAT1A expression and increased non-liver type MAT2A expression) because MATIII (Km for methionine: 215 μM – 7 mM) is the true liver-specific isoform responsible for methionine metabolism [30] and the generation rate of AdoMet by MATII (non-liver type enzyme) was modest with a low Km (80 μM for methionine) [31]; inhibition of the methyltransferases, BHMT [32] and GNMT [33], induces hyperhomocysteinemia; decreases in AdoHcy levels may be caused by reductions in methyltransferase levels. However, the mechanisms by which NECA continuously increased total Hcy levels have not yet been elucidated in detail. 5. Conclusion The present study confirmed that the non-specific adenosine receptor agonist NECA continuously increased total Hcy levels in the serum. The inhibition of adenosine receptors may decrease the risk of cardiovascular diseases because an increase in serum total Hcy levels is a known risk factor.

References

[1] Antoniades, C., Antonopoulos, A.S., Tousoulis, D., Marinou, K. and Stefanadis, C. (2009) Homocysteine and Coronary Atherosclerosis: from Folate Fortification to the Recent Clinical Trials. European Heart Journal, 30, 6-15.
http://dx.doi.org/10.1093/eurheartj/ehn515
[2] Refsum, H., Ueland, P.M., Nygard, O. and Vollset, S.E. (1998) Homocysteine and Cardiovascular Disease. Annual Review of Medicine, 49, 31-62.
http://dx.doi.org/10.1146/annurev.med.49.1.31
[3] Garcia-Tevijano, E.R., Berasain, C., Rodriguez, J.A., Corrales, F.J., Arias, R., Martin-Duce, A., Caballeria, J., Mato, J.M. and Avila, M.A. (2001) Hyperhomocysteinemia in Liver Cirrhosis: Mechanisms and Role in Vascular and Hepatic Fibrosis. Hypertension, 38, 1217-1221.
http://dx.doi.org/10.1161/hy1101.099499
[4] Araki, A., Ito, H., Majima, Y., Hosoi, T. and Orimo, H. (2003) Association between Plasma Homocysteine Concentrations and Asymptomatic Cerebral Infarction or Leukoaraiosis in Elderly Diabetic Patients. Geriatrics & Gerontology International, 3, 15-23.
http://dx.doi.org/10.1046/j.1444-1586.2003.00051.x
[5] Elanchezhian, R., Palsamy, P., Madson, C.J., Lynch, D.W. and Shinohara, T. (2012) Age-Related Cataracts: Homocysteine Coupled Endoplasmic Reticulum Stress and Suppression of Nrf2-Dependent Antioxidant Protection. Chemico-Biological Interactions, 200, 1-10.
http://dx.doi.org/10.1016/j.cbi.2012.08.017
[6] Mudd, S.H., Finkelstein, J.D., Refsum, H., Ueland, P.M., Malinow, M.R., Lentz, S.R., Jacobsen, D.W., Brattstrom, L., Wilcken, B., Wilcken, D.E., Blom, H.J., Stabler, S.P., Allen, R.H., Selhub, J. and Rosenberg, I.H. (2000) Homocysteine and Its Disulfide Derivatives: A Suggested Consensus Terminology. Arteriosclerosis Thrombosis and Vascular Biology, 20, 1704-1706.
http://dx.doi.org/10.1161/01.ATV.20.7.1704
[7] Finkelstein, J.D. (1990) Methionine Metabolism in Mammals. The Journal of Nutritional Biochemistry, 1, 228-237.
http://dx.doi.org/10.1016/0955-2863(90)90070-2
[8] Stipanuk, M.H. (2004) Sulfur Amino Acid Metabolism: Pathways for Production and Removal of Homocysteine and Cysteine. Annual Review of Nutrition, 24, 539-577.
http://dx.doi.org/10.1146/annurev.nutr.24.012003.132418
[9] Chou, J.Y. (2000) Molecular Genetics of Hepatic Methionine Adenosyltransferase Deficiency. Pharmacology & Therapeutics, 85, 1-9.
http://dx.doi.org/10.1016/s0163-7258(99)00047-9
[10] De La Haba, G. and Cantoni, G.L. (1959) The Enzymatic Synthesis of S-Adenosyl-L-Homocysteine from Adenosine and Homocysteine. The Journal of Biological Chemistry, 234, 603-608.
http://www.jbc.org/content/234/3/603.short

…. more

 

 

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Biomarker Development


Biomarker Development

Curator: Larry H. Bernstein, MD, FCAP

 

 

NBDA’s Biomarker R&D Modules

http://nbdabiomarkers.org/

“collaboratively creating the NBDA Standards* required for end-to-end, evidence – based biomarker development to advance precision (personalized) medicine”

http://nbdabiomarkers.org/sites/all/themes/nbda/images/nbda_logo.jpg

http://nbdabiomarkers.org/about/what-we-do/pipeline-overview/assay-development

 

Successful biomarkers should move systematically and seamlessly through specific R&D “modules” – from early discovery to clinical validation. NBDA’s end-to-end systems approach is based on working with experts from all affected multi-sector stakeholder communities to build an in-depth understanding of the existing barriers in each of these “modules” to support decision making at each juncture.  Following extensive “due diligence” the NBDA works with all stakeholders to assemble and/or create the enabling standards (guidelines, best practices, SOPs) needed to support clinically relevant and robust biomarker development.

Mission: Collaboratively creating the NBDA Standards* required for end-to-end, evidence – based biomarker development to advance precision (personalized) medicine.
NBDA Standards include but are not limited to: “official existing standards”, guidelines, principles, standard operating procedures (SOP), and best practices.

https://vimeo.com/83266065

 

“The NBDA’s vision is not to just relegate the current biomarker development processes to history, but also to serve as a working example of what convergence of purpose, scientific knowledge and collaboration can accomplish.”

NBDA Workshop VII – “COLLABORATIVELY BUILDING A FOUNDATION FOR FDA BIOMARKER QUALIFICATION”
NBDA Workshop VII   December 14-15, 2015   Washington Court Hotel, Washington, DC

The upcoming meeting was preceded by an NBDA workshop held on December 1-2, 2014, “The Promising but Elusive Surrogate Endpoint:  What Will It Take?” where we explored in-depth with FDA leadership and experts in the field the current status and future vison for achieving success in surrogate endpoint development.  Through panels and workgroups, the attendees extended their efforts to pursue the FDA’s biomarker qualification pathway through the creation of sequential contexts of use models to support qualification of drug development tools – and ultimately surrogate endpoints.

Although the biomarker (drug development tools) qualification pathway (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentTools…) represents an opportunity to increase the value of predictive biomarkers, animal models, and clinical outcomes across the drug (and biologics) development continuum, there are myriad challenges.  In that regard, the lack of evidentiary standards to support contexts of use-specific biomarkers emerged from the prior NBDA workshop as the major barrier to achieving the promise of biomarker qualification.  It also became clear that overall, the communities do not understand the biomarker qualification process; nor do they fully appreciate that it is up to the stakeholders in the field (academia, non-profit foundations, pharmaceutical and biotechnology companies, and patient advocate organizations) to develop these evidentiary standards.

This NBDA workshop will feature a unique approach to address these problems.  Over the past two years, the NBDA has worked with experts in selected disease areas to develop specific case studies that feature a systematic approach to identifying the evidentiary standards needed for sequential contexts of use for specific biomarkers to drive biomarker qualification.   These constructs, and accompanying whitepapers are now the focus of collaborative discussions with FDA experts.

The upcoming meeting will feature in-depth panel discussions of 3-4 of these cases, including the case leader, additional technical contributors, and a number of FDA experts.  Each of the panels will analyze their respective case for strengths and weaknesses – including suggestions for making the biomarker qualification path for the specific biomarker more transparent and efficient. In addition, the discussions will highlight the problem of poor reproducibility of biomarker discovery results, and its impact on the qualification process.

 

Health Care in the Digital Age

Mobile, big data, the Internet of Things and social media are leading a revolution that is transforming opportunities in health care and research. Extraordinary advancements in mobile technology and connectivity have provided the foundation needed to dramatically change the way health care is practiced today and research is done tomorrow. While we are still in the early innings of using mobile technology in the delivery of health care, evidence supporting its potential to impact the delivery of better health care, lower costs and improve patient outcomes is apparent. Mobile technology for health care, or mHealth, can empower doctors to more effectively engage their patients and provide secure information on demand, anytime and anywhere. Patients demand safety, speed and security from their providers. What are the technologies that are allowing this transformation to take place?

 

https://youtu.be/WeXEa2cL3oA    Monday, April 27, 2015  Milken Institute

Moderator


Michael Milken, Chairman, Milken Institute

 

Speakers


Anna Barker, Fellow, FasterCures, a Center of the Milken Institute; Professor and Director, Transformative Healthcare Networks, and Co-Director, Complex Adaptive Systems Network, Arizona State University
Atul Butte, Director, Institute of Computational Health Sciences, University of California, San Francisco
John Chen, Executive Chairman and CEO, BlackBerry
Victor Dzau, President, Institute of Medicine, National Academy of Sciences; Chancellor Emeritus, Duke University
Patrick Soon-Shiong, Chairman and CEO, NantWorks, LLC

 

Mobile, big data, the Internet of Things and social media are leading a revolution that is transforming opportunities in health care and research. Extraordinary advancements in mobile technology and connectivity have provided the foundation needed to dramatically change the way health care is practiced today and research is done tomorrow. While we are still in the early innings of using mobile technology in the delivery of health care, evidence supporting its potential to impact the delivery of better health care, lower costs and improve patient outcomes is apparent. Mobile technology for health care, or mHealth, can empower doctors to more effectively engage their patients and provide secure information on demand, anytime and anywhere. Patients demand safety, speed and security from their providers. What are the technologies that are allowing this transformation to take place?

 

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Protein Energy Malnutrition and Early Child Development

Curator: Larry H. Bernstein, MD, FCAP

 

 

In the preceding articles we have seen that poverty and low social class combined with cultural strictures or dependence on a sulfur-poor diet results in childhood stunting and impaired brain development. This is a global health issue.

Protein-Energy Malnutrition

  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Romesh Khardori, MD, PhD, FACP

http://emedicine.medscape.com/article/1104623-overview

The World Health Organization (WHO)[1] defines malnutrition as “the cellular imbalance between the supply of nutrients and energy and the body’s demand for them to ensure growth, maintenance, and specific functions.” The term protein-energy malnutrition (PEM) applies to a group of related disorders that includemarasmus, kwashiorkor (see the images below), and intermediate states of marasmus-kwashiorkor. The term marasmus is derived from the Greek wordmarasmos, which means withering or wasting. Marasmus involves inadequate intake of protein and calories and is characterized by emaciation. The term kwashiorkor is taken from the Ga language of Ghana and means “the sickness of the weaning.” Williams first used the term in 1933, and it refers to an inadequate protein intake with reasonable caloric (energy) intake. Edema is characteristic of kwashiorkor but is absent in marasmus.

Studies suggest that marasmus represents an adaptive response to starvation, whereas kwashiorkor represents a maladaptive response to starvation. Children may present with a mixed picture of marasmus and kwashiorkor, and children may present with milder forms of malnutrition. For this reason, Jelliffe suggested the term protein-calorie (energy) malnutrition to include both entities.
Although protein-energy malnutrition affects virtually every organ system, this article primarily focuses on its cutaneous manifestations. Patients with protein-energy malnutrition may also have deficiencies of vitamins, essential fatty acids, and trace elements, all of which may contribute to their dermatosis.

In general, marasmus is an insufficient energy intake to match the body’s requirements. As a result, the body draws on its own stores, resulting in emaciation. In kwashiorkor, adequate carbohydrate consumption and decreased protein intake lead to decreased synthesis of visceral proteins. The resulting hypoalbuminemia contributes to extravascular fluid accumulation. Impaired synthesis of B-lipoprotein produces a fatty liver.

Protein-energy malnutrition also involves an inadequate intake of many essential nutrients. Low serum levels of zinc have been implicated as the cause of skin ulceration in many patients. In a 1979 study of 42 children with marasmus, investigators found that only those children with low serum levels of zinc developed skin ulceration. Serum levels of zinc correlated closely with the presence of edema, stunting of growth, and severe wasting. The classic “mosaic skin” and “flaky paint” dermatosis of kwashiorkor bears considerable resemblance to the skin changes of acrodermatitis enteropathica, the dermatosis of zinc deficiency.

In 2007, Lin et al[2] stated that “a prospective assessment of food and nutrient intake in a population of Malawian children at risk for kwashiorkor” found “no association between the development of kwashiorkor and the consumption of any food or nutrient.”

Marasmus and kwashiorkor can both be associated with impaired glucose clearance that relates to dysfunction of pancreatic beta-cells.[3] In utero, plastic mechanisms appear to operate, adjusting metabolic physiology and adapting postnatal undernutrition and malnutrition to define whether marasmus and kwashiorkor will develop.[4]

In 2012, a report from Texas noted an 18-month-old infant with type 1 glutaric acidemia who had extensive desquamative plaques, generalized nonpitting edema, and red-tinged sparse hair, with low levels of zinc, alkaline phosphatase, albumin, and iron. This patient has a variation on kwashiorkor, and the authors suggest that it be termed acrodermatitis dysmetabolica.[5] On the same note, a boy aged 18 months with type 1 glutaric acidemia suffered from zinc deficiency and acquired protein energy malnutrition.[6]

For complex reasons, sickle cell anemia can predispose suffers to protein malnutrition.[7]

Protein energy malnutrition ramps up arginase activity in macrophages and monocytes.[8]

Protein energy malnutrition (PEM), brain and various facets of child development.

Protein energy malnutrition (PEM) is a global problem. Nearly 150 million children under 5 years in the world and 70-80 million in India suffer from PEM, nearly 20 million in the world and 4 million in India suffer from severe forms of PEM, viz., marasmus, kwashiorkor and marasmic kwashiorkor. The studies in experimental animals in the west and children in developing countries have revealed the adverse effects of PEM on the biochemistry of developing brain which leads to tissue damage and tissue contents, growth arrest, developmental differentiation, myelination, reduction of synapses, synaptic transmitters and overall development of dendritic activity. Many of these adverse effects have been described in children in clinical data, biochemical studies, reduction in brain size, histology of the spinal cord, quantitative studies and electron microscopy of sural nerve, neuro -CT scan, magnetic resonance imaging (MRI) and morphological changes in the cerebellar cells. Longer the PEM, younger the child, poorer the maternal health and literacy, more adverse are the effects of PEM on the nervous system. Just like the importance of nutrients on the developing brain, so are the adverse effects on the child development of lack of environmental stimulation, emotional support and love and affection to the child. When both the adverse factors are combined, the impact is severe. Hence prevention of PEM in pregnant and lactating mothers, breast feeding, adequate home based supplements, family support and love will improve the physical growth, mental development, social competence and academic performance of the child. Hence nutritional rehabilitation, psychosocial and psychomotor development of the child should begin in infancy and continue throughout. It should be at all levels, most important being in family, school, community and various intervention programmes, local, regional and national. Moreover medical students, health personnel, all medical disciplines concerned with total health care and school teachers should learn and concentrate on the developmental stimulation and enrichment of the child.

Cognitive development in children with chronic protein energy malnutrition

Behav Brain Funct. 2008; 4: 31.  http://dx.doi.org:/10.1186/1744-9081-4-31 
Background: Malnutrition is associated with both structural and functional pathology of the brain. A wide range of cognitive deficits has been reported in malnourished children. Effect of chronic protein energy malnutrition (PEM) causing stunting and wasting in children could also affect the ongoing development of higher cognitive processes during childhood (>5 years of age). The present study examined the effect of stunted growth on the rate of development of cognitive processes using neuropsychological measures.
Methods: Twenty children identified as malnourished and twenty as adequately nourished in the age groups of 5–7 years and 8–10 years were examined. NIMHANS neuropsychological battery for children sensitive to the effects of brain dysfunction and age related improvement was employed. The battery consisted of tests of motor speed, attention, visuospatial ability, executive functions, comprehension and learning and memory
Results: Development of cognitive processes appeared to be governed by both age and nutritional status. Malnourished children performed poor on tests of attention, working memory, learning and memory and visuospatial ability except on the test of motor speed and coordination. Age related improvement was not observed on tests of design fluency, working memory, visual construction, learning and memory in malnourished children. However, age related improvement was observed on tests of attention, visual perception, and verbal comprehension in malnourished children even though the performance was deficient as compared to the performance level of adequately nourished children.
Conclusion: Chronic protein energy malnutrition (stunting) affects the ongoing development of higher cognitive processes during childhood years rather than merely showing a generalized cognitive impairment. Stunting could result in slowing in the age related improvement in certain and not all higher order cognitive processes and may also result in long lasting cognitive impairments.
Malnutrition is the consequence of a combination of inadequate intake of protein, carbohydrates, micronutrients and frequent infections [1]. In India malnutrition is rampant. WHO report states that for the years 1990–1997 52% of Indian children less than 5 years of age suffer from severe to moderate under nutrition [2]. About 35% of preschool children in sub-Saharan Africa are reported to be stunted [3]. Malnutrition is associated with both structural and functional pathology of the brain. Structurally malnutrition results in tissue damage, growth retardation, disorderly differentiation, reduction in synapses and synaptic neurotransmitters, delayed myelination and reduced overall development of dendritic arborization of the developing brain. There are deviations in the temporal sequences of brain maturation, which in turn disturb the formation of neuronal circuits [1]. Long term alterations in brain function have been reported which could be related to long lasting cognitive impairments associated with malnutrition [4]. A wide range of cognitive deficits has been observed in malnourished children in India. In a study, malnourished children were assessed on the Gessell’s developmental schedule from 4 to 52 weeks of age. Children with grades II and III malnutrition had poor development in all areas of behaviour i.e., motor, adaptive, language and personal social [5]. Rural children studying in primary school between the ages of 6–8 years were assessed on measures of social maturity (Vineland social maturity scale), visuomotor co-ordination (Bender gestalt test), and memory (free recall of words, pictures and objects). Malnutrition was associated with deficits of social competence, visuomotor coordination and memory. Malnutrition had a greater effect on the immediate memory of boys as compared with those of girls. Malnourished boys had greater impairment of immediate memory for words, pictures and objects, while malnourished girls had greater impairment of immediate memory for only pictures. Delayed recall of words and pictures of malnourished boys was impaired. Malnourished girls had an impairment of delayed recall of only words. The same authors measured the intelligence of malnourished children using Malin’s Indian adaptation of the Wechsler’s intelligence scale for children. IQ scores decreased with the severity of malnutrition. Significant decreases were observed in performance IQ, as well as on the subtests of information and digit span among the verbal subtests [6]. The above study has shown that though there is decrease in full scale IQ, yet performance on all the subtests was not affected. This suggests that malnutrition may affect different neuropsychological functions to different degrees. Studies done in Africa and South America have focused on the effect of stunted growth on cognitive abilities using verbal intelligence tests based on assessment of reasoning [7]. Such an assessment does not provide a comprehensive and specific assessment of cognitive processes like attention, memory, executive functions, visuo-spatial functions, comprehension as conducted in the present study. Information about the functional status of specific cognitive processes has implications for developing a cognitive rehabilitation program for malnourished children. A neuropsychological assessment would throw light on functional status of brain behaviour relationships affected by malnutrition. Deficits of cognitive, emotional and behavioural functioning are linked to structural abnormalities of different regions of the brain. Brain structures and brain circuits compute different components of cognitive processes [8]. Malnutrition has long lasting effects in the realm of cognition and behaviour, although the cognitive processes like executive functions have not been fully assessed [9]. The differential nature of cognitive deficits associated with malnutrition suggests that different areas of the brain are compromised to different degrees. A neuropsychological assessment would be able to delineate the pattern of brain dysfunction. Malnutrition is a grave problem in our country as 52% of our children are malnourished. Effects of protein-calorie malnutrition are inextricably blended with the effects of social cultural disadvantage; even within the disadvantaged class, literacy environment at home and parental expectation regarding children’s education are powerful variables. Perhaps membership in a higher caste confers some advantage in regard to home literacy, and parental expectation. Short and tall children do differ in some cognitive tests, but not in all as demonstrated in a study done in Orissa, India [10]. But whether or not stunted growth alone is the causative variable for cognitive weakness is not determined as yet. Moreover, the functional integrity of specific cognitive processes is less clear. Chronic PEM resulting in stunting and wasting could result in delay in the development of cognitive processes or in permanent cognitive impairments. Neuropsychological measures can demonstrate delay in normally developing cognitive processes as well as permanent cognitive deficits.
Children in the age range of 5–10 years attending a corporation school in the city of Bangalore participated in the study. Corporation schools in India are government schools with minimal fee attended by children from lowmiddle class. There were 20 children in adequately nourished group and 20 in the malnourished group. The gender distribution was equal. Children in both the groups were from the same ethnic/language background. They were natives of Karnataka living in Bangalore.
After identifying the malnourished and adequately nourished children the coloured progressive matrices test [12] was administered to rule out mental retardation. Children falling at or below the fifth percentile were excluded from the sample, as the 5th percentile is suggestive of intellectually defective range. The percentile points were calculated from the raw scores using Indian norms [13]. Mental retardation was ruled out as otherwise scores on neuropsychological tests would be uniformly depressed and a differentiation of deficits might not occur. Intelligence was not treated as a covariate in the study. The groups did not differ significantly in their scores on CPM (a screening instrument to rule out intellectual impairment in both the groups).
Table 1: Demographic details of the participants
                            Adequately nourished N = 20                  Malnourished N = 20
Mean age              5–7 years        8–10 years                     5–7 years      8–10 years
                               5.8 years        8.8 years                          6.3 years      9.3 years
Gender                   Girls:10           Boys: 10                          Girls:10         Boys: 10
Stunted %
(height for age -2 SD from the median) —-                                  70%
Stunted and wasted %
(height for age and
weight for height: -2 SD from the median) —-                               30%
Exclusion of behaviour problems and history of neurological disorders The children’s behaviour questionnaire form B [14] was administered to the class teachers of the identified children. Children who scored above the cut off score of 9 were not included in the sample. The personal data sheet was filled in consultation with the parents and teachers to rule out any history of any neurological/psychiatric disorders including head injury and epilepsy and one child with epilepsy was excluded. This was one of the exclusion criteria.
Exclusion of behaviour problems and history of neurological disorders The children’s behaviour questionnaire form B [14] was administered to the class teachers of the identified children. Children who scored above the cut off score of 9 were not included in the sample. The personal data sheet was filled in consultation with the parents and teachers to rule out any history of any neurological/psychiatric disorders including head injury and epilepsy and one child with epilepsy was excluded. This was one of the exclusion criteria.
The tests have been grouped under specific cognitive domains on the basis of theoretical rationale and factor analysis. Factor analysis has been done for the battery and the grouping of tests under cognitive functions like executive functions, visuospatial functions, comprehension and learning and memory was done on the basis of the clustering observed in factor analysis as well as on theoretical grounds
The neuropsychological battery consisted of the following tests:
1. Motor speed  Finger tapping test [15]
2. Expressive speech  Expressive speech test was administered to rule out speech related deficits
3. Attention  Color trails test [18] is a measure of focused attention and conceptual tracking.
4. Color cancellation test [21] is a measure of visual scanning/selective attention
5. Executive functions FAS phonemic fluency test is a measure of verbal fluency.
6. Design fluency test [24] is a measure of design fluency, cognitive flexibility and imaginative capacity.
7. Visuo-spatial working memory span task [23]: This test is a measure of visuo-spatial working memory (VSWM) span.
8. Visuospatial functions Motor-free visual perception test [29] is a measure of visuoperceptual ability, having 36 items for visual discrimination, visual closure, figure-ground, perceptual matching and visual memory. Since this test has been originally developed for children between 5–8 years of age, it was modified and items in increasing difficulty level were added by the authors to make it applicable for the children above 8 years. Number of correct responses comprises the score.
9. Picture completion test [30] is a measure of visuoconceptual ability, visual organization and visuo-conceptual reasoning.
10. Block design test [30] is a measure of visuoconstructive ability.
11. Comprehension, learning and memory Token test [31] is a measure of verbal comprehension of commands of increasing complexity.
12. Rey’s auditory verbal learning test (RAVLT) [32] is a measure of verbal learning and memory.
13. Memory for designs test [34] is a measure of visual learning and memory.
Comparison between the performance of adequately nourished children and malnourished children Table 2.0 shows that malnourished group differed significantly from the adequately nourished group on tests of phonemic fluency, design fluency, selective attention, visuospatial working memory, visuospatial functions, verbal comprehension and verbal learning and memory showing poor performance. The two groups did not differ on the test of finger tapping. Since expressive speech was a question answer type assessment looking at repetitive speech, nominative speech and narrative speech, which is like an initial screening for aphasia, like symptoms. Since it did not give a quantitative score, hence was not taken for analysis. As a descriptive account of expressive speech it was observed that malnourished children did not have any difficulty with respect to expressive speech.
Comparison of age related differences in cognitive functions between adequately nourished and malnourished children Data was further subjected to post hoc analysis to compare the two groups across the two age groups to study the rate of improvement with age (Table 2). In both the age groups of 5–7 years and 8–10 years the adequately nourished children performed better than the malnourished children. Figures 1, 2, 3, 4, 5, 6 indicate age related improvement in performance across different cognitive functions in adequately nourished children as compared to malnourished children. Motor speed and coordination was not significantly affected in malnourished children as compared to the adequately nourished children (figure 1). The rate of age related improvement across the two age groups was found rapid on certain functions like selective attention (figure 2) and verbal fluency (figure 3) in malnourished children. However, working memory, design fluency, visuospatial functions, comprehension, learning, and memory showed slowing in terms of age related improvement in malnourished children. Most of the cognitive functions like design fluency (figure 3), working memory (figure 3), Visual perception (figure 4), visuoconceptual reasoning (figure 4), visual construction (figure 4), verbal comprehension (figure 5), verbal and visual memory (figures 6) have shown a very slow rate of improvement with respect to the difference in performance between the two age groups of 5–7 and 8–10 years. On the contrary functions like verbal fluency (figure 3), motor speed (figures 1), and selective attention (figure 2) showed similar rates of improvement in adequately nourished children and malnourished children while comparing the two age groups.
Table 2: Mean comparisons for the cognitive functions across the two age groups of adequately nourished and malnourished children (not shown)
Table 3: Post-hoc comparisons between adequately nourished and malnourished groups across the two age groups (not shown)
Figure 1 Age related comparisons between adequately nourished and malnourished children on motor speed (right and left hand) Age related comparisons between adequately nourished and malnourished children on motor speed (right and left hand). (not shown)
Figure 2 Age related comparisons between adequately nourished and malnourished children on selective attention (color cancellation test). (not shown)
Post-hoc comparisons were computed with Tukey’s posthoc tests to compare the means across age groups between malnourished and adequately nourished children for those test scores that showed significant effects. Hence, post hoc tests were not computed for the finger tapping test scores assessing motor speed. Table 3 presents the post-hoc results with the significance (probability level) levels of the differences across age groups and between adequately nourished and malnourished children. Post hoc results have been done to support our theoretical claims about the lack of age related improvement in certain cognitive functions on one hand and the nature of cognitive impairments on the other in malnourished children. Four comparisons were interpreted i.e., comparing performance between the two age groups of adequately nourished and malnourished children separately. The other comparison was between the adequately nourished and malnourished children for the age group of 5–7 years and similarly for the age group of 8–10 years. Results indicate age related differences within each group as well as between the two groups. Age related differences were found significant for some of the test scores between 5–7 and 8–10 year old children in the adequately nourished group but not for most of the test scores for malnourished group indicative of a delay in development of certain cognitive functions. Differences were found significant between the adequately nourished and malnourished children for the same age group for most of the test scores indicative of a deficit in a particular cognitive function. In few of the tests, performance was not found to be significantly different between the two age groups for both adequately nourished and malnourished children.
Discussion The findings of the present study could be discussed in terms of the effect of chronic malnutrition on neuropsychological performance and with respect to the rate of development of cognitive processes.
Effect of malnutrition on neuropsychological performance Our study indicates that malnourished children perform poor on most of the neuropsychological tests except that of motor speed as compared to adequately nourished children. Malnourished children showed poor performance on tests of higher cognitive functions like cognitive flexibility, attention, working memory, visual perception, verbal comprehension, and memory. These findings are supported by another study on Indian malnourished children, which reported memory impairments in undernourished children and spared fine motor coordination [36]. Malnourished children showed poor performance on novel tasks like tests of executive functions i.e., working memory spatial locations. Poor performance on the tests of fluency and working memory also coincides with very slow rate of improvement between the age groups of 5–7 years and 8–10 years. Poor performance on most of the neuropsychological tests indicated a diffuse impairment including attention, executive functions, visuospatial functions, comprehension and memory.
Effect of malnutrition on cognitive development Both the groups were tested on a neuropsychological battery, which has been found to be sensitive to age related differences in cognitive functions in children (5–15 years). The age trends reported in the present study are based on the assessment that employed the NIMHANS neuropsychological battery for children [13]. The test battery has been standardized based on the growth curve modeling approach for empirical validation of age-related differences in performance on neuropsychological tests. The tests in the battery were found sensitive to show age related differences.
Malnourished children showed poor performance with respect to age as compared to adequately nourished children. The performance of malnourished children in the 5–7 years age group was poor and much lower than the adequately nourished children and did not seem to show much improvement in the 8–10 years age group. The rate of cognitive development was found to be different for different cognitive functions. The rate of development was affected for some of the cognitive functions showing minimal age related improvement across the age range of 5–7 years and 8–10 years such as design fluency, working memory, visual construction, verbal comprehension, learning and memory for verbal and visual material. On the contrary, age related improvement was observed on certain other cognitive functions in malnourished children, where the level of performance was low for both the age groups but the rate of improvement between the two age groups was similar to adequately nourished children.
Not shown
Figure 3 Age related comparisons between adequately nourished and malnourished children on executive functions.
Note: VF: verbal fluency; DF: design fluency; WM: working memory; AN: adequately nourished; MN: malnourished.

MN 5–7 vs 8–10 p > .05 5–7 years AN vs MN p > .05 8–10 years AN vs MN p < .05 Visual memory (memory for designs test) AN 5–7 vs 8–10 p > .05 MN 5–7 vs 8–10 p > .05 5–7 years AN vs MN p < .05 8–10 years AN vs MN p < .05

Figure 4 Age related comparisons between adequately nourished and malnourished children on visuospatial functions.
Figure 5 Age related comparisons between adequately nourished and malnourished children on verbal comprehension and verbal learning.
Motor speed (right and left hand) was not found impaired in malnourished children and the rate of development was also found similar to adequately nourished children.
Executive functions such as design fluency, selective attention and working memory were found deficient in malnourished children also showing poor rate of improvement between the two age groups. All the three tests of executive functions like fluency, selective attention and working memory for spatial locations involved novel stimuli and performance required cognitive flexibility as well as faster information processing which was affected in malnourished children. Results also indicate that malnourished children showed a very slow rate of improvement on these functions.
Visuo-spatial functions like visual perception, visual construction and visuo-conceptual reasoning showed significantly poor performance when compared to the adequately nourished children but showed a steep age related improvement in performance. Performance on functions like visual perception (visual discrimination, perceptual matching, visual closure and visuospatial relationships) and visual construction was severely affected in malnourished children and also showed poor rate of improvement with age.
Verbal comprehension, learning and memory for verbal and visual material was found poor as compared to adequately nourished children but the rate of improvement between 5–7 years age group and 8–10 years age group was similar to that of adequately nourished children. These results suggest that development of comprehension with age might not be affected in malnourished children. However, other than the poor performance on the AVLT test of verbal learning, malnourished children also showed minimal improvement between the two age groups as compared to the greater magnitude of difference between the two age groups in adequately nourished children. Visual memory was most severely affected in malnourished children in terms of the poor performance on delayed recall on design learning test as well as in terms of the difference between the two age groups.
Malnutrition affects brain growth and development and hence future behavioral outcomes [37]. School-age children who suffered from early childhood malnutrition have generally been found to have poorer IQ levels, cognitive function, school achievement and greater behavioral problems than matched controls and, to a lesser extent, siblings. The disadvantages last at least until adolescence. There is no consistent evidence of a specific cognitive deficit [38]. The functional integrity of specific cognitive processes is less clear. Stunting in early childhood is common in developing countries and is associated with poorer cognition and school achievement in later childhood [39]. Deficits in children’s scores have been reported to be smaller at age 11 years than at age 8 years in a longitudinal study on malnourished children stunted children suggesting that adverse effects may decline over time [7]. In our study also all the children in malnourished group were stunted and the cross sectional assessment of age related improvement has shown similar rate of improvement across 5–7 years to 8–10 years age groups as observed in adequately nourished children though the baseline performance was low in malnourished children. These results indicate that the adverse effects of malnutrition (stunting in particular) may decline with age only for certain cognitive functions but the rate of cognitive development for most of the cognitive processes particularly higher cognitive processes including executive processes and visuospatial perception could be severely affected during the childhood years. Decline in the effects of malnutrition overtime has been reported to be independent of differences in educational, socioeconomic and psychosocial resources [7]. Hence, malnutrition (particularly stunting) may result in delayed development of cognitive processes during childhood years rather than a permanent generalized cognitive impairment.
The neuropsychological interpretation of the cognitive processes more severely affected in malnourished children suggests a diffuse cortical involvement. This is with reference to deficits pertaining to functions mediated by dorsolateral prefrontal cortex (poor performance on tests of attention, fluency and working memory), right parietal (poor performance on tests of visuospatial functions) and bilateral temporal cortex (poor performance on tests of comprehension, verbal learning, and memory for verbal and visual material). The prefrontal cortex may be particularly vulnerable to malnutrition [4]. The adverse effects of malnutrition (PEM-stunting) on cognitive development could be related to the delay in certain processes of structural and functional maturation like delayed myelination and reduced overall development of dendritic arborization of the developing brain [1].
The present study highlights two ways in which malnutrition particularly stunting could affect cognitive functions. On one hand age related improvement in cognitive performance is compromised and on the other hand there could be long lasting cognitive impairments as well. However, the effect is nor specific to a particular cognitive domain and is rather more diffuse. Results of the study also indicate that: certain cognitive functions could be vulnerable to the effect of malnutrition in terms of showing impairment but the rate of development of these functions may not be affected. On the other hand, rate of development of certain cognitive functions may be affected and may also show impairment when compared with adequately nourished children.
Conclusion Chronic protein energy malnutrition (stunting) results in cognitive impairments as well as slowing in the rate of the development of cognitive processes. Rate of development of cognitive functions may follow different patterns in children with malnutrition. Chronic protein energy malnutrition affects the development of cognitive processes differently during childhood years rather than merely showing an overall cognitive dysfunction as compared to adequately nourished children. Stunting could result in delay in the development of cognitive functions as well as in permanent cognitive impairments which show minimal improvement with increase in age. Rate of development of attention, executive functions like cognitive flexibility, working memory, visuospatial functions like visual construction is more severely affected by protein energy malnutrition in childhood years, a period that is marked by rapid ongoing development of cognitive functions.
The effects of protein energy malnutrition in early childhood on intellectual and motor abilities in later childhood and adolescence.
Dev Med Child Neurol. 1976 Jun;18(3):330-50.

Three groups of Ugandan children (20 in each group) and one comparison group of 20 children were examined between 11 and 17 years of age. The first three groups had been admitted to hospital for treatment of protein energy malnutrition between the ages of eight to 15, 16 to 21 and 22 to 27 months, respectively. The comparison group had not been clinically malnourished throughout the whole period up to 27 months of age. All the children came from one tribe and were individually matched for sex, age, education and home environment. It was found that the three malnourished groups fell significantly below the comparison group in anthropometric measurements and in tests of intellectual and motor abilities. No evidence was found for a relationship between the deficit and age at admission. Further analysis among the 60 malnourished children revealed that anthropometry and intellectual and motor abilities are the more affected the greater the degree of ‘chronic undernutrition’ at admission, but no correlation was found with the severity of the ‘acute malnutrition’. The results show a general impairment of intellectual abilities, with reasoning and spatial abilities most affected, memory and rote learning intermediately and language ability least, if at all, affected. These findings are discussed in the context of a comprehensive and critical appraisal of the existing literature.

Quake-Hit Nepal Gears up to Tackle Stunting in Children

By Gopal Sharma  July 08, 2015  http://www.medscape.com/viewarticle/847572

HECHO, Nepal (Thomson Reuters Foundation) – Shanti Maharjan, who gave birth to a baby girl 10 days ago, has spent the last two months living under corrugated iron sheets with her husband and five others after two major earthquakes reduced her mud-and-brick home to rubble.

Adequate food, drinking water and aid such as tents and blankets have been hard to come by, she says, though scores of aid agencies rushed to the Himalayan nation to help survivors.
What worries the 26-year-old mother most is her inability to produce breastmilk for her new-born daughter, who she fears is at serious risk of malnutrition in the aftermath of the 7.8 and 7.3 magnitude quakes in April and May.

“The earthquake destroyed everything, including our food reserves,” said Maharjan, sitting under the iron sheeting on farmland on the outskirts of the capital, Kathmandu.

“There is not enough food. Getting meat, oil and fruits to eat is difficult in this situation. I am worried about my daughter’s nourishment,” she said as the baby, wrapped in a green cloth, lay sleeping on a wooden bed.

The government, aware that disruption caused by the quakes could worsen the country’s already high rate of child malnutrition is sending out teams of community nurses to give advice and food supplements to women and children in the affected areas.

A 2011 government study showed that more than 40% of Napel’s under-five-year-olds were stunted, showing that the country’s child malnutrition rate was one of the world’s highest.
Experts say the two quakes, which killed 8,895 people and destroyed half a million houses, could make things worse as survivors have inadequate food, water, shelter, healthcare and sanitation.

United Nations officials warn that the rate of stunting among children in the South Asian nation could return to the 2001 level of 57%, if authorities and aid agencies do not respond effectively.

“The risk of malnutrition is high and requires the nutrition and other sectors like agriculture, health, water, sanitation, education and social protection to respond adequately,” said Stanley Chitekwe, UNICEF’s nutrition chief in Nepal.

DRIVE TO NOURISH

Child malnutrition is an underlying cause of death for 3 million children annually around the world – nearly half of all child deaths – most of whom die from preventable illnesses such as diarrhoea due to weak immune systems.

Those lucky enough to survive grow up without enough energy, protein, vitamins and minerals, causing their brains and bodies to be stunted, and they are often unable to fulfill their potential.

Government officials admit the challenges, citing data showing that almost 70% of Nepali children under the age of two suffer from anaemia caused by iron deficiency.

“This shows that (poor) nutrition is a very big problem. The earthquake will further worsen the situation because people simply don’t have enough to eat, let alone have a nutritious diet,” said Health Ministry official Krishna Prasad Paudel.

Supported by UNICEF, authorities have now launched a drive to reach out to more than 500,000 women and children who need supplementary food and medicines.

More than 10,000 female community volunteers will be fanning out across 14 districts affected by the earthquakes, visiting devastated towns and villages and speaking to new and expectant mothers about breast-feeding their infants.

The volunteers will also advise families on eating locally available nutritious foods such as green vegetables and meat and will distribute vitamin A, iron and folic acid, and other micronutrient supplements to pregnant and breastfeeding women.

In Imadole, a prosperous district on the outskirts of the ancient town of Patan, health volunteer Urmila Sharma Dahal found an extremely thin two-year-old boy weighing 7.5 kg (16.5 pounds) last week, suffering from severe acute malnutrition.

Dahal said she provided his family with sachets of ready-to-use therapeutic food – a paste of peanut, sugar, milk powder, vitamin and oil – and the child gained nearly a kilo (2.2 pounds) in weight in just seven days.

“It does not take much. It can be done with small but right interventions,” said Dahal as she sat next to the child in the family’s brick-and-cement home.

Protein-energy malnutrition occurs due to inadequate intake of food and is a major cause of morbidity and mortality in children in developing countries (Grover and Ee 2009).

http://www.wcs-heal.org/global-challenges/public-health-issues-and-costs/malnutrition/protein-energy-malnutrition

http://www.wcs-heal.org/uploads/images/Chris_Golden-malnourished_children_692x513_scaled_cropp.jpg

Protein energy malnutrition (PEM) has significant negative impacts on children’s growth and development (Grover and Ee 2009). Chronic PEM causes children to have stunted growth (low height for age) and to be underweight (low weight for age); it is estimated that among children under age five, one in every four is stunted and one in every six is underweight. PEM also causes two specific conditions in children: marasmus, which is characterized by an emaciated appearance, and kwashiorkor, in which children develop swollen bellies due to edema (abnormal accumulation of fluid) and discoloration of the hair because of pigment loss among other symptoms (UNWFP 2013b, Ahmed et al. 2012). Countries in sub-Saharan Africa and south Asia have the highest proportions of children suffering from PEM (UNWFP 2013a).

PEM causes direct mortality in children and also increases vulnerability to other serious diseases including diarrhea, pneumonia, and malaria. Children suffering from PEM have compromised immune systems, making them particularly susceptible to infectious diseases.  Furthermore, PEM has negative impacts on children’s brain development, resulting in issues with memory and delayed motor function; these children have decreased ability to learn and have lower productivity as adults. PEM also has serious and potentially long-term impacts on other organ systems including the cardiovascular, respiratory, and gastrointestinal systems (Grover and Ee 2009).

Many adults in developing countries also suffer from PEM, with women disproportionately impacted compared with men, particularly in south Asian countries (UNWFP 2013a). Pregnant women who are undernourished can fall even further behind in their nutritional status due to the increased demand for nutrients by the developing fetus. Women who don’t gain sufficient weight during pregnancy are at increased risk for complications including maternal morbidity and mortality, low birth weight, and neonatal mortality. These women can also have difficulty providing sufficient quantities of breast milk, leading to malnutrition among neonates (Ahmed et al. 2012).

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The good, the bad and the ugly of sulfur and volcanic activity

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

Climate change deniers have promulgated much ignorance about the planet and our life on earth.  Nevertheless, I shall deal with geophysical and geochemical issues and indirectly, climate change in this portion of the discussion.  The good, the bad, and the ugly has everything to due with the elements and to life on earth.  This is the case, regardless of claims propagated by the tobacco and the carbon fuels interests.  I shall proceed as I have done in the previous discussions.

Is a Lack of Water to Blame for the Conflict in Syria?

A 2006 drought pushed Syrian farmers to migrate to urban centers, setting the stage for massive uprisings

By Joshua Hammer

SMITHSONIAN MAGAZINE

http://www.smithsonianmag.com/innovation/is-a-lack-of-water-to-blame-for-the-conflict-in-syria-72513729

 

An Iraqi girl stands on former marshland, drained in the 1990s because of politically motivated water policies. (Essam Al-Sudani / AFP / Getty Images)
http://thumbs.media.smithsonianmag.com//filer/Scare-Tactics-Iraqi-girl-631.jpg__800x600_q85_crop.jpg

The world’s earliest documented water war happened 4,500 years ago, when the armies of Lagash and Umma, city-states near the junction of the Tigris and Euphrates rivers, battled with spears and chariots after Umma’s king drained an irrigation canal leading from the Tigris. “Enannatum, ruler of Lagash, went into battle,” reads an account carved into an ancient stone cylinder, and “left behind 60 soldiers [dead] on the bank of the canal.”

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Water loss documented by the Gravity Recovery and Climate Experiment (GRACE), a pair of satellites operated by NASA and Germany’s aerospace center, suggests water-related conflict could be brewing on the riverbank again. GRACE measured groundwater usage between 2003 and 2009 and found that the Tigris-Euphrates Basin—comprising Turkey, Syria, Iraq and western Iran—is losing water faster than any other place in the world except northern India . During those six years, 117 million acre-feet of stored freshwater vanished from the region as a result of dwindling rainfall and poor water management policies. That’s equal to all the water in the Dead Sea. GRACE’s director, Jay Famiglietti, a hydrologist at the University of California, Irvine, calls the data “alarming.”

While the scientists captured dropping water levels, political experts have observed rising tensions. In Iraq, the absence of a strong government since 2003, drought and shrinking aquifers have led to a recent spate of assassinations of irrigation department officials and clashes between rural clans. Some experts say that these local feuds could escalate into full-scale armed conflicts .

In Syria, a devastating drought beginning in 2006 forced many farmers to abandon their fields and migrate to urban centers. There’s some evidence that the migration fueled the civil war there, in which 80,000 people have died. “You had a lot of angry, unemployed men helping to trigger a revolution,” says Aaron Wolf, a water management expert at Oregon State University, who frequently visits the Middle East.

Tensions between nations are also high. Since 1975, Turkey’s dam and hydro­power construction has cut water flow to Iraq by 80 percent and to Syria by 40 percent. Syria and Iraq have accused Turkey of hoarding water.

Hydrologists say that the countries need to find alternatives to sucking the aquifers dry—perhaps recycling wastewater or introducing desalination—and develop equitable ways of sharing their rivers. “Water doesn’t know political boundaries. People have to get together and work,” Famiglietti says. One example lies nearby, in an area not known for cross-border cooperation. Israeli and Jordanian officials met last year for the first time in two decades to discuss rehabilitating the nearly dry Jordan River, and Israel has agreed to release freshwater down the river.

“It could be a model” for the Tigris-Euphrates region, says Gidon Bromberg, a co-director of Friends of the Earth Middle East, who helped get the countries together. Wolf, too, remains optimistic, noting that stress can encourage compromise.

History might suggest a way: The world’s first international water treaty, a cuneiform tablet now hanging in the Louvre, ended the war between Lagash and Umma.

 

http://static.guim.co.uk/ni/1404220722088/Iraq_water_dams.svg

“Rebel forces are targeting water installations to cut off supplies to the largely Shia south of Iraq,” says Matthew Machowski, a Middle East security researcher at the UK houses of parliament and Queen Mary University of London.

“It is already being used as an instrument of war by all sides. One could claim that controlling water resources in Iraq is even more important than controlling the oil refineries, especially in summer. Control of the water supply is fundamentally important. Cut it off and you create great sanitation and health crises,” he said

Isis now controls the Samarra barrage west of Baghdad on the River Tigris and areas around the giant Mosul Dam, higher up on the same river. Because much of Kurdistan depends on the dam, it is strongly defended by Kurdish peshmerga forces and is unlikely to fall without a fierce fight, says Machowski.

Iraqi troops were rushed to defend the massive 8km-long Haditha Dam and its hydroelectrical works on the Euphrates to stop it falling into the hands of Isis forces. Were the dam to fall, say analysts, Isis would control much of Iraq’s electricity and the rebels might fatally tighten their grip on Baghdad.

Isis fighters in Fallujah captured the smaller Nuaimiyah Dam on the Euphrates and deliberately diverted its water to “drown” government forces in the surrounding area. Millions of people in the cities of Karbala, Najaf, Babylon and Nasiriyah had their water cut off but the town of Abu Ghraib was catastrophically flooded along with farms and villages over 200 square miles. According to the UN, around 12,000 families lost their homes.

Earlier, Kurdish forces reportedly diverted water supplies from the Mosul Dam. Equally, Turkey has been accused of reducing flows to the giant Lake Assad, Syria’s largest body of fresh water, to cut off supplies to Aleppo, and Isis forces have reportedly targeted water supplies in the refugee camps set up for internally displaced people.

Iraqis fled from Mosul after Isis cut off power and water and only returned when they were restored, says Machowski. “When they restored water supplies to Mosul, the Sunnis saw it as liberation. Control of water resources in the Mosul area is one reason why people returned,” said Machowski.

Both Isis forces and President Assad’s army are said to have used water tactics to control the city of Aleppo. The Tishrin Dam on the Euphrates, 60 miles east of the city, was captured by Isis in November 2012.

“The deliberate targeting of water supply networks … is now a daily occurrence in the conflict. The water pumping station in Al-Khafsah, Aleppo, stopped working on 10 May, cutting off water supply to half of the city.

https://i.guim.co.uk/img/static/sys-images/Guardian/Pix/pictures/2014/7/2/1404300629581/

A satellite view showing the two main rivers running from Turkey through Syria and Iraq. Credits: MODIS/NASA

The Euphrates River, the Middle East’s second longest river, and the Tigris, have historically been at the centre of conflict. In the 1980s, Saddam Hussein drained 90% of the vast Mesopotamian marshes that were fed by the two rivers to punish the Shias who rose up against his regime. Since 1975, Turkey’s dam and hydropower constructions on the two rivers have cut water flow to Iraq by 80% and to Syria by 40%. Both Syria and Iraq have accused Turkey of hoarding water and threatening their water supply.

http://www.irinnews.org/photo/

The Barada River, shown here in Damascus, is the only notable river flowing entirely within Syrian territory. The city’s water supplies are under huge strain

DAMASCUS, 25 March 2010 (IRIN) – Poor planning and management, wasteful irrigation systems, intensive wheat and cotton farming and a rapidly growing population are straining water resources in Syria in a year which has seen unprecedented internal displacement as a result of drought in eastern and northeastern parts of the country.

In 2007 Syria consumed 19.2 billion cubic metres of water – 3.5 billion more than the amount of water replenished naturally, with the deficit coming from groundwater and reservoirs, according to the Ministry of Irrigation.

Agriculture accounts for almost 90 percent of the country’s water consumption, according to government and private sector.

Agricultural policies encourage water-hungry wheat and cotton cultivation, and inefficient irrigation methods mean much water is wasted.

 

South Asia is a desperately water-insecure region, and India’s shortages are part of a wider continental crisis. According to a recent report authored by UN climate scientists, coastal areas in Asia will be among the worst affected by climate change. Hundreds of millions of people across East, Southeast and South Asia, the report concluded, will be affected by flooding, droughts, famine, increases in the costs of food and energy, and rising sea levels.

Groundwater serves as a vital buffer against the volatility of monsoon rains, and India’s falling water table therefore threatens catastrophe. 60 percent of north India’s irrigated agriculture is dependent on ground water, as is 85 percent of the region’s drinking water. The World Bank predicts that India only has 20 years before its aquifers will reach “critical condition” – when demand for water will outstrip supply – an eventuality that will devastate the region’s food security, economic growth and livelihoods.

Analysts fear that growing competition for rapidly dwindling natural resources will trigger inter-state or intra-state conflict. China and India continue to draw on water sources that supply the wider region, and a particularly concerning flashpoint is the Indus River Valley basin that spans India and Pakistan. The river’s waters are vital to the economies of areas on both sides of the border and a long-standing treaty, agreed by Pakistan and India in 1960, governs rights of access. But during the “dry season,” between October and March, water levels fall to less than half of those seen during the remainder of the year. The fear is that cooperation over access to the Indus River will fray as shortages become more desperate.

http://cdn1.pri.org/sites/default/files/styles/story_main/public/story/images/IMG_5937.jpeg

Farm worker heading for the paddy fields at Gubinder Singh’s farm

The Indo-Gangetic Basin, which lies at the foothills of the Himalayas, is one of the areas in the world facing a huge water crisis.  The Basin spans from Pakistan, across Northern India into Bangladesh. Apart from runoff from mountainous streams and glaciers, it also holds one of the largest underground bodies of water in the world. But it’s also in one of the most populous regions of the world, with more than a billion people living on the subcontinent.  Still, parts of the region are well-resourced when it comes to water supplies – like the Indian state of Punjab, which has three rivers running through it and a network of canals in some parts.

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NASA Satellites Unlock Secret to Northern India’s Vanishing Water

08.12.09

 

NASA Hydrologist Matt Rodell discusses vanishing groundwater in India. Credit:NASA
› Watch Video

http://www.nasa.gov/multimedia/nasatv/index.html

 

soil moisture belt

soil moisture belt

 

Groundwater resides beneath the soil surface in permeable rock, clay and sand as illustrated in this conceptual image. Many aquifers extend hundreds of feet underground and in some instances have filled with water over the course of thousands of years. Credit: NASA
http://www.nasa.gov/images/content/378067main_water_table%20illus_226.jpg

groundwater withdrawals as a percentage of groundwater recharge

groundwater withdrawals as a percentage of groundwater recharge

 

 

The map, showing groundwater withdrawals as a percentage of groundwater recharge, is based on state-level estimates of annual withdrawals and recharge reported by India’s Ministry of Water Resources. The three states included in this study are labeled. Credit:NASA/Matt Rodell

http://www.nasa.gov/images/content/378381main_MattRodell_vid_226.jpg

The averaging function (spatial weighting) used to estimate terrestrial water storage changes from GRACE data is mapped. Warmer colors indicate greater sensitivity to terrestrial water storage changes. Credit: NASA/Matt Rodell

http://www.nasa.gov/images/content/378067main_water_table%20illus_226.jpg

Beneath northern India’s irrigated fields of wheat, rice, and barley … beneath its densely populated cities of Jaiphur and New Delhi, the groundwater has been disappearing. Halfway around the world, hydrologists, including Matt Rodell of NASA, have been hunting for it.

Where is northern India’s underground water supply going? According to Rodell and colleagues, it is being pumped and consumed by human activities — principally to irrigate cropland — faster than the aquifers can be replenished by natural processes. They based their conclusions — published in the August 20 issue of Nature — on observations from NASA’s Gravity Recovery and Climate Experiment (GRACE).

“If measures are not taken to ensure sustainable groundwater usage, consequences for the 114 million residents of the region may include a collapse of agricultural output and severe shortages of potable water,” said Rodell, who is based at NASA’s Goddard Space Flight Center in Greenbelt, Md.

 

https://www.quora.com/Why-are-there-no-earthquakes-or-volcanos-in-the-Himalayas

The Himalayas are representative of a modern and active mountain-building event, called anorogeny in geologic parlance. Both the Himalayas and the Cascade Range are the result of plate-to-plate collision in the Theory of Plate Tectonics.
The difference between the Himalayas and the Cascade Range volcanoes is based on density of the lithospheric plates. Yes. The Cascade Range is caused by subduction of more dense ocean crust into and underneath lighter, lower density continental crust. As the oceanic plate dives deeper and deeper, the ocean crust warms, melts, and rises upward through the overriding continental crust “inland” from the plate collision boundary. As that molten rock punches through the continental crust, a curvilinear series of volcanoes, generally parallel to the plate collision boundary, begins to form.

Cascade Range Subduction

Cascade Range Subduction

 

Cascade Range Subduction from J. Wiley & Sons – 2010
In the case of the Cascade Range, the name of this type of volcanic formation is unique in process, as well as geochemistry, and has been referred to as an Andesitic-type after the Andes Mountains. Regardless, the Cascade Range is comprised of intermediate igneous rocks, with a fairly high silica content. High silica makes for high siliceous acid. That creates “sticky” igneous extrusions that often have quite dramatic eruptions [May 1980 Mt. St. Helens eruption].

 

Igneous Rock Classification

Igneous Rock Classification

Igneous Rock Classification Chart – Public Domain

The Himalayas are also a plate-to-plate collision tectonic boundary. In this case, the Indian Plate [of the Indian Subcontinent] is colliding head-on with the Eurasian Plate. Both plates are comprised of continental lithospheric crust, so there is no appreciable distinction in density. Both have a density of approximately 2.7 g/cm³. This as opposed to ocean crust with a mean density of 3.3 g/cm³. The plates try to compete in the plate-to-plate collision but the equal densities of the two plates cannot push one under the other very deep like that in a subduction zone.  The result is large-scale thickening of the continental crust in the region at and surrounding the collision boundary. Other processes occurring in the Himalayas region associated with the orogeny are metamorphism, thrust [compression] faulting, and plateau uplift.

Depiction of Himalayan Collision

Depiction of Himalayan Collision

Generalized Depiction of Himalayan Collision from FHSU – 2010
A perfect analogy is two trucks of the same make and model colliding head-on. The Himalayan Orogeny is the oft mentioned “crumple zone”. Metal does not deform in a brittle sense like competent rock does, so don’t confuse that too much.

With all that being said, there are tremendous temperatures attained at a continental plate-to-plate collision boundary. However, the crust is simply too thick, and too “squashed together” to allow anything to squeeze up and break through to the surface as volcanic eruptions.
References:

FHSU,  2010.  Image of Himalayan Collision.  Fort Hays State University.  Hays, Kansas.  2010.
Wiley & Sons, J.,  2010.  Image of Cascade Range Subduction Zone.  J. Wiley & Sons.  Hoboken, New Jersey.  2010.

 

Mt. Everest was formed (is forming) by two tectonic plates colliding–the Indo-Australian Plate and the Eurasian plate.

Sometimes, when two tectonic plates collide, volcanoes form (such as the Juan de Fuca plate and the North American Plate forming the Cascades). However, this has to do with one plate–in this case the Juan de Fuca Plate sliding or subducting beneath another–the North American Plate. This happens because the oceanic plate (the Juan de Fuca Plate) is more dense than than the continental plate (the NA Plate). For reasons I won’t get into here, magma forms between the two plates as one subducts beneath the other and volcanoes are formed.

Mt. Everest is formed by two continental plates colliding. Continental plates are generally too buoyant to subduct beneath each other. While some subduction occurred during this collision, most of what happened was crustal shortening. Think about what happens when you have a rug on a wood floor and push two ends toward each other. It buckles and folds up in itself. This is a simplified version of what happened in the Himalaya.

Because little to no subduction is occurring, no magma is forming and Mt. Everest will not become a volcano.

The Himalayas were created by two continental plates colliding. What happens when two masses of rocks with some similarities, like in density, collide? Both of them rise. There is a lot of heat produced. However, there isn’t enough heat to melt rocks completely. For there to be a volcano, there has to be a source of molten rock.

This material can occur if the two masses of rocks have vastly different densities. In this case, the heavier mass will slide above the other. The mass on the bottom will melt. This molten rock material will rise and create a volcano. or two or more. This, however can not happen in the HImalayas. The two masses in action are the Indian Plate and the Eurasian Plate, which have similar rock density.

 

Volcanic Eruptions and the Role of Sulfur Dioxide in Climate Change

In March and April of this year, a series of severe volcanic eruptions shook Alaska’s Mount Redoubt.1  To date, the largest of the eruptions produced an ash plume that reached 50,000 feet above sea level and released a significant amount of sulfur dioxide (CAS Registry Number® 7446-09-5) into the earth’s atmosphere.  According to the Alaska Volcano Observatory, “The main concerns for human health in volcanic haze consist of ash, sulfur dioxide gas (SO2), and sulfuric acid droplets (H2SO4), which forms when volcanic SO2 oxidizes in the atmosphere.”1

While there is obvious reason for alarm among local populations, sulfur dioxide from the Mount Redoubt eruption could also have more widespread impacts, particularly on the climate.  According to a 1997 article published in the Journal of Geology, “The mechanism by which large eruptions affect climate is generally accepted: injection of sulfur into the stratosphere and conversion to sulfate aerosol, which in turn reduces the solar energy reaching the earth’s surface.”2

In the years following a volcanic eruption, sulfate aerosol that remains in the atmosphere is thought to cause surface cooling by reflecting the sun’s energy back into space.  In fact, sulfate aerosol from the massive eruption of Indonesia’s Mount Tambora in 1815 is blamed, at least in part, for the “year without a summer” reported in Europe and North America in 1816:

  • “Daily temperatures (especially the daily minimums) were in many cases abnormally low from late spring through early fall; frequent northwest winds brought snow and frost to northern New England and Canada, and heavy rains fell in western Europe.  Many crops failed to ripen, and the poor harvests led to famine, disease, and social distress…”3

Supporting this claim, sulfate aerosol-related climate changes were also reported after the 1991 eruption of Mount Pinatubo in the Philippines.4  An article published inScience in 2002 summarizes a decade’s worth of research on Pinatubo’s effects on the global climate, highlighting impacts far more widespread and complex than previously thought:

You can use SciFinder® or STN® to search the CAS databases for additional information about sulfur dioxide from volcanic eruptions.  If your organization is enabled to use the web version of SciFinder, you can click the links in this article to directly access details of the substances and references.

 

Volcanic ash vs sulfur aerosols

The primary role of volcanic sulfur aerosols in causing short-term changes in the world’s climate following some eruptions, instead of volcanic ash, was hypothesized by scientists in the early 1980’s. They based their hypothesis on the effects of several explosive eruptions in Indonesia and the world’s largest historical effusive eruption in Iceland.

Scientists studied three historical explosive eruptions of different sizes in Indonesia–Tambora (1815), Krakatau (1883), and Agung (1963). They noted that decreases in surface temperatures after the eruptions were of similar magnitude (0.18-1.3 °C). The amount of material injected into the stratosphere, however, differed greatly. By comparing the estimated amount of ash vs. sulfur injected into the stratosphere by each eruption, it was suggested that the longer residence time of sulfate aerosols, not the ash particles which fall out within a few months of an eruption, was the paramount controlling factor (Rampino and Self, 1982).

In contrast to these explosive eruptions, one of the most severe volcano-related climate effects in historical times was associated with a largely nonexplosive eruption that produced very little ash–the 1783 eruption of Laki crater-row in Iceland. The eruption lasted 8-9 months and extruded about 12.3 km3 of basaltic lava over an area of 565 km2. A bluish haze of sulfur aerosols all over Iceland destroyed most summer crops in the country; the crop failure led to the loss of 75% of all livestock and the deaths of 24% of the population (H. Sigurdsson, 1982). The bluish haze drifted east across Europe during the 1783-1784 winter, which was unusually severe.

Clearly, these examples suggested that the explosivity of an eruption and the amount of ash injected into the stratosphere are not the main factors in causing a change in Earth’s climate. Instead, scientists concluded that it must be the amount of sulfur in the erupting magma.

The eruption of El Chichon, Mexico, in 1982 conclusively demonstrated this idea was correct. The explosive eruption injected at least 8 Mt of sulfur aerosols into the atmosphere, and it was followed by a measureable cooling of parts of the Earth’s surface and a warming of the upper atmosphere. A similar-sized eruption at Mount St. Helens in 1980, however, injected only about 1 Mt of sulfur aerosols into the stratosphere. The eruption of Mount St. Helens injected much less sulfur into the atmosphere–it did not result in a noticeable cooling of the Earth’s surface. The newly launched TOMS satellite (in 1978) made it possible to measure these differences in the eruption clouds. Such direct measurements of the eruption clouds combined with surface temperatures make it possible to study the corrleation between volcanic sulfur aerosols (instead of ash) and temporary changes in the world’s climate after some volcanic eruptions.

 

Hazards Of Volcanic Ash

A multitude of dangerous particals and gases, such as aerosols, are carried in volcanic ash. Some of these include;

  • Carbon dioxide
  • Sulfates (sulfur dioxide)
  • Hydrochloric acid
  • Hydroflouric acid

These each have different but serious effects on human health if exposed, which will be discussed later.

In addition, volcanic ash can cause reduced visibility, and it is recommended that precautions are taken when driving.

Sources: Where Does It Come From?

Figure 1

volcanoes found all over the Earth, particularly at plate boundaries

volcanoes found all over the Earth, particularly at plate boundaries

There are volcanoes found all over the Earth, particularly at plate boundaries (see figure 1). This is due to the collision of plates, which causes uplift in the overlying crust. This uplift results in the formation of mountainous landforms; melting of the crust due to frictional heating is what creates magma, which can erupt out of these mountains when pressure gets too high.

Some of the most notable volcanic eruptions are:

  • the 1783 eruption of Mt. Laki in Iceland
    • released clouds of poisonous flourine and sulfur dioxide which killed off about 50% of the livestock population
    • that summer in Great Britain was known as “sand-summer” due to ash carried over the Atlantic
    • poisonous clouds spread over Europe, and a buildup of aerosols caused a cooling effect in the entire Northern Hemisphere
  • the 1815 eruption of Mt. Tambora in Indonesia
    • gas releases caused the Stratosphere to change drastically
    • noxious ash and poisoned rain clouds killed off vegetation
  • the 1902 eruption of Mt. Pelee in Martinique
    • spewed toxic clouds traveling at speeds of 600mph
    • largest eruption in the 20th century

For further information on volcanoes around the world, visit http://www.mapsofworld.com/major-volcanoes.htm.

http://www.chm.bris.ac.uk/webprojects2003/silvester/Page6Famous.htm

 

  • EEA-33 emissions of sulphur oxides (SOX) have decreased by 74% between 1990 and 2011. In 2011, the most significant sectoral source of SOX emissions was ‘Energy production and distribution’ (58% of total emissions), followed by emissions occurring from ‘Energy use in industry’ (20%) and in the ‘Commercial, institutional and households’ (15%) sector.
  • The reduction in emissions since 1990 has been achieved as a result of a combination of measures, including fuel-switching in energy-related sectors away from high-sulphur solid and liquid fuels to low-sulphur fuels such as natural gas, the fitting of flue gas desulphurisation abatement technology in industrial facilities and the impact of European Union directives relating to the sulphur content of certain liquid fuels.
  • All of the EU-28 Member States have reduced their national SOX emissions below the level of the 2010 emission ceilings set in the National Emission Ceilings Directive (NECD)[1]. Emissions in 2011 for the three EEA countries having emission ceilings set under the UNECE/CLRTAP Gothenburg protocol (Liechtenstein, Norway and Switzerland) were also below the level of their respective 2010 ceilings.
  • Environmental context: Typically, sulphur dioxide is emitted when fuels or other materials containing sulphur are combusted or oxidised. It is a pollutant that contributes to acid deposition, which, in turn, can lead to changes in soil and water quality. The subsequent impacts of acid deposition can be significant, including adverse effects on aquatic ecosystems in rivers and lakes and damage to forests, crops and other vegetation. SO2 emissions also aggravate asthma conditions and can reduce lung function and inflame the respiratory tract. They also contribute, as a secondary particulate pollutant, to the formation of particulate matter in the atmosphere, an important air pollutant in terms of its adverse impact on human health. Furthermore, the formation of sulphate particles in the atmosphere following the release of SO2 results in reflection of solar radiation, which leads to net cooling of the atmosphere.
faults  sn-seafloor

faults sn-seafloor

 

Glacier - Helheim

Glacier – Helheim

 

Making North America

Making North America

 

so2-global-1986

so2-global-1986

 

What caused the Nepal earthquake

What caused the Nepal earthquake

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